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Essential Psychopharmacology
The Prescriber’s
Guide
The Prescriber’s Guide is the latest addition to the Essential Psychopharmacology
collection. In full color throughout, this volume presents to clinicians pragmatic
guidance that complements the conceptual approach of Essential Psychopharmacology.
With four or more pages for each of over 100 psychotropic drugs, Stephen Stahl gives
all the information a prescriber needs to treat patients effectively. For each drug the
information comes in five categories: general therapeutics, dosing and use, side effects,
special populations, and pearls. General Therapeutics covers the class of drug, what the
drug is prescribed for, how the drug works, how long it takes to work, what happens if
it works, what happens if it doesn’t, best augmentation/combination strategies, and any
required tests. Dosing and use covers usual dosage, dosage forms, how to dose,
dosing tips, overdose, long-term use, habit formation, how to stop, pharmacokinetics,
drug interactions, warnings/precautions, and contraindications. Side effects covers how
the drug causes side effects, notable side effects, life-threatening or dangerous side
effects, weight gain, sedation, what to do about side effects, and best augmenting
agents for side effects. Special populations covers renal impairment, hepatic
impairment, cardiac impairment, the elderly, children and adolescents, and key phases
of a woman’s lifecycle. Pearls covers potential advantages, potential disadvantages,
pearls, and suggested reading. Target icons appear next to key categories for each drug
so that the prescriber can go easily and instantly to the information needed. Several
indices are included, one consisting of a comprehensive list of both generic and
proprietary names for all the drugs featured, one categorizing the generic drugs by use,
and one listing the generic drugs by class.

Stephen M. Stahl is Adjunct Professor of Psychiatry at the University of California, San

Diego, and Chairman, Neuroscience Education Institute, Carlsbad. He has conducted
numerous research projects awarded by the National Institute of Mental Health, the
Veteran’s Administration, and the pharmaceutical industry. The author of more than 300
articles and chapters, Stephen Stahl is an internationally recognized clinician, researcher
and teacher in psychiatry with subspecialty expertise in psychopharmacology.

From the reviews of Essential Psychopharmacology

“essential reading . . . I would thoroughly recommend this book to anyone who works
with psychotropic drugs – or who has the task of teaching others about them!”
American Journal of Psychiatry
“Firmly grounded in contemporary neuroscience . . . an excellent and comprehensive
account of the pharmacology of drugs currently used to treat psychiatric disorders. “
Psychological Medicine
“This masterful production will benefit a broad spectrum of readers, from students to
knowledgeable and experienced psychopharmacologists.”
Psychiatric Times
“Finally, an elegant and beautiful psychopharmacology text written by a basic scientist
who is also a clinician.”
Journal of Clinical Psychiatry
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Essential Psychopharmacology
The Prescriber’s
Guide

Stephen M. Stahl, M.D., Ph.D.

Adjunct Professor of Psychiatry
University of California, San Diego
Chairman
Neuroscience Education Institute

Editorial assistant
Meghan M. Grady

With illustrations by
Nancy Muntner
  
Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo

Cambridge University Press

The Edinburgh Building, Cambridge  , UK
Published in the United States of America by Cambridge University Press, New York
www.cambridge.org
Information on this title: www.cambridge.org/9780521011693

© Stephen M. Stahl 2005

This publication is in copyright. Subject to statutory exception and to the provision of

relevant collective licensing agreements, no reproduction of any part may take place
without the written permission of Cambridge University Press.
First published in print format 2004

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To members of the Neuroscience Education Institute

and prescribers of psychopharmacologic agents
everywhere. Your relentless determination to find the
best portfolio of treatments for each individual patient
within your practice is my inspiration.
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Table of contents

Introduction xi

List of icons xiii

1. alprazolam 1
2. amisulpride 7
3. amitriptyline 13
4. amoxapine 19
5. aripiprazole 25
6. atomoxetine 31
7. bupropion 37
8. buspirone 43
9. carbamazepine 47
10. chlordiazepoxide 53
11. chlorpromazine 57
12. citalopram 63
13. clomipramine 69
14. clonazepam 75
15. clonidine 81
16. clorazepate 87
17. clozapine 91
18. d-amphetamine 97
19. desipramine 103
20. diazepam 109
21. d,l-amphetamine 115
22. d,l-methylphenidate 121
23. d-methylphenidate 127
24. donepezil 133
25. dothiepin 139
26. doxepin 145
27. duloxetine 151
28. escitalopram 157
29. estazolam 163
30. flumazenil 167
31. flunitrazepam 171
32. fluoxetine 175
33. flupenthixol 181

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34. fluphenazine 185

35. flurazepam 191
36. fluvoxamine 195
37. gabapentin 201
38. galantamine 207
39. haloperidol 213
40. hydroxyzine 219
41. imipramine 223
42. isocarboxazid 229
43. lamotrigine 235
44. levetiracetam 243
45. lithium 247
46. lofepramine 253
47. loflazepate 259
48. lorazepam 265
49. loxapine 271
50. maprotiline 277
51. memantine 283
52. mesoridazine 287
53. midazolam 291
54. milnacipran 295
55. mirtazapine 301
56. moclobemide 307
57. modafinil 313
58. molindone 319
59. nefazodone 323
60. nortriptyline 329
61. olanzapine 335
62. oxazepam 341
63. oxcarbazepine 345
64. paroxetine 351
65. pemoline 357
66. perospirone 361
67. perphenazine 365
68. phenelzine 371
69. pimozide 377
70. pipothiazine 383
71. pregabalin 387
72. protriptyline 391
73. quazepam 397

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74. quetiapine 401

75. reboxetine 407
76. risperidone 411
77. rivastigmine 417
78. selegiline 423
79. sertraline 429
80. sulpiride 435
81. tacrine 439
82. temazepam 443
83. thioridazine 447
84. thiothixene 453
85. tiagabine 457
86. tianeptine 461
87. topiramate 465
88. tranylcypromine 471
89. trazodone 477
90. triazolam 483
91. trifluoperazine 487
92. trimipramine 493
93. valproate 499
94. venlafaxine 505
95. zaleplon 511
96. ziprasidone 515
97. zolpidem 521
98. zonisamide 525
99. zopiclone 529
100. zotepine 533
101. zuclopenthixol 539

Index by drug name 545

(generic and international trade names)
Index by use 559
Index by class 565

Abbreviations 569

(FDA) Use-In-Pregnancy Ratings 571

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Introduction
This Guide is intended to complement Essential Psychopharmacology. Essential
Psychopharmacology emphasizes mechanisms of action and how psychotropic
drugs work upon receptors and enzymes in the brain. This Guide gives practical
information on how to use these drugs in clinical practice.
It would be impossible to include all available information about any drug in a
single work and no attempt is made here to be comprehensive. The purpose of
this Guide is instead to integrate the art of clinical practice with the science of
psychopharmacology. That means including only essential facts in order to keep
things short. Unfortunately that also means excluding less critical facts as well as
extraneous information, which may nevertheless be useful to the reader but
would make the book too long and dilute the most important information. In
deciding what to include and what to omit, the author has drawn upon common
sense and 30 years of clinical experience with patients. He has also consulted with
many experienced clinicians and analysed the evidence from controlled clinical
trials and regulatory filings with government agencies.
In order to meet the needs of the clinician and to facilitate future updates of
this Guide, the opinions of readers are sincerely solicited. Feedback can be
emailed to [email protected]. Specifically, are the best and most essential
psychotropic drugs included here? Do you find any factual errors? Are there
agreements or disagreements with any of the opinions expressed here? Are there
suggestions for any additional tips or pearls for future editions? Any and all sug-
gestions and comments are welcomed.
All of the selected drugs are presented in the same design format in order to
facilitate rapid access to information. Specifically, each drug is broken down into
five sections, each designated by a unique color background:
therapeutics,

side effects,
dosing and use,
special populations, and
the art of psy-
chopharmacology, followed by key references.
Therapeutics covers the brand names in major countries; the class of drug;
what it is commonly prescribed and approved for by the United States Food and
Drug Administration (FDA); how the drug works; how long it takes to work; what
to do if it works or if it doesn’t work; the best augmenting combinations for par-
tial response or treatment resistance, and the tests (if any) that are required.
Side effects explains how the drug causes side effects; gives a list of notable,
life threatening or dangerous side effects; gives a specific rating for weight gain or
sedation, and advice about how to handle side effects, including best augmenting
agents for side effects.
Dosing and use gives the usual dosing range; dosage forms; how to dose and
dosing tips; symptoms of overdose; long-term use; if habit forming, how to stop;
pharmacokinetics; drug interactions, when not to use and other warnings or pre-
cautions.
Special populations gives specific information about any possible renal,
hepatic and cardiac impairments, and any precautions to be taken for treating the
elderly, children, adolescents, and pregnant and breast-feeding women.
The art of psychopharmacology gives the author’s opinions on issues such as
the potential advantages and disadvantages of any one drug, the primary target
symptoms, and clinical pearls to get the best out of a drug.

xi
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At the back of the Guide are several indices. The first is an index by drug name,
giving both generic names (uncapitalized) and trade names (capitalized and fol-
lowed by the generic name in parentheses). The second is an index of common
uses for the generic drugs included in the Guide and is organized by
disorder/symptom. Agents that are approved by the FDA for a particular use are
shown in bold. The third index is organized by drug class, and lists all the agents
that fall within each particular class. In addition to these indices there is a list of
abbreviations and FDA definitions for the Pregnancy Categories A, B, C, D and X.
A listing of the icons used in the Guide is included on pages xiii–xv.
Readers are encouraged to consult standard references1 and comprehensive
psychiatry and pharmacology textbooks for more in-depth information. They are
also reminded that the art of psychopharmacology section is the author’s opinion.
It is strongly advised that readers familiarize themselves with the standard use
of these drugs before attempting any of the more exotic uses discussed, such as
unusual drug combinations and doses. Reading about both drugs before augment-
ing one with the other is also strongly recommended. Today’s psychopharmacolo-
gist should also regularly track blood pressure, weight and body mass index for
most of their patients. The dutiful clinician will also check out the drug interac-
tions of non-central-nervous-system (CNS) drugs with those that act in the CNS,
including any prescribed by other clinicians.
Certain drugs may be for experts only and might include clozapine, thiori-
dazine, pimozide, tacrine, pemoline, nefazodone, mesoridazine and MAO
inhibitors, among others. Off-label uses not approved by the FDA and inade-
quately studied doses or combinations of drugs may also be for the expert only,
who can weigh risks and benefits in the presence of sometimes vague and conflict-
ing evidence. Pregnant or nursing women, or people with two or more psychiatric
illnesses, substance abuse, and/or a concomitant medical illness may be suitable
patients for the expert only. Controlled substances also require expertise. Use
your best judgement as to your level of expertise and realize that we are all learn-
ing in this rapidly advancing field. The practice of medicine is often not so much
a science as it is an art. It is important to stay within the standards of medical
care for the field, and also within your personal comfort zone, while trying to help
extremely ill and often difficult patients with medicines than can sometimes
transform their lives and relieve their suffering.
Finally, this book is intended to be genuinely helpful for practitioners of psy-
chopharmacology by providing them with the mixture of facts and opinions
selected by the author. Ultimately, prescribing choices are the reader’s responsi-
bility. Every effort has been made in preparing this book to provide accurate and
up-to-date information in accord with accepted standards and practice at the time
of publication. Nevertheless, the psychopharmacology field is evolving rapidly
and the author and publisher make no warranties that the information contained
herein is totally free from error, not least because clinical standards are constant-
ly changing through research and regulation. Furthermore, the author and pub-
lisher disclaim any responsibility for the continued currency of this information
and disclaim all liability for any and all damages, including direct or consequen-
tial damages, resulting from the use of information contained in this book.
Doctors recommending and patients using these drugs are strongly advised to pay
careful attention to, and consult information provided by the manufacturer.

1 For example, Physician’s Desk Reference and Martindale’s

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List of icons

alpha 2 agonist

anticonvulsant

antihistamine

benzodiazepine

cholinesterase inhibitor

conventional antipsychotic

dopamine stabilizer

lithium

modafinil (wake-promoter)

monoamine oxidase inhibitor

nefazodone (serotonin antagonist/reuptake inhibitor)

N-methyl-d-aspartate antagonist

noradrenergic and specific serotonergic antidepressant

xiii
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norepinephrine and dopamine reuptake inhibitor

sedative hypnotic

selective norepinephrine reuptake inhibitor

selective serotonin reuptake inhibitor

serotonin-dopamine antagonist

serotonin and norepinephrine reuptake inhibitor

serotonin 1A partial agonist

stimulant

trazodone (serotonin antagonist/reuptake inhibitor)

tricyclic/tetracyclic antidepressant

How the drug works, mechanism of action

Best augmenting agents to add for partial response or treatment-

resistance

Life-threatening or dangerous side effects

xiv
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Weight Gain: Degrees of weight gain associated with the drug, with
unusual signifying that weight gain has been reported but is not
expected; not unusual signifying that weight gain occurs in a
significant minority; common signifying that many experience
weight gain and/or it can be significant in amount; and problematic
signifying that weight gain occurs frequently, can be significant in
amount, and may be a health problem in some patients

Sedation: Degrees of sedation associated with the drug, with

unusual signifying that sedation has been reported but is not
expected; not unusual signifying that sedation occurs in a significant
minority; common signifying that many experience sedation and/or
it can be significant in amount; and problematic signifying that
sedation occurs frequently, can be significant in amount, and may be
a health problem in some patients

Tips for dosing based on the clinical expertise of the author

Drug interactions that may occur

Warnings and precautions regarding use of the drug

Dosing and other information specific to children and adolescents

Information regarding use of the drug during pregnancy

Clinical pearls of information based on the clinical expertise of the

author

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ALPRAZOLAM
THERAPEUTICS • For long-term symptoms of anxiety,
consider switching to an SSRI or SNRI for
Brands • Xanax, Xanax XR long-term maintenance
see index for additional brand names • If long-term maintenance with a
benzodiazepine is necessary, continue
Generic? Yes (not for XR)
treatment for 6 months after symptoms
resolve, and then taper dose slowly
• If symptoms reemerge, consider treatment
Class with an SSRI or SNRI, or consider
• Benzodiazepine (anxiolytic) restarting the benzodiazepine; sometimes
benzodiazepines have to be used in
Commonly Prescribed For combination with SSRIs or SNRIs for best
(bold for FDA approved) results
• Generalized anxiety disorder (IR)
• Panic disorder (IR and XR) If It Doesn’t Work
• Other anxiety disorders • Consider switching to another agent or
• Anxiety associated with depression adding an appropriate augmenting agent
• Premenstrual dysphoric disorder • Consider psychotherapy, especially
• Irritable bowel syndrome and other cognitive behavioral psychotherapy
somatic symptoms associated with anxiety • Consider presence of concomitant
disorders substance abuse
• Insomnia • Consider presence of alprazolam abuse
• Acute mania (adjunctive) • Consider another diagnosis, such as a
• Acute psychosis (adjunctive) comorbid medical condition

Best Augmenting Combos

How The Drug Works for Partial Response or
• Binds to benzodiazepine receptors at the Treatment-Resistance
GABA-A ligand-gated chloride channel • Benzodiazepines are frequently used as
complex augmenting agents for antipsychotics and
• Enhances the inhibitory effects of GABA mood stabilizers in the treatment of
• Boosts chloride conductance through psychotic and bipolar disorders
GABA-regulated channels • Benzodiazepines are frequently used as
• Inhibits neuronal activity presumably in augmenting agents for SSRIs and SNRIs in
amygdala-centered fear circuits to provide the treatment of anxiety disorders
therapeutic benefits in anxiety disorders • Not generally rational to combine with
other benzodiazepines
How Long Until It Works • Caution if using as an anxiolytic
• Some immediate relief with first dosing is concomitantly with other sedative
common; can take several weeks with daily hypnotics for sleep
dosing for maximal therapeutic benefit
Tests
If It Works • In patients with seizure disorders,
• For short-term symptoms of anxiety – after concomitant medical illness, and/or those
a few weeks, discontinue use or use on an with multiple concomitant long-term
“as-needed” basis medications, periodic liver tests and blood
• For chronic anxiety disorders, the goal of counts may be prudent
treatment is complete remission of
symptoms as well as prevention of future
relapses SIDE EFFECTS
• For chronic anxiety disorders, treatment
most often reduces or even eliminates How Drug Causes Side Effects
symptoms, but not a cure since symptoms • Same mechanism for side effects as for
can recur after medicine stopped therapeutic effects – namely due to

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ALPRAZOLAM (continued)

excessive actions at benzodiazepine Best Augmenting Agents for Side

receptors Effects
• Long-term adaptations in benzodiazepine • Many side effects cannot be improved with
receptors may explain the development of an augmenting agent
dependence, tolerance, and withdrawal
• Side effects are generally immediate, but
immediate side effects often disappear in DOSING AND USE
time
Usual Dosage Range
Notable Side Effects • Anxiety: alprazolam IR: 1–4 mg/day
✽ Sedation, fatigue, depression • Panic: alprazolam IR: 5–6 mg/day
✽ Dizziness, ataxia, slurred speech, • Panic: alprazolam XR: 3–6 mg/day
weakness
✽ Forgetfulness, confusion Dosage Forms
✽ Hyper-excitability, nervousness • Alprazolam IR tablet 0.25 mg scored,
• Rare hallucinations, mania 0.5 mg scored, 1 mg scored, 2 mg multi-
• Rare hypotension scored
• Hypersalivation, dry mouth • Alprazolam IR solution, concentrate
1 mg/mL
Life Threatening or • Alprazolam XR (extended-release) tablet
Dangerous Side Effects 0.5 mg, 1 mg, 2 mg, 3 mg
• Respiratory depression, especially when How to Dose
taken with CNS depressants in overdose
• For anxiety, alprazolam IR should be
• Rare hepatic dysfunction, renal
started at 0.75–1.5 mg/day divided into
dysfunction, blood dyscrasias
3 doses; increase dose every 3–4 days
Weight Gain until desired efficacy is reached; maximum
dose generally 4 mg/day
• For panic, alprazolam IR should be started
at 1.5 mg/day divided into 3 doses;
• Reported but not expected increase 1 mg or less every 3–4 days until
desired efficacy is reached, increasing by
Sedation smaller amounts for dosage over
4 mg/day; may require as much as
10 mg/day for desired efficacy in difficult
• Occurs in significant minority cases
• Especially at initiation of treatment or when • For panic, alprazolam XR should be started
dose increases at 0.5–1 mg/day once daily in the morning;
• Tolerance often develops over time dose may be increased by 1 mg/day every
3–4 days until desired efficacy is reached;
What To Do About Side Effects maximum dose generally 10 mg/day
• Wait
• Wait
• Wait Dosing Tips
• Lower the dose • Use lowest possible effective dose for the
• Switch to alprazolam XR shortest possible period of time (a
• Take largest dose at bedtime to avoid benzodiazepine-sparing strategy)
sedative effects during the day • Assess need for continued treatment
• Switch to another agent regularly
• Administer flumazenil if side effects are • Risk of dependence may increase with
severe or life-threatening dose and duration of treatment
• For inter-dose symptoms of anxiety, can
either increase dose or maintain same total
daily dose but divide into more frequent

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(continued) ALPRAZOLAM

doses, or give as extended-release • For other patients with severe problems

formulation discontinuing a benzodiazepine, dosing
• Can also use an as-needed occasional “top may need to be tapered over many months
up” dose for inter-dose anxiety (i.e., reduce dose by 1% every 3 days by
• Because panic disorder can require doses crushing tablet and suspending or
higher than 4 mg/day, the risk of dissolving in 100 ml of fruit juice and then
dependence may be greater in these disposing of 1 ml while drinking the rest;
patients 3–7 days later, dispose of 2 ml, and so on).
• Some severely ill patients may require This is both a form of very slow biological
8 mg/day or more tapering and a form of behavioral
• Extended release formulation only needs to desensitization
be taken once or twice daily • Be sure to differentiate reemergence of
• Do not break or chew XR tablets as this symptoms requiring reinstitution of
will alter controlled release properties treatment from withdrawal symptoms
• Frequency of dosing in practice is often • Benzodiazepine-dependent anxiety patients
greater than predicted from half-life, as and insulin-dependent diabetics are not
duration of biological activity is often addicted to their medications. When
shorter than pharmacokinetic terminal half- benzodiazepine-dependent patients stop
life their medication, disease symptoms can
• Alprazolam and alprazolam XR generally reemerge, disease symptoms can worsen
dosed about one tenth the dosage of (rebound), and/or withdrawal symptoms
diazepam can emerge
✽ Alprazolam and alprazolam XR generally
dosed about twice the dosage of Pharmacokinetics
clonazepam • Metabolized by CYP450 3A4
• Inactive metabolites
Overdose • Elimination half-life 12–15 hours
• Fatalities have been reported both in
monotherapy and in conjunction with
alcohol; sedation, confusion, poor Drug Interactions
coordination, diminished reflexes, coma • Increased depressive effects when taken
with other CNS depressants
Long-Term Use
• Inhibitors of CYP450 3A, such as
• Risk of dependence, particularly for
nefazodone, fluvoxamine, fluoxetine, and
treatment periods longer than 12 weeks
even grapefruit juice, may decrease
and especially in patients with past or
clearance of alprazolam and thereby raise
current polysubstance abuse
alprazolam plasma levels and enhance
Habit Forming sedative side effects; alprazolam dose may
need to be lowered
• Alprazolam is a Schedule IV drug
• Thus, azole antifungal agents (such as
• Patients may develop dependence and/or
ketoconazole and itraconazole), macrolide
tolerance with long-term use
antibiotics, and protease inhibitors may
How to Stop also raise alprazolam plasma levels
• Seizures may rarely occur on withdrawal, • Inducers of CYP450 3A, such as
especially if withdrawal is abrupt; greater carbamazepine, may increase clearance of
risk for doses above 4 mg and in those alprazolam and lower alprazolam plasma
with additional risks for seizures, including levels and possibly reduce therapeutic
those with a history of seizures effects
• Taper by 0.5 mg every 3 days to reduce
chances of withdrawal effects Other Warnings/
• For difficult to taper cases, consider Precautions
reducing dose much more slowly after • Dosage changes should be made in
reaching 3 mg/day, perhaps by as little as collaboration with prescriber
0.25 mg per week or less

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ALPRAZOLAM (continued)

• Use with caution in patients with • Should generally receive lower doses and
pulmonary disease; rare reports of death be more closely monitored
after initiation of benzodiazepines in
patients with severe pulmonary impairment
• History of drug or alcohol abuse often Pregnancy
creates greater risk for dependency • Risk Category D [positive evidence of risk
• Hypomania and mania have occurred in to human fetus; potential benefits may still
depressed patients taking alprazolam justify its use during pregnancy]
• Use only with extreme caution if patient • Possible increased risk of birth defects
has obstructive sleep apnea when benzodiazepines taken during
• Some depressed patients may experience a pregnancy
worsening of suicidal ideation • Because of the potential risks, alprazolam
• Some patients may exhibit abnormal is not generally recommended as treatment
thinking or behavioral changes similar to for anxiety during pregnancy, especially
those caused by other CNS depressants during the first trimester
(i.e., either depressant actions or • Drug should be tapered if discontinued
disinhibiting actions) • Infants whose mothers received a
benzodiazepine late in pregnancy may
Do Not Use
experience withdrawal effects
• If patient has narrow angle-closure
• Neonatal flaccidity has been reported in
glaucoma
infants whose mothers took a
• If patient is taking ketoconazole or
benzodiazepine during pregnancy
itraconazole (azole antifungal agents)
• Seizures, even mild seizures, may cause
• If there is a proven allergy to alprazolam or
harm to the embryo/fetus
any benzodiazepine
Breast Feeding
• Some drug is found in mother’s breast milk
SPECIAL POPULATIONS ✽ Recommended either to discontinue drug
or bottle feed
Renal Impairment • Effects on infant have been observed and
• Drug should be used with caution include feeding difficulties, sedation, and
weight loss
Hepatic Impairment
• Should begin with lower starting dose
(0.5–0.75 mg/day in 2 or 3 divided doses)
THE ART OF PSYCHOPHARMACOLOGY
Cardiac Impairment
Potential Advantages
• Benzodiazepines have been used to treat
• Rapid onset of action
anxiety associated with acute myocardial
• Less sedation than some other
infarction
benzodiazepines
Elderly • Availability of an XR formulation with
• Should begin with lower starting dose longer duration of action
(0.5–0.75 mg/day in 2 or 3 divided doses)
Potential Disadvantages
and be monitored closely
• Euphoria may lead to abuse
• Abuse especially risky in past or present
substance abusers
Children and Adolescents
• Safety and efficacy not established but Primary Target Symptoms
often used, especially short-term and at the • Panic attacks
lower end of the dosing scale • Anxiety
• Long-term effects of alprazolam in
children/adolescents are unknown

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(continued) ALPRAZOLAM

• When using to treat insomnia, remember

that insomnia may be a symptom of some
Pearls other primary disorder itself, and thus
✽ One of the most popular benzodiazepines warrant evaluation for comorbid psychiatric
for anxiety, especially among primary care and/or medical conditions
physicians and psychiatrists ✽ Alprazolam XR may be less sedating than
• Is a very useful adjunct to SSRIs and immediate release alprazolam
SNRIs in the treatment of numerous ✽ Alprazolam XR may be dosed less
anxiety disorders frequently than immediate release
• Not effective for treating psychosis as a alprazolam, and lead to less inter-dose
monotherapy, but can be used as an breakthrough symptoms and less “clock-
adjunct to antipsychotics watching” in anxious patients
• Not effective for treating bipolar disorder • Slower rises in plasma drug levels for
as a monotherapy, but can be used as an alprazolam XR have the potential to reduce
adjunct to mood stabilizers and euphoria/abuse liability, but this has not
antipsychotics been proven
• May both cause depression and treat • Slower falls in plasma drug levels for
depression in different patients alprazolam XR have the potential to
• Risk of seizure is greatest during the first facilitate drug discontinuation by reducing
3 days after discontinuation of alprazolam, withdrawal symptoms, but this has not
especially in those with prior seizures, head been proven
injuries, or withdrawal from drugs of abuse ✽ Alprozolam XR generally has longer
• Clinical duration of action may be shorter biological duration of action than
than plasma half-life, leading to dosing clonazepam
more frequently than 2–3 times daily in ✽ If clonazepam can be considered a “long-
some patients, especially for immediate acting alprazolam-like anxiolytic”, then
release alprazolam alprazolam XR can be considered “an even
• Adding fluvoxamine, fluoxetine, or longer-acting clonazepam-like anxiolytic”
nefazodone can increase alprazolam levels with the potential of improved tolerability
and make the patient very sleepy unless features in terms of less euphoria, abuse,
the alprazolam dose is lowered by half or dependence, and withdrawal problems, but
more this has not been proven

Suggested Reading
DeVane CL, Ware MR, Lydiard RB. Klein E. The role of extended-release
Pharmacokinetics, pharmacodynamics, and benzodiazepines in the treatment of anxiety: a
treatment issues of benzodiazepines: risk-benefit evaluation with a focus on
alprazolam, adinazolam, and clonazepam. extended-release alprazolam. J Clin Psychiatry
Psychopharmacol Bull 1991;27:463–73. 2002;63 (Suppl 14):27–33.
Greenblatt DJ, Wright CE. Clinical Speigel DA. Efficacy studies of alprazolam in
pharmacokinetics of alprazolam. Therapeutic panic disorder. Psychopharmacol Bull 1998;
implications. Clin Pharmacokinet 1993; 34:191–5.
24:453–71.
Jonas JM, Cohon MS. A comparison of the
safety and efficacy of alprazolam versus other
agents in the treatment of anxiety, panic, and
depression: a review of the literature. J Clin
Psychiatry 1993;54 (Suppl):25–45.

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0521011698s01.qxd 9/2/04 2:26 PM Page 7

AMISULPRIDE
THERAPEUTICS • Most schizophrenic patients do not have a
total remission of symptoms but rather a
Brands • Solian reduction of symptoms by about a third
see index for additional brand names • Perhaps 5–15% of schizophrenic patients
can experience an overall improvement of
Generic? No
greater than 50–60%, especially when
receiving stable treatment for more than a
year
Class • Such patients are considered super-
• Atypical antipsychotic (benzamide; possibly responders or “awakeners” since they may
a dopamine stabilizer and dopamine partial be well enough to be employed, live
agonist) independently, and sustain long-term
relationships
Commonly Prescribed For • Continue treatment until reaching a plateau
(bold for FDA approved) of improvement
• Schizophrenia, acute and chronic (outside • After reaching a satisfactory plateau,
of U.S., especially Europe) continue treatment for at least a year after
• Dysthymia first episode of psychosis
• For second and subsequent episodes of
psychosis, treatment may need to be
How The Drug Works indefinite
• Theoretically blocks presynaptic dopamine • Even for first episodes of psychosis, it may
2 receptors at low doses be preferable to continue treatment
• Theoretically blocks postsynaptic dopamine indefinitely to avoid subsequent episodes
2 receptors at higher doses
✽ May be a partial agonist at dopamine 2 If It Doesn’t Work
receptors, which would theoretically reduce • Try one of the other first-line atypical
dopamine output when dopamine antipsychotics (risperidone, olanzapine,
concentrations are high and increase quetiapine, ziprasidone, aripiprazole)
dopamine output when dopamine • If two or more antipsychotic
concentrations are low monotherapies do not work, consider
• Blocks dopamine 3 receptors, which may clozapine
contribute to its clinical actions • If no atypical antipsychotic is effective,
✽ Unlike other atypical antipsychotics, consider higher doses or augmentation
amisulpride does not have potent actions with valproate or lamotrigine
at serotonin receptors • Some patients may require treatment with
a conventional antipsychotic
How Long Until It Works • Consider noncompliance and switch to
• Psychotic symptoms can improve within another antipsychotic with fewer side
1 week, but it may take several weeks for effects or to an antipsychotic that can be
full effect on behavior as well as on given by depot injection
cognition and affective stabilization • Consider initiating rehabilitation and
• Classically recommended to wait at least psychotherapy
4–6 weeks to determine efficacy of drug, • Consider presence of concomitant drug
but in practice some patients require up to abuse
16–20 weeks to show a good response,
especially on cognitive symptoms Best Augmenting Combos
for Partial Response or
If It Works Treatment-Resistance
• Most often reduces positive symptoms in • Valproic acid (valproate, divalproex,
schizophrenia but does not eliminate them divalproex ER)
• Can improve negative symptoms, as well • Augmentation of amisulpride has not been
as aggressive, cognitive, and affective systematically studied
symptoms in schizophrenia

7
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AMISULPRIDE (continued)

• Other mood stabilizing anticonvulsants monitoring for the rapid onset of polyuria,
(carbamazepine, oxcarbazepine, polydipsia, weight loss, nausea, vomiting,
lamotrigine) dehydration, rapid respiration, weakness
• Lithium and clouding of sensorium, even coma
• Benzodiazepines • EKGs may be useful for selected patients
(e.g., those with personal or family history
Tests of QTc prolongation; cardiac arrhythmia;
✽ Although risk of diabetes and recent myocardial infarction;
dyslipidemia with amisulpride has not been uncompensated heart failure; or taking
systematically studied, monitoring as for all agents that prolong QTc interval such as
other atypical antipsychotics is suggested pimozide, thioridazine, selected
Before starting an atypical antipsychotic antiarrhythmics, moxifloxacin, sparfloxacin,
✽ Weigh all patients and track BMI during etc.)
treatment • Patients at risk for electrolyte disturbances
• Get baseline personal and family history of (e.g., patients on diuretic therapy) should
obesity, dyslipidemia, hypertension, and have baseline and periodic serum
cardiovascular disease potassium and magnesium measurements
• Get waistline circumference (at umbilicus),
blood pressure, fasting plasma glucose,
and fasting lipid profile SIDE EFFECTS
• Determine if patient is
• overweight (BMI 25.0–29.9) How Drug Causes Side Effects
• obese (BMI ≥30) • By blocking dopamine 2 receptors in the
• has pre-diabetes (fasting plasma glucose striatum, it can cause motor side effects,
100–125 mg/dl) especially at high doses
• has diabetes (fasting plasma glucose • By blocking dopamine 2 receptors in the
>126 mg/dl) pituitary, it can cause elevations in
• has hypertension (BP >140/90 mm Hg) prolactin
• has dyslipidemia (increased total • Mechanism of weight gain and possible
cholesterol, LDL cholesterol, and increased incidence of diabetes and
triglycerides; decreased HDL cholesterol) dyslipidemia with atypical antipsychotics is
• Treat or refer such patients for treatment, unknown
including nutrition and weight
management, physical activity counseling, Notable Side Effects
smoking cessation, and medical ✽ Extrapyramidal symptoms
management ✽ Galactorrhea, amenorrhea
Monitoring after starting an atypical
✽ Atypical antipsychotics may increase the
risk for diabetes and dyslipidemia, although
antipsychotic
the specific risks associated with
✽ BMI monthly for 3 months, then quarterly amisulpride are unknown
• Blood pressure, fasting plasma glucose,
• Insomnia, sedation, agitation, anxiety
fasting lipids within 3 months and then
• Constipation, weight gain
annually, but earlier and more frequently
• Rare tardive dyskinesia
for patients with diabetes or who have
gained >5% initial weight
• Treat or refer for treatment and consider Life Threatening or
switching to another atypical antipsychotic Dangerous Side Effects
for patients who become overweight, • Rare neuroleptic malignant syndrome
obese, pre-diabetic, diabetic, hypertensive, • Rare seizures
or dyslipidemic while receiving an atypical • Dose-dependent QTc prolongation
antipsychotic
✽ Even in patients without known diabetes,
be vigilant for the rare but life threatening
onset of diabetic ketoacidosis, which
always requires immediate treatment by

8
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(continued) AMISULPRIDE

Weight Gain
Dosing Tips
✽ Efficacy for negative symptoms in
• Occurs in significant minority schizophrenia may be achieved at lower
doses, while efficacy for positive
Sedation symptoms may require higher doses
• Patients receiving low doses may only
need to take the drug once daily
• Many experience and/or can be significant ✽ For dysthymia and depression, use only
in amount, especially at high doses low doses
✽ Dose-dependent QTc prolongation, so use
What To Do About Side Effects with caution, especially at higher doses
• Wait (>800 mg/day)
• Wait ✽ Amisulpride may accumulate in patients
• Wait with renal insufficiency, requiring lower
• Lower the dose dosing or switching to another
• For motor symptoms, add an antipsychotic to avoid QTc prolongation in
anticholinergic agent these patients
• Take more of the dose at bedtime to help
reduce daytime sedation Overdose
• Weight loss, exercise programs, and • Sedation, coma, hypotension,
medical management for high BMIs, extrapyramidal symptoms
diabetes, dyslipidemia
• Switch to another atypical antipsychotic Long-Term Use
• Amisulpride is used for both acute and
Best Augmenting Agents for Side chronic schizophrenia treatment
Effects
• Benztropine or trihexyphenidyl for motor
Habit Forming
side effects • No
• Many side effects cannot be improved with How to Stop
an augmenting agent
• Slow down-titration (over 6 to 8 weeks),
especially when simultaneously beginning
a new antipsychotic while switching (i.e.,
DOSING AND USE cross-titration)
• Rapid discontinuation may lead to rebound
Usual Dosage Range psychosis and worsening of symptoms
• Schizophrenia: 400–800 mg/day in 2 doses
• Negative symptoms only: 50–300 mg/day Pharmacokinetics
• Dysthymia: 50 mg/day • Elimination half-life approximately 12 hours
• Excreted largely unchanged
Dosage Forms
• Different formulations may be available in
different markets
• Tablet 50 mg, 100 mg, 200 mg, 400 mg Drug Interactions
• Oral solution 100 mg/mL • Can decrease the effects of levodopa,
dopamine agonists
How to Dose • Can increase the effects of antihypertensive
• Initial 400–800 mg/day in 2 doses; daily drugs
doses above 400 mg should be divided in • CNS effects may be increased if used with
2; maximum generally 1200 mg/day a CNS depressant
• May enhance QTc prolongation of other
drugs capable of prolonging QTc interval

9
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AMISULPRIDE (continued)

• Since amisulpride is only weakly SPECIAL POPULATIONS

metabolized, few drug interactions that
could raise amisulpride plasma levels are
Renal Impairment
expected • Use with caution; drug may accumulate
• Amisulpride is eliminated by the renal
route; in cases of severe renal
Other Warnings/ insufficiency, the dose should be decreased
Precautions and intermittent treatment or switching to
• Use cautiously in patients with alcohol another antipsychotic should be considered
withdrawal or convulsive disorders
because of possible lowering of seizure Hepatic Impairment
threshold • Use with caution, but dose adjustment not
• If signs of neuroleptic malignant syndrome generally necessary
develop, treatment should be immediately
discontinued Cardiac Impairment
• Because amisulpride may dose- • Amisulpride produces a dose-dependent
dependently prolong QTc interval, use with prolongation of QTc interval, which may be
caution in patients who have bradycardia enhanced by the existence of bradycardia,
or who are taking drugs that can induce hypokalemia, congenital or acquired long
bradycardia (e.g., beta blockers, calcium QTc interval, which should be evaluated
channel blockers, clonidine, digitalis) prior to administering amisulpride
• Because amisulpride may dose- • Use with caution if treating concomitantly
dependently prolong QTc interval, use with with a medication likely to produce
caution in patients who have hypokalemia prolonged bradycardia, hypokalemia,
and/or hypomagnesemia or who are taking slowing of intracardiac conduction, or
drugs that can induce hypokalemia and/or prolongation of the QTc interval
magnesemia (e.g., diuretics, stimulant • Avoid amisulpride in patients with a known
laxatives, intravenous amphotericin B, history of QTc prolongation, recent acute
glucocorticoids, tetracosactide) myocardial infarction, and uncompensated
• Use only with caution if at all in heart failure
Parkinson’s disease or Lewy Body
dementia, especially at high doses
Elderly
• Some patients may be more susceptible to
Do Not Use sedative and hypotensive effects
• If patient has pheochromocytoma
• If patient has prolactin-dependent tumor
• If patient is pregnant or nursing Children and Adolescents
• If patient is taking agents capable of • Efficacy and safety not established under
significantly prolonging QTc interval (e.g., age 18
pimozide; thioridazine; selected
antiarrhythmics such as quinidine,
disopyramide, amiodarone, and sotalol; Pregnancy
selected antibiotics such as moxifloxacin • Although animal studies have not shown
and sparfloxacin) teratogenic effect, amisulpride is not
• If there is a history of QTc prolongation or recommended for use during pregnancy
cardiac arrhythmia, recent acute • Psychotic symptoms may worsen during
myocardial infarction, uncompensated pregnancy and some form of treatment
heart failure may be necessary
• If patient is taking cisapride, intravenous • Amisulpride may be preferable to
erythromycin, or pentamidine anticonvulsant mood stabilizers if
• In children treatment is required during pregnancy
• If there is a proven allergy to amisulpride

10
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(continued) AMISULPRIDE

Breast Feeding • Mediates its atypical antipsychotic

• Unknown if amisulpride is secreted in properties via novel actions on dopamine
human breast milk, but all psychotropics receptors, perhaps dopamine stabilizing
assumed to be secreted in breast milk partial agonist actions on dopamine 2
✽ Recommended either to discontinue drug receptors
or bottle feed • May be more of a dopamine 2 antagonist
than aripiprazole, but less of a dopamine 2
antagonist than other atypical or
THE ART OF PSYCHOPHARMACOLOGY conventional antipsychotics
• Low dose activating actions may be
Potential Advantages beneficial for negative symptoms in
• Not as clearly associated with weight gain schizophrenia
as some other atypical antipsychotics • Very low doses may be useful in dysthymia
• For patients who are responsive to low • Compared to sulpiride, amisulpride has
dose activation effects that reduce negative better oral bioavailability and more potency,
symptoms and depression thus allowing lower dosing, less weight
gain, and fewer extrapyramidal symptoms
Potential Disadvantages • Compared to other atypical antipsychotics
• Patients who have difficulty being with potent serotonin 2A antagonism,
compliant with twice daily dosing amisulpride may have more extrapyramidal
• Patients for whom elevated prolactin may symptoms and prolactin elevation, but may
not be desired (e.g., possibly pregnant still be classified as an atypical
patients; pubescent girls with amenorrhea; antipsychotic, particularly at low doses
postmenopausal women with low estrogen • Patients have very similar antipsychotic
who do not take estrogen replacement responses to any conventional
therapy) antipsychotic, which is different from
• Patients with severe renal impairment atypical antipsychotics where antipsychotic
responses of individual patients can
Primary Target Symptoms occasionally vary greatly from one atypical
• Positive symptoms of psychosis antipsychotic to another
• Negative symptoms of psychosis • Patients with inadequate responses to
• Depressive symptoms atypical antipsychotics may benefit from a
trial of augmentation with a conventional
antipsychotic or switching to a
Pearls conventional antipsychotic
✽ Efficacy has been particularly well • However, long-term polypharmacy with a
demonstrated in patients with combination of a conventional
predominantly negative symptoms antipsychotic with an atypical antipsychotic
✽ The increase in prolactin caused by may combine their side effects without
amisulpride may cause menstruation to clearly augmenting the efficacy of either
stop • Although a frequent practice by some
• Some treatment-resistant patients with prescribers, adding two conventional
inadequate responses to clozapine may antipsychotics together has little rationale
benefit from amisulpride augmentation of and may reduce tolerability without clearly
clozapine enhancing efficacy
• Risks of diabetes and dyslipidemia not well
studied, but does not seem to cause as
much weight gain as some other atypical
antipsychotics
• Has atypical antipsychotic properties (i.e.,
antipsychotic action without a high
incidence of extrapyramidal symptoms),
especially at low doses, but not a serotonin
dopamine antagonist

11
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AMISULPRIDE (continued)

Suggested Reading
Burns T, Bale R. Clinical advantages of Leucht S, Pitschel-Walz G, Engel RR, Kissling
amisulpride in the treatment of acute W. Amisulpride, an unusual “atypical”
schizophrenia. J Int Med Res 2001; 29 (6): antipsychotic: a meta-analysis of randomized
451–66. controlled trials. Am J Psychiatry 2002; 159
(2): 180–90.
Curran MP, Perry CM. Spotlight on
amisulpride in schizophrenia. CNS Drugs
2002; 16 (3): 207–11.

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AMITRIPTYLINE
THERAPEUTICS If It Works
• The goal of treatment of depression is
Brands • Elavil
complete remission of current symptoms
see index for additional brand names
as well as prevention of future relapses
Generic? Yes • The goal of treatment of chronic pain
conditions such as neuropathic pain,
fibromyalgia, headaches, low back pain,
and neck pain is to reduce symptoms as
Class much as possible, especially in
• Tricyclic antidepressant (TCA) combination with other treatments
• Serotonin and norepinephrine/ • Treatment of depression most often
noradrenaline reuptake inhibitor reduces or even eliminates symptoms, but
not a cure since symptoms can recur after
Commonly Prescribed For medicine stopped
(bold for FDA approved) • Treatment of chronic pain conditions such
• Depression as neuropathic pain, fibromyalgia,
• Endogenous depression headache, low back pain, and neck pain
✽ Neuropathic pain/chronic pain may reduce symptoms, but rarely
✽ Fibromyalgia eliminates them completely, and is not a
✽ Headache cure since symptoms can recur after
✽ Low back pain/neck pain medicine is stopped
• Anxiety • Continue treatment of depression until all
• Insomnia symptoms are gone (remission)
• Treatment-resistant depression • Once symptoms of depression are gone,
continue treating for 1 year for the first
episode of depression
How The Drug Works • For second and subsequent episodes of
• Boosts neurotransmitters serotonin and depression, treatment may need to be
norepinephrine/noradrenaline indefinite
• Blocks serotonin reuptake pump (serotonin • Use in anxiety disorders and chronic pain
transporter), presumably increasing conditions such as neuropathic pain,
serotonergic neurotransmission fibromyalgia, headache, low back pain, and
• Blocks norepinephrine reuptake pump neck pain may also need to be indefinite,
(norepinephrine transporter), presumably but long-term treatment is not well studied
increasing noradrenergic in these conditions
neurotransmission
If It Doesn’t Work
• Presumably desensitizes both serotonin 1A
• Many depressed patients only have a
receptors and beta adrenergic receptors
partial response where some symptoms
• Since dopamine is inactivated by
are improved but others persist (especially
norepinephrine reuptake in frontal cortex,
insomnia, fatigue, and problems
which largely lacks dopamine transporters,
concentrating)
amitriptyline can increase dopamine
• Other depressed patients may be
neurotransmission in this part of the brain
nonresponders, sometimes called
How Long Until It Works treatment-resistant or treatment-refractory
• May have immediate effects in treating • Consider increasing dose, switching to
insomnia or anxiety another agent or adding an appropriate
• Onset of therapeutic actions usually not augmenting agent
immediate, but often delayed 2 to 4 weeks • Consider psychotherapy
• If it is not working within 6 to 8 weeks for • Consider evaluation for another diagnosis
depression, it may require a dosage or for a comorbid condition (e.g., medical
increase or it may not work at all illness, substance abuse, etc.)
• May continue to work for many years to • Some patients may experience apparent
prevent relapse of symptoms lack of consistent efficacy due to activation
of latent or underlying bipolar disorder, and

13
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AMITRIPTYLINE (continued)

require antidepressant discontinuation and SIDE EFFECTS

a switch to a mood stabilizer
How Drug Causes Side Effects
Best Augmenting Combos • Anticholinergic activity may explain
for Partial Response or sedative effects, dry mouth, constipation,
Treatment-Resistance and blurred vision
• Sedative effects and weight gain may be
• Lithium, buspirone, thyroid hormone (for
due to antihistamine properties
depression)
• Blockade of alpha adrenergic 1 receptors
• Gabapentin, tiagabine, other
may explain dizziness, sedation, and
anticonvulsants, even opiates if done by
hypotension
experts while monitoring carefully in
• Cardiac arrhythmias and seizures,
difficult cases (for chronic pain)
especially in overdose, may be caused by
Tests blockade of ion channels
• None for healthy individuals
Notable Side Effects
✽ Since tricyclic and tetracyclic • Blurred vision, constipation, urinary
antidepressants are frequently associated
retention, increased appetite, dry mouth,
with weight gain, before starting treatment,
nausea, diarrhea, heartburn, unusual taste
weigh all patients and determine if the
in mouth, weight gain
patient is already overweight
• Fatigue, weakness, dizziness, sedation,
(BMI 25.0–29.9) or obese (BMI ≥30)
headache, anxiety, nervousness,
• Before giving a drug that can cause weight
restlessness
gain to an overweight or obese patient,
• Sexual dysfunction (impotence, change in
consider determining whether the patient
libido)
already has pre-diabetes (fasting plasma
• Sweating, rash, itching
glucose 100–125 mg/dl), diabetes (fasting
plasma glucose >126 mg/dl), or
dyslipidemia (increased total cholesterol, Life Threatening or
LDL cholesterol and triglycerides; Dangerous Side Effects
decreased HDL cholesterol), and treat or • Paralytic ileus, hyperthermia (TCAs +
refer such patients for treatment, including anticholinergic agents)
nutrition and weight management, physical • Lowered seizure threshold and rare
activity counseling, smoking cessation, and seizures
medical management • Orthostatic hypotension, sudden death,
✽ Monitor weight and BMI during treatment arrhythmias, tachycardia
✽ While giving a drug to a patient who has • QTc prolongation
gained >5% of initial weight, consider • Hepatic failure, extrapyramidal symptoms
evaluating for the presence of pre-diabetes, • Increased intraocular pressure
diabetes, or dyslipidemia, or consider • Rare induction of mania and activation of
switching to a different antidepressant suicidal ideation
• EKGs may be useful for selected patients
(e.g., those with personal or family history Weight Gain
of QTc prolongation; cardiac arrhythmia;
recent myocardial infarction;
uncompensated heart failure; or taking
• Many experience and/or can be significant
agents that prolong QTc interval such as
in amount
pimozide, thioridazine, selected
• Can increase appetite and carbohydrate
antiarrhythmics, moxifloxacin, sparfloxacin,
craving
etc.)
• Patients at risk for electrolyte disturbances Sedation
(e.g., patients on diuretic therapy) should
have baseline and periodic serum
potassium and magnesium measurements
• Many experience and/or can be significant
in amount

14
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(continued) AMITRIPTYLINE

• Tolerance to sedative effects may develop Long-Term Use

with long-term use • Safe

What To Do About Side Effects Habit Forming

• Wait • No
• Wait
• Wait How to Stop
• Lower the dose • Taper to avoid withdrawal effects
• Switch to an SSRI or newer antidepressant • Even with gradual dose reduction, some
withdrawal symptoms may appear within
Best Augmenting Agents for Side the first 2 weeks
Effects • Many patients tolerate 50% dose reduction
• Many side effects cannot be improved with for 3 days, then another 50% reduction for
an augmenting agent 3 days, then discontinuation
• If withdrawal symptoms emerge during
discontinuation, raise dose to stop
DOSING AND USE symptoms and then restart withdrawal
much more slowly
Usual Dosage Range
• 50–150 mg/day Pharmacokinetics
• Substrate for CYP450 2D6 and 1A2
Dosage Forms • Plasma half-life 10–28 hours
• Capsule 25 mg, 50 mg, 100 mg • Metabolized to an active metabolite,
nortriptyline, which is predominantly a
How to Dose norepinephrine reuptake inhibitor, by
• Initial 25 mg/day at bedtime; increase by demethylation via CYP450 1A2
25 mg every 3–7 days
• 75 mg/day in divided doses; increase to
150 mg/day; maximum 300 mg/day Drug Interactions
• Tramadol increases the risk of seizures in
patients taking TCAs
Dosing Tips • Use of TCAs with anticholinergic drugs
• If given in a single dose, should generally may result in paralytic ileus or
be administered at bedtime because of its hyperthermia
sedative properties • Fluoxetine, paroxetine, bupropion,
• If given in split doses, largest dose should duloxetine, and other CYP450 2D6
generally be given at bedtime because of inhibitors may increase TCA concentrations
its sedative properties • Fluvoxamine, a CYP450 1A2 inhibitor, can
• If patients experience nightmares, split decrease the conversion of amitriptyline to
dose and do not give large dose at bedtime nortriptyline and increase amitriptyline
• Patients treated for chronic pain may only plasma concentrations
require lower doses • Cimetidine may increase plasma
• If intolerable anxiety, insomnia, agitation, concentrations of TCAs and cause
akathisia, or activation occur either upon anticholinergic symptoms
dosing initiation or discontinuation, • Phenothiazines or haloperidol may raise
consider the possibility of activated bipolar TCA blood concentrations
disorder, and switch to a mood stabilizer or • May alter effects of antihypertensive drugs;
an atypical antipsychotic may inhibit hypotensive effects of clonidine
• Use of TCAs with sympathomimetic agents
Overdose may increase sympathetic activity
• Death may occur; CNS depression, • Methylphenidate may inhibit metabolism of
convulsions, cardiac dysrhythmias, severe TCAs
hypotension, ECG changes, coma • Activation and agitation, especially
following switching or adding

15
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AMITRIPTYLINE (continued)

antidepressants, may represent the myocardial infarction, uncompensated

induction of a bipolar state, especially a heart failure
mixed dysphoric bipolar II condition • If patient is taking drugs that inhibit TCA
sometimes associated with suicidal metabolism, including CYP450 2D6
ideation, and require the addition of inhibitors, except by an expert
lithium, a mood stabilizer or an atypical • If there is reduced CYP450 2D6 function,
antipsychotic, and/or discontinuation of such as patients who are poor 2D6
amitriptyline metabolizers, except by an expert and at
low doses
• If there is a proven allergy to amitriptyline
Other Warnings/ or nortriptyline
Precautions
• Add or initiate other antidepressants with
caution for up to 2 weeks after
discontinuing amitriptyline
SPECIAL POPULATIONS
• Generally, do not use with MAO inhibitors, Renal Impairment
including 14 days after MAOIs are stopped; • Use with caution; may need to lower dose
do not start an MAOI until 2 weeks after
discontinuing amitriptyline, but see Pearls Hepatic Impairment
• Use with caution in patients with history of • Use with caution; may need to lower dose
seizures, urinary retention, narrow angle-
closure glaucoma, hyperthyroidism Cardiac Impairment
• TCAs can increase QTc interval, especially • TCAs have been reported to cause
at toxic doses, which can be attained not arrhythmias, prolongation of conduction
only by overdose but also by combining time, orthostatic hypotension, sinus
with drugs that inhibit TCA metabolism via tachycardia, and heart failure, especially in
CYP450 2D6, potentially causing torsade the diseased heart
de pointes-type arrhythmia or sudden • Myocardial infarction and stroke have been
death reported with TCAs
• Because TCAs can prolong QTc interval, • TCAs produce QTc prolongation, which
use with caution in patients who have may be enhanced by the existence of
bradycardia or who are taking drugs that bradycardia, hypokalemia, congenital or
can induce bradycardia (e.g., beta blockers, acquired long QTc interval, which should
calcium channel blockers, clonidine, be evaluated prior to administering
digitalis) amitriptyline
• Because TCAs can prolong QTc interval, • Use with caution if treating concomitantly
use with caution in patients who have with a medication likely to produce
hypokalemia and/or hypomagnesemia, or prolonged bradycardia, hypokalemia,
who are taking drugs that can induce slowing of intracardiac conduction, or
hypokalemia and/or magnesemia (e.g., prolongation of the QTc interval
diuretics, stimulant laxatives, intravenous • Avoid TCAs in patients with a known
amphotericin B, glucocorticoids, history of QTc prolongation, recent acute
tetracosactide) myocardial infarction, and uncompensated
heart failure
Do Not Use • TCAs may cause a sustained increase in
• If patient is recovering from myocardial heart rate in patients with ischemic heart
infarction disease and may worsen (decrease) heart
• If patient is taking agents capable of rate variability, an independent risk of
significantly prolonging QTc interval (e.g., mortality in cardiac populations
pimozide, thioridazine, selected • Since SSRIs may improve (increase) heart
antiarrhythmics, moxifloxacin, rate variability in patients following a
sparfloxacin) myocardial infarct and may improve
• If there is a history of QTc prolongation or survival as well as mood in patients with
cardiac arrhythmia, recent acute acute angina or following a myocardial
infarction, these are more appropriate

16
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(continued) AMITRIPTYLINE

agents for cardiac population than • Immediate postpartum period is a high-risk

tricyclic/tetracyclic antidepressants time for depression, especially in women
✽ Risk/benefit ratio may not justify use of who have had prior depressive episodes,
TCAs in cardiac impairment so drug may need to be reinstituted late in
the third trimester or shortly after
Elderly childbirth to prevent a recurrence during
• May be more sensitive to anticholinergic, the postpartum period
cardiovascular, hypotensive, and sedative • Must weigh benefits of breast feeding with
effects risks and benefits of antidepressant
• Initial dose 50 mg/day; increase gradually treatment versus non-treatment to both the
up to 100 mg/day infant and the mother
• For many patients this may mean
continuing treatment during breast feeding
Children and Adolescents
• Use with caution, observing for activation
of known or unknown bipolar disorder THE ART OF PSYCHOPHARMACOLOGY
and/or suicidal ideation, and strongly
consider informing parents or guardian of Potential Advantages
this risk so they can help observe child or • Patients with insomnia
adolescent patients • Severe or treatment-resistant depression
• Not generally recommended for use under • Patients with a wide variety of chronic pain
age 12 syndromes
• Several studies show lack of efficacy of
TCAs for depression Potential Disadvantages
• May be used to treat enuresis or • Pediatric and geriatric patients
hyperactive/impulsive behaviors • Patients concerned with weight gain
• Some cases of sudden death have • Cardiac patients
occurred in children taking TCAs
• Adolescents: initial dose 50 mg/day; Primary Target Symptoms
increase gradually up to 100 mg/day • Depressed mood
• Symptoms of anxiety
• Somatic symptoms
• Chronic pain
Pregnancy • Insomnia
• Risk Category C [some animal studies
show adverse effects, no controlled studies
in humans]
• Crosses the placenta Pearls
• Adverse effects have been reported in • Was once one of the most widely
infants whose mothers took a TCA prescribed agents for depression
(lethargy, withdrawal symptoms, fetal • Remains one of the most favored TCAs for
malformations) treating headache and a wide variety of
• Must weigh the risk of treatment (first chronic pain syndromes, including
trimester fetal development, third trimester neuropathic pain, fibromyalgia, migraine,
newborn delivery) to the child against the neck pain, and low back pain
risk of no treatment (recurrence of ✽ Preference of some prescribers for
depression, maternal health, infant amitriptyline over other tricyclic/tetracyclic
bonding) to the mother and child antidepressants for the treatment of
• For many patients this may mean chronic pain syndromes is based more
continuing treatment during pregnancy upon art and anecdote rather than
controlled clinical trials, since many
Breast Feeding TCAs/tetracylics may be effective for
• Some drug is found in mother’s breast milk chronic pain syndromes
✽ Recommended either to discontinue drug • Tricyclic antidepressants are no longer
or bottle feed generally considered a first-line treatment

17
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AMITRIPTYLINE (continued)

option for depression because of their side observed to prevent hypertensive crises
effect profile and serotonin syndrome, the most
✽ Amitriptyline has been shown to be common side effects of MAOI/tricyclic or
effective in primary insomnia tetracyclic combinations may be weight
• TCAs may aggravate psychotic symptoms gain and orthostatic hypotension
• Alcohol should be avoided because of • Patients on TCAs should be aware that they
additive CNS effects may experience symptoms such as
• Underweight patients may be more photosensitivity or blue-green urine
susceptible to adverse cardiovascular • SSRIs may be more effective than TCAs in
effects women, and TCAs may be more effective
• Children, patients with inadequate than SSRIs in men
hydration, and patients with cardiac • Since tricyclic/tetracyclic antidepressants
disease may be more susceptible to TCA- are substrates for CYP450 2D6, and 7% of
induced cardiotoxicity than healthy adults the population (especially Caucasians) may
• For the expert only: although generally have a genetic variant leading to reduced
prohibited, a heroic but potentially activity of 2D6, such patients may not
dangerous treatment for severely safely tolerate normal doses of
treatment-resistant patients is to give a tricyclic/tetracyclic antidepressants and
tricyclic/tetracyclic antidepressant other may require dose reduction
than clomipramine simultaneously with an • Phenotypic testing may be necessary to
MAO inhibitor for patients who fail to detect this genetic variant prior to dosing
respond to numerous other with a tricyclic/tetracyclic antidepressant,
antidepressants especially in vulnerable populations such
• If this option is elected, start the MAOI with as children, elderly, cardiac populations,
the tricyclic/tetracyclic antidepressant and those on concomitant medications
simultaneously at low doses after • Patients who seem to have extraordinarily
appropriate drug washout, then alternately severe side effects at normal or low doses
increase doses of these agents every few may have this phenotypic CYP450 2D6
days to a week as tolerated variant and require low doses or switching
• Although very strict dietary and to another antidepressant not metabolized
concomitant drug restrictions must be by 2D6

Suggested Reading
Anderson IM. Meta-analytical studies on new Barbui C, Hotopf M. Amitriptyline v. the rest:
antidepressants. Br Med Bull 2001; still the leading antidepressant after 40 years
57:161–178. of randomised controlled trials. Br J
Psychiatry 2001;178:129–144.
Anderson IM. Selective serotonin reuptake
inhibitors versus tricyclic antidepressants: a Bryson HM, Wilde MI. Amitriptyline. A review
meta-analysis of efficacy and tolerability. J Aff of its pharmacological properties and
Disorders 2000;58:19–36. therapeutic use in chronic pain states. Drugs
Aging 1996;8:459–76.

18
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AMOXAPINE
THERAPEUTICS • If it is not working within 6 to 8 weeks for
depression, it may require a dosage
Brands • Asendin increase or it may not work at all
see index for additional brand names • May continue to work for many years to
prevent relapse of symptoms
Generic? Yes
If It Works
• The goal of treatment is complete
Class remission of current symptoms as well as
• Tricyclic antidepressant (TCA), sometimes prevention of future relapses
classified as a tetracyclic antidepressant • Treatment most often reduces or even
• Norepinephrine/noradrenaline reuptake eliminates symptoms, but not a cure since
inhibitor symptoms can recur after medicine
• Serotonin 2A antagonist stopped
• Parent drug and especially an active • Continue treatment until all symptoms are
metabolite are dopamine 2 antagonists gone (remission)
• Once symptoms gone, continue treating for
Commonly Prescribed For 1 year for the first episode of depression
(bold for FDA approved) • For second and subsequent episodes of
• Neurotic or reactive depressive disorder depression, treatment may need to be
• Endogenous and psychotic depressions indefinite
• Depression accompanied by anxiety or • Use in anxiety disorders may also need to
agitation be indefinite
• Depressive phase of bipolar disorder
• Anxiety If It Doesn’t Work
• Insomnia • Many patients only have a partial response
• Neuropathic pain/chronic pain where some symptoms are improved but
• Treatment-resistant depression others persist (especially insomnia, fatigue,
and problems concentrating)
• Other patients may be nonresponders,
sometimes called treatment-resistant or
How The Drug Works treatment-refractory
• Boosts neurotransmitter • Consider increasing dose, switching to
norepinephrine/noradrenaline another agent or adding an appropriate
• Blocks norepinephrine reuptake pump augmenting agent
(norepinephrine transporter), presumably • Consider psychotherapy
increasing noradrenergic • Consider evaluation for another diagnosis
neurotransmission or for a comorbid condition (e.g., medical
• Since dopamine is inactivated by illness, substance abuse, etc.)
norepinephrine reuptake in frontal cortex, • Some patients may experience apparent
which largely lacks dopamine transporters, lack of consistent efficacy due to activation
amoxapine can thus increase dopamine of latent or underlying bipolar disorder, and
neurotransmission in this part of the brain require antidepressant discontinuation and
• A more potent inhibitor of norepinephrine a switch to a mood stabilizer
reuptake pump than serotonin reuptake
pump (serotonin transporter) Best Augmenting Combos
• At high doses may also boost for Partial Response or
neurotransmitter serotonin and presumably Treatment-Resistance
increase serotonergic neurotransmission
• Lithium, buspirone, thyroid hormone
• Blocks dopamine 2 receptors, reducing
positive symptoms of psychosis Tests
• None for healthy individuals
How Long Until It Works
• Onset of therapeutic actions usually not
✽ Since tricyclic and tetracyclic
antidepressants are frequently associated
immediate, but often delayed 2 to 4 weeks
with weight gain, before starting treatment,

19
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AMOXAPINE (continued)

weigh all patients and determine if the Notable Side Effects

patient is already overweight • Blurred vision, constipation, urinary
(BMI 25.0–29.9) or obese (BMI ≥30) retention, increased appetite, dry mouth,
• Before giving a drug that can cause weight nausea, diarrhea, heartburn, unusual taste
gain to an overweight or obese patient, in mouth, weight gain
consider determining whether the patient • Fatigue, weakness, dizziness, sedation,
already has pre-diabetes (fasting plasma headache, anxiety, nervousness,
glucose 100–125 mg/dl), diabetes (fasting restlessness
plasma glucose >126 mg/dl), or • Sexual dysfunction, sweating
dyslipidemia (increased total cholesterol, ✽ Can cause extrapyramidal symptoms,
LDL cholesterol and triglycerides; akathisia, and theoretically, tardive
decreased HDL cholesterol), and treat or dyskinesia
refer such patients for treatment, including
nutrition and weight management, physical
activity counseling, smoking cessation, and Life Threatening or
medical management Dangerous Side Effects
✽ Monitor weight and BMI during treatment • Paralytic ileus, hyperthermia
✽ While giving a drug to a patient who has (TCAs/tetracyclics + anticholinergic agents)
gained >5% of initial weight, consider • Lowered seizure threshold and rare
evaluating for the presence of pre-diabetes, seizures
diabetes, or dyslipidemia, or consider • Orthostatic hypotension, sudden death,
switching to a different antidepressant arrhythmias, tachycardia
• EKGs may be useful for selected patients • QTc prolongation
(e.g., those with personal or family history • Hepatic failure, extrapyramidal symptoms
of QTc prolongation; cardiac arrhythmia; • Increased intraocular pressure
recent myocardial infarction; • Rare induction of mania and activation of
uncompensated heart failure; or taking suicidal ideation
agents that prolong QTc interval such as
pimozide, thioridazine, selected Weight Gain
antiarrhythmics, moxifloxacin, sparfloxacin,
etc.)
• Patients at risk for electrolyte disturbances • Many experience and/or can be significant
(e.g., patients on diuretic therapy) should in amount
have baseline and periodic serum • Can increase appetite and carbohydrate
potassium and magnesium measurements craving

Sedation
SIDE EFFECTS
How Drug Causes Side Effects • Many experience and/or can be significant
• Anticholinergic activity may explain in amount
sedative effects, dry mouth, constipation, • Tolerance to sedative effect may develop
and blurred vision with long-term use
• Sedative effects and weight gain may be
due to antihistamine properties What To Do About Side Effects
• Blockade of alpha adrenergic 1 receptors • Wait
may explain dizziness, sedation, and • Wait
hypotension • Wait
• Cardiac arrhythmias and seizures, • Lower the dose
especially in overdose, may be caused by • Switch to an SSRI or newer antidepressant
blockade of ion channels

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(continued) AMOXAPINE

Best Augmenting Agents for Side How to Stop

Effects • Taper to avoid withdrawal effects
• Many side effects cannot be improved with • Even with gradual dose reduction some
an augmenting agent withdrawal symptoms may appear within
• May use anticholinergics for the first 2 weeks
extrapyramidal symptoms, or switch to • Many patients tolerate 50% dose reduction
another antidepressant for 3 days, then another 50% reduction for
3 days, then discontinuation
• If withdrawal symptoms emerge during
DOSING AND USE discontinuation, raise dose to stop
symptoms and then restart withdrawal
Usual Dosage Range much more slowly
• 200–300 mg/day
Pharmacokinetics
Dosage Forms • Substrate for CYP450 2D6
• Tablets 25 mg, 50 mg, 100 mg, 150 mg • Half-life of parent drug approximately 8
hours
How to Dose ✽ 7- and 8-hydroxymetabolites are active
• Initial 25 mg 2–3 times/day; increase and possess serotonin 2A and dopamine 2
gradually to 100 mg 2–3 times/day or a antagonist properties, similar to atypical
single dose at bedtime; maximum antipsychotics
400 mg/day (may dose up to 600 mg/day ✽ Amoxapine is the N-desmethyl metabolite
in inpatients) of the conventional antipsychotic loxapine
• Half-life of the active metabolites
approximately 24 hours
Dosing Tips
• If given in a single dose, should generally
be administered at bedtime because of its Drug Interactions
sedative properties • Tramadol increases the risk of seizures in
• If given in split doses, largest dose should patients taking TCAs
generally be given at bedtime because of • Use of TCAs/tetracyclics with
its sedative properties anticholinergic drugs may result in
• If patients experience nightmares, split paralytic ileus or hyperthermia
dose and do not give large dose at bedtime • Fluoxetine, paroxetine, bupropion,
• If intolerable anxiety, insomnia, agitation, duloxetine, and other CYP450 2D6
akathisia, or activation occur either upon inhibitors may increase TCA/tetracyclic
dosing initiation or discontinuation, concentrations
consider the possibility of activated bipolar • Cimetidine may increase plasma
disorder, and switch to a mood stabilizer or concentrations of TCAs/tetracyclics and
an atypical antipsychotic cause anticholinergic symptoms
• Phenothiazines or haloperidol may raise
Overdose TCA/tetracyclic blood concentrations
• Death may occur; convulsions, cardiac • May alter effects of antihypertensive drugs;
dysrhythmias, severe hypotension, CNS may inhibit hypotensive effects of clonidine
depression, coma, changes in ECG • Use of TCAs/tetracyclics with
sympathomimetic agents may increase
Long-Term Use sympathetic activity
• Generally safe • Methylphenidate may inhibit metabolism of
• Some patients may develop withdrawal TCAs/tetracyclics
dyskinesias when discontinuing amoxapine • Activation and agitation, especially
after long-term use following switching or adding
antidepressants, may represent the
Habit Forming induction of a bipolar state, especially a
• Some patients may develop tolerance mixed dysphoric bipolar II condition

21
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AMOXAPINE (continued)

sometimes associated with suicidal • If patient is taking drugs that inhibit

ideation, and require the addition of TCA/tetracyclic metabolism, including
lithium, a mood stabilizer or an atypical CYP450 2D6 inhibitors, except by an expert
antipsychotic, and/or discontinuation of • If there is reduced CYP450 2D6 function,
amoxapine such as patients who are poor 2D6
metabolizers, except by an expert and at
low doses
Other Warnings/ • If there is a proven allergy to amoxapine or
Precautions loxapine
• Add or initiate other antidepressants with
caution for up to 2 weeks after
discontinuing amoxapine
• Generally, do not use with MAO inhibitors,
SPECIAL POPULATIONS
including 14 days after MAOIs are stopped; Renal Impairment
do not start an MAOI until 2 weeks after
• Use with caution – may require lower than
discontinuing amoxapine, but see Pearls
usual adult dose
• Use with caution in patients with history of
seizure, urinary retention, narrow angle- Hepatic Impairment
closure glaucoma, hyperthyroidism • Use with caution – may require lower than
• TCAs/tetracyclics can increase QTc interval, usual adult dose
especially at toxic doses, which can be
attained not only by overdose but also by Cardiac Impairment
combining with drugs that inhibit its • TCAs/tetracyclics have been reported to
metabolism via CYP450 2D6, potentially cause arrhythmias, prolongation of
causing torsade de pointes-type arrhythmia conduction time, orthostatic hypotension,
or sudden death sinus tachycardia, and heart failure,
• Because TCAs/tetracyclics can prolong QTc especially in the diseased heart
interval, use with caution in patients who • Myocardial infarction and stroke have been
have bradycardia or who are taking drugs reported with TCAs/tetracyclics
that can induce bradycardia (e.g., beta • TCAs/tetracyclics produce QTc
blockers, calcium channel blockers, prolongation, which may be enhanced by
clonidine, digitalis) the existence of bradycardia, hypokalemia,
• Because TCAs/tetracyclics can prolong QTc congenital or acquired long QTc interval,
interval, use with caution in patients who which should be evaluated prior to
have hypokalemia and/or administering amoxapine
hypomagnesemia, or who are taking drugs • Use with caution if treating concomitantly
that can induce hypokalemia and/or with a medication likely to produce
magnesemia (e.g., diuretics, stimulant prolonged bradycardia, hypokalemia,
laxatives, intravenous amphotericin B, slowing of intracardiac conduction, or
glucocorticoids, tetracosactide) prolongation of the QTc interval
• Avoid TCAs/tetracyclics in patients with a
Do Not Use known history of QTc prolongation, recent
• If patient is recovering from myocardial acute myocardial infarction, and
infarction uncompensated heart failure
• If patient is taking agents capable of • TCAs/tetracyclics may cause a sustained
significantly prolonging QTc interval (e.g., increase in heart rate in patients with
pimozide, thioridazine, selected ischemic heart disease and may worsen
antiarrhythmics, moxifloxacin, (decrease) heart rate variability, an
sparfloxacin) independent risk of mortality in cardiac
• If there is a history of QTc prolongation or populations
cardiac arrhythmia, recent acute • Since SSRIs may improve (increase) heart
myocardial infarction, uncompensated rate variability in patients following a
heart failure myocardial infarct and may improve
survival as well as mood in patients with
acute angina or following a myocardial

22
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(continued) AMOXAPINE

infarction, these are more appropriate • Immediate postpartum period is a high-risk

agents for cardiac population than time for depression, especially in women
tricyclic/tetracyclic antidepressants who have had prior depressive episodes,
✽ Risk/benefit ratio may not justify use of so drug may need to be reinstituted late in
TCAs/tetracyclics in cardiac impairment the third trimester or shortly after
childbirth to prevent a recurrence during
Elderly the postpartum period
• May be more sensitive to anticholinergic, • Evaluate for treatment with an
cardiovascular, hypotensive, and sedative antidepressant with a better risk/benefit
effects ratio
• Initial dose 25 mg/day at bedtime; increase
by 25 mg/day each week; maximum dose
300 mg/day THE ART OF PSYCHOPHARMACOLOGY
Potential Advantages
Children and Adolescents • Severe or treatment-resistant depression
• Use with caution, observing for activation • Treatment-resistant psychotic depression
of known or unknown bipolar disorder
and/or suicidal ideation, and strongly Potential Disadvantages
consider informing parents or guardian of • Pediatric and geriatric patients
this risk so they can help observe child or • Patients concerned with weight gain
adolescent patients • Cardiac patients
• Not generally recommended for use under • Patients with Parkinson’s disease or tardive
age 16 dyskinesia
• Several studies show lack of efficacy of
TCAs/tetracyclics for depression Primary Target Symptoms
• May be used to treat enuresis or • Depressed mood
hyperactive/impulsive behaviors
• Some cases of sudden death have
occurred in children taking Pearls
TCAs/tetracyclics • Tricyclic/tetracyclic antidepressants are no
• Adolescents: initial 25–50 mg/day; increase longer generally considered a first-line
gradually to 100 mg/day in divided doses treatment option for depression because of
or single dose at bedtime their side effect profile
• Tricyclic/tetracyclic antidepressants
continue to be useful for severe or
Pregnancy treatment-resistant depression
• Risk Category C [some animal studies ✽ Because of potential extrapyramidal
show adverse effects, no controlled studies symptoms, akathisia, and theoretical risk of
in humans] tardive dyskinesia, first consider other
• Amoxapine crosses the placenta TCAs/tetracyclics for long-term use in
• Adverse effects have been reported in general and for treatment of chronic
infants whose mothers took a TCA patients
(lethargy, withdrawal symptoms, fetal • TCAs may aggravate psychotic symptoms
malformations) • Alcohol should be avoided because of
• Evaluate for treatment with an additive CNS effects
antidepressant with a better risk/benefit • Underweight patients may be more
ratio susceptible to adverse cardiovascular
effects
Breast Feeding • Children, patients with inadequate
• Some drug is found in mother’s breast milk hydration, and patients with cardiac
✽ Recommended either to discontinue drug disease may be more susceptible to TCA-
or bottle feed induced cardiotoxicity than healthy adults

23
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AMOXAPINE (continued)

• For the expert only: although generally TCAs/tetracyclics may be more effective
prohibited, a heroic but potentially than SSRIs in men
dangerous treatment for severely ✽ May cause some motor effects, possibly
treatment-resistant patients is to give a due to effects on dopamine receptors
tricyclic/tetracyclic antidepressant other ✽ Amoxapine may have a faster onset of
than clomipramine simultaneously with an action than some other antidepressants
MAO inhibitor for patients who fail to ✽ May be pharmacologically similar to an
respond to numerous other atypical antipsychotic in some patients
antidepressants ✽ At high doses, patients who form high
• Use of MAOIs with clomipramine is always concentrations of active metabolites may
prohibited because of the risk of serotonin have akathisia, extrapyramidal symptoms,
syndrome and death and possibly develop tardive dyskinesia
• Amoxapine may be the preferred ✽ Structurally and pharmacologically related
trycyclic/tetracyclic antidepressant to to the antipsychotic loxapine
combine with an MAOI in heroic cases due • Since tricyclic/tetracyclic antidepressants
to its theoretically protective 5HT2A are substrates for CYP450 2D6, and 7% of
antagonist properties the population (especially Caucasians) may
• If this option is elected, start the MAOI with have a genetic variant leading to reduced
the tricyclic/tetracyclic antidepressant activity of 2D6, such patients may not
simultaneously at low doses after safely tolerate normal doses of
appropriate drug washout, then alternately tricyclic/tetracyclic antidepressants and
increase doses of these agents every few may require dose reduction
days to a week as tolerated • Phenotypic testing may be necessary to
• Although very strict dietary and detect this genetic variant prior to dosing
concomitant drug restrictions must be with a tricyclic/tetracyclic antidepressant,
observed to prevent hypertensive crises especially in vulnerable populations such
and serotonin syndrome, the most as children, elderly, cardiac populations,
common side effects of MAOI/tricyclic or and those on concomitant medications
tetracyclic combinations may be weight • Patients who seem to have extraordinarily
gain and orthostatic hypotention severe side effects at normal or low doses
• Patients on TCAs/tetracyclics should be may have this phenotypic CYP450 2D6
aware that they may experience symptoms variant and require low doses or switching
such as photosensitivity or blue-green to another antidepressant not metabolized
urine by 2D6
• SSRIs may be more effective than
TCAs/tetracyclics in women, and

Suggested Reading
Anderson IM. Meta-analytical studies on new Hayes PE, Kristoff CA. Adverse reactions to
antidepressants. Br Med Bull 2001; five new antidepressants. Clin Pharm 1986;
57:161–178. 5:471–80.
Anderson IM. Selective serotonin reuptake Jue SG, Dawson GW, Brogden RN.
inhibitors versus tricyclic antidepressants: a Amoxapine: a review of its pharmacology and
meta-analysis of efficacy and tolerability. J Aff efficacy in depressed states. Drugs 1982;
Disorders 2000;58:19–36. 24:1–23.

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ARIPIPRAZOLE
THERAPEUTICS full effect on behavior as well as on
cognition and affective stabilization
Brands • Abilify • Classically recommended to wait at least
see index for additional brand names 4–6 weeks to determine efficacy of drug,
but in practice some patients require up to
Generic? Not in U.S., Europe, or Japan
16–20 weeks to show a good response,
especially on cognitive symptoms

Class If It Works
• Dopamine partial agonist (dopamine • Most often reduces positive symptoms in
stabilizer, atypical antipsychotic, third schizophrenia but does not eliminate them
generation antipsychotic; sometimes • Can improve negative symptoms, as well
included as a second generation as aggressive, cognitive, and affective
antipsychotic; also a mood stabilizer) symptoms in schizophrenia
• Most schizophrenic patients do not have a
Commonly Prescribed For total remission of symptoms but rather a
(bold for FDA approved) reduction of symptoms by about a third
• Schizophrenia • Perhaps 5–15% of schizophrenic patients
• Maintaining stability in schizophrenia can experience an overall improvement of
• Other psychotic disorders greater than 50–60%, especially when
• Acute mania receiving stable treatment for more than a
• Bipolar maintenance year
• Bipolar depression • Such patients are considered super-
• Behavioral disturbances in dementias responders or “awakeners” since they may
• Behavioral disturbances in children and be well enough to be employed, live
adolescents independently, and sustain long-term
• Disorders associated with problems with relationships
impulse control • Many bipolar patients may experience a
reduction of symptoms by half or more
• Continue treatment until reaching a plateau
How The Drug Works of improvement
✽ Partial agonism at dopamine 2 receptors • After reaching a satisfactory plateau,
• Theoretically reduces dopamine output continue treatment for at least a year after
when dopamine concentrations are high, first episode of psychosis
thus improving positive symptoms and • For second and subsequent episodes of
mediating antipsychotic actions psychosis, treatment may need to be
• Theoretically increases dopamine output indefinite
when dopamine concentrations are low, • Even for first episodes of psychosis, it may
thus improving cognitive, negative, and be preferable to continue treatment
mood symptoms indefinitely to avoid subsequent episodes
• Actions at dopamine 3 receptors could • Treatment may not only reduce mania but
theoretically contribute to aripiprazole’s also prevent recurrences of mania in
efficacy bipolar disorder
• Partial agonism at 5HT1A receptors may be
relevant at clinical doses If It Doesn’t Work
• Blockade of serotonin type 2A receptors • Try one of the other atypical antipsychotics
may contribute at clinical doses to cause (risperidone, olanzapine, quetiapine,
enhancement of dopamine release in ziprasidone, amisulpride)
certain brain regions, thus reducing motor • If two or more antipsychotic
side effects and possibly improving monotherapies do not work, consider
cognitive and affective symptoms clozapine
• If no first-line atypical antipsychotic is
How Long Until It Works effective, consider higher doses or
• Psychotic symptoms can improve within augmentation with valproate or lamotrigine
1 week, but it may take several weeks for

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ARIPIPRAZOLE (continued)

• Some patients may require treatment with for patients with diabetes or who have
a conventional antipsychotic gained >5% of initial weight
• Consider noncompliance and switch to • Treat or refer for treatment and consider
another antipsychotic with fewer side switching to another atypical antipsychotic
effects or to an antipsychotic that can be for patients who become overweight,
given by depot injection obese, pre-diabetic, diabetic, hypertensive,
• Consider initiating rehabilitation and or dyslipidemic while receiving an atypical
psychotherapy antipsychotic
• Consider presence of concomitant drug ✽ Even in patients without known diabetes,
abuse be vigilant for the rare but life threatening
onset of diabetic ketoacidosis, which
Best Augmenting Combos always requires immediate treatment, by
for Partial Response or monitoring for the rapid onset of polyuria,
Treatment-Resistance polydipsia, weight loss, nausea, vomiting,
• Valproic acid (valproate, divalproex, dehydration, rapid respiration, weakness
divalproex ER) and clouding of sensorium, even coma
• Other mood stabilizing anticonvulsants
(carbamazepine, oxcarbazepine,
lamotrigine) SIDE EFFECTS
• Lithium
• Benzodiazepines How Drug Causes Side Effects
• By blocking alpha 1 adrenergic receptors, it
Tests can cause dizziness, sedation, and
Before starting an atypical antipsychotic hypotension
✽ Weigh all patients and track BMI during • Partial agonist actions at dopamine 2
treatment receptors in the striatum can cause motor
• Get baseline personal and family history of side effects, such as akathisia
obesity, dyslipidemia, hypertension, and (occasionally)
cardiovascular disease • Partial agonist actions at dopamine 2
✽ Get waist circumference (at umbilicus), receptors can also cause nausea,
blood pressure, fasting plasma glucose, occasional vomiting, and activating side
and fasting lipid profile effects
• Determine if the patient is ✽ Mechanism of any possible weight gain is
• overweight (BMI 25.0–29.9) unknown; weight gain is not common with
• obese (BMI ≥30) aripiprazole and may thus have a different
• has pre-diabetes (fasting plasma glucose mechanism from atypical antipsychotics
100–125 mg/dl) for which weight gain is common or
• has diabetes (fasting plasma glucose problematic
>126 mg/dl) ✽ Mechanism of any possible increased
• has hypertension (BP >140/90 mm Hg) incidence of diabetes or dyslipidemia is
• has dyslipidemia (increased total unknown; early experience suggests these
cholesterol, LDL cholesterol, and complications are not clearly associated
triglycerides; decreased HDL cholesterol) with aripiprazole and if present may
• Treat or refer such patients for treatment, therefore have a different mechanism from
including nutrition and weight that of atypical antipsychotics associated
management, physical activity counseling, with an increased incidence of diabetes and
smoking cessation, and medical dyslipidemia
management
Notable Side Effects
Monitoring after starting an atypical
✽ Dizziness, insomnia, akathisia, activation
antipsychotic
✽ Nausea, vomiting
✽ BMI monthly for 3 months, then quarterly • Orthostatic hypotension, occasionally
✽ Blood pressure, fasting plasma glucose, during initial dosing
fasting lipids within 3 months and then • Constipation
annually, but earlier and more frequently

26
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(continued) ARIPIPRAZOLE

• Headache, asthenia, sedation DOSING AND USE

• Theoretical risk of tardive dyskinesia
Usual Dosage Range
• 15–30 mg/day
Life Threatening or
Dangerous Side Effects Dosage Forms
• Rare neuroleptic malignant syndrome • Tablet 5 mg, 10 mg, 15 mg, 20 mg, 30 mg
(much reduced risk compared to
conventional antipsychotics) How to Dose
• Rare seizures • Initial approved recommendation is
15 mg/day; maximum approved dose
Weight Gain 30 mg/day

• Reported in a few patients, especially those Dosing Tips

with low BMIs, but not expected ✽ For some, less may be more: frequently,
• Less frequent and less severe than for patients not acutely psychotic may need to
most other antipsychotics be dosed lower (e.g., 5–10 mg/day) in
order to avoid akathisia and activation and
Sedation for maximum tolerability
• For others, more may be more: rarely,
patients may need to be dosed higher than
30 mg/day for optimum efficacy
• Reported in a few patients but not expected • Consider cutting 5 mg tablet in half (tablets
• May be less than for some other not scored) for children and adolescents,
antipsychotics, but never say never as well as for adults very sensitive to side
• Can be activating at moderate to high effects
doses
✽ Although studies suggest patients
switching to aripiprazole from another
What To Do About Side Effects
antipsychotic can do well with rapid switch
• Wait
or with cross-titration, clinical experience
• Wait
suggests many patients may do best by
• Wait
adding a full dose of aripiprazole to the
• Reduce the dose
maintenance dose of the first antipsychotic
• Anticholinergics may reduce akathisia
for several days prior to slow down-
when present
titration of the first antipsychotic
• Weight loss, exercise programs, and
• Rather than raise the dose above these
medical management for high BMIs,
levels in acutely agitated patients requiring
diabetes, dyslipidemia
acute antipsychotic actions, consider
• Switch to another atypical antipsychotic
augmentation with a benzodiazepine or
Best Augmenting Agents for Side conventional antipsychotic, either orally or
intramuscularly
Effects
• Rather than raise the dose above these
• Benztropine or trihexyphenidyl for motor
levels in partial responders, consider
side effects and akathisia
augmentation with a mood stabilizing
• Many side effects cannot be improved with
anticonvulsant, such as valproate or
an augmenting agent
lamotrigine
• Children and elderly should generally be
dosed at the lower end of the dosage
spectrum
• Less expensive than some antipsychotics,
more expensive than others depending on
dose administered
• Due to its very long half-life, aripiprazole
will take longer to reach steady state when

27
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ARIPIPRAZOLE (continued)

initiating dosing, and longer to wash out

when stopping dosing, than other atypical
Other Warnings/
antipsychotics Precautions
• Use with caution in patients with
Overdose conditions that predispose to hypotension
• No fatalities have been reported; sedation, (dehydration, overheating)
vomiting • Dysphagia has been associated with
antipsychotic use, and aripiprazole should
Long-Term Use be used cautiously in patients at risk for
• Approved to delay relapse in long-term aspiration pneumonia
treatment of schizophrenia
• Often used for long-term maintenance in Do Not Use
bipolar disorder and various behavioral • If there is a proven allergy to aripiprazole
disorders

Habit Forming SPECIAL POPULATIONS

• No
Renal Impairment
How to Stop • Dose adjustment not necessary
• Slow down-titration (over 6 to 8 weeks),
especially when simultaneously beginning Hepatic Impairment
a new antipsychotic while switching (i.e., • Dose adjustment not necessary
cross-titration)
• Rapid discontinuation could theoretically Cardiac Impairment
lead to rebound psychosis and worsening • Use in patients with cardiac impairment
of symptoms has not been studied, so use with caution
because of risk of orthostatic hypotension
Pharmacokinetics
• Metabolized primarily by CYP450 2D6 and Elderly
CYP450 3A4 • Dose adjustment generally not necessary,
• Mean elimination half-life 75 hours but some elderly patients may tolerate
(aripiprazole) and 94 hours (major lower doses better
metabolite dehydro-aripiprazole)

Children and Adolescents

Drug Interactions • Not officially recommended for patients
• Ketaconazole and possibly other CYP450 under age 18
3A4 inhibitors such as nefazodone, • Clinical experience and early data suggest
fluvoxamine, and fluoxetine may increase aripiprazole may be safe and effective for
plasma levels of aripiprazole behavioral disturbances in children and
• Carbamazepine and possibly other inducers adolescents, especially at lower doses
of CYP450 3A4 may decrease plasma • Children and adolescents using aripiprazole
levels of aripiprazole may need to be monitored more often than
• Quinidine and possibly other inhibitors of adults and may tolerate lower doses better
CYP450 2D6 such as paroxetine,
fluoxetine, and duloxetine may increase
plasma levels of aripiprazole Pregnancy
• Aripiprazole may enhance the effects of • Risk Category C [some animal studies
antihypertensive drugs show adverse effects, no controlled studies
• Aripiprazole may antagonize levodopa, in humans]
dopamine agonists • Psychotic symptoms may worsen during
pregnancy and some form of treatment
may be necessary

28
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(continued) ARIPIPRAZOLE

• Aripiprazole may be preferable to • Cognitive symptoms

anticonvulsant mood stabilizers if • Unstable mood
treatment is required during pregnancy • Aggressive symptoms

Breast Feeding
• Unknown if aripiprazole is secreted in Pearls
human breast milk, but all psychotropics
assumed to be secreted in breast milk
✽ Well accepted in clinical practice when
wanting to avoid weight gain because less
✽ Recommended either to discontinue drug weight gain than most other antipsychotics
or bottle feed
• Infants of women who choose to breast
✽ Well accepted in clinical practice when
wanting to avoid sedation because less
feed while on aripiprazole should be
sedation than most other antipsychotics at
monitored for possible adverse effects
all doses
✽ Can even be activating, which can be
reduced by lowering the dose or starting at
THE ART OF PSYCHOPHARMACOLOGY a lower dose
• A moderately priced atypical antipsychotic
Potential Advantages within the therapeutic dosing range
• Some cases of psychosis and bipolar ✽ May not have diabetes or dyslipidemia
disorder refractory to treatment with other risk, but monitoring is still indicated
antipsychotics • Anecdotal reports of utility in treatment-
✽ Patients concerned about gaining weight resistant cases
✽ Patients with diabetes • Has a very favorable tolerability profile in
• Patients requiring rapid onset of clinical practice
antipsychotic action without dosage • Favorable tolerability profile leading to “off-
titration label” uses for many indications other than
schizophrenia (e.g., acute bipolar mania;
Potential Disadvantages bipolar II disorder, including hypomanic,
• Patients in whom sedation is desired mixed, rapid cycling, and depressed
• May be more difficult to dose for children, phases; treatment-resistant depression;
elderly, or “off label” uses anxiety disorders)
Primary Target Symptoms
• Positive symptoms of psychosis
• Negative symptoms of psychosis

Suggested Reading
Marder SR, McQuade RD, Stock E, Kaplita S, drug with a unique and robust pharmacology.
Marcus R, Safferman AZ, Saha A, Ali M, Neuropsychopharmacology 2003;28:1400–11.
Iwamoto T. Aripiprazole in the treatment of
schizophrenia: safety and tolerability in short- Stahl SM. Dopamine system stabilizers,
term, placebo-controlled trials. Schizophr Res aripiprazole, and the next generation of
2003;61(2–3):123–36. antipsychotics, part 1: “Goldilocks” actions at
dopamine receptors. J Clin Psychiatry
Sajatovic M. Treatment for mood and anxiety 2001;62:841–2.
disorders: quetiapine and aripiprazole. Curr
Psychiatry Rep 2003;5:320–6. Stahl SM. Dopamine system stabilizers,
aripiprazole, and the next generation of
Shapiro DA, Renock S, Arrington E, Chiodo antipsychotics, part 2: illustrating their
LA, Liu LX, Sibley DR, Roth BL, Mailman R. mechanism of action. J Clin Psychiatry
Aripiprazole, a novel atypical antipsychotic 2001;62 (12):923–4.

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0521011698s01.qxd 9/2/04 2:26 PM Page 31

ATOMOXETINE
THERAPEUTICS and adulthood if continued benefit is
documented
Brands • Strattera
see index for additional brand names If It Doesn’t Work
• Consider adjusting dose or switching to
Generic? No another agent
• Consider behavioral therapy
• Consider the presence of noncompliance
Class and counsel patient and parents
• Selective norepinephrine reuptake inhibitor • Consider evaluation for another diagnosis
(NRI) or for a comorbid condition (e.g., bipolar
disorder, substance abuse, medical illness,
Commonly Prescribed For etc.)
(bold for FDA approved) • Some patients may experience apparent
• Attention deficit hyperactivity disorder lack of consistent efficacy due to activation
(ADHD) in adults and children over 6 of latent or underlying bipolar disorder, and
• Treatment-resistant depression require atomoxetine discontinuation and a
switch to a mood stabilizer

How The Drug Works Best Augmenting Combos

• Boosts neurotransmitters for Partial Response or
norepinephrine/noradrenaline and Treatment-Resistance
dopamine ✽ Best to attempt other monotherapies
• Blocks norepinephrine reuptake pumps, prior to augmenting
also known as norepinephrine transporters • SSRIs, SNRIs, or mirtazapine for
• Presumably this increases noradrenergic treatment-resistant depression (use
neurotransmission combinations of antidepressants with
• Since dopamine is inactivated by atomoxetine with caution as this may
norepinephrine reuptake in frontal cortex, theoretically activate bipolar disorder and
which largely lacks dopamine transporters, suicidal ideation)
atomoxetine can also increase dopamine • Mood stabilizers or atypical antipsychotics
neurotransmission in this part of the brain for comorbid bipolar disorder
• For the expert, can combine with modafinil,
How Long Until It Works methylphenidate, or amphetamine for
✽ Onset of therapeutic actions in ADHD can ADHD
be seen as early as the first day of dosing
• Therapeutic actions may continue to Tests
improve for 4 to 8 weeks • None recommended for healthy patients
• If it is not working within 6 to 8 weeks, it • May be prudent to monitor blood pressure
may not work at all and pulse when initiating treatment and
until dosage increments have stabilized
If It Works
• The goal of treatment of ADHD is reduction
of symptoms of inattentiveness, motor SIDE EFFECTS
hyperactivity, and/or impulsiveness that
disrupt social, school, and/or occupational How Drug Causes Side Effects
functioning • Norepinephrine increases in parts of the
• Continue treatment until all symptoms are brain and body and at receptors other than
under control or improvement is stable and those that cause therapeutic actions (e.g.,
then continue treatment indefinitely as long unwanted actions of norepinephrine on
as improvement persists acetylcholine release causing decreased
• Reevaluate the need for treatment appetite, increased heart rate and blood
periodically pressure, dry mouth, urinary retention,
• Treatment for ADHD begun in childhood etc.)
may need to be continued into adolescence

31
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ATOMOXETINE (continued)

• Most side effects are immediate but often Best Augmenting Agents for Side
go away with time Effects
• Lack of enhancing dopamine activity in • For urinary hesitancy, give an alpha 1
limbic areas theoretically explains blocker such as tamsulosin
atomoxetine’s lack of abuse potential • Often best to try another monotherapy
prior to resorting to augmentation
Notable Side Effects strategies to treat side effects
✽ Sedation, fatigue • Many side effects are dose-dependent (i.e.,
✽ Decreased appetite they increase as dose increases, or they
• Increased heart rate (6–9 beats/min) reemerge until tolerance re-develops)
• Increased blood pressure (2–4 mm Hg) • Many side effects are time-dependent (i.e.,
• Insomnia, dizziness, anxiety, agitation, they start immediately upon dosing and
aggression, irritability upon each dose increase, but go away with
• Dry mouth, constipation, nausea, vomiting, time)
abdominal pain, dyspepsia • Activation and agitation may represent the
• Urinary hesitancy, urinary retention (older induction of a bipolar state, especially a
men) mixed dysphoric bipolar II condition
• Dysmenorrhea, sweating sometimes associated with suicidal
• Sexual dysfunction (men: decreased libido, ideation, and require the addition of
erectile disturbance, impotence, ejaculatory lithium, a mood stabilizer or an atypical
dysfunction, abnormal orgasm; women: antipsychotic, and/or discontinuation of
decreased libido, abnormal orgasm) atomoxetine

Life Threatening or
Dangerous Side Effects DOSING AND USE
• Increased heart rate and hypertension
• Orthostatic hypotension Usual Dosage Range
• Hypomania and, theoretically, rare • 90 mg/day, 1.2 mg/kg/day
induction of mania and activation of
suicidal ideation
Dosage Forms
• Capsule 10 mg, 18 mg, 25 mg, 40 mg,
Weight Gain 60 mg

How to Dose
• For children 70 kg or less: initial dose
• Reported but not expected 0.5 mg/kg/day; after 3 days can increase to
• Patients may experience weight loss 1.2 mg/kg/day either once in the morning
or divided; maximum dose 1.4 mg/kg/day
Sedation or 100 mg/day, whichever is less
• For adults and children over 70 kg: initial
dose 40 mg/day; after 3 days can increase
• Occurs in significant minority to 80 mg/day once in the morning or
divided; after 2–4 weeks can increase to
What To Do About Side Effects 100 mg/day if necessary; maximum daily
• Wait dose 100 mg
• Wait
• Wait
• Lower the dose Dosing Tips
• If giving once daily, can change to split • Can be given once a day in the morning
dose twice daily ✽ Efficacy with once-daily dosing despite a
• In a few weeks, switch or add other drugs half-life of 5 hours suggests therapeutic
effects persist beyond direct
pharmacologic effects, unlike stimulants

32
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(continued) ATOMOXETINE

whose effects are generally closely • Do not use with MAO inhibitors, including
correlated with plasma drug levels 14 days after MAOIs are stopped
• Once-daily dosing may increase
gastrointestinal side effects
• Starting dose is half of therapeutic dose
Other Warnings/
• Lower starting dose allows detection of Precautions
those patients who may be especially • Growth (height and weight) should be
sensitive to side effects such as monitored during treatment with
tachycardia and increased blood pressure atomoxetine; for patients who are not
• Patients especially sensitive to the side growing or gaining weight satisfactorily,
effects of atomoxetine may include those interruption of treatment should be
individuals deficient in the enzyme that considered
metabolizes atomoxetine, CYP450 2D6 • Use with caution in patients with
(i.e., 7% of the population, especially hypertension, tachycardia, cardiovascular
Caucasians) disease, or cerebrovascular disease
• In such individuals, use half the usual dose • Use with caution in patients with bipolar
of atomoxetine if tolerated disorder
• Other individuals may require up to 1.8 • Use with caution in patients with urinary
mg/kg total daily dose retention, benign prostatic hypertrophy
• Use with caution with antihypertensive
Overdose drugs
• No fatalities have been reported; sedation,
agitation, hyperactivity, abnormal behavior, Do Not Use
gastrointestinal symptoms • If patient is taking an MAO inhibitor
• If patient has narrow angle-closure
Long-Term Use glaucoma
• Safe • If there is a proven allergy to atomoxetine

Habit Forming
• No SPECIAL POPULATIONS
How to Stop Renal Impairment
• Taper not necessary • Dose adjustment not generally necessary
Pharmacokinetics Hepatic Impairment
• Metabolized by CYP450 2D6 • For patients with moderate liver
• Half-life approximately 5 hours impairment, dose should be reduced to
50% of normal dose
• For patients with severe liver impairment,
Drug Interactions dose should be reduced to 25% of normal
• Tramadol increases the risk of seizures in dose
patients taking an antidepressant
• Plasma concentrations of atomoxetine may Cardiac Impairment
be increased by drugs that inhibit CYP450 • Use with caution because atomoxetine can
2D6 (e.g., paroxetine, fluoxetine), so increase heart rate and blood pressure
atomoxetine dose may need to be reduced
if co-administered
Elderly
• Co-administration of atomoxetine and • Some patients may tolerate lower doses
albuterol may lead to increases in heart better
rate and blood pressure
• Co-administration with methylphenidate
does not increase cardiovascular side Children and Adolescents
effects beyond those seen with • Approved to treat ADHD in children over
methylphenidate alone age 6
• Recommended dose is 1.2 mg/kg/day

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ATOMOXETINE (continued)

• Since dopamine is inactivated by

norepinephrine reuptake in frontal cortex,
Pregnancy which largely lacks dopamine transporters,
• Risk Category C [some animal studies atomoxetine can increase dopamine as well
show adverse effects, no controlled studies as norepinephrine in this part of the brain,
in humans] presumably causing therapeutic actions in
• Use in women of childbearing potential ADHD
requires weighing potential benefits to the • Since dopamine is inactivated by dopamine
mother against potential risks to the fetus reuptake in nucleus accumbens, which
✽ For ADHD patients, atomoxetine should largely lacks norepinephrine transporters,
generally be discontinued before atomoxetine does not increase dopamine in
anticipated pregnancies this part of the brain, presumably
explaining why atomoxetine lacks abuse
Breast Feeding potential
• Unknown if atomoxetine is secreted in • Preliminary studies and atomoxetine’s
human breast milk, but all psychotropics known mechanism of action as a selective
assumed to be secreted in breast milk norepinephrine reuptake inhibitor suggest
✽ Recommend either to discontinue drug or its efficacy as an antidepressant
bottle feed • Pro-noradrenergic actions may be
theoretically useful for the treatment of
chronic pain
THE ART OF PSYCHOPHARMACOLOGY • Atomoxetine’s mechanism of action and its
potential antidepressant actions suggest it
Potential Advantages has the potential to de-stabilize latent or
• No known abuse potential undiagnosed bipolar disorder, similar to the
known actions of proven antidepressants
Potential Disadvantages • Thus, administer with caution to ADHD
• May not act as rapidly as stimulants when patients who may also have bipolar
initiating treatment in some patients disorder
• Unlike stimulants, atomoxetine may not
Primary Target Symptoms
exacerbate tics in Tourette’s Syndrome
• Concentration, attention span
patients with comorbid ADHD
• Motor hyperactivity
• Urinary retention in men over 50 with
• Depressed mood
borderline urine flow has been observed
with other agents with potent
norepinephrine reuptake blocking
Pearls properties (e.g., reboxetine, milnacipran),
✽ Unlike other agents approved for ADHD, so administer atomoxetine with caution to
atomoxetine does not have abuse potential these patients
and is not a scheduled substance • Atomoxetine was originally called
✽ Despite its name as a selective tomoxetine but the name was changed to
norepinephrine reuptake inhibitor, avoid potential confusion with tamoxifen,
atomoxetine enhances both dopamine and which might lead to errors in drug
norepinephrine in frontal cortex, dispensing
presumably accounting for its therapeutic
actions on attention and concentration

34
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(continued) ATOMOXETINE

Suggested Reading
Kratochvil CJ, Vaughan BS, Harrington MJ, Simpson D, Perry CM. Atomoxetine. Paediatr
Burke WJ. Atomoxetine: a selective Drugs 2003;5(6):407–15.
noradrenaline reuptake inhibitor for the
treatment of attention-deficit/hyperactivity Wernicke JF, Kratochvil CJ. Safety profile of
disorder. Expert Opin Pharmacother atomoxetine in the treatment of children and
2003;4(7):1165–74. adolescents with ADHD. J Clin Psychiatry
2002;63 Suppl 12:50–5.
Michelson D, Adler L, Spencer T, Reimherr
FW, West SA, Allen AJ, Kelsey D, Wernicke J,
Dietrich A, Milton D. Atomoxetine in adults
with ADHD: two randomized, placebo-
controlled studies. Biol Psychiatry
2003;53(2):112–20.

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BUPROPION
THERAPEUTICS If It Works
• The goal of treatment of depression is
Brands • Wellbutrin, Wellbutrin SR,
complete remission of current symptoms
Wellbutrin XL
as well as prevention of future relapses
• Zyban • Treatment of depression most often
see index for additional brand names reduces or even eliminates symptoms, but
is not a cure since symptoms can recur
Generic? Yes (bupropion and bupropion
after medicine stopped
SR)
• Continue treatment of depression until all
symptoms are gone (remission)
• Once symptoms of depression are gone,
Class continue treating for 1 year for the first
• NDRI (norepinephrine dopamine reuptake episode of depression
inhibitor); antidepressant; smoking • For second and subsequent episodes of
cessation treatment depression, treatment may need to be
indefinite
Commonly Prescribed For • Treatment for nicotine addiction should
(bold for FDA approved) consist of a single treatment for 6 weeks
• Major depressive disorder (bupropion,
bupropion SR, and bupropion XL) If It Doesn’t Work
• Nicotine addiction (bupropion SR) • Many patients only have a partial response
• Bipolar depression where some symptoms are improved but
• Attention deficit / hyperactivity disorder others persist (especially insomnia, fatigue,
• Sexual dysfunction and problems concentrating)
• Other patients may be nonresponders,
sometimes called treatment-resistant or
How The Drug Works treatment-refractory
• Boosts neurotransmitters • Some patients who have an initial response
norepinephrine/noradrenaline and may relapse even though they continue
dopamine treatment, sometimes called “poop-out”
• Blocks norepinephrine reuptake pump • Consider increasing dose, switching to
(norepinephrine transporter), presumably another agent or adding an appropriate
increasing norepinephrine augmenting agent
neurotransmission • Consider psychotherapy
• Since dopamine is inactivated by • Consider evaluation for another diagnosis
norepinephrine reuptake in frontal cortex, or for a comorbid condition (e.g., medical
which largely lacks dopamine transporters, illness, substance abuse, etc.)
bupropion can increase dopamine • Some patients may experience apparent
neurotransmission in this part of the brain lack of consistent efficacy due to activation
• Blocks dopamine reuptake pump of latent or underlying bipolar disorder, and
(dopamine transporter), presumably require antidepressant discontinuation and
increasing dopaminergic a switch to a mood stabilizer, although this
neurotransmission may be a less frequent problem with
bupropion than with other antidepressants
How Long Until It Works
• Onset of therapeutic actions usually not Best Augmenting Combos
immediate, but often delayed 2 to 4 weeks for Partial Response or
• If it is not working within 6 to 8 weeks for Treatment-Resistance
depression, it may require a dosage • Trazodone for residual insomnia
increase or it may not work at all • Benzodiazepines for residual anxiety
• May continue to work for many years to ✽ Can be added to SSRIs to reverse SSRI-
prevent relapse of symptoms induced sexual dysfunction, SSRI-induced
apathy (use combinations of
antidepressants with caution as this may

37
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BUPROPION (continued)

activate bipolar disorder and suicidal increases for patients with predisposing
ideation) factors)
✽ Can be added to SSRIs to treat partial • Hypomania (more likely in bipolar patients
responders but perhaps less common than with some
✽ Often used as an augmenting agent to other antidepressants)
mood stabilizers and/or atypical • Rare induction of mania and activation of
antipsychotics in bipolar depression suicidal ideation
• Mood stabilizers or atypical antipsychotics
can also be added to bupropion for Weight Gain
psychotic depression or treatment-resistant
depression
• Hypnotics for insomnia • Reported but not expected
• Mirtazapine, modafinil, atomoxetine (add
with caution and at lower doses since Sedation
bupropion could theoretically raise
atomoxetine levels) both for residual
symptoms of depression and attention
deficit disorder • Reported but not expected

Tests What To Do About Side Effects

• None for healthy individuals • Wait
• Wait
• Wait
• Keep dose as low as possible
SIDE EFFECTS • Take no later than mid-afternoon to avoid
How Drug Causes Side Effects insomnia
• Switch to another drug
• Side effects are probably caused in part by
actions of norepinephrine and dopamine in Best Augmenting Agents for Side
brain areas with undesired effects (e.g.,
Effects
insomnia, tremor, agitation, headache,
• Often best to try another antidepressant
dizziness)
monotherapy prior to resorting to
• Side effects are probably also caused in
augmentation strategies to treat side
part by actions of norepinephrine in the
effects
periphery with undesired effects (e.g.,
• Trazodone or a hypnotic for drug-induced
sympathetic and parasympathetic effects
insomnia
such as dry mouth, constipation, nausea,
• Mirtazapine for insomnia, agitation, and
anorexia, sweating)
gastrointestinal side effects
• Most side effects are immediate but often
• Benzodiazepines or buspirone for drug-
go away with time
induced anxiety, agitation
Notable Side Effects • Many side effects are dose-dependent (i.e.,
• Dry mouth, constipation, nausea, weight they increase as dose increases, or they
loss, anorexia reemerge until tolerance re-develops)
• Insomnia, dizziness, headache, agitation, • Many side effects are time-dependent (i.e.,
tremor, abdominal pain, tinnitus they start immediately upon dosing and
• Sweating upon each dose increase, but go away with
• Hypertension (rare) time)
• Activation and agitation may represent the
induction of a bipolar state, especially a
Life Threatening or mixed dysphoric bipolar II condition
Dangerous Side Effects sometimes associated with suicidal
• Rare seizures (higher incidence for ideation, and require the addition of
immediate release than for sustained lithium, a mood stabilizer or an atypical
release; risk increases with doses above antipsychotic, and/or discontinuation of
the recommended maximums; risk bupropion

38
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(continued) BUPROPION

DOSING AND USE 450 mg/day, experts can prudently increase

dosing beyond the therapeutic range while
Usual Dosage Range monitoring closely, informing the patient of
• Bupropion: 225–450 mg in 3 divided doses the potential risk of seizures and weighing
(maximum single dose 150 mg) risk benefit ratios in difficult-to-treat
• Bupropion SR: 200–450 mg in 2 divided patients
doses (maximum single dose 200 mg) • When used for bipolar depression, it is
• Bupropion XL: 150–450 mg once daily usually as an augmenting agent to mood
stabilizers, lithium, and/or atypical
Dosage Forms
antipsychotics
• Bupropion: tablet 75 mg, 100 mg
• For smoking cessation, may be used in
• Bupropion SR (sustained release): tablet
conjunction with nicotine replacement
100 mg, 150 mg, 200 mg
therapy
• Bupropion XL (extended release): tablet
• Do not break or chew SR or XL tablets as
150 mg, 300 mg
this will alter controlled release properties
How to Dose • The more anxious and agitated the patient,
• Depression: for bupropion immediate the lower the starting dose, the slower the
release, dosing should be in divided doses, titration, and the more likely the need for a
starting at 75 mg twice daily, increasing to concomitant agent such as trazodone or a
100 mg twice daily, then to 100 mg 3 times benzodiazepine
daily; maximum dose 450 mg per day • If intolerable anxiety, insomnia, agitation,
• Depression: for bupropion SR, initial dose akathisia, or activation occur either upon
100 mg twice a day, increase to 150 mg dosing initiation or discontinuation,
twice a day after at least 3 days; wait 4 consider the possibility of activated bipolar
weeks or longer to ensure drug effects disorder and switch to a mood stabilizer or
before increasing dose; maximum dose an atypical antipsychotic
400 mg total per day Overdose
• Depression: for bupropion XL, initial dose
• Rarely lethal; seizures, cardiac
150 mg once daily in the morning; can
disturbances, hallucinations, loss of
increase to 300 mg QD after 4 days;
consciousness
maximum dose 450 mg once daily
• Nicotine addiction [for bupropion SR]: Long-Term Use
Initial dose 150 mg/day once a day, • For smoking cessation, treatment for up to
increase to 150 mg twice a day after at 6 months has been found effective
least 3 days; maximum dose 300 mg/day;
bupropion treatment should begin Habit Forming
1–2 weeks before smoking is discontinued • No

How to Stop
Dosing Tips • Tapering is prudent to avoid withdrawal
• XL formulation has replaced immediate effects, but no well-documented tolerance,
release and SR formulations as the dependence, or withdrawal reactions
preferred option
• XL is best dosed once a day, whereas SR is Pharmacokinetics
best dosed twice daily, and immediate • Inhibits CYP450 2D6
release is best dosed 3 times daily • Parent half-life 10–14 hours
• Dosing higher than 450 mg/day • Metabolite half-life 20–27 hours
(400 mg/day SR) increases seizure risk
• Patients who do not respond to
450 mg/day should discontinue use or get Drug Interactions
blood levels of bupropion and its major • Tramadol increases the risk of seizures in
active metabolite 6-hydroxy-bupropion patients taking an antidepressant
• If levels of parent drug and active • Can increase tricyclic antidepressant levels;
metabolite are low despite dosing at use with caution with tricyclic

39
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BUPROPION (continued)

antidepressants or when switching from a SPECIAL POPULATIONS

TCA to bupropion
• Can be fatal when combined with MAO
Renal Impairment
inhibitors, so do not use with MAO • Lower initial dose, perhaps give less
inhibitors or for at least 14 days after frequently
MAOIs are stopped • Drug concentration may be increased
• Do not start an MAO inhibitor for at least • Patient should be monitored closely
two weeks after discontinuing bupropion
Hepatic Impairment
• Via CYP450 2D6 inhibition, bupropion
• Lower initial dose, perhaps give less
could theoretically interfere with the
frequently
analgesic actions of codeine, and increase
• Patient should be monitored closely
the plasma levels of some beta blockers
• In severe hepatic cirrhosis, bupropion XL
and of atomoxetine
should be administered at no more than
• Via CYP450 2D6 inhibition, bupropion
150 mg every other day
could theoretically increase concentrations
of thioridazine and cause dangerous Cardiac Impairment
cardiac arrhythmias • Limited available data
• Evidence of rise in supine blood pressure
Other Warnings/ • Use with caution
Precautions
• Use cautiously with other drugs that increase
Elderly
seizure risk (TCAs, lithium, phenothiazines, • Some patients may tolerate lower doses
thioxanthenes, some antipsychotics) better
• Bupropion should be used with caution in
patients taking levodopa or amantadine, as
these agents can potentially enhance Children and Adolescents
dopamine neurotransmission and be • Use with caution, observing for activation
activating of known or unknown bipolar disorder
• Do not use if patient has severe insomnia and/or suicidal ideation, and strongly
• Use with caution in patients with bipolar consider informing parents or guardian of
disorder unless treated with concomitant this risk so they can help observe child or
mood stabilizing agent adolescent patients
• Monitor patients for activation of suicidal • Safety and efficacy have not been
ideation, especially children and established
adolescents • May be used for ADHD in children or
adolescents
Do Not Use • May be used for smoking cessation in
• Zyban in combination with any formulation adolescents
of Wellbutrin • Preliminary research suggests efficacy in
• If patient has history of seizures comorbid depression and ADHD
• If patient is anorexic or bulimic, either • Dosage may follow adult pattern for
currently or in the past, but see Pearls adolescents
• If patient is abruptly discontinuing alcohol • Children may require lower doses initially,
or sedative use with a maximum dose of 300 mg/day
• If patient has had recent head injury
• If patient has a nervous system tumor
• If patient is taking an MAO inhibitor Pregnancy
• If patient is taking thioridazine • Risk Category B [animal studies do not
• If there is a proven allergy to bupropion show adverse effects; no controlled studies
in humans]
• Pregnant women wishing to stop smoking
may consider behavioral therapy before
pharmacotherapy

40
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(continued) BUPROPION

• Not generally recommended for use during

pregnancy, especially during first trimester
• Must weigh the risk of treatment (first Pearls
trimester fetal development, third trimester ✽ May be effective if SSRIs have failed or
newborn delivery) to the child against the for SSRI “poop-out”
risk of no treatment (recurrence of • Less likely to produce hypomania than
depression, maternal health, infant some other antidepressants
bonding) to the mother and child ✽ May improve cognitive
• For many patients this may mean slowing/pseudodementia
continuing treatment during pregnancy ✽ Reduces hypersomnia and fatigue
• Approved to help reduce craving during
Breast Feeding smoking cessation
• Some drug is found in mother’s breast milk • Anecdotal use in attention deficit disorder
• If child becomes irritable or sedated, breast • May cause sexual dysfunction only
feeding or drug may need to be infrequently
discontinued • May exacerbate tics
• Immediate postpartum period is a high-risk • Bupropion may not be as effective in
time for depression, especially in women anxiety disorders as many other
who have had prior depressive episodes, antidepressants
so drug may need to be reinstituted late in • Prohibition for use in eating disorders is
the third trimester or shortly after related to past observations when
childbirth to prevent a recurrence during bupropion immediate release was dosed at
the postpartum period especially high levels to low body weight
• Must weigh benefits of breast feeding with patients with active anorexia nervosa
risks and benefits of antidepressant • Current practice suggests that patients of
treatment versus non-treatment to both the normal BMI without additional risk factors
infant and the mother for seizures can benefit from bupropion,
• For many patients, this may mean especially if given prudent doses of the XL
continuing treatment during breast feeding formulation; such treatment should be
administered by experts, and patients
should be monitored closely and informed
of the potential risks
THE ART OF PSYCHOPHARMACOLOGY
• The active enantiomer of the principle
Potential Advantages active metabolite (+6-hydroxy-bupropion)
• Retarded depression is in clinical development as a novel
• Atypical depression antidepressant
• Bipolar depression
• Patients concerned about sexual
dysfunction
• Patients concerned about weight gain

Potential Disadvantages
• Patients experiencing weight loss
associated with their depression
• Patients who are excessively activated

Primary Target Symptoms

• Depressed mood
• Sleep disturbance, especially hypersomnia
• Cravings associated with nicotine
withdrawal
• Cognitive functioning

41
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BUPROPION (continued)

Suggested Reading
Ferry L, Johnston JA. Efficacy and safety of Masand PS, Gupta S. Long-term side effects
bupropion SR for smoking cessation: data of newer-generation antidepressants: SSRIs,
from clinical trials and five years of venlafaxine, nefazodone, bupropion, and
postmarketing experience. Int J Clin Pract mirtazapine. Ann Clin Psychiatry
2003;57(3):224–30. 2002;14(3):175–82.
Hirschfeld RM. Efficacy of SSRIs and newer Nieuwstraten CE, Dolovich LR. Bupropion
antidepressants in severe depression: versus selective serotonin-reuptake inhibitors
comparison with TCAs. Journal of Clinical for treatment of depression. Ann
Psychiatry 1999;60:326–335. Pharmacother 2001;35(12):1608–13.
Horst WD, Preskorn SH. Mechanisms of
action and clinical characteristics of three
atypical antidepressants: venlafaxine,
nefazodone, bupropion. Journal of Affective
Disorders 1998;51:237–254.

42
0521011698s01.qxd 9/2/04 2:27 PM Page 43

BUSPIRONE
THERAPEUTICS Best Augmenting Combos
Brands • BuSpar for Partial Response or
see index for additional brand names Treatment-Resistance
• Sedative hypnotic for insomnia
Generic? Yes • Buspirone is often given as an augmenting
agent to SSRIs or SNRIs

Tests
Class • None for healthy individuals
• Anxiolytic (azapirone; serotonin 1A partial
agonist; serotonin stabilizer)

Commonly Prescribed For SIDE EFFECTS

(bold for FDA approved)
How Drug Causes Side Effects
• Management of anxiety disorders
• Serotonin partial agonist actions in parts of
• Short-term treatment of symptoms of
the brain and body and at receptors other
anxiety
than those that cause therapeutic actions
• Mixed anxiety and depression
• Treatment-resistant depression (adjunctive) Notable Side Effects
✽ Dizziness, headache, nervousness,
sedation, excitement
How The Drug Works • Nausea
• Binds to serotonin type 1A receptors • Restlessness
• Partial agonist actions post-synaptically
may theoretically diminish serotonergic
activity and contribute to anxiolytic actions Life Threatening or
• Partial agonist actions at presynaptic Dangerous Side Effects
somatodendritic serotonin autoreceptors • Rare cardiac symptoms
may theoretically enhance serotonergic
activity and contribute to antidepressant Weight Gain
actions

How Long Until It Works • Reported but not expected

• Generally takes within 2–4 weeks to
achieve efficacy Sedation
• If it is not working within 6 to 8 weeks, it
may require a dosage increase or it may
not work at all
• Occurs in significant minority
If It Works
• The goal of treatment is complete
What To Do About Side Effects
remission of symptoms as well as • Wait
prevention of future relapses • Wait
• Treatment most often reduces or even • Wait
eliminates symptoms, but not a cure since • Lower the dose
symptoms can recur after medicine • Give total daily dose divided into 3, 4, or
stopped more doses
• Chronic anxiety disorders may require • Switch to another agent
long-term maintenance with buspirone to Best Augmenting Agents for Side
control symptoms
Effects
If It Doesn’t Work • Many side effects cannot be improved with
• Consider switching to another agent (a an augmenting agent
benzodiazepine or antidepressant)

43
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BUSPIRONE (continued)

DOSING AND USE • Buspirone may raise levels of nordiazepam,

the active metabolite of diazepam, which
Usual Dosage Range may result in increased symptoms of
• 20–30 mg/day dizziness, headache, or nausea
Dosage Forms
• Tablet 5 mg scored, 10 mg scored, 15 mg Other Warnings/
multi-scored, 30 mg multi-scored Precautions
• None
How to Dose
• Initial 15 mg twice a day; increase in Do Not Use
5 mg/day increments every 2–3 days until • If patient is taking an MAO inhibitor
desired efficacy is reached; maximum dose • If there is a proven allergy to buspirone
generally 60 mg/day

SPECIAL POPULATIONS
Dosing Tips
• Requires dosing 2–3 times a day for full Renal Impairment
effect • Use with caution
• Not recommended for patients with severe
Overdose renal impairment
• No deaths reported in monotherapy;
sedation, dizziness, small pupils, nausea, Hepatic Impairment
vomiting • Use with caution
• Not recommended for patients with severe
Long-Term Use hepatic impairment
• Limited data suggest that it is safe
Cardiac Impairment
Habit Forming • Buspirone has been used to treat hostility
• No in patients with cardiac impairment
How to Stop Elderly
• Taper generally not necessary • Some patients may tolerate lower doses
better
Pharmacokinetics
• Metabolized primarily by CYP450 3A4
• Elimination half-life approximately
Children and Adolescents
2–3 hours
• Studies in children 6–17 do not show
significant reduction in anxiety symptoms
in GAD
Drug Interactions • Safety profile in children encourages use
• Do not use with MAO inhibitors, including
14 days after MAOIs are stopped
• CYP450 3A4 inhibitors (e.g., fluxotine,
Pregnancy
fluvoxamine, nefazodone) may reduce
• Risk Category B [animal studies do not
clearance of buspirone and raise its plasma
show adverse effects, no controlled studies
levels, so the dose of buspirone may need
in humans]
to be lowered when given concomitantly
• Not generally recommended in pregnancy,
with these agents
but may be safer than some other options
• CYP450 3A4 inducers (e.g.,
carbamazepine) may increase clearance of Breast Feeding
buspirone, so the dose of buspirone may
• Some drug is found in mother’s breast milk
need to be raised
• Trace amounts may be present in nursing
• Buspirone may increase plasma
children whose mothers are on buspirone
concentrations of haloperidol

44
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(continued) BUSPIRONE

• If child becomes irritable or sedated, breast • May have less severe side effects than
feeding or drug may need to be benzodiazepines
discontinued ✽ Buspirone generally lacks sexual
dysfunction
• Buspirone may reduce sexual dysfunction
THE ART OF PSYCHOPHARMACOLOGY associated with generalized anxiety
disorder and with serotonergic
Potential Advantages antidepressants
• Safety profile • Sedative effects may be more likely at
• Lack of dependence, withdrawal doses above 20 mg/day
• Lack of sexual dysfunction or weight gain • May have less anxiolytic efficacy than
benzodiazepines for some patients
Potential Disadvantages • Buspirone is generally reserved as an
• Takes 4 weeks for results, whereas augmenting agent to treat anxiety
benzodiazepines have immediate effects • A new controlled-release azapirone related
to buspirone is in late clinical testing as an
Primary Target Symptoms antidepressant (gepirone ER)
• Anxiety

Pearls
✽ Buspirone does not appear to cause
dependence and shows virtually no
withdrawal symptoms

Suggested Reading
Apter JT, Allen LA. Buspirone: future Pecknold JC. A risk-benefit assessment of
directions. J Clin Psychopharmacol 1999; buspirone in the treatment of anxiety
19:86–93. disorders. Drug Saf 1997;16:118–32.
Mahmood I, Sahaiwalla C. Clinical Sramek JJ, Hong WW, Hamid S, Nape B,
pharmacokinetics and pharmacodynamics of Cutler NR. Meta-analysis of the safety and
buspirone, an anxiolytic drug. Clin tolerability of two dose regimens of buspirone
Pharmacokinet 1999;36:277–87. in patients with persistent anxiety. Depress
Anxiety 1999;9:131–4.

45
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0521011698s01.qxd 9/2/04 2:27 PM Page 47

CARBAMAZEPINE
THERAPEUTICS • Continue treatment indefinitely to avoid
recurrence of mania and seizures
Brands • Tegretol • Treatment of chronic neuropathic pain
• Carbatrol most often reduces but does not eliminate
see index for additional brand names pain and is not a cure since symptoms
usually recur after medicine stopped
Generic? Yes (not for extended release
formulation) If It Doesn’t Work (for bipolar
disorder)
✽ Many patients only have a partial
Class response where some symptoms are
• Anticonvulsant, antineuralgic for chronic improved but others persist or continue to
pain, voltage-sensitive sodium channel wax and wane without stabilization of
antagonist mood
• Other patients may be nonresponders,
Commonly Prescribed For sometimes called treatment-resistant or
(bold for FDA approved) treatment-refractory
• Partial seizures with complex • Consider increasing dose, switching to
symptomatology another agent or adding an appropriate
• Generalized tonic-clonic seizures (grand augmenting agent
mal) • Consider adding psychotherapy
• Mixed seizure patterns • Consider biofeedback or hypnosis for pain
• Pain associated with true trigeminal • For bipolar disorder, consider the presence
neuralgia of noncompliance and counsel patient
• Glossopharyngeal neuralgia • Switch to another mood stabilizer with
• Bipolar disorder fewer side effects or to extended release
• Psychosis, schizophrenia (adjunctive) carbamazepine
• Consider evaluation for another diagnosis
or for a comorbid condition (e.g., medical
How The Drug Works illness, substance abuse, etc.)
✽ Acts as a use-dependent blocker of Best Augmenting Combos
voltage-sensitive sodium channels
✽ Interacts with the open channel for Partial Response or
conformation of voltage-sensitive sodium Treatment-Resistance
channels • Carbamazepine is itself a second-line
✽ Interacts at a specific site of the alpha augmenting agent for numerous other
pore-forming subunit of voltage-sensitive anticonvulsants, lithium, and atypical
sodium channels antipsychotics in treating bipolar disorder
• Inhibits release of glutamate • Carbamazepine is itself a second or third-
line augmenting agent for atypical
How Long Until It Works antipsychotics in treating schizophrenia
• For acute mania, effects should occur
within a few weeks Tests
• May take several weeks to months to ✽ Before starting: blood count, liver, kidney,
optimize an effect on mood stabilization and thyroid function tests
• Should reduce seizures by 2 weeks • During treatment: blood count every
2 weeks for 2 months, then every
If It Works 3 months throughout treatment
• The goal of treatment is complete • During treatment: liver, kidney, and thyroid
remission of symptoms (e.g., seizures, function tests every 6–12 months
mania, pain) • Consider monitoring sodium levels
• Continue treatment until all symptoms are because of possibility of hyponatremia
gone or until improvement is stable and
then continue treating indefinitely as long
as improvement persists

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CARBAMAZEPINE (continued)

SIDE EFFECTS • Take with food or split dose to avoid

gastrointestinal effects
How Drug Causes Side Effects • Extended release carbamazepine can be
• CNS side effects theoretically due to sprinkled on soft food
excessive actions at voltage-sensitive • Take at night to reduce daytime sedation
sodium channels • Switch to another agent or to extended
• Major metabolite (carbamazepine-10, 11 release carbamazepine
epoxide) may be the cause of many side
effects Best Augmenting Agents for Side
• Mild anticholinergic effects may contribute Effects
to sedation, blurred vision • Many side effects cannot be improved with
an augmenting agent
Notable Side Effects
✽ Sedation, dizziness, confusion,
unsteadiness, headache
✽ Nausea, vomiting, diarrhea DOSING AND USE
• Blurred vision
Usual Dosage Range
✽ Benign leukopenia (transient; in up to 10%)
✽ Rash • 400–1200 mg/day
• Under age 6: 10–20 mg/kg/day

Life Threatening or Dosage Forms

Dangerous Side Effects • Tablet 100 mg chewable, 200 mg
✽ Rare aplastic anemia, agranulocytosis • Extended release tablet 100 mg, 200 mg,
(unusual bleeding or bruising, mouth 400 mg
sores, infections, fever, sore throat) • Extended release capsule 200 mg, 300 mg
✽ Rare severe dermatologic reactions • Oral suspension 100 mg/5mL (450 mL)
(Stevens Johnson syndrome)
• Rare cardiac problems How to Dose
• Rare induction of psychosis or mania • For bipolar disorder and seizures (ages 13
✽ SIADH (syndrome of inappropriate and older): initial 200 mg twice daily
antidiuretic hormone secretion) with (tablet) or 1 teaspoon (100 mg) 4 times a
hyponatremia day (suspension); each week increase by
• Increased frequency of generalized up to 200 mg/day in divided doses
convulsions (in patients with atypical (2 doses for extended release formulation,
absence seizures) 3–4 doses for other tablets); maximum
dose generally 1200 mg/day for adults and
Weight Gain 1000 mg/day for children under age 15;
maintenance dose generally 800–1200
mg/day for adults; some patients may
require up to 1600 mg/day
• Occurs in significant minority • Seizures (under age 13): see Children and
Sedation Adolescents
• Trigeminal neuralgia: initial 100 mg twice
daily (tablet) or 0.5 teaspoon (50 mg)
4 times a day; each week increase by up to
• Frequent and can be significant in amount 200 mg/day in divided doses (100 mg
• Some patients may not tolerate it every 12 hours for tablet formulations,
• Dose-related 50 mg 4 times a day for suspension
• Can wear off with time, but commonly formulation); maximum dose generally
does not wear off at high doses 1200 mg/day
• Lower initial dose and slower titration
What To Do About Side Effects should be used for carbamazepine
• Wait suspension
• Wait
• Wait

48
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(continued) CARBAMAZEPINE

✽ Rapid discontinuation may increase the

risk of relapse in bipolar disorder
Dosing Tips • Epilepsy patients may seize upon
• Higher peak levels occur with the withdrawal, especially if withdrawal is
suspension formulation than with the same abrupt
dose of the tablet formulation, so • Discontinuation symptoms uncommon
suspension should generally be started at a
lower dose and titrated slowly Pharmacokinetics
• Take carbamazepine with food to avoid • Metabolized in the liver, primarily by
gastrointestinal effects CYP450 3A4
✽ Slow dose titration may delay onset of • Renally excreted
therapeutic action but enhance tolerability • Active metabolite (carbamazepine-
to sedating side effects 10,11 epoxide)
• Should titrate slowly in the presence of • Initial half-life 26–65 hours (35–40 hours
other sedating agents, such as other for extended release formulation); half-life
anticonvulsants, in order to best tolerate 12–17 hours with repeated doses
additive sedative side effects • Half-life of active metabolite is
✽ Can sometimes minimize the impact of approximately 34 hours
carbamazepine upon the bone marrow by ✽ Is not only a substrate for CYP450 3A4,
dosing slowly and monitoring closely when but also an inducer of CYP450 3A4
initiating treatment; initial trend to ✽ Thus, carbamazepine induces its own
leukopenia/neutropenia may reverse with metabolism, often requiring an upward
continued conservative dosing over time dosage adjustment
and allow subsequent dosage increases
with careful monitoring
✽ Carbamazepine often requires a dosage Drug Interactions
adjustment upward with time, as the drug
• Enzyme-inducing antiepileptic drugs
induces its own metabolism, thus lowering
(carbamazepine itself as well as
its own plasma levels over the first several
phenobarbital, phenytoin, and primidone)
weeks to months of treatment
may increase the clearance of
• Do not break or chew carbamazepine
carbamazepine and lower its plasma levels
extended release tablets as this will alter
• CYP450 3A4 inducers, such as
controlled release properties
carbamazepine itself, can lower the plasma
Overdose levels of carbamazepine
• Can be fatal (lowest known fatal dose in • CYP450 3A4 inhibitors, such as
adults is 3.2 g, in adolescents is 4 g, and in nefazodone, fluvoxamine, and fluoxetine,
children is 1.6 g); nausea, vomiting, can increase plasma levels of
involuntary movements, irregular carbamazepine
heartbeat, urinary retention, trouble • Carbamazepine can increase plasma levels
breathing, sedation, coma of clomipramine, phenytoin, primidone
• Carbamazepine can decrease plasma levels
Long-Term Use of acetaminophen, clozapine,
• May lower sex drive benzodiazepines, dicumarol, doxycycline,
• Monitoring of liver, kidney, thyroid theophylline, warfarin, and haloperidol as
functions, blood counts and sodium may well as other anticonvulsants such as
be required phensuximide, methsuximide,
ethosuximide, phenytoin, tiagabine,
Habit Forming topiramate, lamotrigine, and valproate
• No • Carbamazepine can decrease plasma levels
of hormonal contraceptives and adversely
How to Stop affect their efficacy
• Taper; may need to adjust dosage of • Combined use of carbamazepine with other
concurrent medications as carbamazepine anticonvulsants may lead to altered thyroid
is being discontinued function

49
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CARBAMAZEPINE (continued)

• Combined use of carbamazepine and • If there is a proven allergy to any tricyclic

lithium may increase risk of neurotoxic compound
effects • If there is a proven allergy to
• Depressive effects are increased by other carbamazepine
CNS depressants (alcohol, MAOIs, other
anticonvulsants, etc.)
• Combined use of carbamazepine SPECIAL POPULATIONS
suspension with liquid formulations of
chlorpromazine has been shown to result Renal Impairment
in excretion of an orange rubbery • Carbamazepine is renally secreted, so the
precipitate; because of this, combined use dose may need to be lowered
of carbamazepine suspension with any
liquid medicine is not recommended Hepatic Impairment
• Drug should be used with caution
• Rare cases of hepatic failure have occurred
Other Warnings/
Precautions Cardiac Impairment
✽ Patients should be monitored carefully for • Drug should be used with caution
signs of unusual bleeding or bruising,
mouth sores, infections, fever, or sore Elderly
throat, as the risk of aplastic anemia and • Some patients may tolerate lower doses
agranulocytosis with carbamazepine use is better
5–8 times greater than in the general • Elderly patients may be more susceptible
population (risk in the untreated general to adverse effects
population is 6 patients per one million per
year for agranulocytosis and 2 patients per
one million per year for aplastic anemia) Children and Adolescents
• Because carbamazepine has a tricyclic
• Approved use for epilepsy; therapeutic
chemical structure, it is not recommended
range of total carbamazepine in plasma is
to be taken with MAOIs, including 14 days
considered the same for children and
after MAOIs are stopped; do not start an
adults
MAOI until 2 weeks after discontinuing
• Ages 6–12: initial dose 100 mg twice daily
carbamazepine
(tablets) or 0.5 teaspoon (50 mg) 4 times a
• May exacerbate narrow angle-closure
day (suspension); each week increase by
glaucoma
up to 100 mg/day in divided doses (2
• Because carbamazepine can lower plasma
doses for extended release formulation, 3–4
levels of hormonal contraceptives, it may
doses for all other formulations); maximum
also reduce their effectiveness
dose generally 1000 mg/day; maintenance
• May need to restrict fluid intake because of
dose generally 400–800 mg/day
risk of developing syndrome of
• Ages 5 and younger: initial 10–20
inappropriate antidiuretic hormone
mg/kg/day in divided doses (2–3 doses for
secretion, hyponatremia and its
tablet formulations, 4 doses for
complications
suspension); increase weekly as needed;
• Use with caution in patients with mixed
maximum dose generally 35 mg/kg/day
seizure disorders that include atypical
absence seizures because carbamazepine
has been associated with increased
frequency of generalized convulsions in Pregnancy
such patients • Risk category D [positive evidence of risk
to human fetus; potential benefits may still
Do Not Use justify its use during pregnancy]
• If patient is taking an MAOI ✽ Use during first trimester may raise risk
• If patient has history of bone marrow of neural tube defects (e.g., spina bifida) or
suppression other congenital anomalies

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(continued) CARBAMAZEPINE

• Use in women of childbearing potential • Relapse rates may be lower in women who
requires weighing potential benefits to the receive prophylactic treatment for
mother against the risks to the fetus postpartum episodes of bipolar disorder
✽ If drug is continued, perform tests to • Atypical antipsychotics and anticonvulsants
detect birth defects such as valproate may be safer than
✽ If drug is continued, start on folate 1 carbamazepine during the postpartum
mg/day early in pregnancy to reduce risk of period when breast feeding
neural tube defects
• Use of anticonvulsants in combination may
cause a higher prevalence of teratogenic THE ART OF PSYCHOPHARMACOLOGY
effects than anticonvulsant monotherapy
• Taper drug if discontinuing Potential Advantages
• Seizures, even mild seizures, may cause • Treatment-resistant bipolar and psychotic
harm to the embryo/fetus disorders
✽ For bipolar patients, carbamazepine
should generally be discontinued before Potential Disadvantages
anticipated pregnancies • Patients who do not wish to or cannot
• Recurrent bipolar illness during pregnancy comply with blood testing and close
can be quite disruptive monitoring
• For bipolar patients, given the risk of • Patients who cannot tolerate sedation
relapse in the postpartum period, some • Pregnant patients
form of mood stabilizer treatment may
need to be restarted immediately after Primary Target Symptoms
delivery if patient is unmedicated during • Incidence of seizures
pregnancy • Unstable mood, especially mania
✽ Atypical antipsychotics may be preferable • Pain
to lithium or anticonvulsants such as
carbamazepine if treatment of bipolar
disorder is required during pregnancy Pearls
• Bipolar symptoms may recur or worsen • Carbamazepine is the first anticonvulsant
during pregnancy and some form of widely used for the treatment of bipolar
treatment may be necessary disorder
Breast Feeding ✽ Due to the emergence of anticonvulsants
with better documentation of efficacy and
• Some drug is found in mother’s breast milk better tolerability, use in bipolar disorder is
✽ Recommended either to discontinue drug declining
or bottle feed
• If drug is continued while breast feeding,
✽ An extended release formulation has
better evidence of efficacy and improved
infant should be monitored for possible tolerability in bipolar disorder than does
adverse effects, including hematological immediate release carbamazepine
effects • Dosage frequency as well as sedation,
• If infant shows signs of irritability or diplopia, confusion, and ataxia may be
sedation, drug may need to be reduced with extended release
discontinued carbamazepine
• Some cases of neonatal seizures, • Risk of serious side effects is greatest in
respiratory depression, vomiting, and the first few months of treatment
diarrhea have been reported in infants • Common side effects such as sedation
whose mothers received carbamazepine often abate after a few months
during pregnancy
✽ May be effective in patients who fail to
✽ Bipolar disorder may recur during the respond to lithium or other mood
postpartum period, particularly if there is a stabilizers
history of prior postpartum episodes of
either depression or psychosis
✽ Especially preferred as a second or third-
line treatment for mania

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CARBAMAZEPINE (continued)

• Not clearly effective for the depressed • Although less well investigated in bipolar
phase of bipolar disorder disorder, oxcarbazepine, a structural analog
• Can be complicated to dose of carbamazepine, may be better tolerated
• Can be complicated to use with and thus an appropriate alternative to
concomitant medications carbamazepine

Suggested Reading
Brambilla P, Barale F, Soares JC. Perspectives Marson AG, Williamson PR, Hutton JL, Clough
on the use of anticonvulsants in the treatment HE, Chadwick DW. Carbamazepine versus
of bipolar disorder. Int J valproate monotherapy for epilepsy. Cochrane
Neuropsychopharmacol. 2001; 4: 421–46. Database Syst Rev. 2000; (3): CD001030.
Leucht S, McGrath J, White P, Kissling W. Weisler RH, Kalali AH, Ketter TA. A multicenter,
Carbamazepine for schizophrenia and randomized, double-blind, placebo-controlled
schizoaffective psychoses. Cochrane Database trial of extended-release carbamazepine
Syst Rev. 2002;(3):CD001258. capsules as monotherapy for bipolar disorder
patients with manic or mixed episodes. J Clin
Psychiatry 2004; 65: 478–84.

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CHLORDIAZEPOXIDE
THERAPEUTICS treatment for 6 months after symptoms
resolve, and then taper dose slowly
Brands • Limbitrol • If symptoms reemerge, consider treatment
• Librium with an SSRI or SNRI, or consider
• Librax restarting the benzodiazepine; sometimes
see index for additional brand names benzodiazepines have to be used in
combination with SSRIs or SNRIs for best
Generic? Yes
results

If It Doesn’t Work
Class • Consider switching to another agent or
• Benzodiazepine (anxiolytic) adding an appropriate augmenting agent
• Consider psychotherapy, especially
Commonly Prescribed For cognitive behavioral psychotherapy
(bold for FDA approved) • Consider presence of concomitant
• Anxiety disorders substance abuse
• Symptoms of anxiety • Consider presence of chlordiazepoxide
• Preoperative apprehension and anxiety abuse
• Withdrawal symptoms of acute alcoholism • Consider another diagnosis, such as a
comorbid medical condition

How The Drug Works Best Augmenting Combos

• Binds to benzodiazepine receptors at the for Partial Response or
GABA-A ligand-gated chloride channel Treatment-Resistance
complex • Benzodiazepines are frequently used as
• Enhances the inhibitory effects of GABA augmenting agents for antipsychotics and
• Boosts chloride conductance through mood stabilizers in the treatment of
GABA-regulated channels psychotic and bipolar disorders
• Inhibits neuronal activity presumably in • Benzodiazepines are frequently used as
amygdala-centered fear circuits to provide augmenting agents for SSRIs and SNRIs in
therapeutic benefits in anxiety disorders the treatment of anxiety disorders
• Not generally rational to combine with
How Long Until It Works other benzodiazepines
• Some immediate relief with first dosing is • Caution if using as an anxiolytic
common; can take several weeks with daily concomitantly with other sedative
dosing for maximal therapeutic benefit hypnotics for sleep

If It Works Tests
• For short-term symptoms of anxiety – after • In patients with seizure disorders,
a few weeks, discontinue use or use on an concomitant medical illness, and/or those
“as-needed” basis with multiple concomitant long-term
• For chronic anxiety disorders, the goal of medications, periodic liver tests and blood
treatment is complete remission of counts may be prudent
symptoms as well as prevention of future
relapses
• For chronic anxiety disorders, treatment SIDE EFFECTS
most often reduces or even eliminates
symptoms, but not a cure since symptoms How Drug Causes Side Effects
can recur after medicine stopped • Same mechanism for side effects as for
• For long-term symptoms of anxiety, therapeutic effects – namely due to
consider switching to an SSRI or SNRI for excessive actions at benzodiazepine
long-term maintenance receptors
• If long-term maintenance with a • Long-term adaptations in benzodiazepine
benzodiazepine is necessary, continue receptors may explain the development of
dependence, tolerance, and withdrawal

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CHLORDIAZEPOXIDE (continued)

• Side effects are generally immediate, but DOSING AND USE

immediate side effects often disappear in
time
Usual Dosage Range
• Oral: mild to moderate anxiety:
Notable Side Effects 15–40 mg/day in 3–4 doses
✽ Sedation, fatigue, depression • Oral: severe anxiety: 60–100 mg/day in
✽ Dizziness, ataxia, slurred speech, 3–4 doses
weakness
Dosage Forms
✽ Forgetfulness, confusion
✽ Hyper-excitability, nervousness • Capsule 5 mg, 10 mg, 25 mg
✽ Pain at injection site • Injectable 100 mg/5 mL
• Rare hallucinations, mania
How to Dose
• Rare hypotension
• Injectable: acute/severe anxiety: initial
• Hypersalivation, dry mouth
50–100 mg; 25–50 mg 3–4 times/day if
necessary
Life Threatening or • Injectable: alcohol withdrawal: initial
Dangerous Side Effects 50–100 mg; repeat after 2 hours if necessary
• Respiratory depression, especially when • Injectable: preoperative: 50–100 mg 1 hour
taken with CNS depressants in overdose before surgery
• Rare hepatic dysfunction, renal • Patients who receive injectable
dysfunction, blood dyscrasias chlordiazepoxide should be observed for
up to 3 hours
Weight Gain

Dosing Tips
• Reported but not expected ✽ One of the few benzodiazepines available
in an injectable formulation
Sedation • Chlordiazepoxide injection is intended for
acute use; patients who require longer
treatment should be switched to the oral
formulation
• Many experience and/or can be significant
• Use lowest possible effective dose for the
in amount
shortest possible period of time (a
• Especially at initiation of treatment or when
benzodiazepine-sparing strategy)
dose increases
• Assess need for continued treatment
• Tolerance often develops over time
regularly
What To Do About Side Effects • Risk of dependence may increase with
dose and duration of treatment
• Wait
• For inter-dose symptoms of anxiety, can
• Wait
either increase dose or maintain same total
• Wait
daily dose but divide into more frequent
• Lower the dose
doses
• Take largest dose at bedtime to avoid
• Can also use an as-needed occasional “top
sedative effects during the day
up” dose for inter-dose anxiety
• Switch to another agent
• Because anxiety disorders can require
• Administer flumazenil if side effects are
higher doses, the risk of dependence may
severe or life-threatening
be greater in these patients
Best Augmenting Agents for Side • Some severely ill patients may require
Effects doses higher than the generally
• Many side effects cannot be improved with recommended maximum dose
an augmenting agent • Frequency of dosing in practice is often
greater than predicted from half-life, as
duration of biological activity is often shorter
than pharmacokinetic terminal half-life

54
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(continued) CHLORDIAZEPOXIDE

Overdose
Other Warnings/
• Fatalities can occur; hypotension,
tiredness, ataxia, confusion, coma
Precautions
• Dosage changes should be made in
Long-Term Use collaboration with prescriber
• Evidence of efficacy for up to 16 weeks • Use with caution in patients with
• Risk of dependence, particularly for pulmonary disease; rare reports of death
treatment periods longer than 12 weeks, after initiation of benzodiazepines in
and especially in patients with past or patients with severe pulmonary impairment
current polysubstance abuse • History of drug or alcohol abuse often
creates greater risk for dependency
Habit Forming • Some depressed patients may experience a
• Chlordiazepoxide is a Schedule IV drug worsening of suicidal ideation
• Patients may develop dependence and/or • Some patients may exhibit abnormal
tolerance with long-term use thinking or behavioral changes similar to
those caused by other CNS depressants
How to Stop (i.e., either depressant actions or
• Patients with history of seizure may seize disinhibiting actions)
upon withdrawal, especially if withdrawal is
abrupt Do Not Use
• Taper by 10 mg every 3 days to reduce • If patient has narrow angle-closure
chances of withdrawal effects glaucoma
• For difficult to taper patients, consider • If there is a proven allergy to
reducing dose much more slowly after chlordiazepoxide or any benzodiazepine
reaching 20 mg/day, perhaps by as little as
5 mg per week or less
• For other patients with severe problems SPECIAL POPULATIONS
discontinuing a benzodiazepine, dosing
may need to be tapered over many months Renal Impairment
(i.e., reduce dose by 1% every 3 days by • Oral: Initial 10–20 mg/day in 2–4 doses;
crushing tablet and suspending or dissolving increase as needed
in 100 ml of fruit juice and then disposing of • Injectable: 25–50 mg
1 ml while drinking the rest; 3–7 days later,
dispose of 2 ml, and so on). This is both a Hepatic Impairment
form of very slow biological tapering and a • Oral: Initial 10–20 mg/day in 2–4 doses;
form of behavioral desensitization increase as needed
• Be sure to differentiate reemergence of • Injectable: 25–50 mg
symptoms requiring reinstitution of
treatment from withdrawal symptoms Cardiac Impairment
• Benzodiazepine-dependent anxiety patients • Benzodiazepines have been used to treat
and insulin-dependent diabetics are not anxiety associated with acute myocardial
addicted to their medications. When infarction
benzodiazepine-dependent patients stop
their medication, disease symptoms can
Elderly
reemerge, disease symptoms can worsen • Oral: Initial 10–20 mg/day in 2–4 doses;
(rebound), and/or withdrawal symptoms increase as needed
can emerge • Injectable: 25–50 mg
• Elderly patients may be more sensitive to
Pharmacokinetics sedative effects
• Elimination half-life 24–48 hours

Children and Adolescents

Drug Interactions • Oral: Not recommended under age 6
• Increased depressive effects when taken
with other CNS depressants

55
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CHLORDIAZEPOXIDE (continued)

• Oral: Initial 10–20 mg/day in 2–4 doses; • Effects of benzodiazepines on nursing infants
may increase to 20–30 mg/day in 2–3 have been reported and include feeding
doses if ineffective difficulties, sedation, and weight loss
• Injectable: Not recommended under age 12
• Injectable: 25–50 mg
• Hyperactive children should be monitored THE ART OF PSYCHOPHARMACOLOGY
for paradoxical effects
• Long-term effects of chlordiazepoxide in Potential Advantages
children/adolescents are unknown • Rapid onset of action
• Should generally receive lower doses and
be more closely monitored Potential Disadvantages
• Euphoria may lead to abuse
• Abuse especially risky in past or present
Pregnancy substance abusers
• Risk Category D [positive evidence of risk
to human fetus; potential benefits may still
Primary Target Symptoms
justify its use during pregnancy] • Panic attacks
• Possible increased risk of birth defects • Anxiety
when benzodiazepines taken during
pregnancy
• Because of the potential risks, Pearls
chlordiazepoxide is not generally • Can be a useful adjunct to SSRIs and
recommended as treatment for anxiety SNRIs in the treatment of numerous
during pregnancy, especially during the anxiety disorders, but not used as
first trimester frequently as some other benzodiazepines
• Drug should be tapered if discontinued • Not effective for treating psychosis as a
• Infants whose mothers received a monotherapy, but can be used as an
benzodiazepine late in pregnancy may adjunct to antipsychotics
experience withdrawal effects • Not effective for treating bipolar disorder
• Neonatal flaccidity has been reported in as a monotherapy, but can be used as an
infants whose mothers took a adjunct to mood stabilizers and
benzodiazepine during pregnancy antipsychotics
• Seizures, even mild seizures, may cause • Can both cause depression and treat
harm to the embryo/fetus depression in different patients
• When using to treat insomnia, remember
Breast Feeding that insomnia may be a symptom of some
• Unknown if chlordiazepoxide is secreted in other primary disorder itself, and thus
human breast milk, but all psychotropics warrant evaluation for comorbid psychiatric
assumed to be secreted in breast milk and/or medical conditions
✽ Recommended either to discontinue drug ✽ Remains a viable treatment option for
or bottle feed alcohol withdrawal

Suggested Reading
Baskin SI, Esdale A. Is chlordiazepoxide the Fraser AD. Use and abuse of the
rational choice among benzodiazepines? benzodiazepines. Ther Drug Monit 1998;
Pharmacotherapy 1982;2:110–9. 20:481–9.
Erstad BL, Cotugno CL. Management of Murray JB. Effects of valium and librium on
alcohol withdrawal. Am J Health Syst Pharm human psychomotor and cognitive functions.
1995;52:697–709. Genet Psychol Monogr 1984;109(2D
Half):167–97.

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CHLORPROMAZINE
THERAPEUTICS If It Works
• Most often reduces positive symptoms in
Brands • Thorazine
schizophrenia but does not eliminate them
see index for additional brand names
• Most schizophrenic patients do not have a
Generic? Yes total remission of symptoms but rather a
reduction of symptoms by about a third
• Continue treatment in schizophrenia until
reaching a plateau of improvement
Class • After reaching a satisfactory plateau,
• Conventional antipsychotic (neuroleptic, continue treatment for at least a year after
phenothiazine, dopamine 2 antagonist, first episode of psychosis in schizophrenia
antiemetic) • For second and subsequent episodes of
psychosis in schizophrenia, treatment may
Commonly Prescribed For need to be indefinite
(bold for FDA approved) • Reduces symptoms of acute psychotic
• Schizophrenia mania but not proven as a mood stabilizer
• Nausea, vomiting or as an effective maintenance treatment in
• Restlessness and apprehension before bipolar disorder
surgery • After reducing acute psychotic symptoms
• Acute intermittent porphyria in mania, switch to a mood stabilizer
• Manifestations of manic type of manic- and/or an atypical antipsychotic for mood
depressive illness stabilization and maintenance
• Tetanus (adjunct)
• Intractable hiccups If It Doesn’t Work
• Combativeness and/or explosive • Consider trying one of the first-line atypical
hyperexcitable behavior (in children) antipsychotics (risperidone, olanzapine,
• Hyperactive children who show excessive quetiapine, ziprasidone, aripiprazole,
motor activity with accompanying conduct amisulpride)
disorders consisting of some or all of the • Consider trying another conventional
following symptoms: impulsivity, antipsychotic
difficulty sustaining attention, • If 2 or more antipsychotic monotherapies
aggressivity, mood lability, and poor do not work, consider clozapine
frustration tolerance
• Psychosis Best Augmenting Combos
• Bipolar disorder for Partial Response or
Treatment-Resistance
• Augmentation of conventional
How The Drug Works antipsychotics has not been systematically
• Blocks dopamine 2 receptors, reducing studied
positive symptoms of psychosis and • Addition of a mood stabilizing
improving other behaviors anticonvulsant such as valproate,
• Combination of dopamine D2, histamine carbamazepine, or lamotrigine may be
H1, and cholinergic M1 blockade in the helpful in both schizophrenia and bipolar
vomiting center may reduce nausea and mania
vomiting • Augmentation with lithium in bipolar mania
may be helpful
How Long Until It Works • Addition of a benzodiazepine, especially
• Psychotic symptoms can improve within 1 short-term for agitation
week, but it may take several weeks for full
effect on behavior Tests
• Actions on nausea and vomiting are ✽ Since conventional antipsychotics are
immediate frequently associated with weight gain,
before starting treatment, weigh all patients
and determine if the patient is already

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CHLORPROMAZINE (continued)

overweight (BMI 25.0–29.9) or obese dyslipidemia with conventional

(BMI ≥30) antipsychotics is unknown
• Before giving a drug that can cause weight
gain to an overweight or obese patient, Notable Side Effects
consider determining whether the patient ✽ Neuroleptic-induced deficit syndrome
already has pre-diabetes (fasting plasma ✽ Akathisia
glucose 100–125 mg/dl), diabetes (fasting ✽ Priapism
plasma glucose >126 mg/dl), or ✽ Extrapyramidal symptoms, Parkinsonism,
dyslipidemia (increased total cholesterol, tardive dyskinesia
LDL cholesterol and triglycerides; ✽ Galactorrhea, amenorrhea
decreased HDL cholesterol), and treat or • Dizziness, sedation, impaired memory
refer such patients for treatment, including • Dry mouth, constipation, urinary retention,
nutrition and weight management, physical blurred vision
activity counseling, smoking cessation, and • Decreased sweating
medical management • Sexual dysfunction
✽ Monitor weight and BMI during treatment • Hypotension, tachycardia, syncope
✽ While giving a drug to a patient who has • Weight gain
gained >5% of initial weight, consider
evaluating for the presence of pre-diabetes,
Life Threatening or
diabetes, or dyslipidemia, or consider
switching to a different antipsychotic
Dangerous Side Effects
• Should check blood pressure in the elderly • Rare neuroleptic malignant syndrome
before starting and for the first few weeks • Rare jaundice, agranulocytosis
of treatment • Rare seizures
• Monitoring elevated prolactin levels of Weight Gain
dubious clinical benefit
• Phenothiazines may cause false positive
phenylketonuria results
• Many experience and/or can be significant
in amount
SIDE EFFECTS Sedation
How Drug Causes Side Effects
• By blocking dopamine 2 receptors in the
striatum, it can cause motor side effects • Tolerance to sedation can develop over
• By blocking dopamine 2 receptors in the time
pituitary, it can cause elevations in
prolactin What To Do About Side Effects
• By blocking dopamine 2 receptors • Wait
excessively in the mesocortical and • Wait
mesolimbic dopamine pathways, especially • Wait
at high doses, it can cause worsening of • For motor symptoms, add an
negative and cognitive symptoms anticholinergic agent
(neuroleptic-induced deficit syndrome) • Reduce the dose
• Anticholinergic actions may cause • For sedation, give at night
sedation, blurred vision, constipation, dry • Switch to an atypical antipsychotic
mouth • Weight loss, exercise programs, and
• Antihistaminic actions may cause sedation, medical management for high BMIs,
weight gain diabetes dyslipidemia
• By blocking alpha 1 adrenergic receptors, it
can cause dizziness, sedation, and Best Augmenting Agents for Side
hypotension Effects
• Mechanism of weight gain and any • Benztropine or trihexyphenidyl for motor
possible increased incidence of diabetes or side effects

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(continued) CHLORPROMAZINE

• Sometimes amantadine can be helpful for Long-Term Use

motor side effects • Some side effects may be irreversible (e.g.,
• Benzodiazepines may be helpful for tardive dyskinesia)
akathisia
• Many side effects cannot be improved with Habit Forming
an augmenting agent • No

How to Stop
DOSING AND USE • Slow down-titration of oral formulation
(over 6 to 8 weeks), especially when
Usual Dosage Range simultaneously beginning a new
• 200–800 mg/day antipsychotic while switching (i.e., cross-
titration)
Dosage Forms • Rapid oral discontinuation may lead to
• Tablet 10 mg, 25 mg, 50 mg, 100 mg, rebound psychosis and worsening of
200 mg symptoms
• Capsule 30 mg, 75 mg, 150 mg • If antiparkinson agents are being used,
• Ampul 25 mg/mL; 1 mL, 2 mL they should be continued for a few weeks
• Vial 25 mg/mL; 10 mL after chlorpromazine is discontinued
• Liquid 10 mg/5 mL
• Suppository 25 mg, 100 mg Pharmacokinetics
• Half-life approximately 8–33 hours
How to Dose
• Psychosis: increase dose until symptoms
are controlled; after 2 weeks reduce to Drug Interactions
lowest effective dose • May decrease the effects of levodopa,
• Psychosis (intramuscular): varies by dopamine agonists
severity of symptoms and • May increase the effects of
inpatient/outpatient status antihypertensive drugs except for
guanethidine, whose antihypertensive
actions chlorpromazine may antagonize
Dosing Tips • Additive effects may occur if used with
• Low doses may have more sedative actions CNS depressants
than antipsychotic actions • Some pressor agents (e.g., epinephrine)
• Low doses have been used to provide may interact with chlorpromazine to lower
short-term relief of daytime agitation and blood pressure
anxiety and to enhance sedative hypnotic • Alcohol and diuretics may increase the risk
actions in non-psychotic patients, but other of hypotension
treatment options such as atypical • Reduces effects of anticoagulants
antipsychotics are now preferred • May reduce phenytoin metabolism and
• Higher doses may induce or worsen increase phenytoin levels
negative symptoms of schizophrenia • Plasma levels of chlorpromazine and
• Ampuls and vials contain sulfites that may propranolol may increase if used
cause allergic reactions, particularly in concomitantly
patients with asthma • Some patients taking a neuroleptic and
• One of the few antipsychotics available as a lithium have developed an encephalopathic
suppository syndrome similar to neuroleptic malignant
syndrome
Overdose
• Extrapyramidal symptoms, sedation,
Other Warnings/
hypotension, coma, respiratory depression
Precautions
• If signs of neuroleptic malignant syndrome
develop, treatment should be immediately
discontinued

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CHLORPROMAZINE (continued)

• Use cautiously in patients with alcohol 6–8 hours as needed; maximum 40 mg/day
withdrawal or convulsive disorders (under 5), 75 mg/day (5–12)
because of possible lowering of seizure • Do not use if patient shows signs of Reye’s
threshold syndrome
• Use with caution in patients with • Generally consider second-line after
respiratory disorders, glaucoma, or urinary atypical antipsychotics
retention
• Avoid extreme heat exposure
• Avoid undue exposure to sunlight Pregnancy
• Antiemetic effect of chlorpromazine may • Risk Category C [some animal studies
mask signs of other disorders or overdose; show adverse effects, no controlled studies
suppression of cough reflex may cause in humans]
asphyxia • Reports of extrapyramidal symptoms,
• Use only with caution if at all in jaundice, hyperreflexia, hyporeflexia in
Parkinson’s disease or Lewy Body infants whose mothers took a
dementia phenothiazine during pregnancy
• Chlorpromazine should generally not be
Do Not Use
used during the first trimester
• If patient is in a comatose state
• Chlorpromazine should only be used
• If patient is taking metrizamide or large
during pregnancy if clearly needed
doses of CNS depressants
• Psychotic symptoms may worsen during
• If there is a proven allergy to
pregnancy and some form of treatment
chlorpromazine
may be necessary
• If there is a known sensitivity to any
• Atypical antipsychotics may be preferable
phenothiazine
to conventional antipsychotics or
anticonvulsant mood stabilizers if
treatment is required during pregnancy
SPECIAL POPULATIONS
Breast Feeding
Renal Impairment • Some drug is found in mother’s breast milk
• Use with caution • Effects on infant have been observed
(dystonia, tardive dyskinesia, sedation)
Hepatic Impairment ✽ Recommended either to discontinue drug
• Use with caution or bottle feed
Cardiac Impairment
• Cardiovascular toxicity can occur,
especially orthostatic hypotension THE ART OF PSYCHOPHARMACOLOGY

Elderly Potential Advantages

• Lower doses should be used and patient • Intramuscular formulation for emergency
should be monitored closely use
• Often do not tolerate sedating actions of • Patients who require sedation for
chlorpromazine behavioral control

Potential Disadvantages
• Patients with tardive dyskinesia
Children and Adolescents • Children
• Can be used cautiously in children or • Elderly
adolescents over 1 with severe behavioral • Patients who wish to avoid sedation
problems
• Oral – 0.25 mg/lb every 4–6 hours as Primary Target Symptoms
needed; rectal – 0.5 mg/lb every 6–8 hours • Positive symptoms of psychosis
as needed; IM – 0.25 mg/lb every • Motor and autonomic hyperactivity
• Violent or aggressive behavior

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(continued) CHLORPROMAZINE

• Patients have very similar antipsychotic

responses to any conventional
Pearls antipsychotic, which is different from
• Chlorpromazine is one of the earliest atypical antipsychotics where antipsychotic
classical conventional antipsychotics responses of individual patients can
• Chlorpromazine has a broad spectrum of occasionally vary greatly from one atypical
efficacy, but risk of tardive dyskinesia and antipsychotic to another
the availability of alternative treatments • Patients with inadequate responses to
make its utilization outside of psychosis a atypical antipsychotics may benefit from a
short-term and second-line treatment trial of augmentation with a conventional
option antipsychotic such as chlorpromazine or
• Chlorpromazine is a low potency from switching to a conventional
phenothiazine antipsychotic such as chlorpromazine
• Sedative actions of low potency • However, long-term polypharmacy with a
phenothiazines are an important aspect of combination of a conventional
their therapeutic actions in some patients antipsychotic such as chlorpromazine with
and side effect profile in others an atypical antipsychotic may combine
• Conventional antipsychotics are much less their side effects without clearly
expensive than atypical antipsychotics augmenting the efficacy of either
• Low potency phenothiazines like
chlorpromazine have a greater risk of
cardiovascular side effects

Suggested Reading
Davis JM, Chen N, Glick ID. A meta-analysis of potency conventional antipsychotics: a
the efficacy of second-generation systematic review and meta-analysis. The
antipsychotics. Arch Gen Psychiatry Lancet 2003;361:1581–9.
2003;60:553–64.
Thomley B, Adams CE, Awad G.
Frankenburg FR. Choices in antipsychotic Chlorpromazine versus placebo for
therapy in schizophrenia. Harv Rev Psychiatry schizophrenia. Cochrane Database Syst Rev
1999;6:241–9. 2000;(2):CD000284.
Gocke E. Review of the genotoxic properties of Tohen M, Jacobs TG, Feldman PD. Onset of
chlorpromazine and related phenothiazines. action of antipsychotics in the treatment of
Mutat Res 1996;366:9–21. mania. Bipolar Disord 2000;2(3 Pt 2):261–8.
Leucht S, Wahlbeck K, Hamann J, Kissling W.
New generation antipsychotics versus low-

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0521011698s02.qxd 9/2/04 2:29 PM Page 63

CITALOPRAM
THERAPEUTICS • Treatment most often reduces or even
eliminates symptoms, but not a cure since
Brands • Celexa symptoms can recur after medicine
see index for additional brand names stopped
• Continue treatment until all symptoms are
Generic? In Australia and some European
gone (remission) or significantly reduced
countries, but not in U.S.
(e.g., OCD, PTSD)
• Once symptoms are gone, continue
treating for 1 year for the first episode of
Class depression
• SSRI (selective serotonin reuptake • For second and subsequent episodes of
inhibitor); often classified as an depression, treatment may need to be
antidepressant, but it is not just an indefinite
antidepressant • Use in anxiety disorders may also need to
be indefinite
Commonly Prescribed For
(bold for FDA approved) If It Doesn’t Work
• Depression • Many patients only have a partial response
• Premenstrual dysphoric disorder (PMDD) where some symptoms are improved but
• Obsessive-compulsive disorder (OCD) others persist (especially insomnia, fatigue,
• Panic disorder and problems concentrating in depression)
• Generalized anxiety disorder • Other patients may be nonresponders,
• Posttraumatic stress disorder (PTSD) sometimes called treatment-resistant or
• Social anxiety disorder (social phobia) treatment-refractory
• Some patients who have an initial response
may relapse even though they continue
How The Drug Works treatment, sometimes called “poop-out”
• Boosts neurotransmitter serotonin • Consider increasing dose, switching to
• Blocks serotonin reuptake pump (serotonin another agent or adding an appropriate
transporter) augmenting agent
• Desensitizes serotonin receptors, especially • Consider psychotherapy
serotonin 1A autoreceptors • Consider evaluation for another diagnosis
• Presumably increases serotonergic or for a comorbid condition (e.g., medical
neurotransmission illness, substance abuse, etc.)
✽ Citalopram also has mild antagonist • Some patients may experience apparent
actions at H1 histamine receptors lack of consistent efficacy due to activation
✽ Citalopram’s inactive R enantiomer may of latent or underlying bipolar disorder, and
interfere with the therapeutic actions of the require antidepressant discontinuation and
active S enantiomer at serotonin reuptake a switch to a mood stabilizer
pumps
Best Augmenting Combos
How Long Until It Works for Partial Response or
• Onset of therapeutic actions usually not Treatment-Resistance
immediate, but often delayed 2 to 4 weeks • Trazodone, especially for insomnia
• If it is not working within 6 to 8 weeks, it • Bupropion, mirtazapine, reboxetine, or
may require a dosage increase or it may atomoxetine (add with caution and at lower
not work at all doses since citalopram could theoretically
• May continue to work for many years to raise atomoxetine levels); use
prevent relapse of symptoms combinations of antidepressants with
caution as this may activate bipolar
If It Works disorder and suicidal ideation
• The goal of treatment is complete • Modafinil, especially for fatigue, sleepiness,
remission of current symptoms as well as and lack of concentration
prevention of future relapses • Mood stabilizers or atypical antipsychotics
for bipolar depression, psychotic

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CITALOPRAM (continued)

depression, treatment-resistant depression, • SIADH (syndrome of inappropriate

or treatment-resistant anxiety disorders antidiuretic hormone secretion)
• Benzodiazepines
• If all else fails for anxiety disorders,
consider gabapentin or tiagabine
Life Threatening or
• Hypnotics for insomnia Dangerous Side Effects
• Classically, lithium, buspirone, or thyroid • Rare seizures
hormone • Rare induction of mania and activation of
suicidal ideation
Tests
• None for healthy individuals Weight Gain

SIDE EFFECTS • Reported but not expected

• Citalopram has been associated with both
How Drug Causes Side Effects weight gain and weight loss in various
• Theoretically due to increases in serotonin studies, but is relatively weight neutral
concentrations at serotonin receptors in overall
parts of the brain and body other than
those that cause therapeutic actions (e.g., Sedation
unwanted actions of serotonin in sleep
centers causing insomnia, unwanted
actions of serotonin in the gut causing • Occurs in significant minority
diarrhea, etc.)
• Increasing serotonin can cause diminished What To Do About Side Effects
dopamine release and might contribute to • Wait
emotional flattening, cognitive slowing, and • Wait
apathy in some patients • Wait
• Most side effects are immediate but often • Take in the morning if nighttime insomnia
go away with time, in contrast to most • Take at night if daytime sedation
therapeutic effects which are delayed and • In a few weeks, switch to another agent or
are enhanced over time add other drugs
✽ Citalopram’s unique mild antihistamine
properties may contribute to sedation and Best Augmenting Agents for Side
fatigue in some patients Effects
• Often best to try another SSRI or another
Notable Side Effects antidepressant monotherapy prior to
• Sexual dysfunction (men: delayed resorting to augmentation strategies to
ejaculation, erectile dysfunction; men and treat side effects
women: decreased sexual desire, • Trazodone or a hypnotic for insomnia
anorgasmia) • Bupropion, sildenafil, vardenafil, or tadalafil
• Gastrointestinal (decreased appetite, for sexual dysfunction
nausea, diarrhea, constipation, dry mouth) • Bupropion for emotional flattening,
• Mostly central nervous system (insomnia cognitive slowing, or apathy
but also sedation, agitation, tremors, • Mirtazapine for insomnia, agitation, and
headache, dizziness) gastrointestinal side effects
• Note: patients with diagnosed or • Benzodiazepines for jitteriness and anxiety,
undiagnosed bipolar or psychotic disorders especially at initiation of treatment and
may be more vulnerable to CNS-activating especially for anxious patients
actions of SSRIs • Many side effects are dose-dependent (i.e.,
• Autonomic (sweating) they increase as dose increases, or they
• Bruising and rare bleeding reemerge until tolerance re-develops)
• Rare hyponatremia (mostly in elderly • Many side effects are time-dependent (i.e.,
patients and generally reversible on they start immediately upon dosing and
discontinuation of citalopram)

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(continued) CITALOPRAM

upon each dose increase, but go away with Long-Term Use

time) • Safe
• Activation and agitation may represent the
induction of a bipolar state, especially a Habit Forming
mixed dysphoric bipolar II condition • No
sometimes associated with suicidal
ideation, and require the addition of How to Stop
lithium, a mood stabilizer or an atypical • Taper not usually necessary
antipsychotic, and/or discontinuation of • However, tapering to avoid potential
citalopram withdrawal reactions generally prudent
• Many patients tolerate 50% dose reduction
for 3 days, then another 50% reduction for
DOSING AND USE 3 days, then discontinuation
• If withdrawal symptoms emerge during
Usual Dosage Range discontinuation, raise dose to stop
• 20–60 mg/day symptoms and then restart withdrawal
much more slowly
Dosage Forms
• Tablets 10 mg, 20 mg scored, 40 mg Pharmacokinetics
scored • Parent drug has 23–45 hour half-life
• Weak inhibitor of CYP450 2D6
How to Dose
• Initial 20 mg/day; increase by 20 mg/day
after 1 or more weeks until desired efficacy Drug Interactions
is reached; maximum usually 60 mg/day; • Tramadol increases the risk of seizures in
single dose administration, morning or patients taking an antidepressant
evening • Can increase tricyclic antidepressant levels;
use with caution with tricyclic
antidepressants
Dosing Tips • Can cause a fatal “serotonin syndrome”
• Tablets are scored, so to save costs, give when combined with MAO inhibitors, so do
10 mg as half of 20 mg tablet or 20 mg as not use with MAO inhibitors or at least for
half of 40 mg tablet, since the tablets cost 14 days after MAOIs are stopped
about the same in many markets • Do not start an MAO inhibitor for at least
• Many patients respond better to 40 mg 2 weeks after discontinuing citalopram
than to 20 mg • May displace highly protein bound drugs
• Given once daily, any time of day when (e.g., warfarin)
best tolerated by the individual • Can rarely cause weakness, hyperreflexia,
• If intolerable anxiety, insomnia, agitation, and incoordination when combined with
akathisia, or activation occur either upon sumatriptan or possibly other triptans,
dosing initiation or discontinuation, requiring careful monitoring of patient
consider the possibility of activated bipolar • Via CYP450 2D6 inhibition, citalopram
disorder and switch to a mood stabilizer or could theoretically interfere with the
an atypical antipsychotic analgesic actions of codeine, and increase
the plasma levels of some beta blockers
Overdose and of atomoxetine
• Rare fatalities have been reported with • Via CYP450 2D6 inhibition, citalopram
citalopram overdose, both alone and in could theoretically increase concentrations
combination with other drugs of thioridazine and cause dangerous
• Vomiting, sedation, heart rhythm cardiac arrhythmias
disturbances, dizziness, sweating, nausea,
tremor
• Rarely amnesia, confusion, coma,
convulsions

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CITALOPRAM (continued)

consider informing parents or guardian of

Other Warnings/ this risk so they can help observe child or
Precautions adolescent patients
• Use with caution in patients with history of • Not specifically approved, but preliminary
seizures data suggest citalopram is safe and
• Use with caution in patients with bipolar effective in children and adolescents with
disorder unless treated with concomitant OCD and with depression
mood stabilizing agent
• Monitor patients for activation of suicidal
ideation, especially children and
adolescents
Pregnancy
• Risk Category C [some animal studies
Do Not Use show adverse effects, no controlled studies
• If patient is taking an MAO inhibitor in humans]
• If patient is taking thioridazine • Not generally recommended for use during
• If there is a proven allergy to citalopram or pregnancy, especially during first trimester
escitalopram • Nonetheless, continuous treatment during
pregnancy may be necessary and has not
been proven to be harmful to the fetus
• At delivery there may be more bleeding in
SPECIAL POPULATIONS the mother and transient irritability or
Renal Impairment sedation in the newborn
• Must weigh the risk of treatment (first
• No dose adjustment for mild to moderate
trimester fetal development, third trimester
impairment
newborn delivery) to the child against the
• Use cautiously in patients with severe
risk of no treatment (recurrence of
impairment
depression, maternal health, infant
Hepatic Impairment bonding) to the mother and child
• Recommended dose 20 mg/day; can be • For many patients, this may mean
raised to 40 mg/day for nonresponders continuing treatment during pregnancy
• May need to dose cautiously at the lower • Neonates exposed to SSRIs or SNRIs late
end of the dose range in some patients for in the third trimester have developed
maximal tolerability complications requiring prolonged
hospitalization, respiratory support, and
Cardiac Impairment tube feeding; reported symptoms are
• Clinical experience suggests that consistent with either a direct toxic effect
citalopram is safe in these patients of SSRIs and SNRIs or, possibly, a drug
• Treating depression with SSRIs in patients discontinuation syndrome, and include
with acute angina or following myocardial respiratory distress, cyanosis, apnea,
infarction may reduce cardiac events and seizures, temperature instability, feeding
improve survival as well as mood difficulty, vomiting, hypoglycemia,
hypotonia, hypertonia, hyperreflexia,
Elderly tremor, jitteriness, irritability, and constant
• 20 mg/day; 40 mg/day for nonresponders crying
• May need to dose at the lower end of the
dose range in some patients for maximal Breast Feeding
tolerability • Some drug is found in mother’s breast milk
• Citalopram may be an especially well- • Trace amounts may be present in nursing
tolerated SSRI in the elderly children whose mothers are on citalopram
• If child becomes irritable or sedated, breast
feeding or drug may need to be
discontinued
Children and Adolescents • Immediate postpartum period is a high-risk
• Use with caution, observing for activation time for depression, especially in women
of known or unknown bipolar disorder who have had prior depressive episodes,
and/or suicidal ideation, and strongly

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(continued) CITALOPRAM

so drug may need to be reinstituted late in

the third trimester or shortly after
childbirth to prevent a recurrence during Pearls
the postpartum period ✽ May be more tolerable than some other
• Must weigh benefits of breast feeding with antidepressants
risks and benefits of antidepressant • May have less sexual dysfunction than
treatment versus non-treatment to both the some other SSRIs
infant and the mother • May be especially well tolerated in the
• For many patients, this may mean elderly
continuing treatment during breast feeding ✽ May be less well tolerated than
escitalopram
• Documentation of efficacy in anxiety
disorders is less comprehensive than for
THE ART OF PSYCHOPHARMACOLOGY
escitalopram and other SSRIs
Potential Advantages • Can cause cognitive and affective
• Elderly patients “flattening”
• Patients excessively activated or sedated • Some evidence suggests that citalopram
by other SSRIs treatment during only the luteal phase may
be more effective than continuous
Potential Disadvantages treatment for patients with PMDD
• May require dosage titration to attain • SSRIs may be less effective in women over
optimal efficacy 50, especially if they are not taking
• Can be sedating in some patients estrogen
• SSRIs may be useful for hot flushes in
Primary Target Symptoms perimenopausal women
• Depressed mood • Nonresponse to citalopram in elderly may
• Anxiety require consideration of mild cognitive
• Panic attacks, avoidant behavior, re- impairment or Alzheimer disease
experiencing, hyperarousal
• Sleep disturbance, both insomnia and
hypersomnia

Suggested Reading
Bezchlibnyk-Butler K, Aleksic I, Kennedy SH. Pollock BG. Citalopram: a comprehensive
Citalopram – a review of pharmacological and review. Expert Opin Pharmacother
clinical effects. Journal of Psychiatry and 2001;2:681–98.
Neuroscience 2000;25:241–254.
Stahl SM. Placebo-controlled comparison of
Edwards JG, Anderson I. Systematic review the selective serotonin reuptake inhibitors
and guide to selection of selective serotonin citalopram and sertraline. Biol Psychiatry
reuptake inhibitors. Drugs 1999;57:507–533. 2000;48:894–901.
Keller MB. Citalopram therapy for depression:
a review of 10 years of European experience
and data from U.S. clinical trials. Journal of
Clinical Psychiatry 2000;61:896–908.

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CLOMIPRAMINE
THERAPEUTICS • If it is not working within 6 to 8 weeks for
depression, it may require a dosage
Brands • Anafranil increase or it may not work at all
see index for additional brand names • If it is not working within 12 weeks for
OCD, it may not work at all
Generic? Yes
• May continue to work for many years to
prevent relapse of symptoms

Class If It Works
• Tricyclic antidepressant (TCA) • The goal of treatment of depression is
• Parent drug is a potent serotonin reuptake complete remission of current symptoms
inhibitor as well as prevention of future relapses
• Active metabolite is a potent • Treatment most often reduces or even
norepinephrine/noradrenaline reuptake eliminates symptoms, but not a cure since
inhibitor symptoms can recur after medicine stopped
• Although the goal of treatment of OCD is
Commonly Prescribed For also complete remission of symptoms, this
(bold for FDA approved) may be less likely than in depression
✽ Obsessive-compulsive disorder • The goal of treatment of chronic
• Depression neuropathic pain is to reduce symptoms as
✽ Severe and treatment-resistant much as possible, especially in
depression combination with other treatments
✽ Cataplexy syndrome • Continue treatment of depression until all
• Anxiety symptoms are gone (remission)
• Insomnia • Once symptoms of depression are gone,
• Neuropathic pain/chronic pain continue treating for 1 year for the first
episode of depression
• For second and subsequent episodes of
depression, treatment may need to be
How The Drug Works
indefinite
• Boosts neurotransmitters serotonin and
• Use in OCD may also need to be indefinite,
norepinephrine/noradrenaline
starting from the time of initial treatment
• Blocks serotonin reuptake pump (serotonin
• Use in other anxiety disorders and chronic
transporter), presumably increasing
pain may also need to be indefinite, but
serotonergic neurotransmission
long-term treatment is not well studied in
• Blocks norepinephrine reuptake pump
these conditions
(norepinephrine transporter), presumably
increasing noradrenergic If It Doesn’t Work
neurotransmission • Many patients only have a partial response
• Presumably desensitizes both serotonin 1A where some symptoms are improved but
receptors and beta adrenergic receptors others persist (especially insomnia, fatigue,
• Since dopamine is inactivated by and problems concentrating)
norepinephrine reuptake in frontal cortex, • Other patients may be nonresponders,
which largely lacks dopamine transporters, sometimes called treatment-resistant or
clomipramine can increase dopamine treatment-refractory
neurotransmission in this part of the brain • Consider increasing dose, switching to
another agent or adding an appropriate
How Long Until It Works
augmenting agent
• May have immediate effects in treating
• Consider psychotherapy, especially
insomnia or anxiety
behavioral therapy in OCD
• Onset of therapeutic actions in depression
• Consider evaluation for another diagnosis
usually not immediate, but often delayed 2
or for a comorbid condition (e.g., medical
to 4 weeks
illness, substance abuse, etc.)
• Onset of therapeutic action in OCD can be
• Some patients may experience apparent
delayed 6 to 12 weeks
lack of consistent efficacy due to activation

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CLOMIPRAMINE (continued)

of latent or underlying bipolar disorder, and SIDE EFFECTS

require antidepressant discontinuation and
a switch to a mood stabilizer
How Drug Causes Side Effects
• Anticholinergic activity may explain
Best Augmenting Combos sedative effects, dry mouth, constipation,
for Partial Response or and blurred vision
Treatment-Resistance • Sedative effects and weight gain may be
due to antihistamine properties
• Lithium, buspirone, hormone (for
• Blockade of alpha adrenergic 1 receptors
depression and OCD)
may explain dizziness, sedation, and
• For the expert: consider cautious addition
hypotension
of fluvoxamine for treatment-resistant OCD
• Cardiac arrhythmias and seizures,
• Thyroid hormone (for depression)
especially in overdose, may be caused by
• Atypical antipsychotics (for OCD)
blockade of ion channels
Tests
Notable Side Effects
✽ None for healthy individuals, although • Blurred vision, constipation, urinary
monitoring of plasma drug levels is
retention, increased appetite, dry mouth,
potentially available at specialty
nausea, diarrhea, heartburn, unusual taste
laboratories for the expert
in mouth, weight gain
✽ Since tricyclic and tetracyclic • Fatigue, weakness, dizziness, sedation,
antidepressants are frequently associated
headache, anxiety, nervousness,
with weight gain, before starting treatment,
restlessness
weigh all patients and determine if the
• Sexual dysfunction, sweating
patient is already overweight
(BMI 25.0–29.9) or obese (BMI ≥30)
• Before giving a drug that can cause weight Life Threatening or
gain to an overweight or obese patient, Dangerous Side Effects
consider determining whether the patient • Paralytic ileus, hyperthermia (TCAs +
already has pre-diabetes (fasting plasma anticholinergic agents)
glucose 100–125 mg/dl), diabetes (fasting • Lowered seizure threshold and rare
plasma glucose >126 mg/dl), or dyslipidemia seizures
(increased total cholesterol, LDL cholesterol • Orthostatic hypotension, sudden death,
and triglycerides; decreased HDL arrhythmias, tachycardia
cholesterol), and treat or refer such patients • QTc prolongation
for treatment, including nutrition and weight • Hepatic failure, extrapyramidal symptoms
management, physical activity counseling, • Increased intraocular pressure
smoking cessation, and medical management • Rare induction of mania and activation of
✽ Monitor weight and BMI during treatment suicidal ideation
✽ While giving a drug to a patient who has
gained >5% of initial weight, consider Weight Gain
evaluating for the presence of pre-diabetes,
diabetes, or dyslipidemia, or consider
switching to a different antidepressant
• Many experience and/or can be significant
• EKGs may be useful for selected patients
in amount
(e.g., those with personal or family history of
• Can increase appetite and carbohydrate
QTc prolongation; cardiac arrhythmia; recent
craving
myocardial infarction; uncompensated
heart failure; or taking agents that prolong Sedation
QTc interval such as pimozide, thioridazine,
selected antiarrhythmics, moxifloxacin,
sparfloxacin, etc.)
• Patients at risk for electrolyte disturbances • Many experience and/or can be significant
(e.g., patients on diuretic therapy) should in amount
have baseline and periodic serum • Tolerance to sedative effect may develop
potassium and magnesium measurements with long-term use

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(continued) CLOMIPRAMINE

What To Do About Side Effects Overdose

• Wait • Death may occur; convulsions, cardiac
• Wait dysrhythmias, severe hypotension, CNS
• Wait depression, coma, changes in ECG
• Lower the dose
• Switch to an SSRI or newer antidepressant Long-Term Use
• Limited data but appears to be efficacious
Best Augmenting Agents for Side and safe long-term
Effects
• Many side effects cannot be improved with Habit Forming
an augmenting agent • No

How to Stop
• Taper to avoid withdrawal effects
DOSING AND USE • Even with gradual dose reduction some
Usual Dosage Range withdrawal symptoms may appear within
the first 2 weeks
• 100 mg/day – 200 mg/day
• Many patients tolerate 50% dose reduction
Dosage Forms for 3 days, then another 50% reduction for
• Capsule 25 mg, 50 mg, 75 mg 3 days, then discontinuation
• If withdrawal symptoms emerge during
How to Dose discontinuation, raise dose to stop
• Initial 25 mg/day; increase over 2 weeks to symptoms and then restart withdrawal
100 mg/day; maximum dose generally much more slowly
250 mg/day
Pharmacokinetics
• Substrate for CYP450 2D6 and 1A2
• Metabolized to an active metabolite,
Dosing Tips desmethyl-clomipramine, a predominantly
• If given in a single dose, should generally norepinephrine reuptake inhibitor, by
be administered at bedtime because of its demethylation via CYP450 1A2
sedative properties • Half-life approximately 17–28 hours
• If given in split doses, largest dose should
generally be given at bedtime because of
its sedative properties
• If patients experience nightmares, split Drug Interactions
dose and do not give large dose at bedtime • Tramadol increases the risk of seizures in
• Patients treated for chronic pain may only patients taking TCAs
require lower doses • Use of TCAs with anticholinergic drugs
✽ Patients treated for OCD may often may result in paralytic ileus or
hyperthermia
require doses at the high end of the range
(e.g., 200–250 mg/day) • Fluoxetine, paroxetine, bupropion,
• Risk of seizure increases with dose, duloxetine, and other CYP450 2D6
especially with clomipramine at doses inhibitors may increase TCA concentrations
above 250 mg/day • Fluvoxamine, a CYP450 1A2 inhibitor, can
✽ Dose of 300 mg may be associated with decrease the conversion of clomipramine
to desmethyl-clomipramine, and increase
up to 7/1000 incidence of seizures, a
generally unacceptable risk clomipramine plasma concentrations
• If intolerable anxiety, insomnia, agitation, • Cimetidine may increase plasma
akathisia, or activation occur either upon concentrations of TCAs and cause
dosing initiation or discontinuation, anticholinergic symptoms
consider the possibility of activated bipolar • Phenothiazines or haloperidol may raise
disorder, and switch to a mood stabilizer or TCA blood concentrations
an atypical antipsychotic • May alter effects of antihypertensive drugs
• Use of TCAs with sympathomimetic agents
may increase sympathetic activity

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CLOMIPRAMINE (continued)

• TCAs may inhibit hypotensive effects of pimozide, thioridazine, selected

clonidine antiarrhythmics, moxifloxacin,
• Methylphenidate may inhibit metabolism of sparfloxacin)
TCAs • If there is a history of QTc prolongation or
• Activation and agitation, especially cardiac arrhythmia, recent acute
following switching or adding myocardial infarction, uncompensated
antidepressants, may represent the heart failure
induction of a bipolar state, especially a • If patient is taking drugs that inhibit TCA
mixed dysphoric bipolar II condition metabolism, including CYP450 2D6
sometimes associated with suicidal inhibitors, except by an expert
ideation, and require the addition of • If there is reduced CYP450 2D6 function,
lithium, a mood stabilizer or an atypical such as patients who are poor 2D6
antipsychotic, and/or discontinuation of metabolizers, except by an expert and at
clomipramine low doses
• If there is a proven allergy to clomipramine
Other Warnings/
Precautions
• Add or initiate other antidepressants with
SPECIAL POPULATIONS
caution for up to 2 weeks after Renal Impairment
discontinuing clomipramine
• Use with caution
• Generally, do not use with MAO inhibitors,
including 14 days after MAOIs are stopped; Hepatic Impairment
do not start an MAOI until 2 weeks after • Use with caution
discontinuing clomipramine, but see Pearls
• Use with caution in patients with history of Cardiac Impairment
seizures, urinary retention, narrow angle- • TCAs have been reported to cause
closure glaucoma, hyperthyroidism arrhythmias, prolongation of conduction
• TCAs can increase QTc interval, especially time, orthostatic hypotension, sinus
at toxic doses, which can be attained not tachycardia, and heart failure, especially in
only by overdose but also by combining the diseased heart
with drugs that inhibit TCA metabolism via • Myocardial infarction and stroke have been
CYP450 2D6, potentially causing torsade reported with TCAs
de pointes-type arrhythmia or sudden • TCAs produce QTc prolongation, which
death may be enhanced by the existence of
• Because TCAs can prolong QTc interval, bradycardia, hypokalemia, congenital or
use with caution in patients who have acquired long QTc interval, which should
bradycardia or who are taking drugs that be evaluated prior to administering
can induce bradycardia (e.g., beta blockers, clomipramine
calcium channel blockers, clonidine, • Use with caution if treating concomitantly
digitalis) with a medication likely to produce
• Because TCAs can prolong QTc interval, prolonged bradycardia, hypokalemia,
use with caution in patients who have slowing of intracardiac conduction, or
hypokalemia and/or hypomagnesemia or prolongation of the QTc interval
who are taking drugs that can induce • Avoid TCAs in patients with a known
hypokalemia and/or magnesemia (e.g., history of QTc prolongation, recent acute
diuretics, stimulant laxatives, intravenous myocardial infarction, and uncompensated
amphotericin B, glucocorticoids, heart failure
tetracosactide) • TCAs may cause a sustained increase in
heart rate in patients with ischemic heart
Do Not Use disease and may worsen (decrease) heart
• If patient is recovering from myocardial rate variability, an independent risk of
infarction mortality in cardiac populations
• If patient is taking agents capable of • Since SSRIs may improve (increase) heart
significantly prolonging QTc interval (e.g., rate variability in patients following a

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(continued) CLOMIPRAMINE

myocardial infarct and may improve health, infant bonding) to the mother and
survival as well as mood in patients with child
acute angina or following a myocardial • For many patients this may mean
infarction, these are more appropriate continuing treatment during pregnancy
agents for cardiac population than
tricyclic/tetracyclic antidepressants Breast Feeding
✽ Risk/benefit ratio may not justify use of • Some drug is found in mother’s breast milk
TCAs in cardiac impairment ✽ Recommended either to discontinue drug
or bottle feed
Elderly • Immediate postpartum period is a high-risk
• May be more sensitive to anticholinergic, time for depression and worsening of OCD,
cardiovascular, hypotensive, and sedative especially in women who have had prior
effects depressive episodes or OCD symptoms, so
• Dose may need to be lower than usual drug may need to be reinstituted late in the
adult dose, at least initially third trimester or shortly after childbirth to
prevent a recurrence or exacerbation
during the postpartum period
Children and Adolescents • Must weigh benefits of breast feeding with
• Use with caution, observing for activation risks and benefits of antidepressant
of known or unknown bipolar disorder treatment versus non-treatment to both the
and/or suicidal ideation, and strongly infant and the mother
consider informing parents or guardian of • For many patients this may mean
this risk so they can help observe child or continuing treatment during breast feeding
adolescent patients
• Not recommended for use under age 10
• Several studies show lack of efficacy of THE ART OF PSYCHOPHARMACOLOGY
TCAs for depression
• May be used to treat enuresis or Potential Advantages
hyperactive/impulsive behaviors • Patients with insomnia
• Effective for OCD in children • Severe or treatment-resistant depression
• Some cases of sudden death have • Patients with comorbid OCD and
occurred in children taking TCAs depression
• Dose in children/adolescents should be • Patients with cataplexy
titrated to a maximum of 100 mg/day or 3
mg/kg/day after 2 weeks, after which dose Potential Disadvantages
can then be titrated up to a maximum of • Pediatric and geriatric patients
200 mg/day or 3 mg/kg/day • Patients concerned with weight gain
• Cardiac patients
• Patients with seizure disorders
Pregnancy Primary Target Symptoms
• Risk Category C [some animal studies • Depressed mood
show adverse effects, no controlled studies • Obsessive thoughts
in humans] • Compulsive behaviors
• Clomipramine crosses the placenta
• Adverse effects have been reported in
infants whose mothers took a TCA
(lethargy, withdrawal symptoms, fetal
Pearls
malformations) ✽ The only TCA with proven efficacy in OCD
• Must weigh the risk of treatment (first • Normally, clomipramine (CMI), a potent
trimester fetal development, third trimester serotonin reuptake blocker, at steady state
newborn delivery) to the child against the is metabolized extensively to its active
risk of no treatment (recurrence of metabolite desmethyl-clomipramine (de-
depression, worsening of OCD, maternal CMI), a potent nonadrenaline reuptake
blocker, by the enzyme CYP450 1A2

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CLOMIPRAMINE (continued)

• Thus, at steady state, plasma drug activity due to clomipramine’s potent serotonin
is generally more noradrenergic (with reuptake blocking properties
higher de-CMI levels) than serotonergic • TCAs may aggravate psychotic symptoms
(with lower parent CMI levels) • Alcohol should be avoided because of
• Addition of the SSRI and CYP450 1A2 additive CNS effects
inhibitor fluvoxamine blocks this • Underweight patients may be more
conversion and results in higher CMI levels susceptible to adverse cardiovascular effects
than de-CMI levels • Children, patients with inadequate
• For the expert only: addition of the SSRI hydration, and patients with cardiac
fluvoxamine to CMI in treatment-resistant disease may be more susceptible to TCA-
OCD can powerfully enhance serotonergic induced cardiotoxicity than healthy adults
activity, not only due to the inherent additive • Patients on TCAs should be aware that they
pharmacodynamic serotonergic activity of may experience symptoms such as
fluvoxamine added to CMI, but also due to photosensitivity or blue-green urine
a favorable pharmacokinetic interaction • SSRIs may be more effective than TCAs in
inhibiting CYP450 1A2 and thus converting women, and TCAs may be more effective
CMI’s metabolism to a more powerful than SSRIs in men
serotonergic portfolio of parent drug • Since tricyclic/tetracyclic antidepressants
✽ One of the most favored TCAs for treating are substrates for CYP450 2D6, and 7% of
severe depression the population (especially Caucasians) may
• Tricyclic antidepressants are no longer have a genetic variant leading to reduced
generally considered a first-line treatment activity of 2D6, such patients may not
option for depression because of their side safely tolerate normal doses of
effect profile tricyclic/tetracyclic antidepressants and
• Tricyclic antidepressants continue to be may require dose reduction
useful for severe or treatment-resistant • Phenotypic testing may be necessary to
depression detect this genetic variant prior to dosing
• Tricyclic antidepressants are often a first- with a tricyclic/tetracyclic antidepressant,
line treatment option for chronic pain especially in vulnerable populations such
✽ Unique among TCAs, clomipramine has a as children, elderly, cardiac populations,
potentially fatal interaction with MAOIs in and those on concomitant medications
addition to the danger of hypertension • Patients who seem to have extraordinarily
characteristic of all MAOI-TCA combinations severe side effects at normal or low doses
✽ A potentially fatal serotonin syndrome with may have this phenotypic CYP450 2D6
high fever, seizures, and coma, analogous to variant and require low doses or switching
that caused by SSRIs and MAOIs, can occur to another antidepressant not metabolized
with clomipramine and SSRIs, presumably by 2D6

Suggested Reading
Anderson IM. Meta-analytical studies on new Cox BJ, Swinson RP, Morrison B, Lee PS.
antidepressants. Br Med Bull 2001; Clomipramine, fluoxetine, and behavior
57:161–178. therapy in the treatment of obsessive-
compulsive disorder: a meta-analysis. J Behav
Anderson IM. Selective serotonin reuptake Ther Exp Psychiatry 1993;24:149–53.
inhibitors versus tricyclic antidepressants: a
meta-analysis of efficacy and tolerability. J Aff Feinberg M. Clomipramine for obsessive-
Disorders 2000;58:19–36. compulsive disorder. Am Fam Physician 1991;
43:1735–8.

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CLONAZEPAM
THERAPEUTICS • For chronic anxiety disorders, treatment
most often reduces or even eliminates
Brands • Klonopin symptoms, but not a cure since symptoms
see index for additional brand names can recur after medicine stopped
• For long-term symptoms of anxiety,
Generic? Yes (not for disintegrating wafer)
consider switching to an SSRI or SNRI for
long-term maintenance
• If long-term maintenance with a
Class benzodiazepine is necessary, continue
• Benzodiazepine (anxiolytic, anticonvulsant) treatment for 6 months after symptoms
resolve, and then taper dose slowly
Commonly Prescribed For • If symptoms reemerge, consider treatment
(bold for FDA approved) with an SSRI or SNRI, or consider
• Panic disorder, with or without restarting the benzodiazepine; sometimes
agoraphobia benzodiazepines have to be used in
• Lennox-Gastaut syndrome (petit mal combination with SSRIs or SNRIs for best
variant) results
• Akinetic seizure • For long-term treatment of seizure
• Myoclonic seizure disorders, development of tolerance dose
• Absence seizure (petit mal) escalation and loss of efficacy
• Atonic seizures necessitating adding or switching to other
• Other seizure disorders anticonvulsants is not uncommon
• Other anxiety disorders
• Acute mania (adjunctive) If It Doesn’t Work
• Acute psychosis (adjunctive) • Consider switching to another agent or
• Insomnia adding an appropriate augmenting agent
• Consider psychotherapy, especially
cognitive behavioral psychotherapy
How The Drug Works • Consider presence of concomitant
• Binds to benzodiazepine receptors at the substance abuse
GABA-A ligand-gated chloride channel • Consider presence of clonazepam abuse
complex • Consider another diagnosis such as a
• Enhances the inhibitory effects of GABA comorbid medical condition
• Boosts chloride conductance through
GABA-regulated channels Best Augmenting Combos
• Inhibits neuronal activity presumably in for Partial Response or
amygdala-centered fear circuits to provide Treatment-Resistance
therapeutic benefits in anxiety disorders • Benzodiazepines are frequently used as
• Inhibitory actions in cerebral cortex may augmenting agents for antipsychotics and
provide therapeutic benefits in seizure mood stabilizers in the treatment of
disorders psychotic and bipolar disorders
• Benzodiazepines are frequently used as
How Long Until It Works augmenting agents for SSRIs and SNRIs in
• Some immediate relief with first dosing is the treatment of anxiety disorders
common; can take several weeks with daily • Not generally rational to combine with
dosing for maximal therapeutic benefit other benzodiazepines
• Caution if using as an anxiolytic
If It Works concomitantly with other sedative
• For short-term symptoms of anxiety – after hypnotics for sleep
a few weeks, discontinue use or use on an • Clonazepam is commonly combined with
“as-needed” basis other anticonvulsants for the treatment of
• For chronic anxiety disorders, the goal of seizure disorders
treatment is complete remission of
symptoms as well as prevention of future
relapses

75
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CLONAZEPAM (continued)

Tests What To Do About Side Effects

• In patients with seizure disorders, • Wait
concomitant medical illness, and/or those • Wait
with multiple concomitant long-term • Wait
medications, periodic liver tests and blood • Lower the dose
counts may be prudent • Take largest dose at bedtime to avoid
sedative effects during the day
• Switch to another agent
SIDE EFFECTS • Administer flumazenil if side effects are
severe or life-threatening
How Drug Causes Side Effects
• Same mechanism for side effects as for Best Augmenting Agents for Side
therapeutic effects – namely due to Effects
excessive actions at benzodiazepine • Many side effects cannot be improved with
receptors an augmenting agent
• Long-term adaptations in benzodiazepine
receptors may explain the development of
dependence, tolerance, and withdrawal DOSING AND USE
• Side effects are generally immediate, but
immediate side effects often disappear in Usual Dosage Range
time • Seizures: dependent on individual response
of patient, up to 20 mg/day
Notable Side Effects • Panic: 0.5–2 mg/day either as divided
✽ Sedation, fatigue, depression doses or once at bedtime
✽ Dizziness, ataxia, slurred speech,
weakness Dosage Forms
✽ Forgetfulness, confusion • Tablet 0.5 mg scored, 1 mg, 2 mg
✽ Hyper-excitability, nervousness • Disintegrating (wafer): 0.125 mg, 0.25 mg,
• Rare hallucinations, mania 0.5 mg, 1 mg, 2 mg
• Rare hypotension
• Hypersalivation, dry mouth How to Dose
• Seizures – 1.5 mg divided into 3 doses,
raise by 0.5 mg every 3 days until desired
Life Threatening or effect is reached; divide into 3 even doses
Dangerous Side Effects or else give largest dose at bedtime;
• Respiratory depression, especially when maximum dose generally 20 mg/day
taken with CNS depressants in overdose • Panic – 1 mg/day; start at 0.25 mg divided
• Rare hepatic dysfunction, renal into 2 doses, raise to 1 mg after 3 days;
dysfunction, blood dyscrasias dose either twice daily or once at bedtime;
• Grand mal seizures maximum dose generally 4 mg/day
Weight Gain
Dosing Tips
• For anxiety disorders, use lowest possible
• Reported but not expected effective dose for the shortest possible
period of time (a benzodiazepine sparing
Sedation strategy)
• Assess need for continuous treatment
regularly
• Occurs in significant minority • Risk of dependence may increase with
• Especially at initiation of treatment or when dose and duration of treatment
dose increases • For inter-dose symptoms of anxiety, can
• Tolerance often develops over time either increase dose or maintain same daily
dose but divide into more frequent doses

76
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(continued) CLONAZEPAM

• Can also use an as-needed occasional reaching 1.5 mg/day, perhaps by as little as
“top-up” dose for inter-dose anxiety 0.125 mg per week or less
• Because seizure disorder can require doses • For other patients with severe problems
much higher than 2 mg/day, the risk of discontinuing a benzodiazepine, dosing
dependence may be greater in these may need to be tapered over many months
patients (i.e., reduce dose by 1% every 3 days by
• Because panic disorder can require doses crushing tablet and suspending or
somewhat higher than 2 mg/day, the risk of dissolving in 100 ml of fruit juice and then
dependence may be greater in these disposing of 1 ml while drinking the rest;
patients than in anxiety patients maintained 3–7 days later, dispose of 2 ml, and so on).
at lower doses This is both a form of very slow biological
• Some severely ill seizure patients may tapering and a form of behavioral
require more than 20 mg/day desensitization
• Some severely ill panic patients may • Be sure to differentiate reemergence of
require 4 mg/day or more symptoms requiring reinstitution of
• Frequency of dosing in practice is often treatment from withdrawal symptoms
greater than predicted from half-life, as • Benzodiazepine-dependent anxiety patients
duration of biological activity is often and insulin-dependent diabetics are not
shorter than pharmacokinetic terminal half- addicted to their medications. When
life benzodiazepine-dependent patients stop
✽ Clonazepam is generally dosed half the their medication, disease symptoms can
dosage of alprazolam reemerge, disease symptoms can worsen
• Escalation of dose may be necessary if (rebound), and/or withdrawal symptoms
tolerance develops in seizure disorders can emerge
• Escalation of dose usually not necessary in
anxiety disorders, as tolerance to Pharmacokinetics
clonazepam does not generally develop in • Long half-life compared to other
the treatment of anxiety disorders benzodiazepine anxiolytics (elimination
✽ Available as an oral disintegrating wafer half-life approximately 30–40 hours)

Overdose
• Rarely fatal in monotherapy; sedation, Drug Interactions
confusion, coma, diminished reflexes • Increased depressive effects when taken
with other CNS depressants
Long-Term Use
• Inhibitors of CYP450 3A4 may affect the
• May lose efficacy for seizures; dose
clearance of clonazepam, but dosage
increase may restore efficacy
adjustment usually not necessary
• Risk of dependence, particularly for
• Flumazenil (used to reverse the effects of
treatment periods longer than 12 weeks
benzodiazepines) may precipitate seizures
and especially in patients with past or
and should not be used in patients treated
current polysubstance abuse
for seizure disorders with clonazepam
Habit Forming • Use of clonazepam with valproate may
cause absence status
• Clonazepam is a Schedule IV drug
• Patients may develop dependence and/or
tolerance with long-term use Other Warnings/
Precautions
How to Stop • Dosage changes should be made in
• Patients with history of seizures may seize collaboration with prescriber
upon withdrawal, especially if withdrawal is • Use with caution in patients with
abrupt pulmonary disease; rare reports of death
• Taper by 0.25 mg every 3 days to reduce after initiation of benzodiazepines in
chances of withdrawal effects patients with severe pulmonary impairment
• For difficult to taper cases, consider • History of drug or alcohol abuse often
reducing dose much more slowly after creates greater risk for dependency

77
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CLONAZEPAM (continued)

• Clonazepam may induce grand mal

seizures in patients with multiple seizure
disorders Pregnancy
• Use only with extreme caution if patient • Risk Category D [positive evidence of risk
has obstructive sleep apnea to human fetus; potential benefits may still
• Some depressed patients may experience a justify its use during pregnancy, especially
worsening of suicidal ideation for seizure disorders]
• Some patients may exhibit abnormal • Possible increased risk of birth defects
thinking or behavioral changes similar to when benzodiazepines taken during
those caused by other CNS depressants pregnancy
(i.e., either depressant actions or • Because of the potential risks, clonazepam
disinhibiting actions) is not generally recommended as treatment
for anxiety during pregnancy, especially
Do Not Use during the first trimester
• If patient has narrow angle-closure • Drug should be tapered if discontinued
glaucoma • Infants whose mothers received a
• If patient has severe liver disease benzodiazepine late in pregnancy may
• If there is a proven allergy to clonazepam experience withdrawal effects
or any benzodiazepine • Neonatal flaccidity has been reported in
infants whose mothers took a
benzodiazepine during pregnancy
SPECIAL POPULATIONS • Seizures, even mild seizures, may cause
harm to the embryo/fetus
Renal Impairment
• Dose should be reduced
Breast Feeding
• Some drug is found in mother’s breast milk
Hepatic Impairment ✽ Recommended either to discontinue drug
• Dose should be reduced or bottle feed
• Effects on infant have been observed and
Cardiac Impairment include feeding difficulties, sedation, and
• Benzodiazepines have been used to treat weight loss
anxiety associated with acute myocardial
infarction
THE ART OF PSYCHOPHARMACOLOGY
Elderly
• Should receive lower doses and be Potential Advantages
monitored • Rapid onset of action
• Less sedation than some other
benzodiazepines
Children and Adolescents • Longer duration of action than some other
• Seizures – up to 10 years or 30 kg – benzodiazepines
0.01–0.03 mg/kg/day divided into • Availability of oral disintegrating wafer
2–3 doses; maximum dose 0.05 mg/kg/day
• Safety and efficacy not established in panic
Potential Disadvantages
disorder • Development of tolerance may require dose
• For anxiety, children and adolescents increases, especially in seizure disorders
should generally receive lower doses and • Abuse especially risky in past or present
be more closely monitored substance abusers
• Long-term effects of clonazepam in
Primary Target Symptoms
children/adolescents are unknown
• Frequency and duration of seizures
• Spike and wave discharges in absence
seizures (petit mal)
• Panic attacks
• Anxiety

78
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(continued) CLONAZEPAM

✽ Easier to taper than some other

benzodiazepines because of long half-life
Pearls ✽ May have less abuse potential than some
✽ One of the most popular benzodiazepines other benzodiazepines
for anxiety, especially among psychiatrists ✽ May cause less depression, euphoria, or
• Is a very useful adjunct to SSRIs and dependence than some other
SNRIs in the treatment of numerous benzodiazepines
anxiety disorders ✽ Clonazepan is often considered a “longer-
• Not effective for treating psychosis as a acting alprazolam-like anxiolytic” with
monotherapy, but can be used as an improved tolerability features in terms of
adjunct to antipsychotics less euphoria, abuse, dependence, and
• Not effective for treating bipolar disorder withdrawal problems, but this has not been
as a monotherapy, but can be used as an proven
adjunct to mood stabilizers and • When using to treat insomnia, remember
antipsychotics that insomnia may be a symptom of some
• Generally used as second-line treatment for other primary disorder itself, and thus
petit mal seizures if succinimides are warrant evaluation for comorbid psychiatric
ineffective and/or medical conditions
• Can be used as an adjunct or as
monotherapy for seizure disorders
• Clonazepam is the only benzodiazepine that
is used as a solo maintenance treatment
for seizure disorders

Suggested Reading
Davidson JR, Moroz G. Pivotal studies of Iqbal MM, Sobhan T, Ryals T. Effects of
clonazepam in panic disorder. commonly used benzodiazepines on the fetus,
Psychopharmacol Bull 1998;34:169–74. the neonate, and the nursing infant. Psychiatr
Serv 2002;53:39–49.
DeVane CL, Ware MR, Lydiard RB.
Pharmacokinetics, pharmacodynamics, and Panayiotopoulos CP. Treatment of typical
treatment issues of benzodiazepines: absence seizures and related epileptic
alprazolam, adinazolam, and clonazepam. syndromes. Paediatr Drugs 2001;3:379–403.
Psychopharmacol Bull 1991;27:463–73.

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0521011698s02.qxd 9/2/04 2:29 PM Page 81

CLONIDINE
THERAPEUTICS • For CNS uses, can take a few weeks to see
therapeutic benefits
Brands • Duraclon (injection)
• Catapres If It Works
• Catapres-TTS (Clonidine • For hypertension, continue treatment
Transdermal Therapeutic System) indefinitely and check blood pressure
• Clorpres regularly
see index for additional brand names • For CNS uses, continue to monitor
continuing benefits as well as blood
Generic? Yes (not for transdermal) pressure

If It Doesn’t Work (for CNS

Class indications)
• Antihypertensive; centrally acting alpha 2 ✽ Since clonidine is a second-line and
agonist hypotensive agent experimental treatment for CNS disorders,
many patients may not respond
Commonly Prescribed For • Consider adjusting dose or switching to
(bold for FDA approved) another agent with better evidence for CNS
• Hypertension efficacy
• Attention deficit hyperactivity disorder
• Tourette’s syndrome Best Augmenting Combos
• Substance withdrawal, including opiates for Partial Response or
and alcohol Treatment-Resistance
• Anxiety disorders, including PTSD and • Best to attempt another monotherapy prior
social anxiety disorder to augmenting for CNS uses
• Clozapine-induced hypersalivation • Chlorthalidone, thiazide-type diuretics, and
• Menopausal flushing furosemide for hypertension
• Severe pain in cancer patients that is not • Possibly combination with stimulants (with
adequately relieved by opioid analgesics caution as benefits of combination poorly
alone (combination with opiates) documented and there are some reports of
serious adverse events)
• Combinations for CNS uses should be for
How The Drug Works the expert, while monitoring the patient
• For hypertension, stimulates alpha 2 closely, and when other treatment options
adrenergic receptors in the brain stem, have failed
reducing sympathetic outflow from the
CNS and decreasing peripheral resistance, Tests
renal vascular resistance, heart rate, and • Blood pressure should be checked
blood pressure regularly during treatment
• An imidazoline, so also interacts at
imidazoline receptors
✽ For CNS uses, presumably has central SIDE EFFECTS
actions on either pre- or postsynaptic alpha
2 receptors, and/or actions at imidazoline How Drug Causes Side Effects
receptors may cause behavioral changes in • Excessive actions on alpha 2 receptors
numerous conditions (unknown and and/or on imidazoline receptors
speculative)
Notable Side Effects
How Long Until It Works ✽ Dry mouth
• Blood pressure may be lowered 30–60 ✽ Dizziness, constipation, sedation
minutes after first dose; greatest reduction • Weakness, fatigue, impotence, loss of
seen after 2–4 hours libido, insomnia, headache
• May take several weeks to control blood • Major depression
pressure adequately • Dermatologic reactions (especially with
transdermal clonidine)

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CLONIDINE (continued)

• Hypotension, occasional syncope • Injection 100 mg/mL, 500 mg/mL

• Tachycardia
• Nervousness, agitation How to Dose
• Nausea, vomiting • Oral: initial 0.1 mg in 2 divided doses,
morning and night; can increase by
0.1 mg/day each week; maximum dose
Life Threatening or generally 2.4 mg/day
Dangerous Side Effects • Topical: apply once every 7 days in hairless
• Sinus bradycardia, atrioventricular block area; change location with each application
• During withdrawal, hypertensive • Injection: initial 30 mcg/hr; maximum
encephalopathy, cerebrovascular accidents, 40 mcg/hr; 500 mg/mL must be diluted
and death (rare)

Weight Gain
Dosing Tips
• Adverse effects are dose-related and
usually transient
• Reported but not expected • The last dose of the day should occur at
bedtime so that blood pressure is
Sedation controlled overnight
• If clonidine is terminated abruptly, rebound
hypertension may occur within 2–4 days
• Many experience and/or can be significant • Using clonidine in combination with
in amount another antihypertensive agent may
• Some patients may not tolerate it attenuate the development of tolerance to
• Can abate with time clonidine’s antihypertensive effects
• The likelihood of severe discontinuation
What To Do About Side Effects reactions with CNS and cardiovascular
• Wait symptoms may be greater after
• Take larger dose at bedtime to avoid administration of high doses of clonidine
daytime sedation ✽ In patients who have developed localized
• Switch to another medication with better contact sensitization to transdermal
evidence of efficacy clonidine, continuing transdermal dosing
✽ For withdrawal and discontinuation on other skin areas or substituting with
reactions, may need to reinstate clonidine oral clonidine may be associated with the
and taper very slowly when stabilized development of a generalized skin rash,
urticaria, or angioedema
Best Augmenting Agents for Side ✽ If administered with a beta blocker, stop
Effects the beta blocker first for several days
• Dose reduction or switching to another before the gradual discontinuation of
agent may be more effective since most clonidine in cases of planned
side effects cannot be improved with an discontinuation
augmenting agent
Overdose
• Hypotension, hypertension, miosis,
DOSING AND USE respiratory depression, seizures,
bradycardia, hypothermia, coma, sedation,
Usual Dosage Range decreased reflexes, weakness, irritability,
• 0.2–0.6 mg/day in divided doses dysrhythmia

Dosage Forms Long-Term Use

• Tablet 0.1 mg scored, 0.2 mg scored, • Patients may develop tolerance to the
0.3 mg scored antihypertensive effects
• Topical (7 day administration) 0.1 mg/24 ✽ Studies have not established the utility of
hours, 0.2 mg/24 hours, 0.3 mg/24 hours clonidine for long-term CNS uses

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(continued) CLONIDINE

✽ Be aware that forgetting to take clonidine Other Warnings/

or running out of medication can lead to
abrupt discontinuation and associated
Precautions
withdrawal reactions and complications • There have been cases of hypertensive
encephalopathy, cerebrovascular accidents,
Habit Forming and death after abrupt discontinuation
• Reports of some abuse by opiate addicts • If used with a beta blocker, the beta blocker
• Reports of some abuse by non-opioid should be stopped several days before
dependent patients tapering clonidine
• In patients who have developed localized
How to Stop contact sensitization to transdermal
✽ Discontinuation reactions are common clonidine, continuing transdermal dosing
and sometimes severe on other skin areas or substituting with
• Sudden discontinuation can result in oral clonidine may be associated with the
nervousness, agitation, headache, and development of a generalized skin rash,
tremor, with rapid rise in blood pressure urticaria, or angioedema
• Rare instances of hypertensive • Injection is not recommended for use in
encephalopathy, cerebrovascular accident, managing obstetrical, postpartum or peri-
and death have been reported after operative pain
clonidine withdrawal
• Taper over 2–4 days or longer to avoid Do Not Use
rebound effects (nervousness, increased • If there is a proven allergy to clonidine
blood pressure)
• If administered with a beta blocker, stop
the beta blocker first for several days SPECIAL POPULATIONS
before the gradual discontinuation of
clonidine Renal Impairment
• Use with caution and possibly reduce dose
Pharmacokinetics
• Half-life 12–16 hours Hepatic Impairment
• Metabolized by the liver • Use with caution
• Excreted renally
Cardiac Impairment
• Use with caution in patients with recent
myocardial infarction, severe coronary
Drug Interactions insufficiency, cerebrovascular disease
• The likelihood of severe discontinuation
reactions with CNS and cardiovascular Elderly
symptoms may be greater when clonidine • Elderly patients may tolerate a lower initial
is combined with beta blocker treatment dose better
• Increased depressive and sedative effects • Elderly patients may be more sensitive to
when taken with other CNS depressants sedative effects
• Tricyclic antidepressants may reduce the
hypotensive effects of clonidine
• Corneal lesions in rats increased by use of
clonidine with amitriptyline Children and Adolescents
• Use of clonidine with agents that affect • Safety and efficacy not established under
sinus node function or AV nodal function age 12
(e.g., digitalis, calcium channel blockers, • Children may be more sensitive to
beta blockers) may result in bradycardia or hypertensive effects of withdrawing
AV block treatment
✽ Because children commonly have
gastrointestinal illnesses that lead to
vomiting, they may be more likely to
abruptly discontinue clonidine and
therefore be more susceptible to

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CLONIDINE (continued)

hypertensive episodes resulting from

abrupt inability to take medication
• Children may be more likely to experience Pearls
CNS depression with overdose and may ✽ Although not approved for ADHD,
even exhibit signs of toxicity with 0.1 mg clonidine has been shown to be effective
of clonidine treatment for this disorder in several
• ADHD: initial 0.05 mg at bedtime; titrate published studies
over 2–4 weeks; usual dose 0.05–4 mg/day ✽ As monotherapy for ADHD, may be
• Injection may be used in pediatric cancer inferior to other options, including
patients with severe pain unresponsive to stimulants and desipramine
other medications • As monotherapy or in combination with
methylphenidate for ADHD with conduct
disorder or oppositional defiant disorder,
may improve aggression, oppositional, and
Pregnancy conduct disorder symptoms
• Risk Category C [some animal studies • Clonidine is sometimes used in
show adverse effects, no controlled studies combination with stimulants to reduce side
in humans] effects and enhance therapeutic effects on
• Use in women of childbearing potential motor hyperactivity
requires weighing potential benefits to the • Doses of 0.1 mg in 3 divided doses have
mother against potential risks to the fetus been reported to reduce stimulant-induced
✽ For ADHD patients, clonidine should insomnia as well as impulsivity
generally be discontinued before • Considered a third-line treatment option
anticipated pregnancies now for ADHD
Breast Feeding ✽ Clonidine may also be effective for
treatment of tic disorders, including
• Some drug is found in mother’s breast milk
Tourette’s syndrome
• No adverse effects have been reported in
• May suppress tics especially in severe
nursing infants
Tourette’s syndrome, and may be even
• If irritability or sedation develop in nursing
better at reducing explosive violent
infant, may need to discontinue drug or
behaviors in Tourette’s syndrome
bottle feed
• Sedation is often unacceptable in various
patients despite improvement in CNS
symptoms and leads to discontinuation of
THE ART OF PSYCHOPHARMACOLOGY treatment, especially for ADHD and
Tourette’s syndrome
Potential Advantages • Considered an investigational treatment for
• For numerous CNS indications when most other CNS applications
conventional treatments have failed • May block the autonomic symptoms in
(investigational) anxiety and panic disorders (e.g.,
palpitations, sweating) and improve
Potential Disadvantages
subjective anxiety as well
• Poor documentation of efficacy for most
• May be useful in decreasing the autonomic
off-label uses
arousal of PTSD
• Withdrawal reactions
• May be useful as an as needed medication
• Noncompliant patients
for stage fright or other predictable socially
• Patients on concomitant CNS medications
phobic situations
Primary Target Symptoms • May also be useful when added to SSRIs
• High blood pressure for reducing arousal and dissociative
• Miscellaneous CNS, behavioral, and symptoms in PTSD
psychiatric symptoms • May block autonomic symptoms of opioid
withdrawal (e.g., palpitations, sweating)
especially in inpatients, but muscle aches,
irritability, and insomnia may not be well
suppressed by clonidine

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(continued) CLONIDINE

• May be useful in decreasing the • Alcohol may reduce the effects of clonidine
hypertension, tachycardia, and on growth hormone
tremulousness associated with alcohol ✽ Guanfacine is a related centrally active
withdrawal, but not the seizures or delirium alpha 2 agonist hypotensive agent that has
tremens in complicated alcohol withdrawal been used for similar CNS applications but
• Clonidine may improve social relationships, has not been as widely investigated or
affectual responses, and sensory used as clonidine
responses in autistic disorder ✽ Guanfacine may be tolerated better than
• Clonidine may reduce the incidence of clonidine in some patients (e.g., sedation)
menopausal flushing or it may work better in some patients for
• Growth hormone response to clonidine CNS applications than clonidine, but no
may be reduced during menses head-to-head trials
• Clonidine stimulates growth hormone
secretion (no chronic effects have been
observed)

Suggested Reading
Burris JF. The USA experience with the Guay DR. Adjunctive agents in the
clonidine transdermal therapeutic system. Clin management of chronic pain.
Auton Res. 1993; 3: 391–6. Pharmacotherapy. 2001; 21: 1070–81.
Gavras I, Manolis AJ, Gayras H. The alpha2- Silver LB. Alternative (nonstimulant)
adrenergic receptors in hypertension and heart medications in the treatment of attention-
failure: experimental and clinical studies. J deficit/hyperactivity disorder in children.
Hypertens. 2001; 19: 2115–24. Pediatr Clin North Am. 1999; 46: 965–75.

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CLORAZEPATE
THERAPEUTICS • If symptoms reemerge, consider treatment
with an SSRI or SNRI, or consider
Brands • Azene restarting the benzodiazepine; sometimes
• Tranxene benzodiazepines have to be used in
see index for additional brand names combination with SSRIs or SNRIs for best
results
Generic? Yes
If It Doesn’t Work
• Consider switching to another agent or
Class adding an appropriate augmenting agent
• Benzodiazepine (anxiolytic) • Consider psychotherapy, especially
cognitive behavioral psychotherapy
Commonly Prescribed For • Consider presence of concomitant
(bold for FDA approved) substance abuse
• Anxiety disorder • Consider presence of clorazepate abuse
• Symptoms of anxiety • Consider another diagnosis, such as a
• Acute alcohol withdrawal comorbid medical condition
• Partial seizures (adjunct)
Best Augmenting Combos
for Partial Response or
How The Drug Works Treatment-Resistance
• Binds to benzodiazepine receptors at the • Benzodiazepines are frequently used as
GABA-A ligand-gated chloride channel augmenting agents for antipsychotics and
complex mood stabilizers in the treatment of
• Enhances the inhibitory effects of GABA psychotic and bipolar disorders
• Boosts chloride conductance through • Benzodiazepines are frequently used as
GABA-regulated channels augmenting agents for SSRIs and SNRIs in
• Inhibits neuronal activity presumably in the treatment of anxiety disorders
amygdala-centered fear circuits to provide • Not generally rational to combine with
therapeutic benefits in anxiety disorders other benzodiazepines
• Caution if using as an anxiolytic
How Long Until It Works concomitantly with other sedative
• Some immediate relief with first dosing is hypnotics for sleep
common; can take several weeks with daily
dosing for maximal therapeutic benefit Tests
• In patients with seizure disorders,
If It Works concomitant medical illness, and/or those
• For short-term symptoms of anxiety – after with multiple concomitant long-term
a few weeks, discontinue use or use on an medications, periodic liver tests and blood
“as-needed” basis counts may be prudent
• For chronic anxiety disorders, the goal of
treatment is complete remission of
symptoms as well as prevention of future SIDE EFFECTS
relapses
• For chronic anxiety disorders, treatment How Drug Causes Side Effects
most often reduces or even eliminates • Same mechanism for side effects as for
symptoms, but not a cure since symptoms therapeutic effects – namely due to
can recur after medicine stopped excessive actions at benzodiazepine
• For long-term symptoms of anxiety, receptors
consider switching to an SSRI or SNRI for • Long-term adaptations in benzodiazepine
long-term maintenance receptors may explain the development of
• If long-term maintenance with a dependence, tolerance, and withdrawal
benzodiazepine is necessary, continue • Side effects are generally immediate, but
treatment for 6 months after symptoms immediate side effects often disappear in
resolve, and then taper dose slowly time

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CLORAZEPATE (continued)

Notable Side Effects • Alcohol withdrawal: 30–60 mg/day in

✽ Sedation, fatigue, depression divided doses
✽ Dizziness, ataxia, slurred speech,
weakness Dosage Forms
✽ Forgetfulness, confusion • Tablet 3.75 mg scored, 7.5 mg scored,
✽ Hyper-excitability, nervousness 15 mg scored, 22.5 mg single dose,
• Rare hallucinations, mania 11.25 mg single dose half strength
• Rare hypotension
• Hypersalivation, dry mouth How to Dose
• Anxiety: Initial 15 mg/day in divided doses;
adjust dose as needed on subsequent days;
Life Threatening or single dose tablet may be given once daily
Dangerous Side Effects at bedtime after patient is stable; maximum
• Respiratory depression, especially when generally 90 mg/day
taken with CNS depressants in overdose • Alcohol withdrawal: Initial 30 mg, then
• Rare hepatic dysfunction, renal 30–60 mg in divided doses; second day
dysfunction, blood dyscrasias 45–90 mg in divided doses; third day
22.5–45 mg in divided doses; fourth day
Weight Gain 15–30 mg in divided doses; after fourth
day decrease dose gradually and
discontinue when patient is stable;
• Reported but not expected maximum generally 90 mg/day
• Epilepsy: Initial 7.5 mg 3 times/day;
Sedation increase by 7.5 mg weekly; maximum
generally 90 mg/day

• Many experience and/or can be significant

in amount Dosing Tips
• Especially at initiation of treatment or when • Use lowest possible effective dose for the
dose increases shortest possible period of time (a
• Tolerance often develops over time benzodiazepine-sparing strategy)
• Assess need for continued treatment
What To Do About Side Effects regularly
• Wait • Risk of dependence may increase with
• Wait dose and duration of treatment
• Wait • For inter-dose symptoms of anxiety, can
• Lower the dose either increase dose or maintain same total
• Take largest dose at bedtime to avoid daily dose but divide into more frequent
sedative effects during the day doses
• Switch to another agent • Can also use an as-needed occasional “top
• Administer flumazenil if side effects are up” dose for inter-dose anxiety
severe or life-threatening • Because anxiety disorders can require
higher doses, the risk of dependence may
Best Augmenting Agents for Side be greater in these patients
Effects • Frequency of dosing in practice is often
• Many side effects cannot be improved with greater than predicted from half-life, as
an augmenting agent duration of biological activity is often
shorter than pharmacokinetic terminal half-
life
DOSING AND USE Overdose
Usual Dosage Range • Fatalities can occur; hypotension,
tiredness, ataxia, confusion, coma
• Anxiety: 15–60 mg/day in divided doses

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(continued) CLORAZEPATE

Long-Term Use
• Evidence of efficacy for up to 16 weeks
Other Warnings/
• Risk of dependence, particularly for periods Precautions
longer than 12 weeks and especially in • Dosage changes should be made in
patients with past or current polysubstance collaboration with prescriber
abuse • Use with caution in patients with
pulmonary disease; rare reports of death
Habit Forming after initiation of benzodiazepines in
• Clorazepate is a Schedule IV drug patients with severe pulmonary impairment
• Patients may develop dependence and/or • History of drug or alcohol abuse often
tolerance with long-term use creates greater risk for dependency
• Some depressed patients may experience a
How to Stop worsening of suicidal ideation
• Patients with history of seizure may seize • Some patients may exhibit abnormal
upon withdrawal, especially if withdrawal is thinking or behavioral changes similar to
abrupt those caused by other CNS depressants
• Taper by 7.5 mg every 3 days to reduce (i.e., either depressant actions or
chances of withdrawal effects disinhibiting actions)
• For difficult to taper cases, consider
reducing dose much more slowly after Do Not Use
reaching 30 mg/day, perhaps by as little as • If patient has narrow angle-closure
3.75 mg per week or less glaucoma
• For other patients with severe problems • If there is a proven allergy to clorazepate or
discontinuing a benzodiazepine, dosing any benzodiazepine
may need to be tapered over many months
(i.e., reduce dose by 1% every 3 days by
crushing tablet and suspending or dissolving SPECIAL POPULATIONS
in 100 ml of fruit juice and then disposing
of 1 ml while drinking the rest; 3–7 days Renal Impairment
later, dispose of 2 ml, and so on). This is • Initial 7.5–15 mg/day in divided doses or in
both a form of very slow biological tapering 1 dose at bedtime
and a form of behavioral desensitization
• Be sure to differentiate reemergence of Hepatic Impairment
symptoms requiring reinstitution of • Initial 7.5–15 mg/day in divided doses or in
treatment from withdrawal symptoms 1 dose at bedtime
• Benzodiazepine-dependent anxiety patients
and insulin-dependent diabetics are not Cardiac Impairment
addicted to their medications. When • Benzodiazepines have been used to treat
benzodiazepine-dependent patients stop anxiety associated with acute myocardial
their medication, disease symptoms can infarction
reemerge, disease symptoms can worsen
(rebound), and/or withdrawal symptoms
Elderly
can emerge • Initial 7.5–15 mg/day in divided doses or in
1 dose at bedtime
Pharmacokinetics
• Elimination half-life 40–50 hours
Children and Adolescents
• Not recommended for use under age 9
Drug Interactions • Recommended initial dose: 7.5 mg twice a
• Increased depressive effects when taken day
with other CNS depressants

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CLORAZEPATE (continued)

Potential Disadvantages
• Euphoria may lead to abuse
Pregnancy • Abuse especially risky in past or present
• Risk Category D [positive evidence of risk substance abusers
to human fetus; potential benefits may still
justify its use during pregnancy] Primary Target Symptoms
• Possible increased risk of birth defects • Panic attacks
when benzodiazepines taken during • Anxiety
pregnancy • Incidence of seizures (adjunct)
• Because of the potential risks, clorazepate
is not generally recommended as treatment
for anxiety during pregnancy, especially
Pearls
during the first trimester
• Can be very useful as an adjunct to SSRIs
• Drug should be tapered if discontinued
and SNRIs in the treatment of numerous
• Infants whose mothers received a
anxiety disorders
benzodiazepine late in pregnancy may
• Not effective for treating psychosis as a
experience withdrawal effects
monotherapy, but can be used as an
• Neonatal flaccidity has been reported in
adjunct to antipsychotics
infants whose mothers took a
• Not effective for treating bipolar disorder
benzodiazepine during pregnancy
as a monotherapy, but can be used as an
• Seizures, even mild seizures, may cause
adjunct to mood stabilizers and
harm to the embryo/fetus
antipsychotics
Breast Feeding ✽ More commonly used than some other
• Some drug is found in mother’s breast milk benzodiazepines for treating alcohol
✽ Recommended either to discontinue drug withdrawal
• May both cause depression and treat
or bottle feed
• Effects of benzodiazepines on nursing infants depression in different patients
have been reported and include feeding • When using to treat insomnia, remember
difficulties, sedation, and weight loss that insomnia may be a symptom of some
other primary disorder itself, and thus
warrant evaluation for comorbid psychiatric
and/or medical conditions
THE ART OF PSYCHOPHARMACOLOGY
Potential Advantages
• Rapid onset of action

Suggested Reading
Griffith JL, Murray GB. Clorazepate in the nordiazepam on preoperative anxiety].
treatment of complex partial seizures with Anaesthesiol Reanim 1995;20:144–8.
psychic symptomatology. J Nerv Ment Dis
1985;173:185–6. Rickels K, Schweizer E, Csanalosi I, Case WG,
Chung H. Long-term treatment of anxiety and
Kiejna A, Kantorska-Janiec M, Malyszczak K. risk of withdrawal. Prospective comparison of
[The use of chlorazepate dipotassium clorazepate and buspirone. Arch Gen
(Tranxene) in the states of restlessness and Psychiatry 1988;45:444–50.
agitation]. Psychiatr Pol 1997;31:753–60.
Mielke L, Breinbauer B, Schubert M, Kling M,
Entolzner E, Hargasser S, Hipp R.
[Comparison of the effectiveness of orally
administered clorazepate dipotassium and

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CLOZAPINE
THERAPEUTICS but in practice patients often require up to
16–20 weeks to show a good response,
Brands • Clozaril especially in treatment-resistant cases
• Leponex
see index for additional brand names If It Works
• As for other antipsychotics, most often
Generic? Yes reduces positive symptoms in
schizophrenia but does not eliminate them
✽ However, clozapine may reduce positive
Class symptoms in patients who do not respond
• Atypical antipsychotic (serotonin-dopamine to other antipsychotics, especially other
antagonist; second generation conventional antipsychotics
antipsychotic; also a mood stabilizer) • Can improve negative symptoms, as well
as aggressive, cognitive, and affective
Commonly Prescribed For symptoms in schizophrenia
(bold for FDA approved) • Most schizophrenic patients do not have a
• Treatment-resistant schizophrenia total remission of symptoms but rather a
• Reduction in risk of recurrent suicidal reduction of symptoms by about a third
behavior in patients with schizophrenia or • Many patients with bipolar disorder and
schizoaffective disorder other disorders with psychotic, aggressive,
• Treatment-resistant bipolar disorder violent, impulsive, and other types of
• Violent aggressive patients with psychosis behavioral disturbances may respond to
and other brain disorders not responsive to clozapine when other agents have failed
other treatments • Perhaps 5–15% of schizophrenic patients
can experience an overall improvement of
greater than 50–60%, especially when
How The Drug Works receiving stable treatment for more than a
• Blocks dopamine 2 receptors, reducing year
positive symptoms of psychosis and ✽ Such patients are considered super-
stabilizing affective symptoms responders or “awakeners” since they may
• Blocks serotonin 2A receptors, causing be well enough to be employed, live
enhancement of dopamine release in independently, and sustain long-term
certain brain regions and thus reducing relationships; super-responders are
motor side effects and possibly improving anecdotally reported more often with
cognitive and affective symptoms clozapine than with some other
• Interactions at a myriad of other antipsychotics
neurotransmitter receptors may contribute • Continue treatment until reaching a plateau
to clozapine’s efficacy of improvement
✽ Specifically, interactions at 5HT2C and • After reaching a satisfactory plateau,
5HT1A receptors may contribute to efficacy continue treatment for at least a year after
for cognitive and affective symptoms in first episode of psychosis
some patients • For second and subsequent episodes of
• Mechanism of efficacy for psychotic psychosis, treatment may need to be
patients who do not respond to indefinite
conventional antipsychotics is unknown • Even for first episodes of psychosis, it may
be preferable to continue treatment
How Long Until It Works indefinitely to avoid subsequent episodes
• Psychotic symptoms can improve within • Treatment may not only reduce mania but
1 week, especially with first-line use, but also prevent recurrences of mania in
often takes several weeks for full effect on bipolar disorder
behavior as well as on cognition and
affective stabilization, especially in If It Doesn’t Work
treatment-resistant cases • Some patients may respond better if
• Classically recommended to wait at least switched to a conventional antipsychotic
4–6 weeks to determine efficacy of drug,

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CLOZAPINE (continued)

✽ Some patients may require augmentation • Treat or refer such patients for treatment,
with a conventional antipsychotic or with including nutrition and weight
an atypical antipsychotic (especially management, physical activity counseling,
risperidone or amisulpride), but these are smoking cessation, and medical
the most refractory of all psychotic patients management
and such treatment is very expensive Monitoring after starting an atypical
✽ Consider augmentation with valproate or antipsychotic
lamotrigine
✽ BMI monthly for 3 months, then quarterly
• Consider noncompliance and switch to
another antipsychotic with fewer side
✽ Blood pressure, fasting plasma glucose,
fasting lipids within 3 months and then
effects or to an antipsychotic that can be annually, but earlier and more frequently
given by depot injection for patients with diabetes or who have
• Consider initiating rehabilitation and gained >5% of initial weight
psychotherapy • Treat or refer for treatment and consider
• Consider presence of concomitant drug switching to another atypical antipsychotic
abuse for patients who become overweight,
obese, pre-diabetic, diabetic, hypertensive,
Best Augmenting Combos
or dyslipidemic while receiving an atypical
for Partial Response or antipsychotic
Treatment-Resistance ✽ Even in patients without known diabetes,
• Valproic acid (valproate, divalproex, be vigilant for the rare but life threatening
divalproex ER) onset of diabetic ketoacidosis, which
• Lamotrigine always requires immediate treatment, by
• Other mood stabilizing anticonvulsants monitoring for the rapid onset of polyuria,
(carbamazepine, oxcarbazepine) polydipsia, weight loss, nausea, vomiting,
• Conventional antipsychotics dehydration, rapid respiration, weakness
• Benzodiazepines and clouding of sensorium, even coma
• Lithium • Liver function testing, electrocardiogram,
general physical exam, and assessment of
Tests baseline cardiac status before starting
✽ Complete blood count before treatment, treatment
weekly for 6 months of treatment, and • Liver tests may be necessary during
biweekly thereafter treatment in patients who develop nausea,
Before starting an atypical antipsychotic vomiting, or anorexia
✽ Weigh all patients and track BMI during ✽ Electrocardiograms and cardiac
treatment evaluation to rule out myocarditis may be
• Get baseline personal and family history of necessary during treatment in patients who
obesity, dyslipidemia, hypertension, and develop shortness of breath or chest pain
cardiovascular disease
✽ Get waist circumference (at umbilicus),
blood pressure, fasting plasma glucose, SIDE EFFECTS
and fasting lipid profile
• Determine if the patient is How Drug Causes Side Effects
• overweight (BMI 25.0–29.9) • By blocking histamine 1 receptors in the
• obese (BMI ≥30) brain, it can cause sedation and possibly
• has pre-diabetes (fasting plasma glucose weight gain
100–125 mg/dl) • By blocking alpha 1 adrenergic receptors, it
• has diabetes (fasting plasma glucose can cause dizziness, sedation, and
>126 mg/dl) hypotension
• has hypertension (BP >140/90 mm Hg) • By blocking muscarinic 1 receptors, it can
• has dyslipidemia (increased total cause dry mouth, constipation, and
cholesterol, LDL cholesterol, and sedation
triglycerides; decreased HDL cholesterol)

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(continued) CLOZAPINE

• By blocking dopamine 2 receptors in the • More than for some other antipsychotics,
striatum, it can cause motor side effects but never say always as not a problem in
(very rare) everyone
• Mechanism of weight gain and increased • Can wear off over time
incidence of diabetes and dyslipidemia with • Can reemerge as dose increases and then
atypical antipsychotics is unknown wear off again over time

Notable Side Effects What To Do About Side Effects

✽ Probably increases risk for diabetes and • Patients must inform prescriber
dyslipidemia immediately of any flu-like symptoms,
✽ Increased salivation (can be severe) muscle rigidity, altered mental status,
✽ Sweating irregular pulse or blood pressure
• Dizziness, sedation, headache, tachycardia, • Take at bedtime to help reduce daytime
hypotension sedation
• Nausea, constipation, dry mouth, weight • Sedation may wear off with time
gain • Start dosing low and increase slowly as
• Rare tardive dyskinesia (no reports have side effects wear off at each dosing
directly implicated clozapine in the increment
development of tardive dyskinesia) • Weight loss, exercise programs, and
medical management for high BMIs,
diabetes, dyslipidemia
Life Threatening or • Switch to another agent
Dangerous Side Effects
• Hyperglycemia, in some cases extreme and Best Augmenting Agents for Side
associated with ketoacidosis or Effects
hyperosmolar coma or death, has been • Many side effects cannot be improved with
reported in patients taking atypical an augmenting agent
antipsychotics
• Agranulocytosis (includes flu-like
symptoms or signs of infection)
• Seizures (risk increases with dose)
DOSING AND USE
• Neuroleptic malignant syndrome (more Usual Dosage Range
likely when clozapine is used with another
• 300–450 mg/day
agent)
• Pulmonary embolism (may include deep Dosage Forms
vein thrombosis or respiratory symptoms) • Tablet 25 mg scored, 100 mg scored
• Myocarditis
How to Dose
Weight Gain • Initial 25 mg in 2 divided doses; increase
by 25–50 mg/day each day until desired
efficacy is reached; maintenance dose
• Frequent and can be significant in amount 300–450 mg/day; doses above 300 mg/day
• Can become a health problem in some should be divided; increases in doses
• More than for some other antipsychotics, above 450 mg/day should be made weekly;
but never say always as not a problem in maximum dose generally 900 mg/day
everyone

Sedation Dosing Tips

• Prescriptions are generally given 1 week at
a time for the first 6 months of treatment
• Frequent and can be significant in amount because of the risk of agranulocytosis;
• Some patients may not tolerate it after 6 months prescriptions can generally
be given 2 weeks at a time

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CLOZAPINE (continued)

✽ Treatment should be suspended if

absolute neutrophil count falls below
1,000/mm3 Drug Interactions
• Treatment should be suspended if white • Dose may need to be reduced if given in
blood cell count falls below 2,000/mm3 conjunction with CYP450 1A2 inhibitors
• Treatment should be suspended if (e.g., fluvoxamine)
eosinophil count rises above 4,000/mm3, • Dose may need to be raised if given in
and continued once it falls below conjunction with CYP450 1A2 inducers
3,000/mm3 (e.g., cigarette smoke)
• If treatment is discontinued for more than • CYP450 2D6 inhibitors (e.g., paroxetine,
2 days, it may need to be reinitiated at a fluoxetine, duloxetine) can raise clozapine
lower dose and slowly increased in order levels, but dosage adjustment usually not
to maximize tolerability necessary
• Plasma half-life suggests twice daily • CYP450 3A4 inhibitors (e.g., nefazodone,
administration, but in practice it may be fluvoxamine, fluoxetine) can raise clozapine
given once a day at night levels, but dosage adjustment usually not
• Doses over 550 mg/day may require necessary
concomitant anticonvulsant administration • Clozapine may enhance effects of
to reduce the chances of a seizure antihypertensive drugs
✽ Rebound psychosis may occur unless
dose is very slowly tapered, by Other Warnings/
100 mg/week or less Precautions
• Possible association between myocarditis
Overdose
and cardiomyopathy and clozapine use,
• Sometimes lethal; changes in heart rhythm,
even in physically healthy individuals
excess salivation, respiratory depression,
• Should not be used in conjunction with
altered state of consciousness
agents that are known to cause
Long-Term Use agranulocytosis
• Treatment to reduce risk of suicidal • Use with caution in patients with glaucoma
behavior should be continued for at least • Use with caution in patients with enlarged
2 years prostate
• Often used for long-term maintenance in Do Not Use
treatment-resistant schizophrenia
• In patients with myeloproliferative disorder
Habit Forming • In patients with uncontrolled epilepsy
• No • In patients with granulocytopenia
• In patients with CNS depression
How to Stop • If there is a proven allergy to clozapine
• Slow down-titration (over 6 to 8 weeks),
especially when simultaneously beginning
a new antipsychotic while switching (i.e., SPECIAL POPULATIONS
cross-titration)
✽ Rapid discontinuation may lead to Renal Impairment
rebound psychosis and worsening of • Should be used with caution
symptoms
Hepatic Impairment
Pharmacokinetics • Should be used with caution
• Half-life 5–16 hours
• Metabolized by multiple CYP450 enzymes, Cardiac Impairment
including 1A2, 2D6, and 3A4 • Should be used with caution, particularly if
patient is taking concomitant medication

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(continued) CLOZAPINE

Elderly • Affective symptoms

• Some patients may tolerate lower doses • Suicidal behavior
better • Violence and aggression

Children and Adolescents Pearls

• Safety and efficacy have not been ✽ Not a first-line treatment choice in most
established countries
• Preliminary research has suggested ✽ Most efficacious but most dangerous
efficacy in early-onset treatment-resistant ✽ Documented efficacy in treatment-
schizophrenia refractory schizophrenia
• Children and adolescents taking clozapine • May reduce violence and aggression in
should be monitored more often than difficult cases, including forensic cases
adults ✽ Reduces suicide in schizophrenia
• May reduce substance abuse
• May improve tardive dyskinesia
Pregnancy • Little or no prolactin elevation, motor side
• Risk Category B [animal studies do not effects, or tardive dyskinesia
show adverse effects, no controlled studies • Clinical improvements often continue
in humans] slowly over several years
• Psychotic symptoms may worsen during • Cigarette smoke can decrease clozapine
pregnancy and some form of treatment levels and patients may be at risk for
may be necessary relapse if they begin or increase smoking
• Clozapine should be used only when the
potential benefits outweigh potential risks
to the fetus

Breast Feeding
• Unknown if clozapine is secreted in human
breast milk, but all psychotropics assumed
to be secreted in breast milk
✽ Recommended either to discontinue drug
or bottle feed
• Infants of women who choose to breast
feed while on clozapine should be
monitored for possible adverse effects

THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages
✽ Treatment-resistant schizophrenia
✽ Violent, aggressive patients
✽ Patients with tardive dyskinesia
✽ Patients with suicidal behavior
Potential Disadvantages
✽ Patients with diabetes, obesity
• Patients with cardiac impairment

Primary Target Symptoms

• Positive symptoms of psychosis
• Negative symptoms of psychosis
• Cognitive symptoms

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CLOZAPINE (continued)

Suggested Reading
Iqbal MM, Rahman A, Husain Z, Mahmud SZ, Wagstaff A, Perry C. Clozapine: in prevention
Ryan WG, Feldman JM. Clozapine: a clinical of suicide in patients with schizophrenia or
review of adverse effects and management. schizoaffective disorder. CNS Drugs
Ann Clin Psychiatry 2003;15:33–48. 2003;17:273–80
Lieberman JA. Maximizing clozapine therapy: Wahlbeck K, Cheine M, Essali A, Adams C.
managing side effects. J Clin Psychiatry Evidence of clozapine’s effectiveness in
1998;59 (suppl 3):38–43. schizophrenia: a systematic review and meta-
analysis of randomized trials. Am J Psychiatry
Schulte P. What is an adequate trial with 1999;156:990–999.
clozapine?: therapeutic drug monitoring and
time to response in treatment-refractory
schizophrenia. Clin Pharmacokinet
2003;42:607–18.

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D-AMPHETAMINE
THERAPEUTICS • Reevaluate the need for treatment
periodically
Brands • Dexedrine • Treatment for ADHD begun in childhood
• Dexedrine Spansules may need to be continued into adolescence
• Dextro Stat and adulthood if continued benefit is
see index for additional brand names documented
Generic? Yes If It Doesn’t Work (for ADHD)
• Consider adjusting dose or switching to
Class another formulation of d-amphetamine or
• Stimulant to another agent
• Consider behavioral therapy
Commonly Prescribed For • Consider the presence of noncompliance
(bold for FDA approved) and counsel patient and parents
• Attention deficit hyperactivity disorder • Consider evaluation for another diagnosis
(ages 3–16) or for a comorbid condition (e.g., bipolar
• Narcolepsy disorder, substance abuse, medical illness,
• Treatment-resistant depression etc.)
✽ Some ADHD patients and some
depressed patients may experience lack of
How The Drug Works consistent efficacy due to activation of
✽ Increases norepinephrine and especially latent or underlying bipolar disorder, and
dopamine actions by blocking their require either augmenting with a mood
reuptake and facilitating their release stabilizer or switching to a mood stabilizer
• Enhancement of dopamine and
norepinephrine actions in certain brain Best Augmenting Combos
regions may improve attention, for Partial Response or
concentration, executive function and Treatment-Resistance
wakefulness (e.g. dorsolateral prefrontal ✽ Best to attempt other monotherapies
cortex) prior to augmenting
• Enhancement of dopamine actions in other • For the expert, can combine immediate
brain regions (e.g., basal ganglia) may release formulation with a sustained
improve hyperactivity release formulation of d-amphetamine for
• Enhancement of dopamine and ADHD
norepinephrine in yet other brain regions • For the expert, can combine with modafinil
(e.g., medial prefrontal cortex, or atomoxetine for ADHD
hypothalamus) may improve depression, • For the expert, can occasionally combine
fatigue, and sleepiness with atypical antipsychotics in highly
treatment-resistant cases of bipolar
How Long Until It Works disorder or ADHD
• Some immediate effects can be seen with • For the expert, can combine with
first dosing antidepressants to boost antidepressant
• Can take several weeks to attain maximum efficacy in highly treatment-resistant cases
therapeutic benefit of depression while carefully monitoring
patient
If It Works (for ADHD)
• The goal of treatment of ADHD is reduction Tests
of symptoms of inattentiveness, motor • Blood pressure should be monitored
hyperactivity, and/or impulsiveness that regularly
disrupt social, school, and/or occupational • In children, monitor weight and height
functioning
• Continue treatment until all symptoms are
under control or improvement is stable and
then continue treatment indefinitely as long
as improvement persists

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D-AMPHETAMINE (continued)

SIDE EFFECTS Best Augmenting Agents for Side

How Drug Causes Side Effects Effects
• Beta-blockers for peripheral autonomic
• Increases in norepinephrine peripherally
side effects
can cause autonomic side effects, including
• Dose reduction or switching to another
tremor, tachycardia, hypertension, and
agent may be more effective since most
cardiac arrhythmias
side effects cannot be improved with an
• Increases in norepinephrine and dopamine
augmenting agent
centrally can cause CNS side effects such
as insomnia, agitation, psychosis and
substance abuse
DOSING AND USE
Notable Side Effects
✽ Insomnia, headache, exacerbation of tics, Usual Dosage Range
nervousness, irritability, overstimulation, • Narcolepsy: 5–60 mg/day (divided doses
tremor, dizziness for tablet, once-daily morning dose for
• Anorexia, nausea, dry mouth, constipation, Spansule capsule)
diarrhea, weight loss • ADHD: 5–40 mg/day (divided doses for
• Can temporarily slow normal growth in tablet, once-daily morning dose for
children (controversial) Spansule capsule)
• Sexual dysfunction long-term (impotence,
libido changes) but can also improve Dosage Forms
sexual dysfunction short-term • Spansule capsule 5 mg, 10 mg, 15 mg
• Tablet 5 mg scored, 10 mg

Life Threatening or How to Dose

Dangerous Side Effects • Narcolepsy (ages 12 and older): initial
• Psychotic episodes, especially with 10 mg/day; increase by 10 mg each week;
parenteral abuse give first dose on waking
• Seizures • ADHD (ages 6 and older): initial
• Palpitations, tachycardia, hypertension 5–10 mg/day in 1–2 doses; increase by
• Rare activation of hypomania, mania, or 5 mg each week; give first dose on waking
suicidal ideation (controversial) • Can give once-daily dosing with Spansule
capsule or divided dosing with tablet (every
Weight Gain 4–6 hours)

• Reported but not expected Dosing Tips

• Some patients may experience weight loss • Clinical duration of action often differs
from pharmacokinetic half-life
Sedation ✽ Immediate release dextroamphetamine
has 3–6 hour duration of clinical action
✽ Sustained release dextroamphetamine
(Dexedrine spansule) has up to 8-hour
• Reported but not expected
duration of clinical action
• Activation much more common than
• Tablets contain tartrazine, which may cause
sedation
allergic reactions, particularly in patients
What To Do About Side Effects allergic to aspirin
• Wait • Dexedrine spansules are controlled-release
• Adjust dose and should therefore not be chewed but
• Switch to a long-acting stimulant rather should only be swallowed whole
• Switch to another agent ✽ Controlled release delivery of
• For insomnia, avoid dosing in dextroamphetamine may be sufficiently
afternoon/evening long in duration to allow elimination of

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(continued) D-AMPHETAMINE

lunchtime dosing in many but not all How to Stop

patients • Taper to avoid withdrawal effects
✽ This innovation can be an important • Withdrawal following chronic therapeutic
practical element in stimulant utilization, use may unmask symptoms of the
eliminating the hassle and pragmatic underlying disorder and may require
difficulties of lunchtime dosing at school, follow-up and reinstitution of treatment
including storage problems, potential • Careful supervision is required during
diversion, and the need for a medical withdrawal from abusive use since severe
professional to supervise dosing away depression may occur
from home
• Avoid dosing late in the day because of the Pharmacokinetics
risk of insomnia • Half-life approximately 10–12 hours
✽ May be possible to dose only during the
school week for some ADHD patients
• Off-label uses are dosed the same as for Drug Interactions
ADHD • May affect blood pressure and should be
✽ May be able to give drug holidays over used cautiously with agents used to control
the summer in order to reassess blood pressure
therapeutic utility and effects on growth • Gastrointestinal acidifying agents
and to allow catch-up from any growth (guanethidine, reserpine, glutamic acid,
suppression as well as to assess any other ascorbic acid, fruit juices, etc.) and urinary
side effects and the need to reinstitute acidifying agents (ammonium chloride,
stimulant treatment for the next school sodium phosphate, etc.) lower
term amphetamine plasma levels, so such
• Side effects are generally dose-related agents can be useful to administer after an
• Taking with food may delay peak actions overdose but may also lower therapeutic
for 2–3 hours efficacy of amphetamines
• Gastrointestinal alkalinizing agents (sodium
Overdose bicarbonate, etc.) and urinary alkalinizing
• Rarely fatal; panic, hyperreflexia, agents (acetazolamide, some thiazides)
rhabdomyolysis, rapid respiration, increase amphetamine plasma levels and
confusion, coma, hallucination, convulsion, potentiate amphetamine’s actions
arrhythmia, change in blood pressure, • Desipramine and protryptiline can cause
circulatory collapse striking and sustained increases in brain
Long-Term Use concentrations of d-amphetamine and may
also add to d-amphetamine’s
• Often used long-term for ADHD when
cardiovascular effects
ongoing monitoring documents continued
• Theoretically, other agents with
efficacy
norepinephrine reuptake blocking
• Dependence and/or abuse may develop
properties, such as venlafaxine, duloxetine,
• Tolerance to therapeutic effects may
atomoxetine, milnacipran, and reboxetine,
develop in some patients
could also add to amphetamine’s CNS and
• Long-term stimulant use may be
cardiovascular effects
associated with growth suppression in
• Amphetamines may counteract the sedative
children (controversial)
effects of antihistamines
• Periodic monitoring of weight, blood
• Haloperidol, chlorpromazine, and lithium
pressure, CBC, platelet counts, and liver
may inhibit stimulatory effects of
function may be prudent
amphetamines
Habit Forming • Theoretically, atypical antipsychotics
• High abuse potential, Schedule II drug should also inhibit stimulatory effects of
• Patients may develop tolerance, amphetamines
psychological dependence • Theoretically, amphetamines could inhibit
the antipsychotic actions of antipsychotics

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D-AMPHETAMINE (continued)

• Theoretically, amphetamines could inhibit whenever possible or done only with close
the mood stabilizing actions of atypical monitoring, as it may lead to marked
antipsychotics in some patients tolerance and drug dependence, including
• Combinations of amphetamines with mood psychological dependence with varying
stabilizers (lithium, anticonvulsants, degrees of abnormal behavior
atypical antipsychotics) is generally • Particular attention should be paid to the
something for experts only, when possibility of subjects obtaining stimulants
monitoring patients closely and when other for nontherapeutic use or distribution to
options fail others and the drugs should in general be
• Absorption of amphetamines is delayed by prescribed sparingly with documentation of
phenobarbital, phenytoin, ethosuximide appropriate use
• Amphetamines inhibit adrenergic blockers • Not an appropriate first-line treatment for
and enhance adrenergic effects of depression or for normal fatigue
norepinephrine • May lower the seizure threshold
• Amphetamines may antagonize • Emergence or worsening of activation and
hypotensive effects of veratrum alkaloids agitation may represent the induction of a
and other antihypertensives bipolar state, especially a mixed dysphoric
• Amphetamines increase the analgesic bipolar II condition sometimes associated
effects of meperidine with suicidal ideation, and require the
• Amphetamines contribute to excessive CNS addition of a mood stabilizer and/or
stimulation if used with large doses of discontinuation of d-amphetamine
propoxyphene
• Amphetamines can raise plasma Do Not Use
corticosteroid levels • If patient has extreme anxiety or agitation
• MAOIs slow absorption of amphetamines • If patient has motor tics or Tourette’s
and thus potentiate their actions, which can sydrome or if there is a family history of
cause headache, hypertension, and rarely Tourette’s, unless administered by an
hypertensive crisis and malignant expert in cases when the potential benefits
hyperthermia, sometimes with fatal results for ADHD outweigh the risks of worsening
• Use with MAOIs, including within 14 days tics
of MAOI use, is not advised, but this can • Should generally not be administered with
sometimes be considered by experts who an MAOI, including within 14 days of MAOI
monitor depressed patients closely when use, except in heroic circumstances and by
other treatment options for depression fail an expert
• If patient has arteriosclerosis,
cardiovascular disease, or severe
Other Warnings/ hypertension
Precautions • If patient has glaucoma
• Use with caution in patients with any • If there is a proven allergy to any
degree of hypertension, hyperthyroidism, sympathomimetic agent
or history of drug abuse
• Children who are not growing or gaining
weight should stop treatment, at least
SPECIAL POPULATIONS
temporarily
• May worsen motor and phonic tics Renal Impairment
• May worsen symptoms of thought disorder • No dose adjustment necessary
and behavioral disturbance in psychotic
patients Hepatic Impairment
• Stimulants have a high potential for abuse • Use with caution
and must be used with caution in anyone
with a current or past history of substance Cardiac Impairment
abuse or alcoholism or in emotionally • Use with caution, particularly in patients
unstable patients with recent myocardial infarction or other
• Administration of stimulants for prolonged conditions that could be negatively affected
periods of time should be avoided by increased blood pressure

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(continued) D-AMPHETAMINE

Elderly THE ART OF PSYCHOPHARMACOLOGY

• Some patients may tolerate lower doses
Potential Advantages
better
• May work in ADHD patients unresponsive
to other stimulants
• Established long-term efficacy of
Children and Adolescents immediate release and spansule
• Safety and efficacy not established under formulations
age 3
• Use in young children should be reserved Potential Disadvantages
for the expert • Patients with current or past substance
• d-amphetamine may worsen symptoms of abuse
behavioral disturbance and thought • Patients with current or past bipolar
disorder in psychotic children disorder or psychosis
• d-amphetamine has acute effects on
growth hormone; long-term effects are Primary Target Symptoms
unknown but weight and height should be • Concentration, attention span
monitored during long-term treatment • Motor hyperactivity
• Narcolepsy: ages 6–12: initial 5 mg/day; • Impulsiveness
increase by 5 mg each week • Physical and mental fatigue
• ADHD: ages 3–5: initial 2.5 mg/day; • Daytime sleepiness
increase by 2.5 mg each week • Depression

Pregnancy Pearls
• Risk Category C [some animal studies ✽ May be useful for treatment of depressive
show adverse effects, no controlled studies symptoms in medically ill elderly patients
in humans] ✽ May be useful for treatment of post-
• There is a greater risk of premature birth stroke depression
and low birth weight in infants whose ✽ A classical augmentation strategy for
mothers take d-amphetamine during treatment-refractory depression
pregnancy ✽ Specifically, may be useful for treatment
• Infants whose mothers take of cognitive dysfunction and fatigue as
d-amphetamine during pregnancy may residual symptoms of major depressive
experience withdrawal symptoms disorder unresponsive to multiple prior
• Use in women of childbearing potential treatments
requires weighing potential benefits to the ✽ May also be useful for the treatment of
mother against potential risks to the fetus cognitive impairment, depressive
✽ For ADHD patients, d-amphetamine symptoms, and severe fatigue in patients
should generally be discontinued before with HIV infection and in cancer patients
anticipated pregnancies • Can be used to potentiate opioid analgesia
and reduce sedation, particularly in end-of-
Breast Feeding life management
• Some drug is found in mother’s breast milk • Unknown how d-amphetamine’s
✽ Recommended either to discontinue drug mechanism of action differs from that of
or bottle feed d,l-methylphenidate, but some patients
• If infant shows signs of irritability, drug respond to or tolerate d-amphetamine
may need to be discontinued better than d,l-methylphenidate and vice
versa
• Some patients may benefit from an
occasional addition of 5–10 mg of
immediate release d-amphetamine to their
daily base of sustained release Dexedrine
spansules

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D-AMPHETAMINE (continued)

✽ Despite warnings, can be a useful adjunct • Taking with food may delay peak actions
to MAOIs for heroic treatment of highly for 2–3 hours
refractory mood disorders when monitored • Half-life and duration of clinical action tend
with vigilance to be shorter in younger children
✽ Can reverse sexual dysfunction caused by • Drug abuse may actually be lower in ADHD
psychiatric illness and by some drugs such adolescents treated with stimulants than in
as SSRIs, including decreased libido, ADHD adolescents who are not treated
erectile dysfunction, delayed ejaculation,
and anorgasmia
• Atypical antipsychotics may be useful in
treating stimulant or psychotic
consequences of overdose

Suggested Reading
Fry JM. Treatment modalities for narcolepsy. Jadad AR, Boyle M, Cunningham C, Kim M,
Neurology. 1998;50(2 Suppl 1):S43–8. Schachar R. Treatment of attention-
deficit/hyperactivity disorder. Evid Rep Technol
Greenhill LL, Pliszka S, Dulcan MK, Bernet W, Assess (Summ). 1999;(11):i–viii, 1–341.
Arnold V, Beitchman J, Benson RS, Bukstein
O, Kinlan J, McClellan J, Rue D, Shaw JA, Vinson DC. Therapy for attention-deficit
Stock S. Practice parameter for the use of hyperactivity disorder. Arch Fam Med.
stimulant medications in the treatment of 1994;3:445–51.
children, adolescents, and adults. J Am Acad
Child Adolesc Psychiatry. 2002;41(2 Wender PH, Wolf LE, Wasserstein J. Adults
Suppl):26S–49S. with ADHD. An overview. Ann N Y Acad Sci.
2001;931:1–16.

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DESIPRAMINE
THERAPEUTICS If It Works
• The goal of treatment of depression is
Brands • Norpramin
complete remission of current symptoms
see index for additional brand names
as well as prevention of future relapses
Generic? Yes • The goal of treatment of chronic
neuropathic pain is to reduce symptoms as
much as possible, especially in
combination with other treatments
Class • Treatment of depression most often
• Tricyclic antidepressant (TCA) reduces or even eliminates symptoms, but
• Predominantly a norepinephrine/ not a cure since symptoms can recur after
noradrenaline reuptake inhibitor medicine stopped
• Treatment of chronic neuropathic pain may
Commonly Prescribed For reduce symptoms, but rarely eliminates
(bold for FDA approved) them completely, and is not a cure since
• Depression symptoms can recur after medicine is
• Anxiety stopped
• Insomnia • Continue treatment of depression until all
• Neuropathic pain/chronic pain symptoms are gone (remission)
• Treatment-resistant depression • Once symptoms of depression are gone,
continue treating for 1 year for the first
episode of depression
How The Drug Works • For second and subsequent episodes of
• Boosts neurotransmitter depression, treatment may need to be
norepinephrine/noradrenaline indefinite
• Blocks norepinephrine reuptake pump • Use in anxiety disorders and chronic pain
(norepinephrine transporter), presumably may also need to be indefinite, but long-
increasing noradrenergic term treatment is not well studied in these
neurotransmission conditions
• Since dopamine is inactivated by
If It Doesn’t Work
norepinephrine reuptake in frontal cortex,
• Many depressed patients only have a
which largely lacks dopamine transporters,
partial response where some symptoms
desipramine can thus increase dopamine
are improved but others persist (especially
neurotransmission in this part of the brain
insomnia, fatigue, and problems
• A more potent inhibitor of norepinephrine
concentrating)
reuptake pump than serotonin reuptake
• Other depressed patients may be
pump (serotonin transporter)
nonresponders, sometimes called
• At high doses may also boost
treatment-resistant or treatment-refractory
neurotransmitter serotonin and presumably
• Consider increasing dose, switching to
increase serotonergic neurotransmission
another agent or adding an appropriate
How Long Until It Works augmenting agent
• May have immediate effects in treating • Consider psychotherapy
insomnia or anxiety • Consider evaluation for another diagnosis
• Onset of therapeutic actions usually not or for a comorbid condition (e.g., medical
immediate, but often delayed 2 to 4 weeks illness, substance abuse, etc.)
• If it is not working within 6 to 8 weeks for • Some patients may experience apparent
depression, it may require a dosage lack of consistent efficacy due to activation
increase or it may not work at all of latent or underlying bipolar disorder, and
• May continue to work for many years to require antidepressant discontinuation and
prevent relapse of symptoms a switch to a mood stabilizer

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DESIPRAMINE (continued)

Best Augmenting Combos SIDE EFFECTS

for Partial Response or How Drug Causes Side Effects
Treatment-Resistance
• Lithium, buspirone, thyroid hormone (for
✽ Anticholinergic activity for desipramine
may be somewhat less than for some other
depression) TCAs, yet can still explain the presence, if
• Gabapentin, tiagabine, other lower incidence, of sedative effects, dry
anticonvulsants, even opiates if done by mouth, constipation, and blurred vision
experts while monitoring carefully in • Sedative effects and weight gain may be
difficult cases (for chronic pain) due to antihistamine properties
• Blockade of alpha adrenergic 1 receptors
Tests
may explain dizziness, sedation, and
✽ None for healthy individuals, although hypotension
monitoring of plasma drug levels is
• Cardiac arrhythmias and seizures,
available
especially in overdose, may be caused by
✽ Since tricyclic and tetracyclic blockade of ion channels
antidepressants are frequently associated
with weight gain, before starting treatment, Notable Side Effects
weigh all patients and determine if the • Blurred vision, constipation, urinary
patient is already overweight retention, increased appetite, dry mouth,
(BMI 25.0–29.9) or obese (BMI ≥30) nausea, diarrhea, heartburn, unusual taste
• Before giving a drug that can cause weight in mouth, weight gain
gain to an overweight or obese patient, • Fatigue, weakness, dizziness, sedation,
consider determining whether the patient headache, anxiety, nervousness,
already has pre-diabetes (fasting plasma restlessness
glucose 100–125 mg/dl), diabetes (fasting • Sexual dysfunction, sweating
plasma glucose >126 mg/dl), or
dyslipidemia (increased total cholesterol,
LDL cholesterol and triglycerides; Life Threatening or
decreased HDL cholesterol), and treat or Dangerous Side Effects
refer such patients for treatment, including • Paralytic ileus, hyperthermia (TCAs +
nutrition and weight management, physical anticholinergic agents)
activity counseling, smoking cessation, and • Lowered seizure threshold and rare
medical management seizures
✽ Monitor weight and BMI during treatment • Orthostatic hypotension, sudden death,
✽ While giving a drug to a patient who has arrhythmias, tachycardia
gained >5% of initial weight, consider • QTc prolongation
evaluating for the presence of pre-diabetes, • Hepatic failure, extrapyramidal symptoms
diabetes, or dyslipidemia, or consider • Increased intraocular pressure
switching to a different antidepressant • Blood dyscrasias
• EKGs may be useful for selected patients • Rare induction of mania and activation of
(e.g., those with personal or family history suicidal ideation
of QTc prolongation; cardiac arrhythmia;
recent myocardial infarction; Weight Gain
uncompensated heart failure; or taking
agents that prolong QTc interval such as
pimozide, thioridazine, selected • Many experience and/or can be significant
antiarrhythmics, moxifloxacin, sparfloxacin, in amount
etc.) • Can increase appetite and carbohydrate
• Patients at risk for electrolyte disturbances craving
(e.g., patients on diuretic therapy) should
have baseline and periodic serum Sedation
potassium and magnesium measurements

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(continued) DESIPRAMINE

• Many experience and/or can be significant • If intolerable anxiety, insomnia, agitation,

in amount akathisia, or activation occur either upon
• Tolerance to sedative effects may develop dosing initiation or discontinuation,
with long-term use consider the possibility of activated bipolar
disorder, and switch to a mood stabilizer or
What To Do About Side Effects an atypical antipsychotic
• Wait
• Wait Overdose
• Wait • Death may occur; convulsions, cardiac
• Lower the dose dysrhythmias, severe hypotension, CNS
• Switch to an SSRI or newer antidepressant depression, coma, changes in ECG

Best Augmenting Agents for Side Long-Term Use

Effects • Safe
• Many side effects cannot be improved with
an augmenting agent Habit Forming
• No

How to Stop
DOSING AND USE • Taper to avoid withdrawal effects
Usual Dosage Range • Even with gradual dose reduction some
withdrawal symptoms may appear within
• 100–200 mg/day (for depression)
the first 2 weeks
• 50–150 mg/day (for chronic pain)
• Many patients tolerate 50% dose reduction
Dosage Forms for 3 days, then another 50% reduction for
• Tablets 10 mg, 25 mg, 50 mg, 75 mg, 3 days, then discontinuation
100 mg, 150 mg • If withdrawal symptoms emerge during
discontinuation, raise dose to stop
How to Dose symptoms and then restart withdrawal
• Initial 25 mg/day at bedtime; increase by much more slowly
25 mg every 3–7 days
• 75 mg/day once daily or in divided doses;
Pharmacokinetics
gradually increase dose to achieve desired • Substrate for CYP450 2D6 and 1A2
therapeutic effect; maximum dose • Is the active metabolite of imipramine,
300 mg/day formed by demethylation via CYP450 1A2
• Half-life approximately 24 hours

Dosing Tips
• If given in a single dose, should generally
Drug Interactions
be administered at bedtime because of its • Tramadol increases the risk of seizures in
sedative properties patients taking TCAs
• If given in split doses, largest dose should • Use of TCAs with anticholinergic drugs
generally be given at bedtime because of may result in paralytic ileus or
its sedative properties hyperthermia
• If patients experience nightmares, split • Fluoxetine, paroxetine, bupropion,
dose and do not give large dose at bedtime duloxetine, and other CYP450 2D6
• Patients treated for chronic pain may only inhibitors may increase TCA concentrations
require lower doses (e.g., 50–75 mg/day) • Cimetidine may increase plasma
• Risk of seizure increases with dose concentrations of TCAs and cause
✽ Monitoring plasma levels of desipramine anticholinergic symptoms
• Phenothiazines or haloperidol may raise
is recommended in patients who do not
respond to the usual dose or whose TCA blood concentrations
treatment is regarded as urgent • May alter effects of antihypertensive drugs;
may inhibit hypotensive effects of clonidine

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DESIPRAMINE (continued)

• Use of TCAs with sympathomimetic agents pimozide, thioridazine, selected

may increase sympathetic activity antiarrhythmics, moxifloxacin,
• Methylphenidate may inhibit metabolism of sparfloxacin)
TCAs • If there is a history of QTc prolongation or
• Activation and agitation, especially cardiac arrhythmia, recent acute
following switching or adding myocardial infarction, uncompensated
antidepressants, may represent the heart failure
induction of a bipolar state, especially a • If patient is taking drugs that inhibit TCA
mixed dysphoric bipolar II condition metabolism, including CYP450 2D6
sometimes associated with suicidal inhibitors, except by an expert
ideation, and require the addition of • If there is reduced CYP450 2D6 function,
lithium, a mood stabilizer or an atypical such as patients who are poor 2D6
antipsychotic, and/or discontinuation of metabolizers, except by an expert and at
desipramine low doses
• If there is a proven allergy to desipramine,
imipramine, or lofepramine
Other Warnings/
Precautions
• Add or initiate other antidepressants with
caution for up to 2 weeks after
SPECIAL POPULATIONS
discontinuing desipramine Renal Impairment
• Generally, do not use with MAO inhibitors,
• Use with caution; may need to lower dose
including 14 days after MAOIs are stopped;
• May need to monitor plasma levels
do not start an MAOI until 2 weeks after
discontinuing desipramine, but see Pearls Hepatic Impairment
• Use with caution in patients with history of • Use with caution; may need to lower dose
seizures, urinary retention, narrow angle- • May need to monitor plasma levels
closure glaucoma, hyperthyroidism
• TCAs can increase QTc interval, especially Cardiac Impairment
at toxic doses, which can be attained not • TCAs have been reported to cause
only by overdose but also by combining arrhythmias, prolongation of conduction
with drugs that inhibit TCA metabolism via time, orthostatic hypotension, sinus
CYP450 2D6, potentially causing torsade tachycardia, and heart failure, especially in
de pointes-type arrhythmia or sudden the diseased heart
death • Myocardial infarction and stroke have been
• Because TCAs can prolong QTc interval, reported with TCAs
use with caution in patients who have • TCAs produce QTc prolongation, which
bradycardia or who are taking drugs that may be enhanced by the existence of
can induce bradycardia (e.g., beta blockers, bradycardia, hypokalemia, congenital or
calcium channel blockers, clonidine, acquired long QTc interval, which should
digitalis) be evaluated prior to administering
• Because TCAs can prolong QTc interval, desipramine
use with caution in patients who have • Use with caution if treating concomitantly
hypokalemia and/or hypomagnesemia or with a medication likely to produce
who are taking drugs that can induce prolonged bradycardia, hypokalemia,
hypokalemia and/or magnesemia (e.g., slowing of intracardiac conduction, or
diuretics, stimulant laxatives, intravenous prolongation of the QTc interval
amphotericin B, glucocorticoids, • Avoid TCAs in patients with a known
tetracosactide) history of QTc prolongation, recent acute
myocardial infarction, and uncompensated
Do Not Use heart failure
• If patient is recovering from myocardial • TCAs may cause a sustained increase in
infarction heart rate in patients with ischemic heart
• If patient is taking agents capable of disease and may worsen (decrease) heart
significantly prolonging QTc interval (e.g.,

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(continued) DESIPRAMINE

rate variability, an independent risk of • Must weigh the risk of treatment (first
mortality in cardiac populations trimester fetal development, third trimester
• Since SSRIs may improve (increase) heart newborn delivery) to the child against the
rate variability in patients following a risk of no treatment (recurrence of
myocardial infarct and may improve depression, maternal health, infant
survival as well as mood in patients with bonding) to the mother and child
acute angina or following a myocardial • For many patients this may mean
infarction, these are more appropriate continuing treatment during pregnancy
agents for cardiac population than
tricyclic/tetracyclic antidepressants Breast Feeding
✽ Risk/benefit ratio may not justify use of • Some drug is found in mother’s breast milk
TCAs in cardiac impairment ✽ Recommended either to discontinue drug
or bottle feed
Elderly • Immediate postpartum period is a high-risk
• May be more sensitive to anticholinergic, time for depression, especially in women
cardiovascular, hypotensive, and sedative who have had prior depressive episodes,
effects so drug may need to be reinstituted late in
• Initial dose 25–50 mg/day, raise to the third trimester or shortly after
100 mg/day; maximum 150 mg/day childbirth to prevent a recurrence during
• May be useful to monitor plasma levels in the postpartum period
elderly patients • Must weigh benefits of breast feeding with
risks and benefits of antidepressant
treatment versus non-treatment to both the
Children and Adolescents infant and the mother
• Use with caution, observing for activation • For many patients this may mean
of known or unknown bipolar disorder continuing treatment during breast feeding
and/or suicidal ideation, and strongly
consider informing parents or guardian of
this risk so they can help observe child or THE ART OF PSYCHOPHARMACOLOGY
adolescent patients
• Not recommended for use under age 12 Potential Advantages
• Several studies show lack of efficacy of • Patients with insomnia
TCAs for depression • Severe or treatment-resistant depression
• May be used to treat enuresis or • Patients for whom therapeutic drug
hyperactive/impulsive behaviors monitoring is desirable
• May reduce tic symptoms
• Some cases of sudden death have Potential Disadvantages
occurred in children taking TCAs • Pediatric and geriatric patients
• Adolescents: initial dose 25–50 mg/day, • Patients concerned with weight gain
increase to 100 mg/day; maximum dose • Cardiac patients
150 mg/day
• May be useful to monitor plasma levels in
Primary Target Symptoms
children and adolescents • Depressed mood
• Chronic pain

Pregnancy
• Risk Category C [some animal studies
Pearls
show adverse effects, no controlled studies • Tricyclic antidepressants are often a first-
in humans] line treatment option for chronic pain
• Crosses the placenta • Tricyclic antidepressants are no longer
• Adverse effects have been reported in generally considered a first-line option for
infants whose mothers took a TCA depression because of their side effect
(lethargy, withdrawal symptoms, fetal profile
malformations)

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DESIPRAMINE (continued)

• Tricyclic antidepressants continue to be • Patients on TCAs should be aware that they

useful for severe or treatment-resistant may experience symptoms such as
depression photosensitivity or blue-green urine
• Noradrenergic reuptake inhibitors such as • SSRIs may be more effective than TCAs in
desipramine can be used as a second-line women, and TCAs may be more effective
treatment for smoking cessation, cocaine than SSRIs in men
dependence, and attention deficit disorder • Not recommended for first-line use in
• TCAs may aggravate psychotic symptoms children with ADHD because of the
• Alcohol should be avoided because of availability of safer treatments with better
additive CNS effects documented efficacy and because of
• Underweight patients may be more desipramine’s potential for sudden death in
susceptible to adverse cardiovascular children
effects ✽ Desipramine is one of the few TCAs
• Children, patients with inadequate where monitoring of plasma drug levels
hydration, and patients with cardiac has been well studied
disease may be more susceptible to TCA- ✽ Fewer anticholinergic side effects than
induced cardiotoxicity than healthy adults some other TCAs
• For the expert only: although generally • Since tricyclic/tetracyclic antidepressants
prohibited, a heroic but potentially are substrates for CYP450 2D6, and 7% of
dangerous treatment for severely the population (especially Caucasians) may
treatment-resistant patients is to give a have a genetic variant leading to reduced
tricyclic/tetracyclic antidepressant other activity of 2D6, such patients may not
than clomipramine simultaneously with an safely tolerate normal doses of
MAO inhibitor for patients who fail to tricyclic/tetracyclic antidepressants and
respond to numerous other may require dose reduction
antidepressants • Phenotypic testing may be necessary to
• If this option is elected, start the MAOI with detect this genetic variant prior to dosing
the tricyclic/tetracyclic antidepressant with a tricyclic/tetracyclic antidepressant,
simultaneously at low doses after especially in vulnerable populations such
appropriate drug washout, then alternately as children, elderly, cardiac populations,
increase doses of these agents every few and those on concomitant medications
days to a week as tolerated • Patients who seem to have extraordinarily
• Although very strict dietary and severe side effects at normal or low doses
concomitant drug restrictions must be may have this phenotypic CYP450 2D6
observed to prevent hypertensive crises variant and require low doses or switching
and serotonin syndrome, the most to another antidepressant not metabolized
common side effects of MAOI/ tricyclic or by 2D6
tetracyclic combinations may be weight
gain and orthostatic hypotension

Suggested Reading
Anderson IM. Meta-analytical studies on new Janowsky DS, Byerley B. Desipramine: an
antidepressants. Br Med Bull 2001; overview. J Clin Psychiatry 1984;45:3–9.
57:161–178.
Levin FR, Lehman AF. Meta-analysis of
Anderson IM. Selective serotonin reuptake desipramine as an adjunct in the treatment of
inhibitors versus tricyclic antidepressants: a cocaine addiction. J Clin Psychopharmacol
meta-analysis of efficacy and tolerability. J Aff 1991;11:374–8.
Disorders 2000;58:19–36.

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DIAZEPAM
THERAPEUTICS How Long Until It Works
• Some immediate relief with first dosing is
Brands • Valium
common; can take several weeks with daily
• Diastat
dosing for maximal therapeutic benefit
see index for additional brand names
If It Works
Generic? Yes (not Diastat)
• For short-term symptoms of anxiety or
muscle spasms – after a few weeks,
discontinue use or use on an “as-needed”
Class basis
• Benzodiazepine (anxiolytic, muscle • Chronic muscle spasms may require
relaxant, anticonvulsant) chronic diazepam treatment
• For chronic anxiety disorders, the goal of
Commonly Prescribed For treatment is complete remission of
(bold for FDA approved) symptoms as well as prevention of future
• Anxiety disorder relapses
• Symptoms of anxiety (short-term) • For chronic anxiety disorders, treatment
• Acute agitation, tremor, impending or most often reduces or even eliminates
acute delirium tremens and hallucinosis symptoms, but not a cure since symptoms
in acute alcohol withdrawal can recur after medicine stopped
• Skeletal muscle spasm due to reflex • For long-term symptoms of anxiety,
spasm to local pathology consider switching to an SSRI or SNRI for
• Spasticity caused by upper motor neuron long term maintenance
disorder • If long-term maintenance with a
• Athetosis benzodiazepine is necessary, continue
• Stiffman syndrome treatment for 6 months after symptoms
• Convulsive disorder (adjunctive) resolve, and then taper dose slowly
• Anxiety during endoscopic procedures • If symptoms reemerge, consider treatment
(adjunctive) (injection only) with an SSRI or SNRI, or consider
• Pre-operative anxiety (injection only) restarting the benzodiazepine; sometimes
• Anxiety relief prior to cardioversion benzodiazepines have to be used in
(intravenous) combination with SSRIs or SNRIs for best
• Initial treatment of status epilepticus results
(injection only)
• Insomnia If It Doesn’t Work
• Consider switching to another agent or
adding an appropriate augmenting agent
How The Drug Works • Consider psychotherapy, especially
• Binds to benzodiazepine receptors at the cognitive behavioral psychotherapy
GABA-A ligand-gated chloride channel • Consider presence of concomitant
complex substance abuse
• Enhances the inhibitory effects of GABA • Consider presence of diazepam abuse
• Boosts chloride conductance through • Consider another diagnosis, such as a
GABA-regulated channels comorbid medical condition
• Inhibits neuronal activity presumably in
amygdala-centered fear circuits to provide Best Augmenting Combos
therapeutic benefits in anxiety disorders for Partial Response or
• Inhibiting actions in cerebral cortex may Treatment-Resistance
provide therapeutic benefits in seizure • Benzodiazepines are frequently used as
disorders augmenting agents for antipsychotics and
• Inhibitory actions in spinal cord may mood stabilizers in the treatment of
provide therapeutic benefits for muscle psychotic and bipolar disorders
spasms • Benzodiazepines are frequently used as
augmenting agents for SSRIs and SNRIs in
the treatment of anxiety disorders

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DIAZEPAM (continued)

• Not generally rational to combine with Sedation

other benzodiazepines
• Caution if using as an anxiolytic
concomitantly with other sedative
• Many experience and/or can be significant
hypnotics for sleep
in amount
Tests • Especially at initiation of treatment or when
• In patients with seizure disorders, dose increases
concomitant medical illness, and/or those • Tolerance often develops over time
with multiple concomitant long-term
What To Do About Side Effects
medications, periodic liver tests and blood
• Wait
counts may be prudent
• Wait
• Wait
• Lower the dose
SIDE EFFECTS • Take largest dose at bedtime to avoid
sedative effects during the day
How Drug Causes Side Effects • Switch to another agent
• Same mechanism for side effects as for • Administer flumazenil if side effects are
therapeutic effects – namely due to severe or life-threatening
excessive actions at benzodiazepine
receptors Best Augmenting Agents for Side
• Long-term adaptations in benzodiazepine Effects
receptors may explain the development of • Many side effects cannot be improved with
dependence, tolerance, and withdrawal an augmenting agent
• Side effects are generally immediate, but
immediate side effects often disappear in
time
DOSING AND USE
Notable Side Effects
Usual Dosage Range
✽ Sedation, fatigue, depression
✽ Dizziness, ataxia, slurred speech, • Oral: 4–40 mg/day in divided doses
• Intravenous (adults): 5 mg/minute
weakness
✽ Forgetfulness, confusion • Intravenous (children): 0.25 mg/kg/3
✽ Hyper-excitability, nervousness minutes
✽ Pain at injection site Dosage Forms
• Rare hallucinations, mania
• Tablet 2 mg scored, 5 mg scored, 10 mg
• Rare hypotension
scored
• Hypersalivation, dry mouth
• Liquid 5 mg/5 mL, concentrate 5 mg/mL
• Injection vial 5 mg/mL; 10 mL, boxes of 1;
Life Threatening or 2 mL boxes of 10
Dangerous Side Effects • Rectal gel 5 mg/mL; 2.5 mg, 5 mg, 10 mg,
• Respiratory depression, especially when 15 mg, 20 mg
taken with CNS depressants in overdose
• Rare hepatic dysfunction, renal How to Dose
dysfunction, blood dyscrasias • Oral (anxiety, muscle spasm, seizure):
2–10 mg, 2–4 times/day
Weight Gain • Oral (alcohol withdrawal): Initial 10 mg,
3–4 times/day for 1 day; reduce to 5 mg,
3–4 times/day; continue treatment as
needed
• Reported but not expected • Liquid formulation should be mixed with
water or fruit juice, applesauce, or pudding
• Because of risk of respiratory depression,
rectal diazepam treatment should not be

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(continued) DIAZEPAM

given more than once in 5 days or more Habit Forming

than twice during a treatment course, • Diazepam is a Schedule IV drug
especially for alcohol withdrawal or status • Patients may develop dependence and/or
epilepticus tolerance with long-term use

How to Stop
Dosing Tips • Patients with history of seizure may seize
✽ Only benzodiazepine with a formulation upon withdrawal, especially if withdrawal is
abrupt
specifically for rectal administration
✽ One of the few benzodiazepines available • Taper by 2 mg every 3 days to reduce
chances of withdrawal effects
in an oral liquid formulation
✽ One of the few benzodiazepines available • For difficult to taper cases, consider
reducing dose much more slowly after
in an injectable formulation
• Diazepam injection is intended for acute reaching 20 mg/day, perhaps by as little as
use; patients who require long-term 0.5–1 mg every week or less
treatment should be switched to the oral • For other patients with severe problems
formulation discontinuing a benzodiazepine, dosing
• Use lowest possible effective dose for the may need to be tapered over many months
shortest possible period of time (a (i.e., reduce dose by 1% every 3 days by
benzodiazepine-sparing strategy) crushing tablet and suspending or
• Assess need for continued treatment dissolving in 100 ml of fruit juice and then
regularly disposing of 1 ml while drinking the rest;
• Risk of dependence may increase with 3–7 days later, dispose of 2 ml, and so on).
dose and duration of treatment This is both a form of very slow biological
• For inter-dose symptoms of anxiety, can tapering and a form of behavioral
either increase dose or maintain same total desensitization
daily dose but divide into more frequent • Be sure to differentiate reemergence of
doses symptoms requiring reinstitution of
• Can also use an as-needed occasional “top treatment from withdrawal symptoms
up” dose for inter-dose anxiety • Benzodiazepine-dependent anxiety patients
• Because some anxiety disorder patients and insulin-dependent diabetics are not
and muscle spasm patients can require addicted to their medications. When
doses higher than 40 mg/day or more, the benzodiazepine-dependent patients stop
risk of dependence may be greater in these their medication, disease symptoms can
patients reemerge, disease symptoms can worsen
• Frequency of dosing in practice is often (rebound), and/or withdrawal symptoms
greater than predicted from half-life, as can emerge
duration of biological activity is often
Pharmacokinetics
shorter than pharmacokinetic terminal half-
• Elimination half-life 20–50 hours
life

Overdose
• Fatalities can occur; hypotension, Drug Interactions
tiredness, ataxia, confusion, coma • Increased depressive effects when taken
with other CNS depressants
Long-Term Use • Cimetidine may reduce the clearance and
• Evidence of efficacy up to 16 weeks raise the levels of diazepam
• Risk of dependence, particularly for • Flumazenil (used to reverse the effects of
treatment periods longer than 12 weeks benzodiazepines) may precipitate seizures
and especially in patients with past or and should not be used in patients treated
current polysubstance abuse for seizure disorders with diazepam
• Not recommended for long-term treatment
of seizure disorders

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DIAZEPAM (continued)

• Should generally receive lower doses and

Other Warnings/
be more closely monitored
Precautions
• Dosage changes should be made in
collaboration with prescriber
• Use with caution in patients with Pregnancy
pulmonary disease; rare reports of death • Risk Category D [positive evidence of risk
after initiation of benzodiazepines in to human fetus; potential benefits may still
patients with severe pulmonary impairment justify its use during pregnancy]
• History of drug or alcohol abuse often • Possible increased risk of birth defects
creates greater risk for dependency when benzodiazepines taken during
• Some depressed patients may experience a pregnancy
worsening of suicidal ideation • Because of the potential risks, diazepam is
• Some patients may exhibit abnormal not generally recommended as treatment
thinking or behavioral changes similar to for anxiety during pregnancy, especially
those caused by other CNS depressants during the first trimester
(i.e., either depressant actions or • Drug should be tapered if discontinued
disinhibiting actions) • Infants whose mothers received a
benzodiazepine late in pregnancy may
Do Not Use experience withdrawal effects
• If narrow angle-closure glaucoma • Neonatal flaccidity has been reported in
• If there is a proven allergy to diazepam or infants whose mothers took a
any benzodiazepine benzodiazepine during pregnancy
• Seizures, even mild seizures, may cause
harm to the embryo/fetus
SPECIAL POPULATIONS Breast Feeding
Renal Impairment • Unknown if diazepam is secreted in human
• Initial 2–2.5 mg, 1–2 times/day; increase breast milk, but all psychotropics assumed
gradually as needed to be secreted in breast milk
✽ Recommended either to discontinue drug
Hepatic Impairment or bottle feed
• Initial 2–2.5 mg, 1–2 times/day; increase • Effects of benzodiazepines on nursing
gradually as needed infants have been reported and include
feeding difficulties, sedation, and weight
Cardiac Impairment loss
• Benzodiazepines have been used to treat
anxiety associated with acute myocardial
infarction THE ART OF PSYCHOPHARMACOLOGY
• Diazepam may be used as an adjunct
during cardiovascular emergencies Potential Advantages
• Rapid onset of action
Elderly • Availability of oral liquid, rectal, and
• Initial 2–2.5 mg, 1–2 times/day; increase injectable dosage formulations
gradually as needed
Potential Disadvantages
• Euphoria may lead to abuse
Children and Adolescents • Abuse especially risky in past or present
substance abusers
• 6 months and up: Initial 1–2.5 mg,
• Can be sedating at doses necessary to treat
3–4 times/day; increase gradually as
moderately severe anxiety disorders
needed
• Parenteral: 30 days or older Primary Target Symptoms
• Rectal: 2 years or older
• Panic attacks
• Long-term effects of diazepam in
• Anxiety
children/adolescents are unknown

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(continued) DIAZEPAM

• Incidence of seizures (adjunct) • May both cause depression and treat

• Muscle spasms depression in different patients
• Was once one of the most commonly
prescribed drugs in the world and the most
Pearls commonly prescribed benzodiazepine
• Can be a useful adjunct to SSRIs and ✽ Remains a popular benzodiazepine for
SNRIs in the treatment of numerous treating muscle spasms
anxiety disorders, but not used as • A commonly used benzodiazepine to treat
frequently as other benzodiazepines for this sleep disorders
purpose ✽ Remains a popular benzodiazepine to
• Not effective for treating psychosis as a treat acute alcohol withdrawal
monotherapy, but can be used as an • Not especially useful as an oral
adjunct to antipsychotics anticonvulsant
• Not effective for treating bipolar disorder ✽ Multiple dosage formulations (oral tablet,
as a monotherapy, but can be used as an oral liquid, rectal gel, injectable) allow
adjunct to mood stabilizers and more flexibility of administration compared
antipsychotics to most other benzodiazepines
✽ Diazepam is often the first choice • When using to treat insomnia, remember
that insomnia may be a symptom of some
benzodiazepine to treat status epilepticus,
and is administered either intravenously or other primary disorder itself, and thus
rectally warrant evaluation for comorbid psychiatric
• Because diazepam suppresses stage 4 and/or medical conditions
sleep, it may prevent night terrors in adults

Suggested Reading
Ashton H. Guidelines for the rational use of Mandelli M, Tognoni G, Garattini S. Clinical
benzodiazepines. When and what to use. pharmacokinetics of diazepam. Clin
Drugs 1994;48:25–40. Pharmacokinet 1978;3:72–91.
De Negri M, Baglietto MG. Treatment of status Rey E. Treluver JM, Pons G. Pharmacokinetic
epilepticus in children. Paediatr Drugs 2001; optimization of benzodiazepine therapy for
3:411–20. acute seizures. Focus on delivery routes. Clin
Pharmacokinet 1999;36:409–24.

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0521011698s03.qxd 9/2/04 2:31 PM Page 115

D,L-AMPHETAMINE
THERAPEUTICS then continue treatment indefinitely as long
as improvement persists
Brands • Adderall • Reevaluate the need for treatment
• Adderall XR periodically
see index for additional brand names • Treatment for ADHD begun in childhood
may need to be continued into adolescence
Generic? No
and adulthood if continued benefit is
documented
Class
• Stimulant If It Doesn’t Work (for ADHD)
• Consider adjusting dose or switching to
Commonly Prescribed For another formulation of d,l-amphetamine or
(bold for FDA approved) to another agent
• Attention deficit hyperactivity disorder in • Consider behavioral therapy
children • Consider the presence of noncompliance
• Attention deficit hyperactivity disorder in and counsel patient and parents
adults (Adderall XR) • Consider evaluation for another diagnosis
• Narcolepsy (Adderall) or for a comorbid condition (e.g., bipolar
• Treatment-resistant depression disorder, substance abuse, medical illness,
etc.)
✽ Some ADHD patients and some
How The Drug Works depressed patients may experience lack of
✽ Increases norepinephrine and especially consistent efficacy due to activation of
dopamine actions by blocking their latent or underlying bipolar disorder, and
reuptake and facilitating their release require either augmenting with a mood
• Enhancement of dopamine and stabilizer or switching to a mood stabilizer
norepinephrine actions in certain brain
regions (e.g., dorsolateral prefrontal Best Augmenting Combos
cortex) may improve attention, for Partial Response or
concentration, executive function, and Treatment-Resistance
wakefulness • Best to attempt other monotherapies prior
• Enhancement of dopamine actions in other to augmenting
brain regions (e.g., basal ganglia) may • For the expert, can combine immediate
improve hyperactivity release formulation with a sustained
• Enhancement of dopamine and release formulation of d,l-amphetamine for
norepinephrine in yet other brain regions ADHD
(e.g., medial prefrontal cortex, • For the expert, can combine with modafinil
hypothalamus) may improve depression, or atomoxetine for ADHD
fatigue, and sleepiness • For the expert, can occasionally combine
with atypical antipsychotics in highly
How Long Until It Works treatment-resistant cases of bipolar
• Some immediate effects can be seen with disorder or ADHD
first dosing • For the expert, can combine with
• Can take several weeks to attain maximum antidepressants to boost antidepressant
therapeutic benefit efficacy in highly treatment-resistant cases
of depression while carefully monitoring
If It Works (for ADHD) patient
• The goal of treatment of ADHD is reduction
of symptoms of inattentiveness, motor Tests
hyperactivity, and/or impulsiveness that • Blood pressure should be monitored
disrupt social, school, and/or occupational regularly
functioning • In children, monitor weight and height
• Continue treatment until all symptoms are
under control or improvement is stable and

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D,L-AMPHETAMINE (continued)

SIDE EFFECTS Best Augmenting Agents for Side

How Drug Causes Side Effects Effects
• Beta-blockers for peripheral autonomic
• Increases in norepinephrine peripherally
side effects
can cause autonomic side effects, including
• Dose reduction or switching to another
tremor, tachycardia, hypertension, and
agent may be more effective since most
cardiac arrhythmias
side effects cannot be improved with an
• Increases in norepinephrine and dopamine
augmenting agent
centrally can cause CNS side effects such
as insomnia, agitation, psychosis and
substance abuse
DOSING AND USE
Notable Side Effects
✽ Insomnia, headache, exacerbation of tics, Usual Dosage Range
nervousness, irritability, overstimulation, • Narcolepsy: 5–60 mg/day in divided doses
tremor, dizziness • ADHD: 5–40 mg/day (divided doses for
• Anorexia, nausea, dry mouth, constipation, immediate release tablet, once-daily
diarrhea, weight loss morning dose for extended release tablet)
• Can temporarily slow normal growth in
children (controversial) Dosage Forms
• Sexual dysfunction long-term (impotence, • Immediate release tablet 5 mg double-
libido changes) but can also improve scored, 7.5 mg double-scored, 10 mg
sexual dysfunction short-term double-scored, 12.5 mg double-scored,
15 mg double-scored, 20 mg double-
scored, 30 mg double-scored
Life Threatening or • Extended release tablet 5 mg, 10 mg,
Dangerous Side Effects 15 mg, 20 mg, 25 mg, 30 mg
• Psychotic episodes, especially with
parenteral abuse How to Dose
• Seizures • Immediate release formulation in ADHD
• Palpitations, tachycardia, hypertension (ages 6 and older): initial 5 mg once or
• Rare activation of hypomania, mania, or twice per day; can increase by 5 mg each
suicidal ideation (controversial) week; maximum dose generally 40 mg/day;
split daily dose with first dose on waking
Weight Gain and every 4–6 hours thereafter
• Immediate release formulation in
narcolepsy (ages 12 and older): initial
10 mg/day; increase by 10 mg each week;
• Reported but not expected
give first dose on waking and every
• Some patients may experience weight loss
4–6 hours thereafter
Sedation • Extended release formulation in ADHD:
initial 10 mg/day in the morning; can
increase by 5–10 mg/day at weekly
intervals; maximum dose generally
• Reported but not expected 30 mg/day
• Activation much more common than
sedation

What To Do About Side Effects Dosing Tips

• Wait • Clinical duration of action often differs
• Adjust dose from pharmacokinetic half-life
• Switch to a long-acting stimulant ✽ Immediate release d,l-amphetamine has
• Switch to another agent 3–6 hour duration of clinical action
• For insomnia, avoid dosing in ✽ Extended release d,l-amphetamine has up
afternoon/evening to 8-hour duration of clinical action

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(continued) D,L-AMPHETAMINE

• Adderall XR is controlled-release and Habit Forming

should therefore not be chewed but rather • High abuse potential, Schedule II drug
should only be swallowed whole • Patients may develop tolerance,
✽ Controlled release delivery of psychological dependence
d,l-amphetamine is sufficiently long in
duration to allow elimination of lunchtime How to Stop
dosing • Taper to avoid withdrawal effects
✽ This innovation can be an important • Withdrawal following chronic therapeutic
practical element in stimulant utilization, use may unmask symptoms of the
eliminating the hassle and pragmatic underlying disorder and may require
difficulties of lunchtime dosing at school, follow-up and reinstitution of treatment
including storage problems, potential • Careful supervision is required during
diversion, and the need for a medical withdrawal from abusive use since severe
professional to supervise dosing away depression may occur
from home
• Avoid dosing late in the day because of the Pharmacokinetics
risk of insomnia • Adderall and Adderall XR are a mixture of
• May be possible to dose only during the d-amphetamine and l-amphetamine salts in
school week for some ADHD patients the ratio of 3:1
• Off-label uses are dosed the same as for • A single dose of Adderall XR 20 mg gives
ADHD drug levels of both d-amphetamine and
✽ May be able to give drug holidays over l-amphetamine comparable to Adderall
the summer in order to reassess immediate release 20 mg administered in
therapeutic utility and effects on growth 2 divided doses 4 hours apart
and to allow catch-up from any growth • In adults, half-life for d-amphetamine is 10
suppression as well as to assess any other hours and for l-amphetamine is 13 hours
side effects and the need to reinstitute • For children ages 6–12, half-life for
stimulant treatment for the next school d-amphetamine is 9 hours and for
term l-amphetamine is 11 hours
• Side effects are generally dose-related
• Taking with food may delay peak actions
for 2–3 hours Drug Interactions
• May affect blood pressure and should be
Overdose used cautiously with agents used to control
• Rarely fatal; panic, hyperreflexia, blood pressure
rhabdomyolysis, rapid respiration, • Gastrointestinal acidifying agents
confusion, coma, hallucinations, (guanethidine, reserpine, glutamic acid,
convulsions, arrhythmia, change in blood ascorbic acid, fruit juices, etc.) and urinary
pressure, circulatory collapse acidifying agents (ammonium chloride,
sodium phosphate, etc.) lower
Long-Term Use amphetamine plasma levels, so such
• Often used long-term for ADHD when agents can be useful to administer after an
ongoing monitoring documents continued overdose but may also lower therapeutic
efficacy efficacy of amphetamines
• Dependence and/or abuse may develop • Gastrointestinal alkalinizing agents (sodium
• Tolerance to therapeutic effects may bicarbonate, etc.) and urinary alkalinizing
develop in some patients agents (acetazolamide, some thiazides)
• Long-term stimulant use may be increase amphetamine plasma levels and
associated with growth suppression in potentiate amphetamine’s actions
children (controversial) • Desipramine and protryptiline can cause
• Periodic monitoring of weight, blood striking and sustained increases in brain
pressure, CBC, platelet counts, and liver concentrations of amphetamine and may
function may be prudent also add to amphetamine’s cardiovascular
effects

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D,L-AMPHETAMINE (continued)

• Theoretically, other agents with

Other Warnings/
norepinephrine reuptake blocking
properties, such as venlafaxine, duloxetine,
Precautions
atomoxetine, milnacipran, and reboxetine, • Use with caution in patients with any
could also add to amphetamine’s CNS and degree of hypertension, hyperthyroidism,
cardiovascular effects or history of drug abuse
• Amphetamines may counteract the sedative • Children who are not growing or gaining
effects of antihistamines weight should stop treatment, at least
• Haloperidol, chlorpromazine, and lithium temporarily
may inhibit stimulatory effects of • May worsen motor and phonic tics
amphetamines • May worsen symptoms of thought disorder
• Theoretically, atypical antipsychotics and behavioral disturbance in psychotic
should also inhibit stimulatory effects of patients
amphetamines • Stimulants have a high potential for abuse
• Theoretically, amphetamines could inhibit and must be used with caution in anyone
the antipsychotic actions of antipsychotics with a current or past history of substance
• Theoretically, amphetamines could inhibit abuse or alcoholism or in emotionally
the mood stabilizing actions of atypical unstable patients
antipsychotics in some patients • Administration of stimulants for prolonged
• Combinations of amphetamines with mood periods of time should be avoided
stabilizers (lithium, anticonvulsants, whenever possible or done only with close
atypical antipsychotics) is generally monitoring, as it may lead to marked
something for experts only, when tolerance and drug dependence, including
monitoring patients closely and when other psychological dependence with varying
options fail degrees of abnormal behavior
• Absorption of amphetamine is delayed by • Particular attention should be paid to the
phenobarbital, phenytoin, ethosuximide possibility of subjects obtaining stimulants
• Amphetamines inhibit adrenergic blockers for nontherapeutic use or distribution to
and enhance adrenergic effects of others and the drugs should in general be
norepinephrine prescribed sparingly with documentation of
• Amphetamines may antagonize appropriate use
hypotensive effects of veratrum alkaloids • Not an appropriate first-line treatment for
and other antihypertensives depression or for normal fatigue
• Amphetamines increase the analgesic • May lower the seizure threshold
effects of meperidine • Emergence or worsening of activation and
• Amphetamines contribute to excessive CNS agitation may represent the induction of a
stimulation if used with large doses of bipolar state, especially a mixed dysphoric
propoxyphene bipolar II condition sometimes associated
• Amphetamines can raise plasma with suicidal ideation, and require the
corticosteroid levels addition of a mood stabilizer and/or
• MAOIs slow absorption of amphetamines discontinuation of d,l-amphetamine
and thus potentiate their actions, which can Do Not Use
cause headache, hypertension, and rarely
• If patient has extreme anxiety or agitation
hypertensive crisis and malignant
• If patient has motor tics or Tourette’s
hyperthermia, sometimes with fatal results
sydrome or if there is a family history of
• Use with MAOIs, including within 14 days
Tourette’s, unless administered by an
of MAOI use, is not advised, but this can
expert in cases when the potential benefits
sometimes be considered by experts who
for ADHD outweigh the risks of worsening
monitor depressed patients closely when
tics
other treatment options for depression fail
• Should generally not be administered with
an MAOI, including within 14 days of MAOI
use, except in heroic circumstances and by
an expert

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(continued) D,L-AMPHETAMINE

• If patient has arteriosclerosis, • Use in women of childbearing potential

cardiovascular disease, or severe requires weighing potential benefits to the
hypertension mother against potential risks to the fetus
• If patient has glaucoma ✽ For ADHD patients, d,l-amphetamine
• If there is a proven allergy to any should generally be discontinued before
sympathomimetic agent anticipated pregnancies

Breast Feeding
SPECIAL POPULATIONS • Some drug is found in mother’s breast milk
✽ Recommended either to discontinue drug
Renal Impairment or bottle feed
• No dose adjustment necessary • If infant shows signs of irritability, drug
may need to be discontinued
Hepatic Impairment
• No dose adjustment necessary
THE ART OF PSYCHOPHARMACOLOGY
Cardiac Impairment
• Use with caution, particularly in patients Potential Advantages
with recent myocardial infarction or other • May work in ADHD patients unresponsive
conditions that could be negatively affected to other stimulants, including pure
by increased blood pressure d-amphetamine sulfate
• New sustained release option
Elderly
• Some patients may tolerate lower doses Potential Disadvantages
better • Patients with current or past substance
abuse
• Patients with current or past bipolar
Children and Adolescents disorder or psychosis
• Safety and efficacy not established under
age 3 Primary Target Symptoms
• Use in young children should be reserved • Concentration, attention span
for the expert • Motor hyperactivity
• d,l-amphetamine may worsen symptoms of • Impulsiveness
behavioral disturbance and thought • Physical and mental fatigue
disorder in psychotic children • Daytime sleepiness
• d,l-amphetamine has acute effects on • Depression
growth hormone; long-term effects are
unknown but weight and height should be
monitored during long-term treatment Pearls
• ADHD: ages 3–5: initial 2.5 mg/day; can ✽ May be useful for treatment of depressive
increase by 2.5 mg each week symptoms in medically ill elderly patients
• Narcolepsy: ages 6–12: initial 5 mg/day; ✽ May be useful for treatment of post-
increase by 5 mg each week stroke depression
✽ A classical augmentation strategy for
treatment-refractory depression
Pregnancy ✽ Specifically, may be useful for treatment
• Risk Category C [some animal studies of cognitive dysfunction and fatigue as
show adverse effects, no controlled studies residual symptoms of major depressive
in humans] disorder unresponsive to multiple prior
• Infants whose mothers take treatments
d,l-amphetamine during pregnancy may ✽ May also be useful for the treatment of
experience withdrawal symptoms cognitive impairment, depressive
symptoms, and severe fatigue in patients
with HIV infection and in cancer patients

119
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D,L-AMPHETAMINE (continued)

• Can be used to potentiate opioid analgesia ✽ Specifically, Adderall and Adderall XR

and reduce sedation, particularly in end-of- combine 1 part dextro-amphetamine
life management saccharate, 1 part dextro-amphetamine
✽ Despite warnings, can be a useful adjunct sulfate, 1 part d,l-amphetamine aspartate,
to MAOIs for heroic treatment of highly and 1 part d,l-amphetamine sulfate
refractory mood disorders when monitored ✽ This mixture of salts may have a different
with vigilance pharmacologic profile, including
✽ Can reverse sexual dysfunction caused by mechanism of therapeutic action and
psychiatric illness and by some drugs such duration of action, compared to pure
as SSRIs, including decreased libido, dextro-amphetamine, which is given as the
erectile dysfunction, delayed ejaculation, sulfate salt
and anorgasmia ✽ Specifically, d-amphetamine may have
• Atypical antipsychotics may be useful in more profound action on dopamine than
treating stimulant or psychotic norepinephrine whereas l-amphetamine
consequences of overdose may have a more balanced action on both
• Taking with food may delay peak actions dopamine and norepinephrine
for 2–3 hours ✽ Theoretically, this could lead to relatively
• Half-life and duration of clinical action tend more noradrenergic actions of the Adderall
to be shorter in younger children mixture of amphetamine salts than that of
• Drug abuse may actually be lower in ADHD pure dextro-amphetamine sulfate, but this
adolescents treated with stimulants than in is unproven and of no clear clinical
ADHD adolescents who are not treated significance
• Unknown how d,l-amphetamine’s • Nevertheless, some patients may respond
mechanism of action differs from that of to or tolerate Adderall/Adderall XR
d,l-methylphenidate, but some patients differently than they do pure dextro-
respond to or tolerate d,l-amphetamine amphetamine sulfate
better than d,l-methylphenidate and vice • Adderall XR capsules also contain 2 types
versa of drug-containing beads designed to give
✽ Adderall and Adderall XR are a mixture of a double-pulsed delivery of amphetamines
d-amphetamine and l-amphetamine salts in to prolong their release
the ratio of 3:1

Suggested Reading
Fry JM. Treatment modalities for narcolepsy. Jadad AR, Boyle M, Cunningham C, Kim M,
Neurology 1998;50(2 Suppl 1):S43–8. Schachar R. Treatment of attention-
deficit/hyperactivity disorder. Evid Rep Technol
Greenhill LL, Pliszka S, Dulcan MK, Bernet W, Assess (Summ) 1999;(11):i–viii,1–341.
Arnold V, Beitchman J, Benson RS, Bukstein
O, Kinlan J, McClellan J, Rue D, Shaw JA, Vinson DC. Therapy for attention-deficit
Stock S. Practice parameter for the use of hyperactivity disorder. Arch Fam Med
stimulant medications in the treatment of 1994;3:445–51.
children, adolescents, and adults. J Am Acad
Child Adolesc Psychiatry 2002;41(2 Wender PH, Wolf LE, Wasserstein J. Adults
Suppl):26S–49S. with ADHD. An overview. Ann N Y Acad Sci
2001;931:1–16.

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D,L-METHYLPHENIDATE
THERAPEUTICS • Continue treatment until all symptoms are
under control or improvement is stable and
Brands • Concerta then continue treatment indefinitely as long
• Metadate CD as improvement persists
• Ritalin • Reevaluate the need for treatment
• Ritalin LA periodically
see index for additional brand names • Treatment for ADHD begun in childhood
may need to be continued into adolescence
Generic? Yes (for immediate release
and adulthood if continued benefit is
methylphenidate)
documented

Class If It Doesn’t Work (for ADHD)

• Stimulant • Consider adjusting dose or switching to
another formulation of d,l-methylphenidate
Commonly Prescribed For or to another agent
(bold for FDA approved) • Consider behavioral therapy
• Attention deficit hyperactivity disorder • Consider the presence of noncompliance
(ADHD) and counsel patient and parents
• Narcolepsy (Metadate ER, Methylin ER, • Consider evaluation for another diagnosis
Ritalin, Ritalin SR) or for a comorbid condition (e.g., bipolar
• Treatment-resistant depression disorder, substance abuse, medical illness,
etc.)
✽ Some ADHD patients and some
How The Drug Works depressed patients may experience lack of
✽ Increases norepinephrine and especially consistent efficacy due to activation of
dopamine actions by blocking their latent or underlying bipolar disorder, and
reuptake and facilitating their release require either augmenting with a mood
• Enhancement of dopamine and stabilizer or switching to a mood stabilizer
norepinephrine actions in certain brain
regions (e.g., dorsolateral prefrontal Best Augmenting Combos
cortex) may improve attention, for Partial Response or
concentration, executive function, and Treatment-Resistance
wakefulness ✽ Best to attempt other monotherapies
• Enhancement of dopamine actions in other prior to augmenting
brain regions (e.g., basal ganglia) may • For the expert, can combine immediate
improve hyperactivity release formulation with a sustained
• Enhancement of dopamine and release formulation of d,l-methylphenidate
norepinephrine in yet other brain regions for ADHD
(e.g., medial prefrontal cortex, • For the expert, can combine with modafinil
hypothalamus) may improve depression, or atomoxetine for ADHD
fatigue, and sleepiness • For the expert, can occasionally combine
with atypical antipsychotics in highly
How Long Until It Works treatment-resistant cases of bipolar
• Some immediate effects can be seen with disorder or ADHD
first dosing • For the expert, can combine with
• Can take several weeks to attain maximum antidepressants to boost antidepressant
therapeutic benefit efficacy in highly treatment-resistant cases
of depression while carefully monitoring
If It Works (for ADHD) patient
• The goal of treatment of ADHD is reduction
of symptoms of inattentiveness, motor Tests
hyperactivity, and/or impulsiveness that • Blood pressure should be monitored
disrupt social, school, and/or occupational regularly
functioning • In children, monitor weight and height

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D,L-METHYLPHENIDATE (continued)

• Periodic complete blood cell and platelet • Switch to another formulation of

counts may be considered during prolonged d,l-methylphenidate
therapy (rare leukopenia and/or anemia) • Switch to another agent
• For insomnia, avoid dosing in
afternoon/evening
SIDE EFFECTS
Best Augmenting Agents for Side
How Drug Causes Side Effects Effects
• Increases in norepinephrine peripherally • Beta-blockers for peripheral autonomic
can cause autonomic side effects, including side effects
tremor, tachycardia, hypertension, and • Dose reduction or switching to another
cardiac arrhythmias agent may be more effective since most
• Increases in norepinephrine and dopamine side effects cannot be improved with an
centrally can cause CNS side effects such augmenting agent
as insomnia, agitation, psychosis, and
substance abuse
DOSING AND USE
Notable Side Effects
✽ Insomnia, headache, exacerbation of tics, Usual Dosage Range
nervousness, irritability, overstimulation, • ADHD: up to 2 mg/kg/day in children 6
tremor, dizziness years and older, with a maximum daily
• Anorexia, nausea, abdominal pain, weight dose of 60 mg/day; in adults usually
loss 20–30 mg/day, but may use up to
• Can temporarily slow normal growth in 40–60 mg/day
children (controversial) • Narcolepsy: 20–60 mg/day in 2–3 divided
• Blurred vision doses

Dosage Forms
Life Threatening or • Immediate release tablets 5 mg, 10 mg,
Dangerous Side Effects 20 mg (Ritalin, Methylin, generic
• Psychotic episodes, especially with methylphenidate)
parenteral abuse • Older sustained release tablets 10 mg,
• Seizures 20 mg (Metadate ER, Methylin ER); 20 mg
• Palpitations, tachycardia, hypertension (Ritalin SR)
• Rare neuroleptic malignant syndrome ✽ Newer sustained release capsules 20 mg,
• Rare activation of hypomania, mania, or 30 mg, 40 mg (Ritalin LA); 10 mg, 20 mg,
suicidal ideation (controversial) 30 mg (Metadate CD)
Weight Gain ✽ Newer sustained release tablets 18 mg,
27 mg, 36 mg, 54 mg (Concerta)

How to Dose
• Reported but not expected • Immediate release Ritalin, Methylin, and
• Some patients may experience weight loss generic methylphenidate (2–4 hour
duration of action)
Sedation • ADHD: initial 5 mg in morning, 5 mg at
lunch; can increase by 5–10 mg each
week; maximum dose generally
60 mg/day
• Reported but not expected
• Narcolepsy: give each dose 30–45
• Activation much more common than
minutes before meals; maximum dose
sedation
generally 60 mg/day
What To Do About Side Effects • Older extended release Ritalin SR, Methylin
• Wait SR, and Metadate ER
• Adjust dose • These formulations have a duration of
action of approximately 4–6 hours;

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(continued) D,L-METHYLPHENIDATE

therefore, these formulations may be ✽ All 3 newer sustained release

used in place of immediate release formulations have a sufficiently long
formulations when the 4–6 hour dosage duration of clinical action to eliminate the
of these sustained release formulations need for a lunchtime dosing if taken in the
corresponds to the titrated 4–6 hour morning
dosage of the immediate release ✽ This innovation can be an important
formulation practical element in stimulant utilization,
• Average dose is 20–30 mg/day, usually eliminating the hassle and pragmatic
in 2 divided doses difficulties of lunchtime dosing at school,
✽ Newer sustained release formulations for including storage problems, potential
ADHD diversion, and the need for a medical
• Concerta (up to 12 hours duration of professional to supervise dosing away
action): initial 18 mg/day in morning; from home
can increase by 18 mg each week; • Off-label uses are dosed the same as for
maximum dose generally 54 mg/day ADHD
• Ritalin LA and Metadate CD (up to 8 ✽ May be possible to dose only during the
hours duration of action): initial 20 mg school week for some ADHD patients
once daily; dosage may be adjusted in ✽ May be able to give drug holidays over
weekly 10 mg increments to a maximum the summer in order to reassess
of 60 mg/day taken in the morning therapeutic utility and effects on growth
and to allow catch-up from any growth
suppression as well as to assess any other
Dosing Tips side effects and the need to reinstitute
• Clinical duration of action often differs stimulant treatment for the next school
from pharmacokinetic half-life term
• Taking with food may delay peak actions • Avoid dosing late in the day because of the
for 2–3 hours risk of insomnia
✽ Immediate release formulations (Ritalin, • Concerta tablet does not change shape in
the GI tract and generally should not be
Methylin, generic methylphenidate) have
2–4 hour durations of clinical action used in patients with gastrointestinal
✽ Older sustained release formulations such narrowing because of the risk of intestinal
obstruction
as Methylin ER, Ritalin SR, Metadate ER,
and generic methylphenidate sustained • Side effects are generally dose-related
release all have approximately 4–6 hour
Overdose
durations of clinical action, which for most
• Vomiting, tremor, coma, convulsion,
patients is generally not long enough for
hyperreflexia, euphoria, confusion,
once daily dosing in the morning and thus
hallucination, tachycardia, flushing,
generally requires lunchtime dosing at
palpitations, sweating, hyperprexia,
school
hypertension, arrhythmia, mydriasis
✽ The newer sustained release Metadate CD
has an early peak and an 8-hour duration Long-Term Use
of action
• Often used long-term for ADHD when
✽ The newer sustained release Ritalin LA ongoing monitoring documents continued
also has an early peak and an 8-hour
efficacy
duration of action, with 2 pulses
• Dependence and/or abuse may develop
(immediate and after 4 hours)
• Tolerance to therapeutic effects may
✽ The newer sustained release Concerta develop in some patients
trilayer tablet has longest duration of action
• Long-term stimulant use may be
(12 hours)
associated with growth suppression in
• Sustained release formulations (especially
children (controversial)
Concerta, Metadate CD, and Ritalin LA)
• Periodic monitoring of weight, blood
should not be chewed but rather should
pressure, CBC, platelet counts, and liver
only be swallowed whole
function may be prudent

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D,L-METHYLPHENIDATE (continued)

Habit Forming • Theoretically, d,l-methylphenidate could

• High abuse potential, Schedule II drug inhibit the mood stabilizing actions of
• Patients may develop tolerance, atypical antipsychotics in some patients
psychological dependence • Combination of d,l-methylphenidate with
mood stabilizers (lithium, anticonvulsants,
How to Stop atypical antipsychotics) is generally
• Taper to avoid withdrawal effects something for experts only, when
• Withdrawal following chronic therapeutic monitoring patients closely and when other
use may unmask symptoms of the options fail
underlying disorder and may require
follow-up and reinstitution of treatment
• Careful supervision is required during Other Warnings/
withdrawal from abusive use since severe Precautions
depression may occur • Use with caution in patients with any
degree of hypertension, hyperthyroidism,
Pharmacokinetics or history of drug abuse
• Average half-life in adults is 3.5 hours • Children who are not growing or gaining
(1.3–7.7 hours) weight should stop treatment, at least
• Average half-life in children is 2.5 hours temporarily
(1.5–5 hours) • May worsen motor and phonic tics
• May worsen symptoms of thought disorder
and behavioral disturbance in psychotic
Drug Interactions patients
• Stimulants have a high potential for abuse
• May affect blood pressure and should be
and must be used with caution in anyone
used cautiously with agents used to control
with a current or past history of substance
blood pressure
abuse or alcoholism or in emotionally
• May inhibit metabolism of SSRIs,
unstable patients
anticonvulsants (phenobarbital, phenytoin,
• Administration of stimulants for prolonged
primidone), tricyclic antidepressants, and
periods of time should be avoided
coumarin anticoagulants, requiring
whenever possible or done only with close
downward dosage adjustments of these
monitoring, as it may lead to marked
drugs
tolerance and drug dependence, including
• Serious adverse effects may occur if
psychological dependence with varying
combined with clonidine (controversial)
degrees of abnormal behavior
• Use with MAOIs, including within 14 days
• Particular attention should be paid to the
of MAOI use, is not advised, but this can
possibility of subjects obtaining stimulants
sometimes be considered by experts who
for nontherapeutic use or distribution to
monitor depressed patients closely when
others and the drugs should in general be
other treatment options for depression fail
prescribed sparingly with documentation of
• CNS and cardiovascular actions of
appropriate use
d,l-methylphenidate could theoretically be
• Not an appropriate first-line treatment for
enhanced by combination with agents that
depression or for normal fatigue
block norepinephrine reuptake, such as the
• May lower the seizure threshold
tricyclic antidepressants desipramine or
• Emergence or worsening of activation and
protriptyline, venlafaxine, duloxetine,
agitation may represent the induction of a
atomoxetine, milnacipran, and reboxetine
bipolar state, especially a mixed dysphoric
• Theoretically, antipsychotics should inhibit
bipolar II condition sometimes associated
the stimulatory effects of
with suicidal ideation, and require the
d,l-methylphenidate
addition of a mood stabilizer and/or
• Theoretically, d,l-methylphenidate could
discontinuation of d,l-methylphenidate
inhibit the antipsychotic actions of
antipsychotics Do Not Use
• If patient has extreme anxiety or agitation

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(continued) D,L-METHYLPHENIDATE

• If patient has motor tics or Tourette’s • Use in women of childbearing potential

sydrome or if there is a family history of requires weighing potential benefits to the
Tourette’s, unless administered by an mother against potential risks to the fetus
expert in cases when the potential benefits ✽ For ADHD patients, methylphenidate
for ADHD outweigh the risks of worsening should generally be discontinued before
tics anticipated pregnancies
• If patient has glaucoma
• Should generally not be administered with Breast Feeding
an MAOI, including within 14 days of MAOI • Unknown if methylphenidate is secreted in
use, except in heroic circumstances and by human breast milk, but all psychotropics
an expert assumed to be secreted in breast milk
• If there is a proven allergy to ✽ Recommended either to discontinue drug
methylphenidate or bottle feed
• If infant shows signs of irritability, drug
may need to be discontinued
SPECIAL POPULATIONS
Renal Impairment THE ART OF PSYCHOPHARMACOLOGY
• No dose adjustment necessary
Potential Advantages
Hepatic Impairment • Established long-term efficacy as a first-
• No dose adjustment necessary line treatment for ADHD
• Multiple options for drug delivery, peak
Cardiac Impairment actions, and duration of action
• Use with caution, particularly in patients
with recent myocardial infarction or other Potential Disadvantages
conditions that could be negatively affected • Patients with current or past substance
by increased blood pressure abuse
• Patients with current or past bipolar
Elderly disorder or psychosis
• Some patients may tolerate lower doses
better Primary Target Symptoms
• Concentration, attention span
• Motor hyperactivity
Children and Adolescents • Impulsiveness
• Safety and efficacy not established under • Physical and mental fatigue
age 6 • Daytime sleepiness
• Use in young children should be reserved • Depression
for the expert
• Methylphenidate has acute effects on
growth hormone; long-term effects are Pearls
unknown but weight and height should be ✽ May be useful for treatment of depressive
monitored during long-term treatment symptoms in medically ill elderly patients
✽ May be useful for treatment of post-
stroke depression
Pregnancy ✽ A classical augmentation strategy for
• Risk Category C [some animal studies treatment-refractory depression
show adverse effects, no controlled studies ✽ Specifically, may be useful for treatment
in humans] of cognitive dysfunction and fatigue as
• Infants whose mothers took residual symptoms of major depressive
methylphenidate during pregnancy may disorder unresponsive to multiple prior
experience withdrawal symptoms treatments
✽ May also be useful for the treatment of
cognitive impairment, depressive

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D,L-METHYLPHENIDATE (continued)

symptoms, and severe fatigue in patients ✽ Metadate CD and Ritalin LA are

with HIV infection and in cancer patients somewhat similar to each other, both with
• Can be used to potentiate opioid analgesia an early peak and duration of action of
and reduce sedation, particularly in end-of- about 8 hours
life management ✽ Concerta has less of an early peak but a
• Atypical antipsychotics may be useful in longer duration of action (up to 12 hours)
treating stimulant or psychotic ✽ Concerta trilayer tablet consists of 3
consequences of overdose compartments (2 containing drug, 1 a
• Unknown how methylphenidate’s “push” compartment) and an orifice at the
mechanism of action differs from that of head of the first drug compartment; water
amphetamine, but some patients respond fills the push compartment and gradually
to or tolerate methylphenidate better than pushes drug up and out of the tablet
amphetamine and vice versa through the orifice
• Taking with food may delay peak actions ✽ Concerta may be preferable for those
for 2–3 hours ADHD patients who work in the evening or
• Half-life and duration of clinical action tend do homework up to 12 hours after morning
to be shorter in younger children dosing
• Drug abuse may actually be lower in ADHD ✽ Metadate CD and Ritalin LA may be
adolescents treated with stimulants than in preferable for those ADHD patients who
ADHD adolescents who are not treated lose their appetite for dinner or have
• Older sustained release technologies for insomnia with Concerta
methylphenidate were not significant • Some patients may benefit from an
advances over immediate release occasional addition of 5–10 mg of
methylphenidate because they did not immediate release methylphenidate to their
eliminate the need for lunchtime dosing or daily base of sustained release
allow once daily administration methylphenidate
✽ Newer sustained release technologies are • A transdermal methylphenidate patch is in
truly once a day dosing systems development

Suggested Reading
Challman TD, Lipsky JJ. Methylphenidate: its Wolraich ML, Greenhill LL, Pelham W,
pharmacology and uses. Mayo Clin Proc Swanson J, Wilens T, Palumbo D, Atkins M,
2000;75:711–21. McBurnett K, Bukstein O, August G.
Randomized, controlled trial of oros
Kimko HC, Cross JT, Abemethy DR. methylphenidate once a day in children with
Pharmacokinetics and clinical effectiveness of attention-deficit/hyperactivity disorder.
methylphenidate. Clin Pharmacokinet Pediatrics 2001;108:883–92.
1999;37:457–70.

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D-METHYLPHENIDATE
THERAPEUTICS • Treatment for ADHD begun in childhood
may need to be continued into adolescence
Brands • Focalin and adulthood if continued benefit is
see index for additional brand names documented
Generic? No If It Doesn’t Work (for ADHD)
• Consider adjusting dose or switching to a
Class formulation of d,l-methylphenidate or to
• Stimulant another agent
• Consider behavioral therapy
Commonly Prescribed For • Consider the presence of noncompliance
(bold for FDA approved) and counsel patient and parents
• Attention deficit hyperactivity disorder • Consider evaluation for another diagnosis
(ADHD) or for a comorbid condition (e.g., bipolar
• Narcolepsy disorder, substance abuse, medical illness,
• Treatment-resistant depression etc.)
✽ Some ADHD patients and some
depressed patients may experience lack of
How The Drug Works consistent efficacy due to activation of
✽ Increases norepinephrine and especially latent or underlying bipolar disorder, and
dopamine actions by blocking their require either augmenting with a mood
reuptake and facilitating their release stabilizer or switching to a mood stabilizer
• Enhancement of dopamine and
norepinephrine actions in certain brain Best Augmenting Combos
regions (e.g., dorsolateral prefrontal for Partial Response or
cortex) may improve attention, Treatment-Resistance
concentration, executive function, and ✽ Best to attempt other monotherapies
wakefulness prior to augmenting
• Enhancement of dopamine actions in other • For the expert, can combine immediate
brain regions (e.g., basal ganglia) may release formulation of d-methylphenidate
improve hyperactivity with a sustained release formulation of
• Enhancement of dopamine and d,l-methylphenidate for ADHD
norepinephrine in yet other brain regions • For the expert, can combine with modafinil
(e.g., medial prefrontal cortex, or atomoxetine for ADHD
hypothalamus) may improve depression, • For the expert, can occasionally combine
fatigue, and sleepiness with atypical antipsychotics in highly
treatment-resistant cases of bipolar
How Long Until It Works disorder or ADHD
• Some immediate effects can be seen with • For the expert, can combine with
first dosing antidepressants to boost antidepressant
• Can take several weeks to attain maximum efficacy in highly treatment-resistant cases
therapeutic benefit of depression while carefully monitoring
patient
If It Works (for ADHD)
• The goal of treatment of ADHD is reduction Tests
of symptoms of inattentiveness, motor • Blood pressure should be monitored
hyperactivity, and/or impulsiveness that regularly
disrupt social, school, and/or occupational • In children, monitor weight and height
functioning • Periodic complete blood cell and platelet
• Continue treatment until all symptoms are counts may be considered during
under control or improvement is stable and prolonged therapy (rare leukopenia and/or
then continue treatment indefinitely as long anemia)
as improvement persists
• Reevaluate the need for treatment
periodically

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D-METHYLPHENIDATE (continued)

SIDE EFFECTS Best Augmenting Agents for Side

How Drug Causes Side Effects Effects
• Beta-blockers for peripheral autonomic
• Increases in norepinephrine peripherally
side effects
can cause autonomic side effects, including
• Dose reduction or switching to another
tremor, tachycardia, hypertension, and
agent may be more effective since most
cardiac arrhythmias
side effects cannot be improved with an
• Increases in norepinephrine and dopamine
augmenting agent
centrally can cause CNS side effects such
as insomnia, agitation, psychosis, and
substance abuse
DOSING AND USE
Notable Side Effects
✽ Insomnia, headache, exacerbation of tics, Usual Dosage Range
nervousness, irritability, overstimulation, • 2.5–10 mg twice per day
tremor, dizziness
• Anorexia, nausea, abdominal pain, weight Dosage Forms
loss • Tablet 2.5 mg, 5 mg, 10 mg
• Can temporarily slow normal growth in
How to Dose
children (controversial)
• Patients who are not taking racemic
• Blurred vision
d,l-methylphenidate: initial 2.5 mg twice
per day in 4-hour intervals; may adjust
Life Threatening or dose in weekly intervals by 2.5–5 mg/day;
Dangerous Side Effects maximum dose generally 10 mg twice per
• Psychotic episodes, especially with day
parenteral abuse • Patients currently taking racemic
• Seizures d,l-methylphenidate: initial dose should be
• Palpitations, tachycardia, hypertension half the current dose of racemic
• Rare neuroleptic malignant syndrome d,l-methylphenidate; maximum dose
• Rare activation of hypomania, mania, or generally 10 mg twice per day
suicidal ideation (controversial)

Weight Gain Dosing Tips

✽ d-methylphenidate is an immediate
release formulation with the same onset of
• Reported but not expected action and duration of action as immediate
• Some patients may experience weight loss release racemic d,l-methylphenidate (i.e.,
2–4 hours) but at half the dose
Sedation • Although d-methylphenidate is generally
considered to be twice as potent as
racemic d,l-methylphenidate, some studies
suggest that the d-isomer is actually more
• Reported but not expected
than twice as effective as racemic
• Activation much more common than
d,l-methylphenidate
sedation
• Side effects are generally dose-related
What To Do About Side Effects • Off-label uses are dosed the same as for
• Wait ADHD
• Adjust dose ✽ May be possible to dose only during the
• Switch to a formulation of school week for some ADHD patients
d,l-methylphenidate ✽ May be able to give drug holidays over
• Switch to another agent the summer in order to reassess
• For insomnia, avoid dosing in therapeutic utility and effects on growth
afternoon/evening and to allow catch-up from any growth
suppression as well as to assess any other

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(continued) D-METHYLPHENIDATE

side effects and the need to reinstitute

stimulant treatment for the next school
term Drug Interactions
• Avoid dosing late in the day because of the • May affect blood pressure and should be
risk of insomnia used cautiously with agents used to control
• Taking with food may delay peak actions blood pressure
for 2–3 hours • May inhibit metabolism of SSRIs,
anticonvulsants (phenobarbital, phenytoin,
Overdose primidone), tricyclic antidepressants, and
• Vomiting, tremor, coma, convulsion, coumarin anticoagulants, requiring
hyperreflexia, euphoria, confusion, downward dosage adjustments of these
hallucination, tachycardia, flushing, drugs
palpitations, sweating, hyperpyrexia, • Serious adverse effects may occur if
hypertension, arrhythmia, mydriasis, combined with clonidine (controversial)
agitation, delirium, headache • Use with MAOIs, including within 14 days
of MAOI use, is not advised, but this can
Long-Term Use sometimes be considered by experts who
• Often used long-term for ADHD when monitor depressed patients closely when
ongoing monitoring documents continued other treatment options for depression fail
efficacy • CNS and cardiovascular actions of
• Dependence and/or abuse may develop d-methylphenidate could theoretically be
• Tolerance to therapeutic effects may enhanced by combination with agents that
develop in some patients block norepinephrine reuptake, such as the
• Long-term stimulant use may be tricyclic antidepressants desipramine or
associated with growth suppression in protriptyline, venlafaxine, duloxetine,
children (controversial) atomoxetine, milnacipran, and reboxetine
• Periodic monitoring of weight, blood • Theoretically, antipsychotics should inhibit
pressure, CBC, platelet counts, and liver the stimulatory effects of
function may be prudent d-methylphenidate
• Theoretically, d-methylphenidate could
Habit Forming inhibit the antipsychotic actions of
• High abuse potential, Schedule II drug antipsychotics
• Patients may develop tolerance, • Theoretically, d-methylphenidate could
psychological dependence inhibit the mood stabilizing actions of
atypical antipsychotics in some patients
How to Stop • Combinations of d-methylphenidate with
• Taper to avoid withdrawal effects mood stabilizers (lithium, anticonvulsants,
• Withdrawal following chronic therapeutic atypical antipsychotics) is generally
use may unmask symptoms of the something for experts only, when
underlying disorder and may require monitoring patients closely and when other
follow-up and reinstitution of treatment options fail
• Careful supervision is required during
withdrawal from abusive use since severe
depression may occur Other Warnings/
Precautions
Pharmacokinetics • Use with caution in patients with any
• d-threo-enantiomer of racemic degree of hypertension, hyperthyroidism,
d,l-methylphenidate or history of drug abuse
• Mean plasma elimination half-life • Children who are not growing or gaining
approximately 2.2 hours (same as weight should stop treatment, at least
d,l-methylphenidate) temporarily
• Does not inhibit CYP450 enzymes • May worsen motor and phonic tics
• May worsen symptoms of thought disorder
and behavioral disturbance in psychotic
patients

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D-METHYLPHENIDATE (continued)

• Stimulants have a high potential for abuse Cardiac Impairment

and must be used with caution in anyone • Use with caution, particularly in patients
with a current or past history of substance with recent myocardial infarction or other
abuse or alcoholism or in emotionally conditions that could be negatively affected
unstable patients by increased blood pressure
• Administration of stimulants for prolonged
periods of time should be avoided Elderly
whenever possible or done only with close • Some patients may tolerate lower doses
monitoring, as it may lead to marked better
tolerance and drug dependence, including
psychological dependence with varying
degrees of abnormal behavior Children and Adolescents
• Particular attention should be paid to the • Safety and efficacy not established under
possibility of subjects obtaining stimulants age 6
for nontherapeutic use or distribution to • Use in young children should be reserved
others and the drugs should in general be for the expert
prescribed sparingly with documentation of • Methylphenidate has acute effects on
appropriate use growth hormone; long-term effects are
• Not an appropriate first-line treatment for unknown but weight and height should be
depression or for normal fatigue monitored during long-term treatment
• May lower the seizure threshold
• Emergence or worsening of activation and
agitation may represent the induction of a
bipolar state, especially a mixed dysphoric
Pregnancy
bipolar II condition sometimes associated • Risk Category C [some animal studies
with suicidal ideation, and require the show adverse effects, no controlled studies
addition of a mood stabilizer and/or in humans]
discontinuation of d-methylphenidate • Infants whose mothers took
methylphenidate during pregnancy may
Do Not Use experience withdrawal symptoms
• If patient has extreme anxiety or agitation • Use in women of childbearing potential
• If patient has motor tics or Tourette’s requires weighing potential benefits to the
sydrome or if there is a family history of mother against potential risks to the fetus
Tourette’s, unless administered by an ✽ For ADHD patients, methylphenidate
expert in cases when the potential benefits should generally be discontinued before
for ADHD outweigh the risks of worsening anticipated pregnancies
tics
• If patient has glaucoma
Breast Feeding
• Should generally not be administered with • Unknown if methylphenidate is secreted in
an MAOI, including within 14 days of MAOI human breast milk, but all psychotropics
use, except in heroic circumstances and by assumed to be secreted in breast milk
an expert ✽ Recommended either to discontinue drug
• If there is a proven allergy to or bottle feed
methylphenidate • If infant shows signs of irritability, drug
may need to be discontinued

SPECIAL POPULATIONS
THE ART OF PSYCHOPHARMACOLOGY
Renal Impairment
• No dose adjustment necessary
Potential Advantages
• The active d enantiomer of
Hepatic Impairment methylphenidate may be slightly more than
• No dose adjustment necessary twice as efficacious as racemic
d,l-methylphenidate

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(continued) D-METHYLPHENIDATE

Potential Disadvantages • Specifically, may be useful for treatment of

• Patients with current or past substance cognitive dysfunction and fatigue as
abuse, bipolar disorder, or psychosis residual symptoms of major depressive
• No controlled release formulations disorder unresponsive to multiple prior
currently available treatments
• May also be useful for the treatment of
Primary Target Symptoms cognitive impairment, depressive
• Concentration, attention span symptoms, and severe fatigue in patients
• Motor hyperactivity with HIV infection and in cancer patients
• Impulsiveness • Can be used to potentiate opioid analgesia
• Physical and mental fatigue and reduce sedation, particularly in end-of-
• Daytime sleepiness life management
• Depression • Atypical antipsychotics may be useful in
treating stimulant or psychotic
consequences of overdose
Pearls • Unknown how methylphenidate’s
✽ Unclear what its advantages are over mechanism of action differs from that of
immediate release racemic amphetamine, but some patients respond
d,l-methylphenidate to or tolerate methylphenidate better than
• A controlled release formulation for once amphetamine, and vice versa
daily administration is in development • Taking with food may delay peak actions
• May be useful for treatment of depressive for 2–3 hours
symptoms in medically ill elderly patients • Half-life and duration of clinical action tend
• May be useful for treatment of post-stroke to be shorter in younger children
depression • Drug abuse may actually be lower in ADHD
• A classical augmentation strategy for adolescents treated with stimulants than in
treatment-refractory depression ADHD adolescents who are not treated

Suggested Reading
Dexmethylphenidate—Novartis/Celgene. Keating GM, Figgitt DP. Dexmethylphenidate.
Focalin, D-MPH, D-methylphenidate Drugs. 2002;62(13):1899–904.
hydrochloride, D-methylphenidate,
dexmethylphenidate, dexmethylphenidate
hydrochloride. Drugs R D. 2002;3(4):279–82.

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DONEPEZIL
THERAPEUTICS Best Augmenting Combos
Brands • Aricept for Partial Response or
• Memac Treatment-Resistance
see index for additional brand names ✽ Atypical antipsychotics to reduce
behavioral disturbances
Generic? No ✽ Antidepressants if concomitant
depression, apathy, or lack of interest
✽ Memantine for moderate to severe
Alzheimer disease
Class
• Divalproex, carbamazepine, or
• Cholinesterase inhibitor (selective
oxcarbazepine for behavioral disturbances
acetylcholinesterase inhibitor); cognitive
• Not rational to combine with another
enhancer
cholinesterase inhibitor
Commonly Prescribed For Tests
(bold for FDA approved)
• None for healthy individuals
• Alzheimer disease
• Memory disorders in other conditions
• Mild cognitive impairment
SIDE EFFECTS
How Drug Causes Side Effects
How The Drug Works • Peripheral inhibition of acetylcholinesterase
✽ Reversibly but noncompetitively inhibits can cause gastrointestinal side effects
centrally-active acetylcholinesterase • Central inhibition of acetylcholinesterase
(AChE), making more acetylcholine may contribute to nausea, vomiting, weight
available loss, and sleep disturbances
• Increased availability of acetylcholine
compensates in part for degenerating Notable Side Effects
cholinergic neurons in neocortex that ✽ Nausea, diarrhea, vomiting, appetite loss,
regulate memory increased gastric acid secretion, weight loss
• Does not inhibit butyrylcholinesterase • Insomnia, dizziness
• May release growth factors or interfere • Muscle cramps, fatigue, depression,
with amyloid deposition abnormal dreams
How Long Until It Works
• May take up to 6 weeks before any Life Threatening or
improvement in baseline memory or Dangerous Side Effects
behavior is evident • Rare seizures
• May take months before any stabilization in • Rare syncope
degenerative course is evident
Weight Gain
If It Works
• May improve symptoms and slow
progression of disease, but does not • Reported but not expected
reverse the degenerative process • Some patients may experience weight loss
If It Doesn’t Work Sedation
• Consider adjusting dose, switching to a
different cholinesterase inhibitor or adding
an appropriate augmenting agent
• Reconsider diagnosis and rule out other • Reported but not expected
conditions such as depression or a
dementia other than Alzheimer disease What To Do About Side Effects
• Wait
• Wait

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DONEPEZIL (continued)

• Wait weakness (weakness of respiratory

• Take in daytime to reduce insomnia muscles can lead to death)
• Use slower dose titration
• Consider lowering dose, switching to a Long-Term Use
different agent or adding an appropriate • Drug may lose effectiveness in slowing
augmenting agent degenerative course of Alzheimer disease
after 6 months
Best Augmenting Agents for Side • Can be effective in some patients for
Effects several years
• Hypnotics or trazodone may improve
insomnia Habit Forming
• Many side effects cannot be improved with • No
an augmenting agent
How to Stop
• Taper to avoid withdrawal effects
• Discontinuation may lead to notable
DOSING AND USE deterioration in memory and behavior,
Usual Dosage Range which may not be restored when drug is
restarted or another cholinesterase
• 5–10 mg at night
inhibitor is initiated
Dosage Forms
Pharmacokinetics
• Tablet 5 mg, 10 mg
• Metabolized by CYP450 2D6 and CYP450
How to Dose 3A4
• Initial 5 mg/day; may increase to 10 • Elimination half-life approximately 70 hours
mg/day after 4–6 weeks

Drug Interactions
Dosing Tips • Donepezil may increase the effects of
✽ Only cholinesterase inhibitor with once anesthetics and should be discontinued
prior to surgery
daily dosing
• Side effects occur more frequently at • Inhibitors of CYP450 2D6 and CYP450 3A4
10 mg/day than at 5 mg/day may inhibit donepezil metabolism and
• Slower titration (e.g., 6 weeks to increase its plasma levels
10 mg/day) may reduce the risk of side • Inducers of CYP450 2D6 and CYP450 3A4
effects may increase clearance of donepezil and
• Food does not affect the absorption of decrease its plasma levels
donepezil • Donepezil may interact with anticholinergic
• Probably best to utilize highest tolerated agents and the combination may decrease
dose within the usual dosage range the efficacy of both
• Some off-label uses for cognitive • May have synergistic effect if administered
disturbances other than Alzheimer disease with cholinomimetics (e.g., bethanechol)
have anecdotally utilized doses higher than • Bradycardia may occur if combined with
10 mg/day beta blockers
✽ When switching to another cholinesterase • Theoretically, could reduce the efficacy of
levodopa in Parkinson’s disease
inhibitor, probably best to cross-titrate
from one to the other to prevent • Not rational to combine with another
precipitous decline in function if the patient cholinesterase inhibitor
washes out of one drug entirely
Other Warnings/
Overdose Precautions
• Can be lethal; nausea, vomiting, excess
• May exacerbate asthma or other pulmonary
salivation, sweating, hypotension,
disease
bradycardia, collapse, convulsions, muscle

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(continued) DONEPEZIL

• Increased gastric acid secretion may THE ART OF PSYCHOPHARMACOLOGY

increase the risk of ulcers
• Bradycardia or heart block may occur in
Potential Advantages
patients with or without cardiac impairment • Once a day dosing
• May be used in vascular dementia
Do Not Use • May work in some patients who do not
• If there is a proven allergy to donepezil respond to other cholinesterase inhibitors
• May work in some patients who do not
tolerate other cholinesterase inhibitors
SPECIAL POPULATIONS Potential Disadvantages
• Patients with insomnia
Renal Impairment
• Few data available but dose adjustment is Primary Target Symptoms
most likely unnecessary • Memory loss in Alzheimer disease
• Behavioral symptoms in Alzheimer disease
Hepatic Impairment
• Memory loss in other dementias
• Few data available; may need to lower dose

Cardiac Impairment
• Should be used with caution Pearls
• Syncopal episodes have been reported with • Dramatic reversal of symptoms of
the use of donepezil Alzheimer disease is not generally seen
with cholinesterase inhibitors
Elderly • Can lead to therapeutic nihilism among
• Some patients may tolerate lower doses prescribers and lack of an appropriate trial
better of a cholinesterase inhibitor
✽ Perhaps only 50% of Alzheimer patients
are diagnosed, and only 50% of those
Children and Adolescents diagnosed are treated, and only 50% of
• Safety and efficacy have not been those treated are given a cholinesterase
established inhibitor, and then only for 200 days in a
• Preliminary reports of efficacy as an disease that lasts 7–10 years
adjunct in ADHD (ages 8–17) • Must evaluate lack of efficacy and loss of
efficacy over months, not weeks
✽ Treats behavioral and psychological
symptoms of Alzheimer dementia as well
Pregnancy as cognitive symptoms (i.e., especially
• Risk Category C [some animal studies apathy, disinhibition, delusions, anxiety,
show adverse effects, no controlled studies cooperation, pacing)
in humans] • Patients who complain themselves of
✽ Not recommended for use in pregnant memory problems may have depression,
women or women of childbearing potential whereas patients whose spouses or
children complain of the patient’s memory
Breast Feeding
problems may have Alzheimer disease
• Unknown if donepezil is secreted in human
• Treat the patient but ask the caregiver
breast milk, but all psychotropics assumed
about efficacy
to be secreted in breast milk
• What you see may depend upon how early
✽ Recommended either to discontinue drug you treat
or bottle feed
• The first symptoms of Alzheimer disease
• Donepezil is not recommended for use in
are generally mood changes; thus,
nursing women
Alzheimer disease may initially be
diagnosed as depression
• Women may experience cognitive
symptoms in perimenopause as a result of

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DONEPEZIL (continued)

hormonal changes that are not a sign of • Use with caution in underweight or frail
dementia or Alzheimer disease patients
• Aggressively treat concomitant symptoms • Cognitive improvement may be linked to
with augmentation (e.g., atypical substantial (>65%) inhibition of
antipsychotics for agitation, acetylcholinesterase
antidepressants for depression) • Donepezil has greater action on CNS
• If treatment with antidepressants fails to acetylcholinesterase than on peripheral
improve apathy and depressed mood in the acetylcholinesterase
elderly, it is possible that this represents • Some Alzheimer patients who fail to
early Alzheimer disease and a respond to donepezil may respond to
cholinesterase inhibitor like donepezil may another cholinesterase inhibitor
be helpful • Some Alzheimer patients who fail to
• What to expect from a cholinesterase respond to another cholinesterase inhibitor
inhibitor: may respond when switched to donepezil
• Patients do not generally improve • To prevent potential clinical deterioration,
dramatically although this can be generally switch from long-term treatment
observed in a significant minority of with one cholinesterase inhibitor to another
patients without a washout period
• Onset of behavioral problems and ✽ Donepezil may slow the progression of
nursing home placement can be delayed mild cognitive impairment to Alzheimer
• Functional outcomes, including activities disease
of daily living, can be preserved ✽ May be useful for dementia with Lewy
• Caregiver burden and stress can be bodies (DLB, constituted by early loss of
reduced attentiveness and visual perception with
• Delay in progression in Alzheimer disease possible hallucinations, Parkinson-like
is not evidence of disease-modifying movement problems, fluctuating cognition
actions of cholinesterase inhibition such as daytime drowsiness and lethargy,
• Cholinesterase inhibitors like donepezil staring into space for long periods,
depend upon the presence of intact targets episodes of disorganized speech)
for acetylcholine for maximum • May decrease delusions, apathy, agitation,
effectiveness and thus may be most and hallucinations in dementia with Lewy
effective in the early stages of Alzheimer bodies
disease ✽ May be useful for vascular dementia
• The most prominent side effects of (e.g., acute onset with slow stepwise
donepezil are gastrointestinal effects, which progression that has plateaus, often with
are usually mild and transient gait abnormalities, focal signs, imbalance,
✽ May cause more sleep disturbances than and urinary incontinence)
some other cholinesterase inhibitors • May be helpful for dementia in Down’s
• For patients with intolerable side effects, Syndrome
generally allow a washout period with • Suggestions of utility in some cases of
resolution of side effects prior to switching treatment-resistant bipolar disorder
to another cholinesterase inhibitor • Theoretically, may be useful for ADHD, but
• Weight loss can be a problem in Alzheimer not yet proven
patients with debilitation and muscle • Theoretically, could be useful in any
wasting memory condition characterized by
• Women over 85, particularly with low body cholinergic deficiency (e.g., some cases of
weights, may experience more adverse brain injury, cancer chemotherapy-induced
effects cognitive changes, etc.)

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(continued) DONEPEZIL

Suggested Reading
Bentue-Ferrer D, Tribut O, Polard E, Allain H. Stahl SM. Cholinesterase inhibitors for
Clinically significant drug interactions with Alzheimer’s disease. Hosp Pract (Off Ed)
cholinesterase inhibitors: a guide for 1998;33:131–6.
neurologists. CNS Drugs 2003;17:947–63.
Stahl SM. The new cholinesterase inhibitors
Birks, JS, Harvey R. Donepezil for dementia for Alzheimer’s disease, part 1. J Clin
due to Alzheimer’s disease. Cochrane Database Psychiatry 2000;61:710–11.
Syst Rev 2003;CD001190.
Stahl SM. The new cholinesterase inhibitors
Bonner LT, Peskind ER. Pharmacologic for Alzheimer’s disease, part 2. J Clin
treatments of dementia. Med Clin North Am Psychiatry 2000;61:813–14.
2002;86:657–74.
Jones RW. Have cholinergic therapies reached
their clinical boundary in Alzheimer’s disease?
Int J Geriatr Psychiatry 2003;18(Suppl 1):
S7–S13.

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DOTHIEPIN
THERAPEUTICS If It Works
• The goal of treatment of depression is
Brands • Prothiaden
complete remission of current symptoms
see index for additional brand names
as well as prevention of future relapses
Generic? In United Kingdom • The goal of treatment of chronic
neuropathic pain is to reduce symptoms as
much as possible, especially in
combination with other treatments
Class • Treatment of depression most often
• Tricyclic antidepressant (TCA) reduces or even eliminates symptoms, but
• Serotonin and norepinephrine/ not a cure since symptoms can recur after
noradrenaline reuptake inhibitor medicine stopped
• Treatment of chronic neuropathic pain may
Commonly Prescribed For reduce symptoms, but rarely eliminates
(bold for FDA approved) them completely, and is not a cure since
• Major depressive disorder symptoms can recur after medicine is
• Anxiety stopped
• Insomnia • Continue treatment of depression until all
• Neuropathic pain/chronic pain symptoms are gone (remission)
• Treatment-resistant depression • Once symptoms of depression are gone,
continue treating for 1 year for the first
episode of depression
How The Drug Works • For second and subsequent episodes of
• Boosts neurotransmitters serotonin and depression, treatment may need to be
norepinephrine/noradrenaline indefinite
• Blocks serotonin reuptake pump (serotonin • Use in anxiety disorders and chronic pain
transporter), presumably increasing may also need to be indefinite, but long-
serotonergic neurotransmission term treatment is not well studied in these
• Blocks norepinephrine reuptake pump conditions
(norepinephrine transporter), presumably
If It Doesn’t Work
increasing noradrenergic
• Many depressed patients only have a
neurotransmission
partial response where some symptoms
• Presumably desensitizes both serotonin 1A
are improved but others persist (especially
receptors and beta adrenergic receptors
insomnia, fatigue, and problems
• Since dopamine is inactivated by
concentrating)
norepinephrine reuptake in frontal cortex,
• Other depressed patients may be
which largely lacks dopamine transporters,
nonresponders, sometimes called
dothiepin can increase dopamine
treatment-resistant or treatment-refractory
neurotransmission in this part of the brain
• Consider increasing dose, switching to
How Long Until It Works another agent or adding an appropriate
• May have immediate effects in treating augmenting agent
insomnia or anxiety • Consider psychotherapy
• Onset of therapeutic actions usually not • Consider evaluation for another diagnosis
immediate, but often delayed 2 to 4 weeks or for a comorbid condition (e.g, medical
• If it is not working within 6 to 8 weeks for illness, substance abuse, etc.)
depression, it may require a dosage • Some patients may experience apparent
increase or it may not work at all lack of consistent efficacy due to activation
• May continue to work for many years to of latent or underlying bipolar disorder, and
prevent relapse of symptoms require antidepressant discontinuation and
a switch to a mood stabilizer

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DOTHIEPIN (continued)

Best Augmenting Combos SIDE EFFECTS

for Partial Response or How Drug Causes Side Effects
Treatment-Resistance • Anticholinergic activity may explain
• Lithium, buspirone, thyroid hormone (for sedative effects, dry mouth, constipation,
depression) and blurred vision
• Gabapentin, tiagabine, other • Sedative effects and weight gain may be
anticonvulsants, even opiates if done by due to antihistamine properties
experts while monitoring carefully in • Blockade of alpha adrenergic 1 receptors
difficult cases (for chronic pain) may explain dizziness, sedation, and
hypotension
Tests
• Cardiac arrhythmias and seizures,
• None for healthy individuals
especially in overdose, may be caused by
✽ Since tricyclic and tetracyclic blockade of ion channels
antidepressants are frequently associated
with weight gain, before starting treatment, Notable Side Effects
weigh all patients and determine if the • Blurred vision, constipation, urinary
patient is already overweight retention, increased appetite, dry mouth,
(BMI 25.0–29.9) or obese (BMI ≥30) nausea, diarrhea, heartburn, unusual taste
• Before giving a drug that can cause weight in mouth, weight gain
gain to an overweight or obese patient, • Fatigue, weakness, dizziness, sedation,
consider determining whether the patient headache, anxiety, nervousness,
already has pre-diabetes (fasting plasma restlessness
glucose 100–125 mg/dl), diabetes (fasting • Sexual dysfunction, sweating
plasma glucose >126 mg/dl), or
dyslipidemia (increased total cholesterol,
LDL cholesterol and triglycerides; Life Threatening or
decreased HDL cholesterol), and treat or Dangerous Side Effects
refer such patients for treatment including • Paralytic ileus, hyperthermia (TCAs +
nutrition and weight management, physical anticholinergic agents)
activity counseling, smoking cessation, and • Lowered seizure threshold and rare
medical management seizures
✽ Monitor weight and BMI during treatment • Orthostatic hypotension, sudden death,
✽ While giving a drug to a patient who has arrhythmias, tachycardia
gained >5% of initial weight, consider • QTc prolongation
evaluating for the presence of pre-diabetes, • Hepatic failure, extrapyramidal symptoms
diabetes, or dyslipidemia, or consider • Increased intraocular pressure
switching to a different antidepressant • Rare induction of mania and activation of
• EKGs may be useful for selected patients suicidal ideation
(e.g., those with personal or family history
of QTc prolongation; cardiac arrhythmia; Weight Gain
recent myocardial infarction;
uncompensated heart failure; or taking
agents that prolong QTc interval such as • Many experience and/or can be significant
pimozide, thioridazine, selected in amount
antiarrhythmics, moxifloxacin, sparfloxacin, • Can increase appetite and carbohydrate
etc.) craving
• Patients at risk for electrolyte disturbances
(e.g., patients on diuretic therapy) should Sedation
have baseline and periodic serum
potassium and magnesium measurements

• Many experience and/or can be significant

in amount
• Tolerance to sedative effect may develop
with long-term use

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(continued) DOTHIEPIN

What To Do About Side Effects Long-Term Use

• Wait • Safe
• Wait
• Wait Habit Forming
• Lower the dose • No
• Switch to an SSRI or newer antidepressant
How to Stop
Best Augmenting Agents for Side • Taper to avoid withdrawal effects
Effects • Even with gradual dose reduction some
• Many side effects cannot be improved with withdrawal symptoms may appear within
an augmenting agent the first 2 weeks
• Many patients tolerate 50% dose reduction
for 3 days, then another 50% reduction for
3 days, then discontinuation
DOSING AND USE
• If withdrawal symptoms emerge during
Usual Dosage Range discontinuation, raise dose to stop
• 75–150 mg/day symptoms and then restart withdrawal
much more slowly
Dosage Forms
• Capsule 25 mg Pharmacokinetics
• Tablet 75 mg • Substrate for CYP450 2D6
• Half-life approximately 14–40 hours
How to Dose
• 75 mg/day once daily or in divided doses;
gradually increase dose to achieve desired Drug Interactions
therapeutic effect; maximum dose • Tramadol increases the risk of seizures in
300 mg/day patients taking TCAs
• Use of TCAs with anticholinergic drugs
may result in paralytic ileus or
Dosing Tips hyperthermia
• If given in a single dose, should generally • Fluoxetine, paroxetine, bupropion,
be administered at bedtime because of its duloxetine, and other CYP450 2D6
sedative properties inhibitors may increase TCA concentrations
• If given in split doses, largest dose should • Cimetidine may increase plasma
generally be given at bedtime because of concentrations of TCAs and cause
its sedative properties anticholinergic symptoms
• If patients experience nightmares, split • Phenothiazines or haloperidol may raise
dose and do not give large dose at bedtime TCA blood concentrations
• Patients treated for chronic pain may only • May alter effects of antihypertensive drugs;
require lower doses may inhibit hypotensive effects of clonidine
• Risk of seizure increases with dose • Use of TCAs with sympathomimetic agents
• If intolerable anxiety, insomnia, agitation, may increase sympathetic activity
akathisia, or activation occur either upon • Methylphenidate may inhibit metabolism of
dosing initiation or discontinuation, TCAs
consider the possibility of activated bipolar • Activation and agitation, especially
disorder, and switch to a mood stabilizer or following switching or adding
an atypical antipsychotic antidepressants, may represent the
induction of a bipolar state, especially a
Overdose mixed dysphoric bipolar II condition
• Death may occur; convulsions, cardiac sometimes associated with suicidal
dysrhythmias, severe hypotension, CNS ideation, and require the addition of
depression, coma, changes in ECG lithium, a mood stabilizer or an atypical
antipsychotic, and/or discontinuation of
dothiepin

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DOTHIEPIN (continued)

metabolizers, except by an expert and at

Other Warnings/ low doses
Precautions • If there is a proven allergy to dothiepin
• Add or initiate other antidepressants with
caution for up to 2 weeks after
discontinuing dothiepin
SPECIAL POPULATIONS
• Generally, do not use with MAO inhibitors,
including 14 days after MAOIs are stopped; Renal Impairment
do not start an MAOI until 2 weeks after • Use with caution
discontinuing dothiepin, but see Pearls
• Use with caution in patients with history of Hepatic Impairment
seizures, urinary retention, narrow angle- • Use with caution
closure glaucoma, hyperthyroidism, and in
patients recovering from myocardial Cardiac Impairment
infarction • TCAs have been reported to cause
• TCAs can increase QTc interval, especially arrhythmias, prolongation of conduction
at toxic doses, which can be attained not time, orthostatic hypotension, sinus
only by overdose but also by combining tachycardia, and heart failure, especially in
with drugs that inhibit TCA metabolism via the diseased heart
CYP450 2D6, potentially causing torsade • Myocardial infarction and stroke have been
de pointes-type arrhythmia or sudden reported with TCAs
death • TCAs produce QTc prolongation, which
• Because TCAs can prolong QTc interval, may be enhanced by the existence of
use with caution in patients who have bradycardia, hypokalemia, congenital or
bradycardia or who are taking drugs that acquired long QTc interval, which should
can induce bradycardia (e.g., beta blockers, be evaluated prior to administering
calcium channel blockers, clonidine, dothiepin
digitalis) • Use with caution if treating concomitantly
• Because TCAs can prolong QTc interval, with a medication likely to produce
use with caution in patients who have prolonged bradycardia, hypokalemia,
hypokalemia and/or hypomagnesemia or slowing of intracardiac conduction, or
who are taking drugs that can induce prolongation of the QTc interval
hypokalemia and/or magnesemia (e.g., • Avoid TCAs in patients with a known
diuretics, stimulant laxatives, intravenous history of QTc prolongation, recent acute
amphotericin B, glucocorticoids, myocardial infarction, and uncompensated
tetracosactide) heart failure
• TCAs may cause a sustained increase in
Do Not Use heart rate in patients with ischemic heart
• If patient is recovering from myocardial disease and may worsen (decrease) heart
infarction rate variability, an independent risk of
• If patient is taking agents capable of mortality in cardiac populations
significantly prolonging QTc interval (e.g., • Since SSRIs may improve (increase) heart
pimozide, thioridazine, selected rate variability in patients following a
antiarrhythmics, moxifloxacin, myocardial infarct and may improve
sparfloxacin) survival as well as mood in patients with
• If there is a history of QTc prolongation or acute angina or following a myocardial
cardiac arrhythmia, recent acute infarction, these are more appropriate
myocardial infarction, uncompensated agents for cardiac population than
heart failure tricyclic/tetracyclic antidepressants
• If patient is taking drugs that inhibit TCA ✽ Risk/benefit ratio may not justify use of
metabolism, including CYP450 2D6 TCAs in cardiac impairment
inhibitors, except by an expert
• If there is reduced CYP450 2D6 function,
such as patients who are poor 2D6

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(continued) DOTHIEPIN

Elderly • Must weigh benefits of breast feeding with

• May be more sensitive to anticholinergic, risks and benefits of antidepressant
cardiovascular, hypotensive, and sedative treatment versus non-treatment to both the
effects infant and the mother
• For many patients this may mean
continuing treatment during breast feeding
Children and Adolescents
• Use with caution, observing for activation
of known or unknown bipolar disorder THE ART OF PSYCHOPHARMACOLOGY
and/or suicidal ideation, and strongly
consider informing parents or guardian of Potential Advantages
this risk so they can help observe child or • Patients with insomnia
adolescent patients • Severe or treatment-resistant depression
• Not recommended for use under age 18 • Anxious depression
• Several studies show lack of efficacy of
TCAs for depression
Potential Disadvantages
• May be used to treat enuresis or • Pediatric and geriatric patients
hyperactive/impulsive behaviors • Patients concerned with weight gain
• Some cases of sudden death have • Cardiac patients
occurred in children taking TCAs
Primary Target Symptoms
• Depressed mood
• Chronic pain
Pregnancy
• Risk Category C [some animal studies
show adverse effects, no controlled studies
Pearls
in humans]
• Crosses the placenta ✽ Close structural similarity to amitriptyline
• Tricyclic antidepressants are often a first-
• Adverse effects have been reported in
line treatment option for chronic pain
infants whose mothers took a TCA
• Tricyclic antidepressants are no longer
(lethargy, withdrawal symptoms, fetal
generally considered a first-line option for
malformations)
depression because of their side effect
• Not generally recommended for use during
profile
pregnancy, especially during first trimester
• Tricyclic antidepressants continue to be
• Must weigh the risk of treatment (first
useful for severe or treatment-resistant
trimester fetal development, third trimester
depression
newborn delivery) to the child against the
• TCAs may aggravate psychotic symptoms
risk of no treatment (recurrence of
• Alcohol should be avoided because of
depression, maternal health, infant
additive CNS effects
bonding) to the mother and child
• Underweight patients may be more
• For many patients this may mean
susceptible to adverse cardiovascular
continuing treatment during pregnancy
effects
Breast Feeding • Children, patients with inadequate
• Some drug is found in mother’s breast milk hydration, and patients with cardiac
✽ Recommended either to discontinue drug disease may be more susceptible to TCA-
induced cardiotoxicity than healthy adults
or bottle feed
• Immediate postpartum period is a high-risk • For the expert only: a heroic treatment (but
time for depression, especially in women potentially dangerous) for severely
who have had prior depressive episodes, treatment-resistant patients is to give
so drug may need to be reinstituted late in simultaneously with monoamine oxidase
the third trimester or shortly after inhibitors for patients who fail to respond
childbirth to prevent a recurrence during to numerous other antidepressants, but
the postpartum period generally recommend a different TCA than
dothiepin for this use

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DOTHIEPIN (continued)

• If this option is elected, start the MAOI with • Since tricyclic/tetracyclic antidepressants
the tricyclic/tetracyclic antidepressant are substrates for CYP450 2D6, and 7% of
simultaneously at low doses after the population (especially Caucasians) may
appropriate drug washout, then alternately have a genetic variant leading to reduced
increase doses of these agents every few activity of 2D6, such patients may not
days to a week as tolerated safely tolerate normal doses of
• Although very strict dietary and tricyclic/tetracyclic antidepressants and
concomitant drug restrictions must be may require dose reduction
observed to prevent hypertensive crises • Phenotypic testing may be necessary to
and serotonin syndrome, the most detect this genetic variant prior to dosing
common side effects of MAOI and with a tricyclic/tetracyclic antidepressant,
tricyclic/tetracyclic antidepressant especially in vulnerable populations such
combinations may be weight gain and as children, elderly, cardiac populations,
orthostatic hypotension and those on concomitant medications
• Patients on TCAs should be aware that they • Patients who seem to have extraordinarily
may experience symptoms such as severe side effects at normal or low doses
photosensitivity or blue-green urine may have this phenotypic CYP450 2D6
• SSRIs may be more effective than TCAs in variant and require low doses or switching
women, and TCAs may be more effective to another antidepressant not metabolized
than SSRIs in men by 2D6

Suggested Reading
Anderson IM. Meta-analytical studies on new Lancaster SG, Gonzalez JP. Dothiepin. A
antidepressants. Br Med Bull. 2001; review of its pharmacodynamic and
57:161–178. pharmacokinetic properties, and therapeutic
efficacy in depressive illness. Drugs. 1989;
Anderson IM. Selective serotonin reuptake 38:123–47.
inhibitors versus tricyclic antidepressants: a
meta-analysis of efficacy and tolerability. J Aff
Disorders. 2000;58:19–36.
Donovan S, Dearden L, Richardson L. The
tolerability of dothiepin: a review of clinical
studies between 1963 and 1990 in over
13,000 depressed patients. Prog
Neuropsychopharmacol Biol Psychiatry. 1994;
18:1143–62.

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DOXEPIN
THERAPEUTICS How Long Until It Works
• May have immediate effects in treating
Brands • Sinequan
insomnia or anxiety
see index for additional brand names
• Onset of therapeutic actions usually not
Generic? Yes immediate, but often delayed 2 to 4 weeks
• If it is not working within 6 to 8 weeks for
depression, it may require a dosage
increase or it may not work at all
Class • May continue to work for many years to
• Tricyclic antidepressant (TCA) prevent relapse of symptoms
• Serotonin and norepinephrine/
noradrenaline reuptake inhibitor If It Works
• The goal of treatment of depression is
Commonly Prescribed For complete remission of current symptoms
(bold for FDA approved) as well as prevention of future relapses
• Psychoneurotic patient with depression • The goal of treatment of chronic
and/or anxiety neuropathic pain is to reduce symptoms as
• Depression and/or anxiety associated much as possible, especially in
with alcoholism combination with other treatments
• Depression and/or anxiety associated • Treatment of depression most often
with organic disease reduces or even eliminates symptoms, but
• Psychotic depressive disorders with not a cure since symptoms can recur after
associated anxiety medicine stopped
• Involutional depression • Treatment of chronic neuropathic pain may
• Manic-depressive disorder reduce symptoms, but rarely eliminates
✽ Pruritus/itching (topical) them completely, and is not a cure since
• Dermatitis, atopic (topical) symptoms can recur after medicine is
• Lichen simplex chronicus (topical) stopped
• Anxiety • Continue treatment of depression until all
• Insomnia symptoms are gone (remission)
• Neuropathic pain/chronic pain • Once symptoms of depression are gone,
• Treatment-resistant depression continue treating for 1 year for the first
episode of depression
• For second and subsequent episodes of
How The Drug Works depression, treatment may need to be
indefinite
• Boosts neurotransmitters serotonin and
• Use in anxiety disorders, chronic pain, and
norepinephrine/noradrenaline
skin conditions may also need to be
• Blocks serotonin reuptake pump (serotonin
indefinite, but long-term treatment is not
transporter), presumably increasing
well studied in these conditions
serotonergic neurotransmission
• Blocks norepinephrine reuptake pump If It Doesn’t Work
(norepinephrine transporter), presumably
• Many depressed patients only have a
increasing noradrenergic
partial response where some symptoms
neurotransmission
are improved but others persist (especially
• Presumably desensitizes both serotonin 1A
insomnia, fatigue, and problems
receptors and beta adrenergic receptors
concentrating)
• Since dopamine is inactivated by
• Other depressed patients may be
norepinephrine reuptake in frontal cortex,
nonresponders, sometimes called
which largely lacks dopamine transporters,
treatment-resistant or treatment-refractory
doxepin can thus increase dopamine
• Consider increasing dose, switching to
neurotransmission in this part of the brain
another agent or adding an appropriate
• May be effective in treating skin conditions
augmenting agent
because of its strong antihistamine
• Consider psychotherapy
properties

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DOXEPIN (continued)

• Consider evaluation for another diagnosis • Patients at risk for electrolyte disturbances
or for a comorbid condition (e.g., medical (e.g., patients on diuretic therapy) should
illness, substance abuse, etc.) have baseline and periodic serum
• Some patients may experience apparent potassium and magnesium measurements
lack of consistent efficacy due to activation
of latent or underlying bipolar disorder, and
require antidepressant discontinuation and SIDE EFFECTS
a switch to a mood stabilizer
How Drug Causes Side Effects
Best Augmenting Combos • Anticholinergic activity may explain
for Partial Response or sedative effects, dry mouth, constipation,
Treatment-Resistance and blurred vision
• Lithium, buspirone, thyroid hormone (for • Sedative effects and weight gain may be
depression) due to antihistamine properties
• Gabapentin, tiagabine, other • Blockade of alpha adrenergic 1 receptors
anticonvulsants, even opiates if done by may explain dizziness, sedation, and
experts while monitoring carefully in hypotension
difficult cases (for chronic pain) • Cardiac arrhythmias and seizures,
especially in overdose, may be caused by
Tests blockade of ion channels
• None for healthy individuals
✽ Since tricyclic and tetracyclic Notable Side Effects
antidepressants are frequently associated • Blurred vision, constipation, urinary
with weight gain, before starting treatment, retention, increased appetite, dry mouth,
weigh all patients and determine if the nausea, diarrhea, heartburn, unusual taste
patient is already overweight in mouth, weight gain
(BMI 25.0–29.9) or obese (BMI ≥30) • Fatigue, weakness, dizziness, sedation,
• Before giving a drug that can cause weight headache, anxiety, nervousness, restlessness
gain to an overweight or obese patient, • Sexual dysfunction, sweating
consider determining whether the patient • Topical: burning, stinging, itching, or
already has pre-diabetes (fasting plasma swelling at application site
glucose 100–125 mg/dl), diabetes (fasting
plasma glucose >126 mg/dl), or
dyslipidemia (increased total cholesterol, Life Threatening or
LDL cholesterol and triglycerides; Dangerous Side Effects
decreased HDL cholesterol), and treat or • Paralytic ileus, hyperthermia (TCAs +
refer such patients for treatment including anticholinergic agents)
nutrition and weight management, physical • Lowered seizure threshold and rare seizures
activity counseling, smoking cessation, and • Orthostatic hypotension, sudden death,
medical management arrhythmias, tachycardia
✽ Monitor weight and BMI during treatment • QTc prolongation
✽ While giving a drug to a patient who has • Hepatic failure, extrapyramidal symptoms
gained >5% of initial weight, consider • Increased intraocular pressure, increased
evaluating for the presence of pre-diabetes, psychotic symptoms
diabetes, or dyslipidemia, or consider • Rare induction of mania and activation of
switching to a different antidepressant suicidal ideation
• EKGs may be useful for selected patients
(e.g., those with personal or family history
Weight Gain
of QTc prolongation; cardiac arrhythmia;
recent myocardial infarction;
uncompensated heart failure; or taking • Many experience and/or can be significant
agents that prolong QTc interval such as in amount
pimozide, thioridazine, selected • Can increase appetite and carbohydrate
antiarrhythmics, moxifloxacin, sparfloxacin, craving
etc.)

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(continued) DOXEPIN

Sedation • Liquid formulation should be diluted with

water or juice, excluding grape juice
• 150 mg capsule available only for
maintenance use, not initial therapy
• Many experience and/or can be significant
in amount ✽ Topical administration is absorbed
systematically and can cause the same
• Tolerance to sedative effect may develop
systematic side effects as oral
with long-term use
administration
What To Do About Side Effects • If intolerable anxiety, insomnia, agitation,
• Wait akathisia, or activation occur either upon
• Wait dosing initiation or discontinuation,
• Wait consider the possibility of activated bipolar
• Lower the dose disorder, and switch to a mood stabilizer or
• Switch to an SSRI or newer antidepressant an atypical antipsychotic

Best Augmenting Agents for Side Overdose

• Death may occur; convulsions, cardiac
Effects
dysrhythmias, severe hypotension, CNS
• Many side effects cannot be improved with
depression, coma, changes in ECG
an augmenting agent
Long-Term Use
• Safe
DOSING AND USE
Habit Forming
Usual Dosage Range • No
• 75–150 mg/day
How to Stop
Dosage Forms • Taper to avoid withdrawal effects
• Capsule 10 mg, 25 mg, 50 mg, 75 mg, • Even with gradual dose reduction some
100 mg, 150 mg withdrawal symptoms may appear within
• Solution 10 mg/mL the first 2 weeks
• Topical 5% • Many patients tolerate 50% dose reduction
for 3 days, then another 50% reduction for
How to Dose 3 days, then discontinuation
• Initial 25 mg/day at bedtime; increase by • If withdrawal symptoms emerge during
25 mg every 3–7 days discontinuation, raise dose to stop
• 75 mg/day; increase gradually until desired symptoms and then restart withdrawal
efficacy is achieved; can be dosed once a much more slowly
day at bedtime or in divided doses;
maximum dose 300 mg/day Pharmacokinetics
• Topical: apply thin film 4 times a day (or • Substrate for CYP450 2D6
every 3–4 hours while awake) • Half-life approximately 8–24 hours

Dosing Tips Drug Interactions

• If given in a single dose, should generally • Tramadol increases the risk of seizures in
be administered at bedtime because of its patients taking TCAs
sedative properties • Use of TCAs with anticholinergic drugs
• If given in split doses, largest dose should may result in paralytic ileus or
generally be given at bedtime because of hyperthermia
its sedative properties • Fluoxetine, paroxetine, bupropion,
• If patients experience nightmares, split duloxetine, and other CYP450 2D6
dose and do not give large dose at bedtime inhibitors may increase TCA concentrations
• Patients treated for chronic pain may only
require lower doses

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DOXEPIN (continued)

• Cimetidine may increase plasma Do Not Use

concentrations of TCAs and cause • If patient is recovering from myocardial
anticholinergic symptoms infarction
• Phenothiazines or haloperidol may raise • If patient is taking agents capable of
TCA blood concentrations significantly prolonging QTc interval (e.g.,
• May alter effects of antihypertensive drugs; pimozide, thioridazine, selected
may inhibit hypotensive effects of clonidine antiarrhythmics, moxifloxacin,
• Use with sympathomimetic agents may sparfloxacin)
increase sympathetic activity • If there is a history of QTc prolongation or
• Methylphenidate may inhibit metabolism of cardiac arrhythmia, recent acute
TCAs myocardial infarction, uncompensated
• Activation and agitation, especially following heart failure
switching or adding antidepressants, may • If patient is taking drugs that inhibit TCA
represent the induction of a bipolar state, metabolism, including CYP450 2D6
especially a mixed dysphoric bipolar II inhibitors, except by an expert
condition sometimes associated with • If there is reduced CYP450 2D6 function,
suicidal ideation, and require the addition such as patients who are poor 2D6
of lithium, a mood stabilizer or an atypical metabolizers, except by an expert and at
antipsychotic, and/or discontinuation of low doses
doxepin • If patient has narrow angle-closure
glaucoma
• If there is a proven allergy to doxepin
Other Warnings/
Precautions
• Add or initiate other antidepressants with
caution for up to 2 weeks after
SPECIAL POPULATIONS
discontinuing doxepin Renal Impairment
• Generally, do not use with MAO inhibitors,
• Use with caution
including 14 days after MAOIs are stopped;
do not start an MAOI until 2 weeks after Hepatic Impairment
discontinuing doxepin, but see Pearls • Use with caution – may need lower than
• Use with caution in patients with history of usual adult dose
seizures, urinary retention, narrow angle-
closure glaucoma, hyperthyroidism Cardiac Impairment
• TCAs can increase QTc interval, especially • TCAs have been reported to cause
at toxic doses, which can be attained not arrhythmias, prolongation of conduction
only by overdose but also by combining time, orthostatic hypotension, sinus
with drugs that inhibit TCA metabolism via tachycardia, and heart failure, especially in
CYP450 2D6, potentially causing torsade the diseased heart
de pointes-type arrhythmia or sudden • Myocardial infarction and stroke have been
death reported with TCAs
• Because TCAs can prolong QTc interval, • TCAs produce QTc prolongation, which
use with caution in patients who have may be enhanced by the existence of
bradycardia or who are taking drugs that bradycardia, hypokalemia, congenital or
can induce bradycardia (e.g., beta blockers, acquired long QTc interval, which should
calcium channel blockers, clonidine, be evaluated prior to administering doxepin
digitalis) • Use with caution if treating concomitantly
• Because TCAs can prolong QTc interval, with a medication likely to produce
use with caution in patients who have prolonged bradycardia, hypokalemia,
hypokalemia and/or hypomagnesemia or slowing of intracardiac conduction, or
who are taking drugs that can induce prolongation of the QTc interval
hypokalemia and/or magnesemia (e.g., • Avoid TCAs in patients with a known
diuretics, stimulant laxatives, intravenous history of QTc prolongation, recent acute
amphotericin B, glucocorticoids, myocardial infarction, and uncompensated
tetracosactide) heart failure

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(continued) DOXEPIN

• TCAs may cause a sustained increase in risk of no treatment (recurrence of

heart rate in patients with ischemic heart depression, maternal health, infant
disease and may worsen (decrease) heart bonding) to the mother and child
rate variability, an independent risk of • For many patients this may mean
mortality in cardiac populations continuing treatment during pregnancy
• Since SSRIs may improve (increase) heart
rate variability in patients following a Breast Feeding
myocardial infarct and may improve • Some drug is found in mother’s breast milk
survival as well as mood in patients with • Significant drug levels have been detected
acute angina or following a myocardial in some nursing infants
infarction, these are more appropriate ✽ Recommended either to discontinue drug
agents for cardiac population than or bottle feed
tricyclic/tetracyclic antidepressants • Immediate postpartum period is a high-risk
✽ Risk/benefit ratio may not justify use of time for depression, especially in women
TCAs in cardiac impairment who have had prior depressive episodes,
so drug may need to be reinstituted late in
Elderly the third trimester or shortly after
• May be more sensitive to anticholinergic, childbirth to prevent a recurrence during
cardiovascular, hypotensive, and sedative the postpartum period
effects • Must weigh benefits of breast feeding with
risks and benefits of antidepressant
treatment versus non-treatment to both the
Children and Adolescents infant and the mother
• Use with caution, observing for activation • For many patients this may mean
of known or unknown bipolar disorder continuing treatment during breast feeding
and/or suicidal ideation, and strongly
consider informing parents or guardian of
this risk so they can help observe child or THE ART OF PSYCHOPHARMACOLOGY
adolescent patients
• Not recommended for use under age 12 Potential Advantages
• Several studies show lack of efficacy of • Patients with insomnia
TCAs for depression • Severe or treatment-resistant depression
• May be used to treat enuresis or • Patients with neuro-dermatitis and itching
hyperactive/impulsive behaviors
• Some cases of sudden death have Potential Disadvantages
occurred in children taking TCAs • Pediatric and geriatric patients
• Initial dose 25–50 mg/day; maximum 100 • Patients concerned with weight gain
mg/day • Cardiac patients

Primary Target Symptoms

• Depressed mood
Pregnancy • Anxiety
• Risk Category C [some animal studies • Disturbed sleep, energy
show adverse effects, no controlled studies • Somatic symptoms
in humans] • Itching skin
• Crosses the placenta
• Adverse effects have been reported in
infants whose mothers took a TCA
(lethargy, withdrawal symptoms, fetal
Pearls
malformations) ✽ Only TCA available in topical formulation
• Not generally recommended for use during ✽ Topical administration may reduce
pregnancy, especially during first trimester symptoms in patients with various neuro-
• Must weigh the risk of treatment (first dermatitis syndromes, especially itching
trimester fetal development, third trimester • Tricyclic antidepressants are often a first-
newborn delivery) to the child against the line treatment option for chronic pain

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DOXEPIN (continued)

• Tricyclic antidepressants are no longer observed to prevent hypertensive crises

generally considered a first-line option for and serotonin syndrome, the most
depression because of their side effect common side effects of MAOI/tricyclic or
profile tetracyclic combinations may be weight
• Tricyclic antidepressants continue to be gain and orthostatic hypotension
useful for severe or treatment-resistant • Patients on TCAs should be aware that they
depression may experience symptoms such as
• TCAs may aggravate psychotic symptoms photosensitivity or blue-green urine
• Alcohol should be avoided because of • SSRIs may be more effective than TCAs in
additive CNS effects women, and TCAs may be more effective
• Underweight patients may be more than SSRIs in men
susceptible to adverse cardiovascular • Since tricyclic/tetracyclic antidepressants
effects are substrates for CYP450 2D6, and 7% of
• Children, patients with inadequate the population (especially Caucasians) may
hydration, and patients with cardiac have a genetic variant leading to reduced
disease may be more susceptible to TCA- activity of 2D6, such patients may not
induced cardiotoxicity than healthy adults safely tolerate normal doses of
• For the expert only: although generally tricyclic/tetracyclic antidepressants and
prohibited, a heroic but potentially may require dose reduction
dangerous treatment for severely • Phenotypic testing may be necessary to
treatment-resistant patients is to give a detect this genetic variant prior to dosing
tricyclic/tetracyclic antidepressant other with a tricyclic/tetracyclic antidepressant,
than clomipramine simultaneously with an especially in vulnerable populations such
MAO inhibitor for patients who fail to as children, elderly, cardiac populations,
respond to numerous other and those on concomitant medications
antidepressants • Patients who seem to have extraordinarily
• If this option is elected, start the MAOI with severe side effects at normal or low doses
the tricyclic/tetracyclic antidepressant may have this phenotypic CYP450 2D6
simultaneously at low doses after variant and require low doses or switching
appropriate drug washout, then alternately to another antidepressant not metabolized
increase doses of these agents every few by 2D6
days to a week as tolerated
• Although very strict dietary and
concomitant drug restrictions must be

Suggested Reading
Anderson IM. Meta-analytical studies on new Godfrey RG. A guide to the understanding and
antidepressants. Br Med Bull 2001; use of tricyclic antidepressants in the overall
57:161–178. management of fibromyalgia and other chronic
pain syndromes. Arch Intern Med 1996;
Anderson IM. Selective serotonin reuptake 156:1047–52.
inhibitors versus tricyclic antidepressants: a
meta-analysis of efficacy and tolerability. J Aff
Disorders 2000;58:19–36.

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DULOXETINE
THERAPEUTICS If It Works
• The goal of treatment of depression and
Brands • Cymbalta
anxiety disorders is complete remission of
see index for additional brand names
current symptoms as well as prevention of
Generic? No future relapses
• The goal of treatment of fibromyalgia and
chronic neuropathic pain is to reduce
symptoms as much as possible, especially
Class in combination with other treatments
• SNRI (dual serotonin and norepinephrine • Treatment of depression most often
reuptake inhibitor); may be classified as an reduces or even eliminates symptoms, but
antidepressant, but it is not just an is not a cure since symptoms can recur
antidepressant after medicine stopped
• Treatment of fibromyalgia and chronic
Commonly Prescribed For neuropathic pain may reduce symptoms,
(bold for FDA approved) but rarely eliminates them completely, and
• Major depressive disorder is not a cure since symptoms can recur
• Stress urinary incontinence after medicine is stopped
• Neuropathic pain/chronic pain • Continue treatment of depression and
• Fibromyalgia anxiety disorders until all symptoms are
• Generalized anxiety disorder gone (remission)
• Other anxiety disorders • Once symptoms of depression are gone,
continue treating for 1 year for the first
episode of depression
How The Drug Works • For second and subsequent episodes of
• Boosts neurotransmitters serotonin, depression, treatment may need to be
norepinephrine/noradrenaline, and indefinite
dopamine • Use in fibromyalgia and chronic
• Blocks serotonin reuptake pump (serotonin neuropathic pain may also need to be
transporter), presumably increasing indefinite, but long-term treatment is not
serotonergic neurotransmission well studied in these conditions
• Blocks norepinephrine reuptake pump
(norepinephrine transporter), presumably If It Doesn’t Work
increasing noradrenergic • Many depressed patients only have a
neurotransmission partial response where some symptoms
• Presumably desensitizes both serotonin 1A are improved but others persist (especially
receptors and beta adrenergic receptors insomnia, fatigue, and problems
• Since dopamine is inactivated by concentrating)
norepinephrine reuptake in frontal cortex, • Other patients may be nonresponders,
which largely lacks dopamine transporters, sometimes called treatment-resistant or
duloxetine can increase dopamine treatment-refractory
neurotransmission in this part of the brain • Some patients who have an initial response
• Weakly blocks dopamine reuptake pump may relapse even though they continue
(dopamine transporter), and may increase treatment, sometimes called “poop-out”
dopamine neurotransmission • Consider increasing dose, switching to
another agent or adding an appropriate
How Long Until It Works augmenting agent
• Onset of therapeutic actions usually not • Consider psychotherapy
immediate, but often delayed 2 to 4 weeks • Consider evaluation for another diagnosis
• If it is not working within 6 to 8 weeks for or for a comorbid condition (e.g., medical
depression, it may require a dosage illness, substance abuse, etc.)
increase or it may not work at all • Some patients may experience apparent
• May continue to work for many years to lack of consistent efficacy due to activation
prevent relapse of symptoms of latent or underlying bipolar disorder, and

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DULOXETINE (continued)

require antidepressant discontinuation and receptors in parts of the brain and body
a switch to a mood stabilizer other than those that cause therapeutic
actions (e.g., unwanted actions of
Best Augmenting Combos serotonin in sleep centers causing
for Partial Response or insomnia, unwanted actions of
Treatment-Resistance norepinephrine on acetylcholine release
✽ Augmentation experience is limited causing decreased appetite, increased
compared to other antidepressants blood pressure, urinary retention, etc.)
✽ Adding other agents to duloxetine for • Most side effects are immediate but often
treating depression could follow the same go away with time
practice for augmenting SSRIs or other
SNRIs if done by experts while monitoring Notable Side Effects
carefully in difficult cases • Insomnia, sedation
• Although no controlled studies and little • Nausea, diarrhea, decreased appetite
clinical experience, adding other agents for • Sexual dysfunction (men: abnormal
treating fibromyalgia and neuropathic pain ejaculation/orgasm, impotence, decreased
could theoretically include gabapentin, libido; women: abnormal orgasm)
pregabalin, and tiagabine, if done by • Sweating
experts while monitoring carefully in • Increase in blood pressure (up to 2 mm Hg)
difficult cases
• Mirtazapine (“California rocket fuel”; a Life Threatening or
potentially powerful dual serotonin and
Dangerous Side Effects
norepinephrine combination, but observe
• Rare seizures
for activation of bipolar disorder and
• Rare induction of hypomania and activation
suicidal ideation)
of suicidal ideation, suicide attempts, and
• Bupropion, reboxetine, nortriptyline,
completed suicide
desipramine, maprotiline, atomoxetine (all
potentially powerful enhancers of Weight Gain
noradrenergic action, but observe for
activation of bipolar disorder and suicidal
ideation)
• Modafinil, especially for fatigue, sleepiness, • Reported but not expected
and lack of concentration
• Mood stabilizers or atypical antipsychotics Sedation
for bipolar depression, psychotic
depression or treatment-resistant
depression • Occurs in significant minority
• Benzodiazepines • May also be activating in some patients
• If all else fails for anxiety disorders,
consider gabapentin or tiagabine What To Do About Side Effects
• Hypnotics or trazodone for insomnia • Wait
• Classically, lithium, buspirone, or thyroid • Wait
hormone • Wait
• Lower the dose
Tests • In a few weeks, switch or add other drugs
• Check blood pressure before initiating
treatment and regularly during treatment Best Augmenting Agents for Side
Effects
• For urinary hesitancy, give an alpha 1
SIDE EFFECTS blocker such as tamsulosin
• Often best to try another antidepressant
How Drug Causes Side Effects monotherapy prior to resorting to
• Theoretically due to increases in serotonin augmentation strategies to treat side
and norepinephrine concentrations at effects

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(continued) DULOXETINE

• Trazodone or a hypnotic for insomnia • Some studies suggest that both serotonin
• Bupropion, sildenafil, vardenafil, or tadalafil and norepinephrine reuptake blockade are
for sexual dysfunction present at 40–60 mg/day
• Benzodiazepines for jitteriness and anxiety, • Do not chew or crush and do not sprinkle
especially at initiation of treatment and on food or mix with food, but rather always
especially for anxious patients swallow whole to avoid affecting enteric
• Mirtazapine for insomnia, agitation, and coating
gastrointestinal side effects
• Many side effects are dose-dependent (i.e., Overdose
they increase as dose increases, or they • No fatalities have been reported
reemerge until tolerance re-develops)
• Many side effects are time-dependent (i.e., Long-Term Use
they start immediately upon dosing and • Blood pressure should be monitored
upon each dose increase, but go away with regularly
time)
• Activation and agitation may represent the Habit Forming
induction of a bipolar state, especially a • No
mixed dysphoric bipolar II condition
How to Stop
sometimes associated with suicidal
• Taper to avoid withdrawal effects
ideation, and require the addition of
(dizziness, nausea, vomiting, headache,
lithium, a mood stabilizer or an atypical
paresthesias, irritability)
antipsychotic, and/or discontinuation of
• Many patients tolerate 50% dose reduction
duloxetine
for 3 days, then another 50% reduction for
3 days, then discontinuation
DOSING AND USE
✽ If withdrawal symptoms emerge during
discontinuation, raise dose to stop
symptoms and then restart withdrawal
Usual Dosage Range
much more slowly
• 40–60 mg/day in 1–2 doses for depression
• 40 mg twice daily for stress urinary Pharmacokinetics
incontinence • Elimination half-life approximately 12 hours
• Metabolized mainly by CYP450 2D6 and
Dosage Forms
CYP450 1A2
• Capsule 20 mg, 30 mg, 60 mg
• Inhibitor of CYP450 2D6 and CYP450 1A2
How to Dose • Absorption may be delayed by up to
3 hours and clearance may be increased by
• Initial 40 mg/day in 1–2 doses; can
one-third after an evening dose as
increase to 60 mg/day if necessary;
compared to a morning dose
maximum dose generally 120 mg/day

Dosing Tips Drug Interactions

• Can increase tricyclic antidepressant levels;
• Studies have not demonstrated increased
use with caution with tricyclic
efficacy beyond 60 mg/day
antidepressants or when switching from a
✽ Some patients may require up to or more TCA to duloxetine
than 120 mg/day, but clinical experience is
• Can cause a fatal “serotonin syndrome”
quite limited with high dosing
when combined with MAO inhibitors, so do
• Dosing for neuropathic pain and
not use with MAO inhibitors or for at least
fibromyalgia may be similar to that for
14 days after MAOIs are stopped
depression but different from dosing for
• Do not start an MAO inhibitor for at least 5
stress urinary incontinence, but clinical
days after discontinuing duloxetine
experience is still evolving
• Inhibitors of CYP450 1A2, such as
fluvoxamine, may increase plasma levels of

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DULOXETINE (continued)

duloxetine and require a dosage reduction SPECIAL POPULATIONS

of duloxetine
• Cigarette smoking induces CYP450 1A2
Renal Impairment
and may reduce plasma levels of • Dose adjustment generally not necessary
duloxetine, but dosage modifications are for mild impairment
not recommended for smokers • Not recommended for use in patients with
✽ Inhibitors of CYP450 2D6, such as end-stage renal disease
paroxetine, fluoxetine, and quinidine, may
Hepatic Impairment
increase plasma levels of duloxetine and
• Not recommended for use in patients with
require a dosage reduction of duloxetine
hepatic impairment
• Via CYP450 1A2 inhibition, duloxetine
could theoretically reduce clearance of Cardiac Impairment
theophylline and clozapine; however, • Drug should be used with caution
studies of co-administration with • Duloxetine may raise blood pressure
theophylline did not demonstrate
significant effects of duloxetine on Elderly
theophylline pharmacokinetics • Some patients may tolerate lower doses
• Via CYP450 2D6 inhibition, duloxetine better
could theoretically interfere with the
analgesic actions of codeine, and increase
the plasma levels of some beta blockers
and of atomoxetine
Children and Adolescents
• Via CYP450 2D6 inhibition, duloxetine • Use with caution, observing for activation
could theoretically increase concentrations of known or unknown bipolar disorder
of thioridazine and cause dangerous and/or suicidal ideation, and strongly
cardiac arrhythmias consider informing parents or guardian of
this risk so they can help observe child or
adolescent patients
Other Warnings/ • Not specifically approved, but can be used
Precautions by experts
• Use with caution in patients with history of
seizures
• Use with caution in patients with bipolar Pregnancy
disorder unless treated with concomitant • Risk Category C [some animal studies
mood stabilizing agent show adverse effects, no controlled studies
• Monitor patients for activation of suicidal in humans]
ideation, especially children and • Not generally recommended for use during
adolescents pregnancy, especially during first trimester
• Duloxetine may increase blood pressure, • Nonetheless, continuous treatment during
so blood pressure should be monitored pregnancy may be necessary and has not
during treatment been proven to be harmful to the fetus
• Must weigh the risk of treatment (first
Do Not Use trimester fetal development, third trimester
• If patient has uncontrolled narrow angle- newborn delivery) to the child against the
closure glaucoma risk of no treatment (recurrence of
• If patient has substantial alcohol use depression, maternal health, infant
• If patient is taking an MAO inhibitor bonding) to the mother and child
• If patient is taking thioridazine • For many patients this may mean
• If there is a proven allergy to duloxetine continuing treatment during pregnancy
• Neonates exposed to SSRIs or SNRIs late
in the third trimester have developed
complications requiring prolonged
hospitalization, respiratory support, and
tube feeding; reported symptoms are
consistent with either a direct toxic effect

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(continued) DULOXETINE

of SSRIs and SNRIs or, possibly, a drug Potential Disadvantages

discontinuation syndrome, and include • Patients with urologic disorders, prostate
respiratory distress, cyanosis, apnea, disorders (e.g., older men)
seizures, temperature instability, feeding • Patients sensitive to nausea
difficulty, vomiting, hypoglycemia,
hypotonia, hypertonia, hyperreflexia, Primary Target Symptoms
tremor, jitteriness, irritability, and constant • Depressed mood
crying • Energy, motivation, and interest
• Sleep disturbance
Breast Feeding • Physical symptoms
• Unknown if duloxetine is secreted in • Pain
human breast milk, but all psychotropics
assumed to be secreted in breast milk
• If child becomes irritable or sedated, breast Pearls
feeding or drug may need to be
discontinued
✽ Duloxetine has well-documented efficacy
for the physical symptoms of depression
• Immediate postpartum period is a high-risk • Duloxetine has only somewhat greater
time for depression, especially in women potency for serotonin reuptake blockade
who have had prior depressive episodes, than for norepinephrine reuptake blockade,
so drug may need to be reinstituted late in but this is of unclear clinical significance as
the third trimester or shortly after a differentiator from other SNRIs
childbirth to prevent a recurrence during • No head-to-head studies, but may have
the postpartum period less hypertension than venlafaxine XR
• Must weigh benefits of breast feeding with • Powerful pro-noradrenergic actions may
risks and benefits of antidepressant occur at doses greater than 60 mg/day
treatment versus non-treatment to both the • Not well-studied in ADHD or anxiety
infant and the mother disorders, but may be effective
• For many patients, this may mean
continuing treatment during breast feeding
✽ Well-studied in stress urinary
incontinence and approval for this use is
expected
• Patients may have higher remission rate
THE ART OF PSYCHOPHARMACOLOGY for depression on SNRIs than on SSRIs
• Add or switch to or from pro-noradrenergic
Potential Advantages agents (e.g., atomoxetine, reboxetine, other
• Patients with physical symptoms of SNRIs, mirtazapine, maprotiline,
depression nortriptyline, desipramine, bupropion) with
• Patients with retarded depression caution
• Patients with atypical depression • Add or switch to or from CYP450 2D6
• Patients with depression may have higher substrates with caution (e.g., atomoxetine,
remission rates on SNRIs than on SSRIs maprotiline, nortriptyline, desipramine)
• Depressed patients with somatic • Mechanism of action as SNRI suggests it
symptoms, fatigue, and pain may be effective in some patients who fail
• Patients who do not respond or do not to respond to SSRIs
remit on treatment with SSRIs

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DULOXETINE (continued)

Suggested Reading
Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld Goldstein DJ, Mallinckrodt C, Lu Y, Demitrack
PG, Shaw JL, Thompson L, Nelson DL, MA. Duloxetine in the treatment of major
Hemrick-Luecke SK, Wong DT. Comparative depressive disorder: a double-blind clinical
affinity of duloxetine and venlafaxine for trial. J Clin Psychiatry 2002;63(3):225–31.
serotonin and norepinephrine transporters in
vitro and in vivo, human serotonin receptor Karpa KD, Cavanaugh JE, Lakoski JM.
subtypes, and other neuronal receptors. Duloxetine pharmacology: profile of a dual
Neuropsychopharmacology 2001; monoamine modulator. CNS Drug Rev
25(6):871–80. 2002;8(4):361–76.

Detke MJ, Lu Y, Goldstein DJ, Hayes JR, Zinner NR. Duloxetine: a serotonin-
Demitrack MA. Duloxetine, 60 mg once daily, noradrenaline re-uptake inhibitor for the
for major depressive disorder: a randomized treatment of stress urinary incontinence.
double-blind placebo-controlled trial. J Clin Expert Opin Investig Drugs 2003;
Psychiatry 2002;63(4):308–15. 12(9):1559–66.

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ESCITALOPRAM
THERAPEUTICS • Once symptoms gone, continue treating for
1 year for the first episode of depression
Brands • Lexapro • For second and subsequent episodes of
see index for additional brand names depression, treatment may need to be
indefinite
Generic? Not in the U.S. or Europe
• Use in anxiety disorders may also need to
be indefinite

Class If It Doesn’t Work

• SSRI (selective serotonin reuptake • Many patients only have a partial response
inhibitor); often classified as an where some symptoms are improved but
antidepressant, but it is not just an others persist (especially insomnia, fatigue,
antidepressant and problems concentrating in depression)
• Other patients may be nonresponders,
Commonly Prescribed For sometimes called treatment-resistant or
(bold for FDA approved) treatment-refractory
• Major depressive disorder • Some patients who have an initial response
• Generalized anxiety disorder may relapse even though they continue
• Panic disorder treatment, sometimes called “poop-out”
• Obsessive-compulsive disorder (OCD) • Consider increasing dose, switching to
• Posttraumatic stress disorder (PTSD) another agent or adding an appropriate
• Social anxiety disorder (social phobia) augmenting agent
• Premenstrual dysphoric disorder (PMDD) • Consider psychotherapy
• Consider evaluation for another diagnosis
or for a comorbid condition (e.g., medical
How The Drug Works illness, substance abuse, etc.)
• Boosts neurotransmitter serotonin • Some patients may experience apparent
• Blocks serotonin reuptake pump (serotonin lack of consistent efficacy due to activation
transporter) of latent or underlying bipolar disorder, and
• Desensitizes serotonin receptors, especially require antidepressant discontinuation and
serotonin 1A autoreceptors a switch to a mood stabilizer
• Presumably increases serotonergic
neurotransmission Best Augmenting Combos
for Partial Response or
How Long Until It Works Treatment-Resistance
• Onset of therapeutic actions usually not • Trazodone, especially for insomnia
immediate, but often delayed 2 to 4 weeks • Bupropion, mirtazapine, reboxetine, or
• If it is not working within 6 to 8 weeks, it atomoxetine (use combinations of
may require a dosage increase or it may antidepressants with caution as this may
not work at all activate bipolar disorder and suicidal
• May continue to work for many years to ideation)
prevent relapse of symptoms • Modafinil, especially for fatigue, sleepiness,
and lack of concentration
If It Works • Mood stabilizers or atypical antipsychotics
• The goal of treatment is complete for bipolar depression, psychotic
remission of current symptoms as well as depression, treatment-resistant depression,
prevention of future relapses or treatment-resistant anxiety disorders
• Treatment most often reduces or even • Benzodiazepines
eliminates symptoms, but not a cure since • If all else fails for anxiety disorders,
symptoms can recur after medicine consider gabapentin or tiagabine
stopped • Hypnotics for insomnia
• Continue treatment until all symptoms are • Classically, lithium, buspirone, or thyroid
gone (remission) or significantly reduced hormone
(e.g., OCD, PTSD)

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ESCITALOPRAM (continued)

Tests Weight Gain

• None for healthy individuals

• Reported but not expected

SIDE EFFECTS
Sedation
How Drug Causes Side Effects
• Theoretically due to increases in serotonin
concentrations at serotonin receptors in
parts of the brain and body other than • Reported but not expected
those that cause therapeutic actions (e.g.,
What To Do About Side Effects
unwanted actions of serotonin in sleep
• Wait
centers causing insomnia, unwanted
• Wait
actions of serotonin in the gut causing
• Wait
diarrhea, etc.)
• In a few weeks, switch to another agent or
• Increasing serotonin can cause diminished
add other drugs
dopamine release and might contribute to
emotional flattening, cognitive slowing, and Best Augmenting Agents for Side
apathy in some patients
Effects
• Most side effects are immediate but often
• Often best to try another SSRI or another
go away with time, in contrast to most
antidepressant monotherapy prior to
therapeutic effects which are delayed and
resorting to augmentation strategies to
are enhanced over time
treat side effects
✽ As escitalopram has no known important • Trazodone or a hypnotic for insomnia
secondary pharmacologic properties, its
• Bupropion, sildenafil, vardenafil, or tadalafil
side effects are presumably all mediated by
for sexual dysfunction
its serotonin reuptake blockade
• Bupropion for emotional flattening,
Notable Side Effects cognitive slowing, or apathy
• Sexual dysfunction (men: delayed • Mirtazapine for insomnia, agitation, and
ejaculation, erectile dysfunction; men and gastrointestinal side effects
women: decreased sexual desire, • Benzodiazepines for jitteriness and anxiety,
anorgasmia) especially at initiation of treatment and
• Gastrointestinal (decreased appetite, especially for anxious patients
nausea, diarrhea, constipation, dry mouth) • Many side effects are dose-dependent (i.e.,
• Mostly central nervous system (insomnia they increase as dose increases, or they
but also sedation, agitation, tremors, reemerge until tolerance re-develops)
headache, dizziness) • Many side effects are time-dependent (i.e.,
• Note: patients with diagnosed or they start immediately upon dosing and
undiagnosed bipolar or psychotic disorders upon each dose increase, but go away with
may be more vulnerable to CNS-activating time)
actions of SSRIs • Activation and agitation may represent the
• Autonomic (sweating) induction of a bipolar state, especially a
• Bruising and rare bleeding mixed dysphoric bipolar II condition
• Rare hyponatremia (mostly in elderly sometimes associated with suicidal
patients and generally reversible on ideation, and require the addition of
discontinuation of escitalopram lithium, a mood stabilizer or an atypical
antipsychotic, and/or discontinuation of
escitalopram
Life Threatening or
Dangerous Side Effects
• Rare seizures
• Rare induction of mania and activation of
suicidal ideation

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(continued) ESCITALOPRAM

DOSING AND USE • Many patients tolerate 50% dose reduction

for 3 days, then another 50% reduction for
Usual Dosage Range 3 days, then discontinuation
• 10–20 mg/day • If withdrawal symptoms emerge during
• Oral solution 5 mg/5 mL discontinuation, raise dose to stop
symptoms and then restart withdrawal
Dosage Forms
much more slowly
• Tablets 10 mg, 20 mg
Pharmacokinetics
How to Dose
• Mean terminal half-life 27–32 hours
• Initial 10 mg/day; increase to 20 mg/day if
• Steady-state plasma concentrations
necessary; single dose administration,
achieved within 1 week
morning or evening
• No significant actions on CYP450 enzymes

Dosing Tips Drug Interactions

• Given once daily, any time of day tolerated
• Tramadol increases the risk of seizures in
✽ 10 mg of escitalopram may be patients taking an antidepressant
comparable in efficacy to 40 mg of
• Can cause a fatal “serotonin syndrome”
citalopram with fewer side effects
when combined with MAO inhibitors, so do
• Thus, give an adequate trial of 10 mg prior
not use with MAO inhibitors or for at least
to giving 20 mg
14 days after MAOIs are stopped
• Some patients require dosing with 30 or
• Do not start an MAO inhibitor for at least
40 mg
2 weeks after discontinuing escitalopram
• If intolerable anxiety, insomnia, agitation,
• Could theoretically cause weakness,
akathisia, or activation occur either upon
hyperreflexia, and incoordination when
dosing initiation or discontinuation,
combined with sumatriptan or possibly
consider the possibility of activated bipolar
other triptans, requiring careful monitoring
disorder and switch to a mood stabilizer or
of patient
an atypical antipsychotic
• Few known adverse drug interactions
Overdose
• Few reports of escitalopram overdose, but Other Warnings/
probably similar to citalopram overdose Precautions
• Rare fatalities have been reported in • Use with caution in patients with history of
citalopram overdose, both in combination seizures
with other drugs and alone • Use with caution in patients with bipolar
• Symptoms associated with citalopram disorder unless treated with concomitant
overdose include vomiting, sedation, heart mood stabilizing agent
rhythm disturbances, dizziness, sweating, • Monitor patients for activation of suicidal
nausea, tremor, and rarely amnesia, ideation, especially children and
confusion, coma, convulsions adolescents
Long-Term Use Do Not Use
• Safe • If patient is taking an MAO inhibitor
• If there is a proven allergy to escitalopram
Habit Forming or citalopram
• No

How to Stop
• Taper not usually necessary SPECIAL POPULATIONS
• However, tapering to avoid potential
withdrawal reactions generally prudent
Renal Impairment
• Few data available for use in patients with
renal impairment, but start with 10 mg/day

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ESCITALOPRAM (continued)

Hepatic Impairment consistent with either a direct toxic effect

• Recommended dose 10 mg/day of SSRIs and SNRIs or, possibly, a drug
discontinuation syndrome, and include
Cardiac Impairment respiratory distress, cyanosis, apnea,
• Not systematically evaluated in patients seizures, temperature instability, feeding
with cardiac impairment difficulty, vomiting, hypoglycemia,
• Preliminary data suggest that citalopram is hypotonia, hypertonia, hyperreflexia,
safe in patients with cardiac impairment, tremor, jitteriness, irritability, and constant
suggesting that escitalopram is also safe crying
• Treating depression with SSRIs in patients
with acute angina or following myocardial Breast Feeding
infarction may reduce cardiac events and • Some drug is found in mother’s breast milk
improve survival as well as mood • Trace amounts may be present in nursing
children whose mothers are on
Elderly escitalopram
• Recommended dose 10 mg/day • If child becomes irritable or sedated, breast
feeding or drug may need to be
discontinued
Children and Adolescents • Immediate postpartum period is a high-risk
• Safety and efficacy have not been time for depression, especially in women
established who have had prior depressive episodes,
• Use with caution, observing for activation so drug may need to be reinstituted late in
of known or unknown bipolar disorder the third trimester or shortly after
and/or suicidal ideation, and strongly childbirth to prevent a recurrence during
consider informing parents or guardian of the postpartum period
this risk so they can help observe child or • Must weigh benefits of breast feeding with
adolescent patients risks and benefits of antidepressant
treatment versus non-treatment to both the
infant and the mother
• For many patients, this may mean
Pregnancy continuing treatment during breast feeding
• Risk Category C [some animal studies
show adverse effects, no controlled studies
in humans]
• Not generally recommended for use during THE ART OF PSYCHOPHARMACOLOGY
pregnancy, especially during first trimester
Potential Advantages
• Nonetheless, continuous treatment during
• Patients taking concomitant medications
pregnancy may be necessary and has not
(few drug interactions and fewer even than
been proven to be harmful to the fetus
with citalopram)
• At delivery there may be more bleeding in
• Patients requiring faster onset of action
the mother and transient irritability or
sedation in the newborn Potential Disadvantages
• Must weigh the risk of treatment (first • More expensive than citalopram in markets
trimester fetal development, third trimester where citalopram is generic
newborn delivery) to the child against the
risk of no treatment (recurrence of Primary Target Symptoms
depression, maternal health, infant • Depressed mood
bonding) to the mother and child • Anxiety
• For many patients, this may mean • Panic attacks, avoidant behavior, re-
continuing treatment during pregnancy experiencing, hyperarousal
• Neonates exposed to SSRIs or SNRIs late • Sleep disturbance, both insomnia and
in the third trimester have developed hypersomnia
complications requiring prolonged
hospitalization, respiratory support, and
tube feeding; reported symptoms are

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(continued) ESCITALOPRAM

norepinephrine reuptake inhibitors, but this

is not proven
Pearls ✽ Escitalopram is commonly used with
✽ May be among the best-tolerated augmenting agents, as it is the SSRI with
antidepressants the least interaction at either CYP450 2D6
• May have less sexual dysfunction than or 3A4, therefore causing fewer
some other SSRIs pharmacokinetically-mediated drug
• May be better tolerated than citalopram interactions with augmenting agents than
• Can cause cognitive and affective other SSRIs
“flattening” • SSRIs may be less effective in women over
✽ R-citalopram may interfere with the 50, especially if they are not taking
binding of S-citalopram at the serotonin estrogen
transporter • SSRIs may be useful for hot flushes in
✽ For this reason, S-citalopram may be perimenopausal women
more than twice as potent as • Some postmenopausal women’s
R,S-citalopram (i.e., citalopram) depression will respond better to
• Thus, 10 mg starting dose of S-citalopram escitalopram plus estrogen augmentation
may have the therapeutic efficacy of 40 mg than to escitalopram alone
of R,S-citalopram • Nonresponse to escitalopram in elderly
• Thus, escitalopram may have faster onset may require consideration of mild cognitive
and better efficacy with reduced side impairment or Alzheimer disease
effects compared to R,S-citalopram
• Some data may actually suggest remission
rates comparable to dual serotonin and

Suggested Reading
Baldwin DS. Escitalopram: efficacy and Waugh J, Goa KL. Escitalopram : a review of
tolerability in the treatment of depression. its use in the management of major depressive
Hosp Med. 2002;63:668–71. and anxiety disorders. CNS Drugs.
2003;17:343–62.
Burke WJ. Escitalopram. Expert Opin Investig
Drugs. 2002;11(10):1477–86.
Edwards JG, Anderson I. Systematic review
and guide to selection of selective serotonin
reuptake inhibitors. Drugs. 1999;57:507–533.

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ESTAZOLAM
THERAPEUTICS • Agents with antihistamine actions (e.g.,
diphenhydramine, tricyclic antidepressants)
Brands • ProSom
see index for additional brand names Tests
• In patients with seizure disorders,
Generic? Yes concomitant medical illness, and/or those
with multiple concomitant long-term
medications, periodic liver tests and blood
Class counts may be prudent
• Benzodiazepine (hypnotic)

Commonly Prescribed For SIDE EFFECTS

(bold for FDA approved)
• Insomnia characterized by difficulty in How Drug Causes Side Effects
falling asleep, frequent nocturnal • Same mechanism for side effects as for
awakenings, and/or early morning therapeutic effects – namely due to excessive
awakenings actions at benzodiazepine receptors
• Actions at benzodiazepine receptors that
carry over to next day can cause daytime
How The Drug Works sedation, amnesia, and ataxia
• Binds to benzodiazepine receptors at the • Long-term adaptations in benzodiazepine
GABA-A ligand-gated chloride channel receptors may explain the development of
complex dependence, tolerance, and withdrawal
• Enhances the inhibitory effects of GABA
• Boosts chloride conductance through Notable Side Effects
GABA-regulated channels ✽ Sedation, fatigue, depression
• Inhibitory actions in sleep centers may ✽ Dizziness, ataxia, slurred speech,
provide sedative hypnotic effects weakness
✽ Forgetfulness, confusion
How Long Until It Works ✽ Hyper-excitability, nervousness
• Generally takes effect in less than an hour • Rare hallucinations, mania
• Rare hypotension
If It Works • Hypersalivation, dry mouth
• Improves quality of sleep • Rebound insomnia when withdrawing from
• Effects on total wake-time and number of long-term treatment
nighttime awakenings may be decreased
over time
Life Threatening or
If It Doesn’t Work Dangerous Side Effects
• If insomnia does not improve after • Respiratory depression, especially when
7–10 days, it may be a manifestation of a taken with CNS depressants in overdose
primary psychiatric or physical illness such • Rare hepatic dysfunction, renal
as obstructive sleep apnea or restless leg dysfunction, blood dyscrasias
syndrome, which requires independent
evaluation Weight Gain
• Increase the dose
• Improve sleep hygiene
• Switch to another agent • Reported but not expected
Best Augmenting Combos Sedation
for Partial Response or
Treatment-Resistance
• Generally, best to switch to another agent
• Many experience and/or can be significant
• Trazodone
in amount

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ESTAZOLAM (continued)

What To Do About Side Effects • Some patients may develop dependence

• Wait and/or tolerance; risk may be greater with
• To avoid problems with memory, only take higher doses
estazolam if planning to have a full night’s • History of drug addiction may increase risk
sleep of dependence
• Lower the dose
• Switch to a shorter-acting sedative How to Stop
hypnotic • If taken for more than a few weeks, taper
• Switch to a non-benzodiazepine hypnotic to reduce chances of withdrawal effects
• Administer flumazenil if side effects are • Patients with seizure history may seize
severe or life-threatening upon sudden withdrawal
• Rebound insomnia may occur the first
Best Augmenting Agents for Side 1–2 nights after stopping
Effects • For patients with severe problems
• Many side effects cannot be improved with discontinuing a benzodiazepine, dosing
an augmenting agent may need to be tapered over many months
(i.e., reduce dose by 1% every 3 days by
crushing tablet and suspending or
DOSING AND USE dissolving in 100 ml of fruit juice and then
disposing of 1 ml while drinking the rest;
Usual Dosage Range 3–7 days later, dispose of 2 ml, and so on).
• 1–2 mg/day at bedtime This is both a form of very slow biological
tapering and a form of behavioral
Dosage Forms desensitization
• Tablet 1 mg scored, 2 mg scored
Pharmacokinetics
How to Dose • Half-life 10–24 hours
• Initial 1 mg/day at bedtime; increase to • Inactive metabolites
2 mg/day at bedtime if ineffective

Drug Interactions
Dosing Tips • Increased clearance and thus decreased
• Use lowest possible effective dose and estazolam levels in smokers
assess need for continued treatment • Increased depressive effects when taken
regularly with other CNS depressants
• Estazolam should generally not be
prescribed in quantities greater than a Other Warnings/
1-month supply
Precautions
• Patients with lower body weights may
• Insomnia may be a symptom of a primary
require lower doses
disorder, rather than a primary disorder
• Risk of dependence may increase with
itself
dose and duration of treatment
• Some patients may exhibit abnormal
Overdose thinking or behavioral changes similar to
• No death reported in monotherapy; those caused by other CNS depressants
sedation, slurred speech, poor (i.e., either depressant actions or
coordination, confusion, coma, respiratory disinhibiting actions)
depression • Some depressed patients may experience a
worsening of suicidal ideation
Long-Term Use • Use only with extreme caution in patients
• Not generally intended for long-term use with impaired respiratory function or
• Evidence of efficacy up to 12 weeks obstructive sleep apnea
• Estazolam should only be administered at
Habit Forming bedtime
• Estazolam is a Schedule IV drug

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(continued) ESTAZOLAM

Do Not Use • Neonatal flaccidity has been reported in

• If patient is pregnant infants whose mothers took a
• If patient has narrow angle-closure glaucoma benzodiazepine during pregnancy
• If there is a proven allergy to estazolam or
any benzodiazepine Breast Feeding
• Unknown if estazolam is secreted in human
breast milk, but all psychotropics assumed
SPECIAL POPULATIONS to be secreted in breast milk
✽ Recommended either to discontinue drug
Renal Impairment or bottle feed
• Drug should be used with caution • Effects on infant have been observed and
include feeding difficulties, sedation, and
Hepatic Impairment weight loss
• Drug should be used with caution

Cardiac Impairment THE ART OF PSYCHOPHARMACOLOGY

• Benzodiazepines have been used to treat
insomnia associated with acute myocardial Potential Advantages
infarction • Transient insomnia

Elderly Potential Disadvantages

• No dose adjustment in healthy patients • Smokers (may need higher dose)
• Debilitated patients: recommended initial
dose of 0.5 mg/day Primary Target Symptoms
• Time to sleep onset
• Total sleep time
Children and Adolescents • Nighttime awakenings
• Safety and efficacy have not been
established
• Long-term effects of estazolam in Pearls
children/adolescents are unknown • If tolerance develops, it may result in
• Should generally receive lower doses and increased anxiety during the day and/or
be more closely monitored increased wakefulness during the latter
part of the night
• Best short-term use is for less than 10
Pregnancy consecutive days, and for less than half of
• Risk Category X [positive evidence of risk the nights in a month
to human fetus; contraindicated for use in • Drug holidays may restore drug
pregnancy] effectiveness if tolerance develops
• Infants whose mothers received a
benzodiazepine late in pregnancy may
experience withdrawal effects

Suggested Reading
Pierce MW, Shu VS. Efficacy of estazolam. The Vogel GW, Morris D. The effects of estazolam
United States clinical experience. Am J Med on sleep, performance, and memory: a long-
1990;88:6S–11S. term sleep laboratory study of elderly
insomniacs. J Clin Pharmacol 1992;
Pierce MW, Shu VS, Groves LJ. Safety of 32:647–51.
estazolam. The United States clinical
experience. Am J Med 1990;88:12S–17S.

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FLUMAZENIL
THERAPEUTICS If It Doesn’t Work
• Sedation is most likely not due to a
Brands • Romazicon
benzodiazepine, and treatment with
• Anexate
flumazenil should be discontinued and
• Lanexat
other causes of sedation investigated
see index for additional brand names
Best Augmenting Combos
Generic? No
for Partial Response or
Treatment-Resistance
• None – flumazenil is basically used as a
Class monotherapy antidote to reverse the
• Benzodiazepine receptor antagonist actions of benzodiazepines
Commonly Prescribed For Tests
(bold for FDA approved) • None for healthy individuals
• Reversal of sedative effects of
benzodiazepines after general anesthesia
has been induced and/or maintained with
benzodiazepines
SIDE EFFECTS
• Reversal of sedative effects of How Drug Causes Side Effects
benzodiazepines after sedation has been
• Blocks benzodiazepine receptors at GABA-
produced with benzodiazepines for
A ligand-gated chloride channel complex,
diagnostic and therapeutic procedures
preventing benzodiazepines from binding
• Management of benzodiazepine overdose
there
• Reversal of conscious sedation induced
with benzodiazepines (pediatric patients) Notable Side Effects
• May precipitate benzodiazepine withdrawal
in patients dependent upon or tolerant to
How The Drug Works benzodiazepines
• Blocks benzodiazepine receptors at GABA- • Dizziness, injection site pain, sweating,
A ligand-gated chloride channel complex, headache, blurred vision
preventing benzodiazepines from binding
there
Life Threatening or
How Long Until It Works Dangerous Side Effects
• Onset of action 1–2 minutes; peak effect • Seizures
6–10 minutes • Death (majority occurred in patients with
severe underlying disease or who
If It Works overdosed with non-benzodiazepines)
✽ Reverses sedation and psychomotor • Cardiac dysrhythmia
retardation rapidly, but may not restore
memory completely Weight Gain
✽ Patients treated for benzodiazepine
overdose may experience CNS excitation
✽ Patients who receive flumazenil to reverse • Reported but not expected
benzodiazepine effects should be
monitored for up to 2 hours for resedation, Sedation
respiratory depression, or other lingering
benzodiazepine effects
• Flumazenil has not been shown to treat
hypoventilation due to benzodiazepine • Reported but not expected
treatment • Patients may experience resedation if the
effects of flumazenil wear off before the
effects of the benzodiazepine

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FLUMAZENIL (continued)

What To Do About Side Effects Pharmacokinetics

• Monitor patient • Terminal half-life 41–79 minutes
• Restrict ambulation because of dizziness,
blurred vision, and possibility of resedation
Drug Interactions
Best Augmenting Agents for Side
• Food increases its clearance
Effects
• None – augmenting agents are not
appropriate to treat side effects associated Other Warnings/
with flumazenil use Precautions
• Flumazenil may induce seizures,
particularly in patients tolerant to or
DOSING AND USE dependent on benzodiazepines, or who
have overdosed on cyclic antidepressants,
Usual Dosage Range received recent/repeated doses of
• 0.4–1 mg generally causes complete parenteral benzodiazepines, or have jerking
antagonism of therapeutic doses of or convulsion during overdose
benzodiazepines • Patients dependent on benzodiazepines or
• 1–3 mg generally reverses benzodiazepine receiving benzodiazepines to suppress
overdose seizures in cyclic antidepressant overdose
should receive the minimally effective dose
Dosage Forms of flumazenil
• Intravenous 0.1 mg/mL – 5 mL multiple- • Use with caution in patients with head
use vial, 10 mL multiple-use vial injury
• Greater risk of resedation if administered to
How to Dose a patient who took a long-acting
• Conscious sedation, general anesthesia: benzodiazepine or a large dose of a short-
0.2 mg (2 mL) over 15 seconds; can acting benzodiazepine
administer 0.2 mg again after 45 seconds; • Flumazenil may induce panic attacks in
can administer 0.2 mg each additional patients with panic disorder
60 seconds; maximum 1 mg • Use with caution in cases of mixed
• Benzodiazepine overdose: 0.2 mg over 30 overdose because toxic effects of other
seconds; can administer 0.3 mg over next drugs used in overdose (e.g., convulsions)
30 seconds; can administer 0.5 mg over may appear when the effects of the
30 seconds after 1 minute; maximum 5 mg benzodiazepine are reversed

Do Not Use
Dosing Tips • Should not be used until after effects of
• May need to administer follow up doses to neuromuscular blockers have been
reverse actions of benzodiazepines that reversed
have a longer half-life than flumazenil (i.e., • If benzodiazepine was prescribed to control
longer than 1 hour) a life-threatening condition (e.g., status
epilepticus, intracranial pressure)
Overdose • If there is a high risk of seizure
• Anxiety, agitation, increased muscle tone, • If patient exhibits signs of serious cyclic
hyperesthesia, convulsions antidepressant overdose
• If there is a proven allergy to flumazenil or
Long-Term Use benzodiazepines
• Not a long-term treatment

Habit Forming
• No

How to Stop
• N/A

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(continued) FLUMAZENIL

SPECIAL POPULATIONS • Not recommended to treat the effects of

benzodiazepines during labor and delivery
Renal Impairment because the effects on the infant have not
• Dosage adjustment may not be necessary been studied
Hepatic Impairment Breast Feeding
• Prolongation of half-life • Unknown if flumazenil is secreted in
• Moderate: clearance reduced by half human breast milk, but all psychotropics
• Severe: clearance reduced by three- assumed to be secreted in breast milk
quarters • If treatment with flumazenil is necessary, it
should be administered with caution
Cardiac Impairment
• Dosage adjustment may not be necessary

Elderly THE ART OF PSYCHOPHARMACOLOGY

• Dosage adjustment may not be necessary
Potential Advantages
• To reverse a low dose of a short-acting
benzodiazepine
Children and Adolescents
• More variability of pharmacokinetics than Potential Disadvantages
in adults • May be too short-acting
• Safety and efficacy established for reversal of
conscious sedation for children over age 1 Primary Target Symptoms
• Initial 0.01 mg/kg (up to 0.2 mg) over • Effects of benzodiazepines
15 seconds; same dosing pattern as adults; • Sedative effects
maximum 0.05 mg/kg or 1 mg • Recall and psychomotor impairments
• Safety and efficacy for reversal of • Ventilatory depression
benzodiazepine overdose, general
anesthesia induction or resuscitation of a
newborn have not been established, but
Pearls
anecdotal data suggest similar safety and
• Can precipitate benzodiazepine withdrawal
efficacy as for conscious sedation
seizures
✽ Can wear off before the benzodiazepine it
is reversing
Pregnancy ✽ Can precipitate anxiety or panic in
• Risk Category C [some animal studies conscious patients with anxiety disorders
show adverse effects, no controlled studies
in humans]

Suggested Reading
Malizia AL, Nutt DJ. The effects of flumazenil flumazenil in the management of
in neuropsychiatric disorders. Clin benzodiazepine overdose. Drug Saf 1997;
Neuropharmacol 1995;18:215–32. 17:181–96.
McCloy RF. Reversal of conscious sedation by Whitwam JG, Amrein R. Pharmacology of
flumazenil: current status and future flumazenil. Acta Anaesthesiol Scand Suppl
prospects. Acta Anaesthesiol Scand Suppl 1995;108:3–14.
1995;108:35–42.
Whitwam JG. Flumazenil and midazolam in
Weinbroum AA, Flaishon R, Sorkine P, Szold anaesthesia. Acta Anaesthesiol Scand Suppl
O, Rudick V. A risk-benefit assessment of 1995;108:15–22.

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FLUNITRAZEPAM
THERAPEUTICS Tests
• In patients with seizure disorders,
Brands • Rohypnol
concomitant medical illness, and/or those
see index for additional brand names
with multiple concomitant long-term
Generic? No medications, periodic liver tests and blood
counts may be prudent

Class
SIDE EFFECTS
• Benzodiazepine (hypnotic)
How Drug Causes Side Effects
Commonly Prescribed For
• Same mechanism for side effects as for
(bold for FDA approved)
therapeutic effects – namely due to
• Short-term treatment of insomnia (severe,
excessive actions at benzodiazepine
disabling)
receptors
• Actions at benzodiazepine receptors that
carry over to next day can cause daytime
How The Drug Works sedation, amnesia, and ataxia
• Binds to benzodiazepine receptors at the • Long-term adaptations in benzodiazepine
GABA-A ligand-gated chloride channel receptors may explain the development of
complex dependence, tolerance, and withdrawal
• Enhances the inhibitory effects of GABA
• Boosts chloride conductance through Notable Side Effects
GABA-regulated channels ✽ Sedation, fatigue, depression
• Inhibitory actions in sleep centers may ✽ Dizziness, ataxia, slurred speech,
provide sedative hypnotic effects weakness
✽ Forgetfulness, confusion
How Long Until It Works ✽ Hyper-excitability, nervousness
• Generally takes effect in less than an hour • Rare hallucinations, mania
• Rare hypotension
If It Works • Hypersalivation, dry mouth
• Improves quality of sleep • Rebound insomnia when withdrawing from
• Effects on total wake-time and number of long-term treatment
nighttime awakenings may be decreased
over time
Life Threatening or
If It Doesn’t Work Dangerous Side Effects
• If insomnia does not improve after • Respiratory depression, especially when
7–10 days, it may be a manifestation of a taken with CNS depressants in overdose
primary psychiatric or physical illness such • Rare hepatic dysfunction, renal
as obstructive sleep apnea or restless leg dysfunction, blood dyscrasias
syndrome, which requires independent
evaluation Weight Gain
• Increase the dose
• Improve sleep hygiene
• Switch to another agent • Reported but not expected
Best Augmenting Combos Sedation
for Partial Response or
Treatment-Resistance
• Generally, best to switch to another agent
• Trazodone • Many experience and/or can be significant
• Agents with antihistamine actions (e.g., in amount
diphenhydramine, tricyclic antidepressants)

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FLUNITRAZEPAM (continued)

What To Do About Side Effects Long-Term Use

• Wait • Not generally intended for long-term use
• To avoid problems with memory, only take • Use is not recommended to exceed 4
flunitrazepam if planning to have a full weeks
night’s sleep
• Lower the dose Habit Forming
• Switch to a shorter-acting sedative • Some patients may develop dependence
hypnotic and/or tolerance; risk may be greater with
• Switch to a non-benzodiazepine hypnotic higher doses
• Administer flumazenil if side effects are • History of drug addiction may increase risk
severe or life-threatening of dependence
• Currently classified as Schedule III by the
Best Augmenting Agents for Side World Health Organization
Effects • Currently classified as a Schedule IV drug
• Many side effects cannot be improved with in the U.S., but not legally available in the
an augmenting agent U.S.

How to Stop
• If taken for more than a few weeks, taper
DOSING AND USE
to reduce chances of withdrawal effects
Usual Dosage Range • Patients with seizure history may seize
• 0.5–1 mg/day at bedtime upon sudden withdrawal
• Rebound insomnia may occur the first
Dosage Forms 1–2 nights after stopping
• Tablet 0.5 mg, 1 mg, 2 mg, 4 mg • For patients with severe problems
discontinuing a benzodiazepine, dosing
How to Dose may need to be tapered over many months
• Initial 0.5–1 mg/day at bedtime; maximum (i.e., reduce dose by 1% every 3 days by
generally 2 mg/day at bedtime crushing tablet and suspending or
dissolving in 100 ml of fruit juice and then
disposing of 1 ml while drinking the rest;
Dosing Tips 3–7 days later, dispose of 2 ml, and so on).
This is both a form of very slow biological
• Use lowest possible effective dose and
tapering and a form of behavioral
assess need for continued treatment
desensitization
regularly
• Flunitrazepam should generally not be Pharmacokinetics
prescribed in quantities greater than a
• Elimination half-life 16–35 hours
1-month supply
• Half-life of active metabolite 23–33 hours
• Patients with lower body weights may
require lower doses
• Risk of dependence may increase with
dose and duration of treatment Drug Interactions
• Use doses over 1 mg only in exceptional • Increased depressive effects when taken
circumstances with other CNS depressants
• Patients who request or who require doses • Cisapride may hasten the absorption of
over 1 mg may be more likely to have flunitrazepam and thus cause a temporary
present or past substance abuse increase in the sedative effects of
• Flunitrazepam is 10 times more potent than flunitrazepam
diazepam
Other Warnings/
Overdose
• Sedation, slurred speech, poor
Precautions
coordination, confusion, coma, respiratory • Insomnia may be a symptom of a primary
depression disorder, rather than a primary disorder
itself

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(continued) FLUNITRAZEPAM

• Some patients may exhibit abnormal • Not recommended for use in children or
thinking or behavioral changes similar to adolescents
those caused by other CNS depressants • Paradoxical reactions with restlessness and
(i.e., either depressant actions or agitation are more likely to occur in
disinhibiting actions) children
• Some depressed patients may experience a
worsening of suicidal ideation
• Use only with extreme caution in patients Pregnancy
with impaired respiratory function or • Positive evidence of risk to human fetus;
obstructive sleep apnea contraindicated for use in pregnancy
• Flunitrazepam should only be administered • Infants whose mothers received a
at bedtime benzodiazepine late in pregnancy may
experience withdrawal effects
Do Not Use
• Neonatal flaccidity has been reported in
• If patient is pregnant
infants whose mothers took a
• If patient has severe chronic hypercapnia,
benzodiazepine during pregnancy
myasthenia gravis, severe respiratory
insufficiency, sleep apnea, or severe Breast Feeding
hepatic insufficiency • Unknown if flunitrazepam is secreted in
• In children human breast milk, but all psychotropics
• If patient has narrow angle-closure assumed to be secreted in breast milk
glaucoma
• If there is a proven allergy to flunitrazepam
✽ Recommended either to discontinue drug
or bottle feed
or any benzodiazepine • Effects on infant have been observed and
include feeding difficulties, sedation, and
weight loss
SPECIAL POPULATIONS
Renal Impairment
THE ART OF PSYCHOPHARMACOLOGY
• Drug should be used with caution
Potential Advantages
Hepatic Impairment
• For severe, disabling insomnia
• Dose should be lowered
unresponsive to other sedative hypnotics
• Should not be used in patients with severe
hepatic insufficiency, as it may precipitate Potential Disadvantages
encephalopathy • For those who need treatment for longer
than a few weeks
Cardiac Impairment
• For those with current or past substance
• Benzodiazepines have been used to treat
abuse
insomnia associated with acute myocardial
infarction Primary Target Symptoms
• Time to sleep onset
Elderly
• Total sleep time
• Initial starting dose 0.5 mg at bedtime;
• Nighttime awakenings
maximum generally 1 mg/day at bedtime
• Paradoxical reactions with restlessness and
agitation are more likely to occur in the
elderly Pearls
✽ Psychiatric symptoms and “paradoxical”
reactions may be quite severe with
flunitrazepam and may be more frequent
Children and Adolescents
than with other benzodiazepines
• Safety and efficacy have not been
established
✽ “Paradoxical” reactions include
symptoms such as restlessness, agitation,
irritability, aggressiveness, delusions, rage,

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FLUNITRAZEPAM (continued)

nightmares, hallucinations, psychosis, • Illicit use since 1999 has fallen in part due
inappropriate behavior, and other adverse to this additive
behavioral effects • Illicit use has also fallen in the U.S. due to
• Although legally available in Europe, the Drug-Induced Rape Prevention and
Mexico, South America, and many other Punishment act of 1996, making it
countries, it is not legally available in the punishable to commit a violent crime using
U.S. a controlled substance such as
• Although currently classified as a Schedule flunitrazepam
IV drug, the U.S. drug enforcement agency • Street names for flunitrazepam, based in
is considering reclassifying it as Schedule I part upon its trade name of Rohypnol,
✽ Has earned a reputation as a “date rape manufacturer Roche, and the presence of
drug” in which sexual predators have RO-2 on the surface of the tablets, include
allegedly slipped flunitrazepam into “roofies”, “ruffies”, “roapies”, “la roacha”,
women’s drinks to induce sexual relations “roach-2”, “Mexican valium”, “rope”,
✽ Flunitrazepam, especially in combination “roache vitamins”, and others
with alcohol, is claimed to reduce the • If tolerance develops, it may result in
woman’s judgment, inhibitions, or physical increased anxiety during the day and/or
ability to resist sexual advances, as well as increased wakefulness during the latter
to reduce or eliminate her recall of the part of the night
events • Best short-term use is for less than 10
✽ Until 1999 was colorless, but a consecutive days, and for less than half of
colorimetric compound is now added that the nights in a month
turns the drug blue when added to a liquid, • Drug holidays may restore drug
making it obvious that a drink was effectiveness if tolerance develops
tampered with

Suggested Reading
Simmons MM, Cupp MJ. Use and abuse of Woods JH, Winger G. Abuse liability of
flunitrazepam. Ann Pharmacother. flunitrazepam. J Clin Psychopharmacol.
1998;32(1):117–9. 1997;17(3 Suppl 2):1S–57S.

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FLUOXETINE
THERAPEUTICS If It Works
• The goal of treatment is complete
Brands • Prozac • Prozac weekly
remission of current symptoms as well as
• Sarafem
prevention of future relapses
see index for additional brand names
• Treatment most often reduces or even
Generic? Yes eliminates symptoms, but not a cure since
symptoms can recur after medicine
stopped
• Continue treatment until all symptoms are
Class gone (remission) or significantly reduced
• SSRI (selective serotonin reuptake (e.g., OCD, PTSD)
inhibitor); often classified as an • Once symptoms gone, continue treating for
antidepressant, but it is not just an 1 year for the first episode of depression
antidepressant • For second and subsequent episodes of
depression, treatment may need to be
Commonly Prescribed For indefinite
(bold for FDA approved) • For anxiety disorders and bulimia,
• Major depressive disorder treatment may also need to be indefinite
• Obsessive-compulsive disorder (OCD)
• Premenstrual dysphoric disorder (PMDD) If It Doesn’t Work
• Bulimia nervosa • Many patients only have a partial response
• Panic disorder where some symptoms are improved but
• Bipolar depression [in combination with others persist (especially insomnia, fatigue,
olanzapine (Symbyax)] and problems concentrating in depression)
• Social anxiety disorder (social phobia) • Other patients may be nonresponders,
• Posttraumatic stress disorder (PTSD) sometimes called treatment-resistant or
treatment-refractory
• Some patients who have an initial response
How The Drug Works may relapse even though they continue
• Boosts neurotransmitter serotonin treatment, sometimes called “poop-out”
• Blocks serotonin reuptake pump (serotonin • Consider increasing dose, switching to
transporter) another agent or adding an appropriate
• Desensitizes serotonin receptors, especially augmenting agent
serotonin 1A receptors • Consider psychotherapy
• Presumably increases serotonergic • Consider evaluation for another diagnosis
neurotransmission or for a comorbid condition (e.g., medical
✽ Fluoxetine also has antagonist properties illness, substance abuse, etc.)
at 5HT2C receptors, which could increase • Some patients may experience apparent
norepinephrine and dopamine lack of consistent efficacy due to activation
neurotransmission of latent or underlying bipolar disorder, and
require antidepressant discontinuation and
How Long Until It Works a switch to a mood stabilizer
✽ Some patients may experience increased
energy or activation early after initiation of Best Augmenting Combos
treatment for Partial Response or
• Onset of therapeutic actions usually not Treatment-Resistance
immediate, but often delayed 2 to 4 weeks • Trazodone, especially for insomnia
• If it is not working within 6 to 8 weeks, it • Bupropion, mirtazapine, reboxetine, or
may require a dosage increase or it may atomoxetine (add with caution and at lower
not work at all doses since fluoxetine could theoretically
• May continue to work for many years to raise atomoxetine levels); use
prevent relapse of symptoms combinations of antidepressants with
caution as this may activate bipolar
disorder and suicidal ideation

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FLUOXETINE (continued)

• Modafinil, especially for fatigue, sleepiness, • Mostly central nervous system (insomnia
and lack of concentration but also sedation, agitation, tremors,
• Mood stabilizers or atypical antipsychotics headache, dizziness)
for bipolar depression, psychotic • Note: patients with diagnosed or
depression, treatment-resistant depression, undiagnosed bipolar or psychotic disorders
or treatment-resistant anxiety disorders may be more vulnerable to CNS-activating
✽ Fluoxetine has been specifically studied in actions of SSRIs
combination with olanzapine (olanzapine- • Autonomic (sweating)
fluoxetine combination) with excellent • Bruising and rare bleeding
results for bipolar depression, treatment-
resistant unipolar depression, and
psychotic depression
Life Threatening or
• Benzodiazepines Dangerous Side Effects
• If all else fails for anxiety disorders, • Rare seizures
consider gabapentin or tiagabine • Rare induction of mania and activation of
• Hypnotics for insomnia suicidal ideation
• Classically, lithium, buspirone, or thyroid
hormone
Weight Gain

Tests
• None for healthy individuals • Reported but not expected
• Possible weight loss, especially short-term

SIDE EFFECTS Sedation

How Drug Causes Side Effects

• Theoretically due to increases in serotonin • Reported but not expected
concentrations at serotonin receptors in
parts of the brain and body other than What To Do About Side Effects
those that cause therapeutic actions (e.g., • Wait
unwanted actions of serotonin in sleep • Wait
centers causing insomnia, unwanted • Wait
actions of serotonin in the gut causing • If fluoxetine is activating, take in the
diarrhea, etc.) morning to help reduce insomnia
• Increasing serotonin can cause diminished • Reduce dose to 10 mg, and either stay at
dopamine release and might contribute to this dose if tolerated and effective, or
emotional flattening, cognitive slowing, and consider increasing again to 20 mg or
apathy in some patients more if tolerated but not effective at 10 mg
• Most side effects are immediate but often • In a few weeks, switch or add other drugs
go away with time, in contrast to most
therapeutic effects which are delayed and Best Augmenting Agents for Side
are enhanced over time Effects
✽ Fluoxetine’s unique 5HT2C antagonist • Often best to try another SSRI or another
properties could contribute to agitation, antidepressant monotherapy prior to
anxiety, and undesirable activation, resorting to augmentation strategies to
especially early in dosing treat side effects
• Trazodone or a hypnotic for insomnia
Notable Side Effects • Bupropion, sildenafil, vardenafil, or tadalafil
• Sexual dysfunction (men: delayed for sexual dysfunction
ejaculation, erectile dysfunction; men and • Bupropion for emotional flattening,
women: decreased sexual desire, cognitive slowing, or apathy
anorgasmia) • Mirtazapine for insomnia, agitation, and
• Gastrointestinal (decreased appetite, gastrointestinal side effects
nausea, diarrhea, constipation, dry mouth)

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(continued) FLUOXETINE

• Benzodiazepines for jitteriness and anxiety, • Often available in capsules, not tablets, so
especially at initiation of treatment and unable to break capsules in half
especially for anxious patients • Occasional patients are dosed above 80 mg
• Many side effects are dose-dependent (i.e., • Liquid formulation easiest for doses below
they increase as dose increases, or they 10 mg when used for cases that are very
reemerge until tolerance re-develops) intolerant to fluoxetine or for very slow up
• Many side effects are time-dependent (i.e., and down titration needs
they start immediately upon dosing and ✽ For some patients, weekly dosing with
upon each dose increase, but go away with the weekly formulation may enhance
time) compliance
• Activation and agitation may represent the • The more anxious and agitated the patient,
induction of a bipolar state, especially a the lower the starting dose, the slower the
mixed dysphoric bipolar II condition titration, and the more likely the need for a
sometimes associated with suicidal concomitant agent such as trazodone or a
ideation, and require the addition of benzodiazepine
lithium, a mood stabilizer or an atypical • If intolerable anxiety, insomnia, agitation,
antipsychotic, and/or discontinuation of akathisia, or activation occur either upon
fluoxetine dosing initiation or discontinuation,
consider the possibility of activated bipolar
disorder and switch to a mood stabilizer or
DOSING AND USE an atypical antipsychotic

Usual Dosage Range Overdose

• 20–80 mg for depression and anxiety • Rarely lethal in monotherapy overdose;
disorders respiratory depression especially with
• 60–80 mg for bulimia alcohol, ataxia, sedation, possible seizures

Dosage Forms Long-Term Use

• Capsules 10 mg, 20 mg, 40 mg • Safe
• Tablet 10 mg
• Liquid 20 mg / 5 ml – 120 ml bottles
Habit Forming
• Weekly capsule 90 mg • No

How to Dose How to Stop

• Depression and OCD: Initial dose • Taper rarely necessary since fluoxetine
20 mg/day in morning, usually wait a few tapers itself after immediate
weeks to assess drug effects before discontinuation, due to the long half-life of
increasing dose; maximum dose generally fluoxetine and its active metabolites
80 mg/day
Pharmacokinetics
• Bulimia: Initial dose 60 mg/day in morning;
• Active metabolite (norfluoxetine) has
some patients may need to begin at lower
2 week half-life
dose and titrate over several days
• Parent drug has 2–3 day half-life
• Inhibits CYP450 2D6
• Inhibits CYP450 3A4
Dosing Tips
• The long half-lives of fluoxetine and its
active metabolites mean that dose changes
Drug Interactions
will not be fully reflected in plasma for
• Tramadol increases the risk of seizures in
several weeks, lengthening titration to final
patients taking an antidepressant
dose and extending withdrawal from
• Can increase tricyclic antidepressant levels;
treatment
use with caution with tricyclic
• Give once daily, often in the mornings, but
antidepressants or when switching from a
at any time of day tolerated
TCA to fluoxetine

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FLUOXETINE (continued)

• Can cause a fatal “serotonin syndrome” • Monitor patients for activation of suicidal
when combined with MAO inhibitors, so do ideation, especially children and
not use with MAO inhibitors or for at least adolescents
14 days after MAOIs are stopped
• Do not start an MAO inhibitor for at least Do Not Use
5 weeks after discontinuing fluoxetine • If patient is taking an MAO inhibitor
• May displace highly protein bound drugs • If patient is taking thioridazine
(e.g., warfarin) • If patient is taking pimozide
• Can rarely cause weakness, hyperreflexia, • If there is a proven allergy to fluoxetine
and incoordination when combined with
sumatriptan, or possibly with other
triptans, requiring careful monitoring of SPECIAL POPULATIONS
patient
• Via CYP450 2D6 inhibition, could Renal Impairment
theoretically interfere with the analgesic • No dose adjustment
actions of codeine, and increase the • Not removed by hemodialysis
plasma levels of some beta blockers and of
atomoxetine Hepatic Impairment
• Via CYP450 2D6 inhibition, fluoxetine could • Lower dose or give less frequently, perhaps
theoretically increase concentrations of by half
thioridazine and cause dangerous cardiac
arrhythmias Cardiac Impairment
• May reduce the clearance of diazepam or • Preliminary research suggests that
trazodone, thus increasing their levels fluoxetine is safe in these patients
• Via CYP450 3A4 inhibition, may increase • Treating depression with SSRIs in patients
the levels of alprazolam, buspirone, and with acute angina or following myocardial
triazolam infarction may reduce cardiac events and
• Via CYP450 3A4 inhibition, fluoxetine could improve survival as well as mood
theoretically increase concentrations of
certain cholesterol lowering HMG CoA Elderly
reductase inhibitors, especially simvastatin, • Some patients may tolerate lower doses
atorvastatin, and lovastatin, but not better
pravastatin or fluvastatin, which would
increase the risk of rhabdomyolysis; thus,
coadministration of fluoxetine with certain Children and Adolescents
HMG CoA reductase inhibitors should • Use with caution, observing for activation
proceed with caution of known or unknown bipolar disorder
• Via CYP450 3A4 inhibition, fluoxetine could and/or suicidal ideation, and strongly
theoretically increase the concentrations of consider informing parents or guardian of
pimozide, and cause QTc prolongation and this risk so they can help observe child or
dangerous cardiac arrhythmias adolescent patients
• Approved for OCD and depression
• Adolescents often receive adult dose, but
Other Warnings/ doses slightly lower for children
Precautions • Children taking fluoxetine may have slower
✽ Add or initiate other antidepressants with growth; long-term effects are unknown
caution for up to 5 weeks after
discontinuing fluoxetine
• Use with caution in patients with history of
seizure Pregnancy
• Use with caution in patients with bipolar • Risk Category C [some animal studies
disorder unless treated with concomitant show adverse effects, no controlled studies
mood stabilizing agent in humans]
• Not generally recommended for use during
pregnancy, especially during first trimester

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(continued) FLUOXETINE

• Nonetheless, continuous treatment during THE ART OF PSYCHOPHARMACOLOGY

pregnancy may be necessary and has not
been proven to be harmful to the fetus
Potential Advantages
• Current patient registries of children whose • Patients with atypical depression
mothers took fluoxetine during pregnancy (hypersomnia, increased appetite)
do not show adverse consequences • Patients with fatigue and low energy
• At delivery there may be more bleeding in • Patients with comorbid eating and affective
the mother and transient irritability or disorders
sedation in the newborn • Generic is less expensive than brand name
• Must weigh the risk of treatment (first where available
trimester fetal development, third trimester • Patients for whom weekly administration is
newborn delivery) to the child against the desired
risk of no treatment (recurrence of • Children with OCD or depression
depression, maternal health, infant
Potential Disadvantages
bonding) to the mother and child
• Patients with anorexia
• For many patients this may mean
• Initiating treatment in anxious, agitated
continuing treatment during pregnancy
patients
• Neonates exposed to SSRIs or SNRIs late
• Initiating treatment in severe insomnia
in the third trimester have developed
complications requiring prolonged Primary Target Symptoms
hospitalization, respiratory support, and • Depressed mood
tube feeding; reported symptoms are • Energy, motivation, and interest
consistent with either a direct toxic effect • Anxiety (eventually, but can actually
of SSRIs and SNRIs or, possibly, a drug increase anxiety, especially short-term)
discontinuation syndrome, and include • Sleep disturbance, both insomnia and
respiratory distress, cyanosis, apnea, hypersomnia (eventually, but may actually
seizures, temperature instability, feeding cause insomnia, especially short-term)
difficulty, vomiting, hypoglycemia,
hypotonia, hypertonia, hyperreflexia,
tremor, jitteriness, irritability, and constant
crying Pearls
✽ May be a first-line choice for atypical
Breast Feeding depression (e.g., hypersomnia,
• Some drug is found in mother’s breast milk hyperphagia, low energy, mood reactivity)
• Trace amounts may be present in nursing • Consider avoiding in agitated insomniacs
children whose mothers are on fluoxetine • Can cause cognitive and affective
• If child becomes irritable or sedated, breast “flattening”
feeding or drug may need to be • Not as well tolerated as some other SSRIs
discontinued for panic disorder and other anxiety
• Immediate postpartum period is a high-risk disorders, especially when dosing is
time for depression, especially in women initiated, unless given with co-therapies
who have had prior depressive episodes, such as benzodiazepines or trazodone
so drug may need to be reinstituted late in • Long half-life; even longer lasting active
the third trimester or shortly after metabolite
childbirth to prevent a recurrence during ✽ Actions at 5HT2C receptors may explain
the postpartum period its activating properties
• Must weigh benefits of breast feeding with ✽ Actions at 5HT2C receptors may explain
risks and benefits of antidepressant in part fluoxetine’s efficacy in combination
treatment versus non-treatment to both the with olanzapine for bipolar depression and
infant and the mother treatment-resistant depression, since both
• For many patients this may mean agents have this property
continuing treatment during breast feeding • For sexual dysfunction, can augment with
bupropion, sildenafil, vardenafil, or
tadalafil, or switch to a non-SSRI such as
bupropion or mirtazapine

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FLUOXETINE (continued)

• Mood disorders can be associated with • Nonresponse to fluoxetine in elderly may

eating disorders (especially in adolescent require consideration of mild cognitive
females) and be treated successfully with impairment or Alzheimer disease
fluoxetine • SSRIs may not cause as many patients to
• SSRIs may be less effective in women over attain remission of depression as some
50, especially if they are not taking other classes of antidepressants (e.g.,
estrogen SNRIs)
• SSRIs may be useful for hot flushes in • A single pill containing both fluoxetine and
perimenopausal women olanzapine is available for combination
• Some postmenopausal women’s treatment of bipolar depression, psychotic
depression will respond better to fluoxetine depression, and treatment-resistant
plus estrogen augmentation than to unipolar depression
fluoxetine alone

Suggested Reading
Anderson IM. Selective serotonin reuptake Calil HM. Fluoxetine: a suitable long-term
inhibitors versus tricyclic antidepressants: a treatment. J Clin Psychiatry. 2001;62 (suppl
meta-analysis of efficacy and tolerability. 22):24–9.
Journal of Affective Disorders. 2000;58:19–36.
Edwards JG, Anderson I. Systematic review
Beasley CM Jr, Koke SC, Nilsson ME, Gonzales and guide to selection of selective serotonin
JS. Adverse events and treatment reuptake inhibitors. Drugs. 1999;57:507–533.
discontinuations in clinical trials of fluoxetine
in major depressive disorder: an updated Wagstaff AJ, Goa KL. Once-weekly fluoxetine.
meta-analysis. Clinical Therapeutics. Drugs. 2001;61:2221–8.
2000;22:1319–1330.

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FLUPENTHIXOL
THERAPEUTICS If It Doesn’t Work
• Consider trying one of the first-line atypical
Brands • Depixol
antipsychotics (risperidone, olanzapine,
see index for additional brand names
quetiapine, ziprasidone, aripiprazole,
Generic? No amisulpride)
• Consider trying another conventional
antipsychotic
• If 2 or more antipsychotic monotherapies
Class do not work, consider clozapine
• Conventional antipsychotic (neuroleptic,
thioxanthene, dopamine 2 antagonist) Best Augmenting Combos
for Partial Response or
Commonly Prescribed For Treatment-Resistance
(bold for FDA approved)
• Augmentation of conventional
• Schizophrenia
antipsychotics has not been systematically
• Depression (low dose)
studied
• Other psychotic disorders
• Addition of a mood stabilizing
• Bipolar disorder
anticonvulsant such as valproate,
carbamazepine, or lamotrigine may be
helpful in both schizophrenia and bipolar
How The Drug Works mania
• Blocks dopamine 2 receptors, reducing • Augmentation with lithium in bipolar mania
positive symptoms of psychosis may be helpful
• Addition of a benzodiazepine, especially
How Long Until It Works short-term for agitation
• With injection, psychotic symptoms can
improve within a few days, but it may take Tests
1–2 weeks for notable improvement ✽ Since conventional antipsychotics are
• With oral formulation, psychotic symptoms frequently associated with weight gain,
can improve within 1 week, but it may take before starting treatment, weigh all patients
several weeks for full effect on behavior and determine if the patient is already
overweight (BMI 25.0–29.9) or obese
If It Works (BMI ≥30)
• Most often reduces positive symptoms in • Before giving a drug that can cause weight
schizophrenia but does not eliminate them gain to an overweight or obese patient,
• Most schizophrenic patients do not have a consider determining whether the patient
total remission of symptoms but rather a already has pre-diabetes (fasting plasma
reduction of symptoms by about a third glucose 100–125 mg/dl), diabetes (fasting
• Continue treatment in schizophrenia until plasma glucose >126 mg/dl), or
reaching a plateau of improvement dyslipidemia (increased total cholesterol,
• After reaching a satisfactory plateau, LDL cholesterol and triglycerides;
continue treatment for at least a year after decreased HDL cholesterol), and treat or
first episode of psychosis in schizophrenia refer such patients for treatment, including
• For second and subsequent episodes of nutrition and weight management, physical
psychosis in schizophrenia, treatment may activity counseling, smoking cessation, and
need to be indefinite medical management
• Reduces symptoms of acute psychotic ✽ Monitor weight and BMI during treatment
mania but not proven as a mood stabilizer ✽ While giving a drug to a patient who has
or as an effective maintenance treatment in gained >5% of initial weight, consider
bipolar disorder evaluating for the presence of pre-diabetes,
• After reducing acute psychotic symptoms diabetes, or dyslipidemia, or consider
in mania, switch to a mood stabilizer switching to a different antipsychotic
and/or an atypical antipsychotic for mood • Monitoring elevated prolactin levels of
stabilization and maintenance dubious clinical benefit

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FLUPENTHIXOL (continued)

SIDE EFFECTS Sedation

How Drug Causes Side Effects
• By blocking dopamine 2 receptors in the
striatum, it can cause motor side effects • Occurs in significant minority
• By blocking dopamine 2 receptors in the
pituitary, it can cause elevations in What To Do About Side Effects
prolactin • Wait
• By blocking dopamine 2 receptors • Wait
excessively in the mesocortical and • Wait
mesolimbic dopamine pathways, especially • For motor symptoms, add an
at high doses, it can cause worsening of anticholinergic agent
negative and cognitive symptoms • Reduce the dose
(neuroleptic-induced deficit syndrome) • For sedation, give at night
• Anticholinergic actions may cause • Switch to an atypical antipsychotic
sedation, blurred vision, constipation, dry • Weight loss, exercise programs, and
mouth medical management for high BMIs,
• Antihistaminic actions may cause sedation, diabetes, dyslipidemia
weight gain
• By blocking alpha 1 adrenergic receptors, it Best Augmenting Agents for Side
can cause dizziness, sedation, and Effects
hypotension • Benztropine or trihexyphenidyl for motor
• Mechanism of weight gain and any side effects
possible increased incidence of diabetes or • Sometimes amantadine can be helpful for
dyslipidemia with conventional motor side effects
antipsychotics is unknown • Benzodiazepines may be helpful for
akathisia
Notable Side Effects • Many side effects cannot be improved with
✽ Neuroleptic-induced deficit syndrome an augmenting agent
✽ Extrapyramidal symptoms (more
common at start of treatment),
Parkinsonism DOSING AND USE
✽ Insomnia, restlessness, agitation,
sedation Usual Dosage Range
✽ Tardive dyskinesia (risk increases with • Oral 3–6 mg/day in divided doses
duration of treatment and with dose) • Intramuscular 40–120 mg every 1–4 weeks
✽ Galactorrhea, amenorrhea
• Tachycardia Dosage Forms
• Weight gain • Tablet 0.5 mg, 3 mg
• Hypomania • Injection 20 mg/mL, 100 mg/mL
• Rare eosinophilia
How to Dose
• Oral: initial 1 mg 3 times a day; increase by
Life Threatening or 1 mg every 2–3 days; maximum generally
Dangerous Side Effects 18 mg/day
• Rare neuroleptic malignant syndrome • Intramuscular: initial dose 20 mg for
• Rare seizures patients who have not been exposed to
• Rare jaundice, leucopenia long-acting depot antipsychotics, 40 mg
for patients who have previously
Weight Gain demonstrated tolerance to long-acting
depot antipsychotics; after 4–10 days can
give additional 20 mg dose; maximum
• Many experience and/or can be significant 200 mg every 1–4 weeks
in amount

182
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(continued) FLUPENTHIXOL

• Combined use with epinephrine may lower

blood pressure
Dosing Tips • Ritonavir may increase plasma levels of
• The peak of action for the decanoate is flupenthixol
usually 7–10 days, and doses generally • May increase carbamazepine plasma levels
have to be administered every 2–3 weeks • Some patients taking a neuroleptic and
• May have more activating effects at low lithium have developed an encephalopathic
doses, which can sometimes be useful as a syndrome similar to neuroleptic malignant
second-line, short-term treatment of syndrome
depression
• Some evidence that flupenthixol may
improve anxiety and depression at low Other Warnings/
doses Precautions
• If signs of neuroleptic malignant syndrome
Overdose develop, treatment should be immediately
• Agitation, confusion, sedation, discontinued
extrapyramidal symptoms, respiratory • Use cautiously in patients with alcohol
collapse, circulatory collapse withdrawal or convulsive disorders because
of possible lowering of seizure threshold
Long-Term Use • In epileptic patients, dose 10–20 mg every
• Safe 15 days for intramuscular formulation
• Use with caution if at all in patients with
Habit Forming Parkinson’s disease, severe
• No arteriosclerosis, or Lewy Body dementia
• Possible antiemetic effect of flupenthixol
How to Stop
may mask signs of other disorders or
• Slow down-titration of oral formulation
overdose; suppression of cough reflex may
(over 6 to 8 weeks), especially when
cause asphyxia
simultaneously beginning a new
• Avoid extreme heat exposure
antipsychotic while switching (i.e., cross-
• Do not use epinephrine in event of
titration)
overdose as interaction with some pressor
• Rapid oral discontinuation may lead to
agents may lower blood pressure
rebound psychosis and worsening of
symptoms Do Not Use
• If antiparkinson agents are being used, • If patient is taking a large concomitant
they should be continued for a few weeks dose of a sedative hypnotic
after flupenthixol is discontinued • If patient has CNS depression
• If patient is comatose or if there is brain
Pharmacokinetics
damage
• Oral: maximum plasma concentrations
• If there is blood dyscrasia
within 3 to 8 hours
• In patient has phaeochromocytoma
• Intramuscular: rate-limiting half-life
• If patient has liver damage
approximately 8 days with single dose,
• If patient has a severe cardiovascular
approximately 17 days with multiple doses
disorder
• If patient has renal insufficiency
• If patient has cerebrovascular insufficiency
Drug Interactions • If there is a proven allergy to flupenthixol
• May decrease the effects of levodopa,
dopamine agonists
• May increase the effects of SPECIAL POPULATIONS
antihypertensive drugs except for
guanethidine, whose antihypertensive Renal Impairment
actions flupenthixol may antagonize • Oral: recommended to take half or less of
• CNS effects may be increased if used with usual adult dose
other CNS depressants

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FLUPENTHIXOL (continued)

• Intramuscular: recommended dose THE ART OF PSYCHOPHARMACOLOGY

schedule generally 10–20 mg every
15 days
Potential Advantages
• Non-compliant patients
Hepatic Impairment
• Use with caution
Potential Disadvantages
• Oral: recommended to take half or less of • Children
usual adult dose • Elderly
• Patients with tardive dyskinesia
Cardiac Impairment
• Use with caution
Primary Target Symptoms
• Oral: recommended to take half or less of • Positive symptoms of psychosis
usual adult dose • Negative symptoms of psychosis
• Aggressive symptoms
Elderly
• Intramuscular: recommended initial dose
generally 5 mg; recommended dose Pearls
schedule generally 10–20 mg every 15 days • May activate manic patients
• Oral: recommended to take half or less of • Less sedation and orthostatic hypotension
usual adult dose but more extrapyramidal symptoms than
some other conventional antipsychotics
• Patients have very similar antipsychotic
Children and Adolescents responses to any conventional
• Not recommended for use in children antipsychotic, which is different from
atypical antipsychotics where antipsychotic
responses of individual patients can
occasionally vary greatly from one atypical
Pregnancy antipsychotic to another
• Not recommended for use during pregnancy • Patients with inadequate responses to
• Reports of extrapyramidal symptoms, atypical antipsychotics may benefit from a
jaundice, hyperreflexia, hyporeflexia in trial of augmentation with a conventional
infants whose mothers took a conventional antipsychotic such as flupenthixol or from
antipsychotic during pregnancy switching to a conventional antipsychotic
• Psychotic symptoms may worsen during such as flupenthixol
pregnancy and some form of treatment • However, long-term polypharmacy with a
may be necessary combination of a conventional
• Atypical antipsychotics may be preferable antipsychotic such as flupenthixol with an
to conventional antipsychotics or atypical antipsychotic may combine their
anticonvulsant mood stabilizers if side effects without clearly augmenting the
treatment is required during pregnancy efficacy of either
• Although a frequent practice by some
Breast Feeding
prescribers, adding 2 conventional
• Some drug is found in mother’s breast milk
antipsychotics together has little rationale
✽ Recommended either to discontinue drug and may reduce tolerability without clearly
or bottle feed
enhancing efficacy

Suggested Reading
Gerlach J. Depot neuroleptics in relapse psychotic disorders. Cochrane Database Syst
prevention: advantages and disadvantages. Int Rev 2000; (2): CD001470.
Clin Psychopharmacol 1995; 9 Suppl 5:
17–20. Soyka M, De Vry J. Flupenthixol as a potential
pharmacotreatment of alcohol and cocaine
Quraishi S, David A. Depot flupenthixol abuse/dependence. Eur
decanoate for schizophrenia or other similar Neuropsychopharmacol 2000; 10 (5): 325–32.
184
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FLUPHENAZINE
THERAPEUTICS • Consider trying another conventional
antipsychotic
Brands • Prolixin • If 2 or more antipsychotic monotherapies
see index for additional brand names do not work, consider clozapine
Generic? Yes Best Augmenting Combos
for Partial Response or
Treatment-Resistance
Class • Augmentation of conventional
• Conventional antipsychotic (neuroleptic, antipsychotics has not been systematically
phenothiazine, dopamine 2 antagonist) studied
• Addition of a mood stabilizing
Commonly Prescribed For anticonvulsant such as valproate,
(bold for FDA approved) carbamazepine, or lamotrigine may be
• Psychotic disorders helpful in both schizophrenia and bipolar
• Bipolar disorder mania
• Augmentation with lithium in bipolar mania
may be helpful
How The Drug Works • Addition of a benzodiazepine, especially
• Blocks dopamine 2 receptors, reducing short-term for agitation
positive symptoms of psychosis
Tests
How Long Until It Works ✽ Since conventional antipsychotics are
• Psychotic symptoms can improve within frequently associated with weight gain,
1 week, but it may take several weeks for before starting treatment, weigh all patients
full effect on behavior and determine if the patient is already
overweight (BMI 25.0–29.9) or obese
If It Works (BMI ≥30)
• Most often reduces positive symptoms in • Before giving a drug that can cause weight
schizophrenia but does not eliminate them gain to an overweight or obese patient,
• Most schizophrenic patients do not have a consider determining whether the patient
total remission of symptoms but rather a already has pre-diabetes (fasting plasma
reduction of symptoms by about a third glucose 100–125 mg/dl), diabetes (fasting
• Continue treatment in schizophrenia until plasma glucose >126 mg/dl), or
reaching a plateau of improvement dyslipidemia (increased total cholesterol,
• After reaching a satisfactory plateau, LDL cholesterol and triglycerides;
continue treatment for at least a year after decreased HDL cholesterol), and treat or
first episode of psychosis in schizophrenia refer such patients for treatment, including
• For second and subsequent episodes of nutrition and weight management, physical
psychosis in schizophrenia, treatment may activity counseling, smoking cessation, and
need to be indefinite medical management
• Reduces symptoms of acute psychotic ✽ Monitor weight and BMI during treatment
mania but not proven as a mood stabilizer ✽ While giving a drug to a patient who has
or as an effective maintenance treatment in gained >5% of initial weight, consider
bipolar disorder evaluating for the presence of pre-diabetes,
• After reducing acute psychotic symptoms diabetes, or dyslipidemia, or consider
in mania, switch to a mood stabilizer switching to a different antipsychotic
and/or an atypical antipsychotic for mood • Should check blood pressure in the elderly
stabilization and maintenance before starting and for the first few weeks
of treatment
If It Doesn’t Work • Monitoring elevated prolactin levels of
• Consider trying one of the first-line atypical dubious clinical benefit
antipsychotics (risperidone, olanzapine, • Phenothiazines may cause false-positive
quetiapine, ziprasidone, aripiprazole, phenylketonuria results
amisulpride)

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FLUPHENAZINE (continued)

SIDE EFFECTS • Occurs in significant minority

How Drug Causes Side Effects What To Do About Side Effects
• By blocking dopamine 2 receptors in the • Wait
striatum, it can cause motor side effects • Wait
• By blocking dopamine 2 receptors in the • Wait
pituitary, it can cause elevations in prolactin • For motor symptoms, add an
• By blocking dopamine 2 receptors anticholinergic agent
excessively in the mesocortical and • Reduce the dose
mesolimbic dopamine pathways, especially • For sedation, take at night
at high doses, it can cause worsening of • Switch to an atypical antipsychotic
negative and cognitive symptoms • Weight loss, exercise programs, and
(neuroleptic-induced deficit syndrome) medical management for high BMIs,
• Anticholinergic actions may cause sedation, diabetes, dyslipidemia
blurred vision, constipation, dry mouth
• Antihistaminic actions may cause sedation, Best Augmenting Agents for Side
weight gain Effects
• By blocking alpha 1 adrenergic receptors, it • Benztropine or trihexyphenidyl for motor
can cause dizziness, sedation, and side effects
hypotension • Sometimes amantadine can be helpful for
• Mechanism of weight gain and any motor side effects
possible increased incidence of diabetes or • Benzodiazepines may be helpful for
dyslipidemia with conventional akathisia
antipsychotics is unknown • Many side effects cannot be improved with
an augmenting agent
Notable Side Effects
✽ Neuroleptic-induced deficit syndrome
✽ Akathisia DOSING AND USE
✽ Priapism
✽ Extrapyramidal symptoms, Parkinsonism, Usual Dosage Range
tardive dyskinesia, tardive dystonia
• Oral: 1–20 mg/day maintenance
✽ Galactorrhea, amenorrhea • Intramuscular: generally 1/3 to 1/2 the oral
• Dizziness, sedation
dose
• Dry mouth, constipation, urinary retention,
• Decanoate for intramuscular or
blurred vision
subcutaneous administration:
• Decreased sweating, depression
12.5 mg/0.5 mL – 50 mg/2 mL
• Sexual dysfunction
• Hypotension, tachycardia, syncope Dosage Forms
• Weight gain
• Tablet 1 mg, 2.5 mg scored, 5 mg scored,
10 mg scored
Life Threatening or • Decanoate for long-acting intramuscular or
Dangerous Side Effects subcutaneous administration 25 mg/mL
• Rare neuroleptic malignant syndrome • Injection for acute intramuscular
• Rare jaundice, agranulocytosis administration 2.5 mg/mL
• Rare seizures • Elixir 2.5 mg/5 mL
• Concentrate 5 mg/mL
Weight Gain
How to Dose
• Oral: initial 0.5–10 mg/day in divided
doses; maximum 40 mg/day
• Occurs in significant minority • Intramuscular (short-acting): initial
1.25 mg; 2.5–10 mg/day can be given in
Sedation divided doses every 6–8 hours; maximum
dose generally 10 mg/day

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(continued) FLUPHENAZINE

• Decanoate (long-acting): initial 12.5–25 mg • Mean half-life of intramuscular formulation

(0.5 to 1 mL); subsequent doses and approximately 6.8–9.6 days
intervals determined in accordance with the
patient’s response; generally no more than
50 mg/2 mL given at intervals not longer Drug Interactions
than 4 weeks • May decrease the effects of levodopa,
dopamine agonists
• May increase the effects of
Dosing Tips antihypertensive drugs except for
• Patients receiving atypical antipsychotics guanethidine, whose antihypertensive
may occasionally require a “top up” of a actions fluphenazine may antagonize
conventional antipsychotic to control • Additive effects may occur if used with
aggression or violent behavior CNS depressants
• Fluphenazine tablets 2.5 mg, 5 mg, and • Additive anticholinergic effects may occur
10 mg contain tartrazine, which can cause if used with atropine or related compounds
allergic reactions, especially in patients • Alcohol and diuretics may increase the risk
sensitive to aspirin of hypotension
• Oral solution should not be mixed with • Some patients taking a neuroleptic and
drinks containing caffeine, tannic acid lithium have developed an encephalopathic
(tea), or pectinates (apple juice) syndrome similar to neuroleptic malignant
• 12.5 mg/0.5 mL of the long-acting syndrome
decanoate may be comparable to 10 mg of • Combined use with epinephrine may lower
oral fluphenazine blood pressure
• Onset of action of decanoate at 24–72
hours after injection with significant
antipsychotic actions within 48–96 hours
Other Warnings/
Precautions
Overdose • If signs of neuroleptic malignant syndrome
• Extrapyramidal symptoms, coma, develop, treatment should be immediately
hypotension, sedation, seizures, respiratory discontinued
depression • Use cautiously in patients with alcohol
withdrawal or convulsive disorders
Long-Term Use because of possible lowering of seizure
• Some side effects may be irreversible (e.g., threshold
tardive dyskinesia) • Avoid undue exposure to sunlight
• Use cautiously in patients with respiratory
Habit Forming disorders
• No • Avoid extreme heat exposure
• Antiemetic effect can mask signs of other
How to Stop disorders or overdose
• Slow down-titration of oral formulation • Do not use epinephrine in event of
(over 6 to 8 weeks), especially when overdose as interaction with some pressor
simultaneously beginning a new agents may lower blood pressure
antipsychotic while switching (i.e., cross- • Use only with caution if at all in
titration) Parkinson’s disease or Lewy Body
• Rapid oral discontinuation may lead to dementia
rebound psychosis and worsening of
symptoms Do Not Use
• If antiparkinson agents are being used, • If patient is in a comatose state or has CNS
they should be continued for a few weeks depression
after fluphenazine is discontinued • If patient is taking cabergoline, pergolide,
or metrizamide
Pharmacokinetics • If there is a proven allergy to fluphenazine
• Mean half-life of oral formulation • If there is a known sensitivity to any
approximately 15 hours phenothiazine

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FLUPHENAZINE (continued)

SPECIAL POPULATIONS THE ART OF PSYCHOPHARMACOLOGY

Renal Impairment Potential Advantages
• Use with caution; titration should be slower • Intramuscular formulation for emergency
use
Hepatic Impairment
• Use with caution; titration should be slower Potential Disadvantages
• Patients with tardive dyskinesia
Cardiac Impairment • Children
• Cardiovascular toxicity can occur, • Elderly
especially orthostatic hypotension
Primary Target Symptoms
Elderly • Positive symptoms of psychosis
• Titration should be slower; lower initial • Motor and autonomic hyperactivity
dose (1–2.5 mg/day) • Violent or aggressive behavior
• Elderly patients may be more susceptible
to adverse effects
Pearls
• Fluphenazine is a high potency
Children and Adolescents phenothiazine
• Safety and efficacy not established • Less risk of sedation and orthostatic
• Decanoate and enanthate injectable hypotension but greater risk of
formulations are contraindicated under extrapyramidal symptoms than with low
age 12 potency phenothiazines
• Generally consider second-line after • Conventional antipsychotics are much less
atypical antipsychotics expensive than atypical antipsychotics
• Not shown to be effective for behavioral
problems in mental retardation
Pregnancy • Patients have very similar antipsychotic
• Risk Category C [some animal studies responses to any conventional
show adverse effects, no controlled studies antipsychotic, which is different from
in humans] atypical antipsychotics where antipsychotic
• Reports of extrapyramidal symptoms, responses of individual patients can
jaundice, hyperreflexia, hyporeflexia in occasionally vary greatly from one atypical
infants whose mothers took a antipsychotic to another
phenothiazine during pregnancy • Patients with inadequate responses to
• Fluphenazine should only be used during atypical antipsychotics may benefit from a
pregnancy if clearly indicated trial of augmentation with a conventional
• Psychotic symptoms may worsen during antipsychotic such as fluphenazine or from
pregnancy and some form of treatment switching to a conventional antipsychotic
may be necessary such as fluphenazine
• Atypical antipsychotics may be preferable • However, long-term polypharmacy with a
to conventional antipsychotics or combination of a conventional
anticonvulsant mood stabilizers if antipsychotic such as fluphenazine with an
treatment is required during pregnancy atypical antipsychotic may combine their
side effects without clearly augmenting the
Breast Feeding efficacy of either
• Some drug is found in mother’s breast milk • Although a frequent practice by some
• Effects on infant have been observed prescribers, adding 2 conventional
(dystonia, tardive dyskinesia, sedation) antipsychotics together has little rationale
✽ Recommended either to discontinue drug and may reduce tolerability without clearly
or bottle feed enhancing efficacy

188
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(continued) FLUPHENAZINE

Suggested Reading
Adams CE, Eisenbruch M. Depot fluphenazine Milton GV, Jann MW. Emergency treatment of
for schizophrenia. Cochrane Database Syst psychotic symptoms. Pharmacokinetic
Rev 2000; (2): CD000307. considerations for antipsychotic drugs. Clin
Pharmacokinet 1995; 28 (6): 494–504.
King DJ. Drug treatment of the negative
symptoms of schizophrenia. Eur
Neuropsychopharmacol 1998; 8 (1): 33–42.

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0521011698s04.qxd 9/2/04 2:34 PM Page 191

FLURAZEPAM
THERAPEUTICS Best Augmenting Combos
Brands • Dalmane for Partial Response or
see index for additional brand names Treatment-Resistance
• Generally, best to switch to another agent
Generic? Yes • Trazodone
• Agents with antihistamine actions (e.g.,
diphenhydramine, tricyclic antidepressants)
Class Tests
• Benzodiazepine (hypnotic) • In patients with seizure disorders,
concomitant medical illness, and/or those
Commonly Prescribed For
with multiple concomitant long-term
(bold for FDA approved)
medications, periodic liver tests and blood
• Insomnia characterized by difficulty in
counts may be prudent
falling asleep, frequent nocturnal
awakenings, and/or early morning
awakening
• Recurring insomnia or poor sleeping SIDE EFFECTS
habits
How Drug Causes Side Effects
• Acute or chronic medical situations
• Same mechanism for side effects as for
requiring restful sleep
therapeutic effects – namely due to
excessive actions at benzodiazepine
receptors
How The Drug Works • Actions at benzodiazepine receptors that
• Binds to benzodiazepine receptors at the carry over to the next day can cause
GABA-A ligand-gated chloride channel daytime sedation, amnesia, and ataxia
complex • Long-term adaptations in benzodiazepine
• Enhances the inhibitory effects of GABA receptors may explain the development of
• Boosts chloride conductance through dependence, tolerance, and withdrawal
GABA-regulated channels
• Inhibitory actions in sleep centers may Notable Side Effects
provide sedative hypnotic effects ✽ Sedation, fatigue, depression
How Long Until It Works
✽ Dizziness, ataxia, slurred speech,
weakness
• Generally takes effect in less than an hour ✽ Forgetfulness, confusion
If It Works ✽ Hyper-excitability, nervousness
• Rare hallucinations, mania
• Improves quality of sleep • Rare hypotension
• Effects on total wake-time and number of • Hypersalivation, dry mouth
nighttime awakenings may be decreased • Rebound insomnia when withdrawing from
over time long-term treatment
If It Doesn’t Work
• If insomnia does not improve after Life Threatening or
7–10 days, it may be a manifestation of a Dangerous Side Effects
primary psychiatric or physical illness such • Respiratory depression, especially when
as obstructive sleep apnea or restless leg taken with CNS depressants in overdose
syndrome, which requires independent • Rare hepatic dysfunction, renal
evaluation dysfunction, blood dyscrasias
• Increase the dose
• Improve sleep hygiene Weight Gain
• Switch to another agent

• Reported but not expected

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FLURAZEPAM (continued)

Sedation Overdose
• No death reported in monotherapy;
sedation, slurred speech, poor
coordination, confusion, coma, respiratory
• Many experience and/or can be significant
depression
in amount

What To Do About Side Effects Long-Term Use

• Not generally intended for long-term use
• Wait
• To avoid problems with memory, only take ✽ Because of its relatively longer half-life,
flurazepam may cause some daytime
flurazepam if planning to have a full night’s
sedation and/or impaired motor/cognitive
sleep
function, and may do so progressively over
• Lower the dose
time
• Switch to a shorter-acting sedative
hypnotic Habit Forming
• Switch to a non-benzodiazepine hypnotic
• Flurazepam is a Schedule IV drug
• Administer flumazenil if side effects are
• Some patients may develop dependence
severe or life-threatening
and/or tolerance; risk may be greater with
Best Augmenting Agents for Side higher doses
• History of drug addiction may increase risk
Effects
of dependence
• Many side effects cannot be improved with
an augmenting agent How to Stop
• If taken for more than a few weeks, taper
to reduce chances of withdrawal effects
DOSING AND USE • Patients with seizure history may seize
upon sudden withdrawal
Usual Dosage Range • Rebound insomnia may occur the first
• 15–30 mg/day at bedtime for 7–10 days 1–2 nights after stopping
• For patients with severe problems
Dosage Forms discontinuing a benzodiazepine, dosing
• Capsule 15 mg, 30 mg may need to be tapered over many months
(i.e., reduce dose by 1% every 3 days by
How to Dose crushing tablet and suspending or
• 15 mg/day at bedtime; may increase to dissolving in 100 ml of fruit juice and then
30 mg/day at bedtime if ineffective disposing of 1 ml while drinking the rest;
3–7 days later, dispose of 2 ml, and so on).
This is both a form of very slow biological
Dosing Tips tapering and a form of behavioral
✽ Because flurazepam tends to accumulate desensitization
over time, perhaps not the best hypnotic
for chronic nightly use Pharmacokinetics
• Use lowest possible effective dose and • Elimination half-life approximately
assess need for continued treatment 24–100 hours
regularly • Active metabolites
• Flurazepam should generally not be
prescribed in quantities greater than a
1-month supply Drug Interactions
• Patients with lower body weights may • Cimetidine may decrease flurazepam
require lower doses clearance and thus raise flurazepam levels
• Risk of dependence may increase with • Flurazepam and kava combined use may
dose and duration of treatment affect clearance of either drug
• Increased depressive effects when taken
with other CNS depressants

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(continued) FLURAZEPAM

Other Warnings/
Precautions Pregnancy
• Insomnia may be a symptom of a primary • Risk Category X [positive evidence of risk
disorder, rather than a primary disorder to human fetus; contraindicated for use in
itself pregnancy]
• Some patients may exhibit abnormal • Infants whose mothers received a
thinking or behavioral changes similar to benzodiazepine late in pregnancy may
those caused by other CNS depressants experience withdrawal effects
(i.e., either depressant actions or • Neonatal flaccidity has been reported in
disinhibiting actions) infants whose mothers took a
• Some depressed patients may experience a benzodiazepine during pregnancy
worsening of suicidal ideation
• Use only with extreme caution in patients Breast Feeding
with impaired respiratory function or • Unknown if flurazepam is secreted in
obstructive sleep apnea human breast milk, but all psychotropics
• Flurazepam should only be administered at assumed to be secreted in breast milk
bedtime ✽ Recommended either to discontinue drug
or bottle feed
Do Not Use • Effects on infant have been observed and
• If patient is pregnant include feeding difficulties, sedation, and
• If patient has narrow angle-closure weight loss
glaucoma
• If there is a proven allergy to flurazepam or
any benzodiazepine THE ART OF PSYCHOPHARMACOLOGY
Potential Advantages
SPECIAL POPULATIONS • Transient insomnia

Renal Impairment Potential Disadvantages

• Recommended dose: 15 mg/day • Chronic nightly insomnia

Hepatic Impairment Primary Target Symptoms

• Recommended dose: 15 mg/day • Time to sleep onset
• Total sleep time
Cardiac Impairment • Nighttime awakenings
• Benzodiazepines have been used to treat
insomnia associated with acute myocardial
infarction Pearls
Elderly ✽ Flurazepam has a longer half-life than
some other sedative hypnotics, so it may
• Recommended dose: 15 mg/day
be less likely to cause rebound insomnia
on discontinuation
• Flurazepam may not be as effective on the
Children and Adolescents first night as it is on subsequent nights
• Safety and efficacy have not been • Was once one of the most widely used
established hypnotics
• Long-term effects of flurazepam in ✽ Long-term accumulation of flurazepam
children/adolescents are unknown and its active metabolites may cause
• Should generally receive lower doses and insidious onset of confusion or falls,
be more closely monitored especially in the elderly

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FLURAZEPAM (continued)

Suggested Reading
Greenblatt DJ. Pharmacology of Johnson LC, Chernik DA, Sateia MJ. Sleep,
benzodiazepine hypnotics. J Clin Psychiatry performance, and plasma levels in chronic
1992;53 (Suppl):7–13. insomniacs during 14-day use of flurazepam
and midazolam: an introduction. J Clin
Hilbert JM, Battista D. Quazepam and Psychopharmacol 1990;10(4 Suppl):5S–9S.
flurazepam: differential pharmacokinetic and
pharmacodynamic characteristics. J Clin Roth T, Roehrs TA. A review of the safety
Psychiatry 1991;52(Suppl):21–6. profiles of benzodiazepine hypnotics. J Clin
Psychiatry 1991;52(Suppl):38–41.

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FLUVOXAMINE
THERAPEUTICS • Continue treatment until all symptoms are
gone (remission) or significantly reduced
Brands • Luvox (e.g., OCD)
see index for additional brand names • Once symptoms gone, continue treating for
1 year for the first episode of depression
Generic? Yes
• For second and subsequent episodes of
depression, treatment may need to be
indefinite
Class • Use in anxiety disorders may also need to
• SSRI (selective serotonin reuptake be indefinite
inhibitor); often classified as an
antidepressant, but it is not just an If It Doesn’t Work
antidepressant • Many patients only have a partial response
where some symptoms are improved but
Commonly Prescribed For others persist (especially insomnia, fatigue,
(bold for FDA approved) and problems concentrating in depression)
• Obsessive-compulsive disorder (OCD) • Other patients may be nonresponders,
• Depression sometimes called treatment-resistant or
• Panic disorder treatment-refractory
• Generalized anxiety disorder (GAD) • Some patients who have an initial response
• Social anxiety disorder (social phobia) may relapse even though they continue
• Posttraumatic stress disorder (PTSD) treatment, sometimes called “poop-out”
• Consider increasing dose, switching to
another agent or adding an appropriate
How The Drug Works augmenting agent
• Boosts neurotransmitter serotonin • Consider psychotherapy
• Blocks serotonin reuptake pump (serotonin • Consider evaluation for another diagnosis
transporter) or for a comorbid condition (e.g., medical
• Desensitizes serotonin receptors, especially illness, substance abuse, etc.)
serotonin 1A receptors • Some patients may experience apparent
• Presumably increases serotonergic lack of consistent efficacy due to activation
neurotransmission of latent or underlying bipolar disorder, and
✽ Fluvoxamine also has antagonist require antidepressant discontinuation and
properties at sigma 1 receptors a switch to a mood stabilizer

How Long Until It Works Best Augmenting Combos

✽ Some patients may experience relief of for Partial Response or
insomnia or anxiety early after initiation of Treatment-Resistance
treatment • For the expert, consider cautious addition
• Onset of therapeutic actions usually not of clomipramine for treatment-resistant
immediate, but often delayed 2 to 4 weeks OCD
• If it is not working within 6 to 8 weeks, it • Trazodone, especially for insomnia
may require a dosage increase or it may • Bupropion, mirtazapine, reboxetine, or
not work at all atomoxetine (use combinations of
• May continue to work for many years to antidepressants with caution as this may
prevent relapse of symptoms activate bipolar disorder and suicidal
ideation)
If It Works • Modafinil, especially for fatigue, sleepiness,
• The goal of treatment is complete and lack of concentration
remission of current symptoms as well as • Mood stabilizers or atypical antipsychotics
prevention of future relapses for bipolar depression, psychotic
• Treatment most often reduces or even depression, treatment-resistant depression,
eliminates symptoms, but not a cure since or treatment-resistant anxiety disorders
symptoms can recur after medicine • Benzodiazepines
stopped

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FLUVOXAMINE (continued)

• If all else fails for anxiety disorders, • Mostly central nervous system (insomnia
consider gabapentin or tiagabine but also sedation, agitation, tremors,
• Hypnotics for insomnia headache, dizziness)
• Classically, lithium, buspirone, or thyroid • Note: patients with diagnosed or
hormone undiagnosed bipolar or psychotic disorders
• In Europe and Japan, augmentation is may be more vulnerable to CNS-activating
more commonly administered for the actions of SSRIs
treatment of depression and anxiety • Autonomic (sweating)
disorders, especially with benzodiazepines • Bruising and rare bleeding
and lithium • Rare hyponatremia
• In the US, augmentation is more
commonly administered for the treatment
of OCD, especially with atypical
Life Threatening or
antipsychotics, buspirone, or even Dangerous Side Effects
clomipramine; clomipramine should be • Rare seizures
added with caution and at low doses as • Rare induction of mania and activation of
fluvoxamine can alter clomipramine suicidal ideation
metabolism and raise its levels
Weight Gain
Tests
• None for healthy individuals
• Reported but not expected
• Patients may actually experience weight
SIDE EFFECTS loss

How Drug Causes Side Effects Sedation

• Theoretically due to increases in serotonin
concentrations at serotonin receptors in
parts of the brain and body other than • Many experience and/or can be significant
those that cause therapeutic actions (e.g., in amount
unwanted actions of serotonin in sleep
centers causing insomnia, unwanted What To Do About Side Effects
actions of serotonin in the gut causing • Wait
diarrhea, etc.) • Wait
• Increasing serotonin can cause diminished • Wait
dopamine release and might contribute to • If fluvoxamine is sedating, take at night to
emotional flattening, cognitive slowing, and reduce drowsiness
apathy in some patients • Reduce dose
• Most side effects are immediate but often • In a few weeks, switch or add other drugs
go away with time, in contrast to most
therapeutic effects which are delayed and Best Augmenting Agents for Side
are enhanced over time Effects
✽ Fluvoxamine’s sigma 1 antagonist • Often best to try another SSRI or another
properties may contribute to sedation and antidepressant monotherapy prior to
fatigue in some patients resorting to augmentation strategies to
treat side effects
Notable Side Effects • Trazodone or a hypnotic for insomnia
• Sexual dysfunction (men: delayed • Bupropion, sildenafil, vardenafil, or tadalafil
ejaculation, erectile dysfunction; men and for sexual dysfunction
women: decreased sexual desire, • Bupropion for emotional flattening,
anorgasmia) cognitive slowing, or apathy
• Gastrointestinal (decreased appetite, • Mirtazapine for insomnia, agitation, and
nausea, diarrhea, constipation, dry mouth) gastrointestinal side effects

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(continued) FLUVOXAMINE

• Benzodiazepines for jitteriness and anxiety, asymmetrically, usually with more of the
especially at initiation of treatment and dose given at night
especially for anxious patients • Some patients take more than 300 mg/day
• Many side effects are dose-dependent (i.e., • If intolerable anxiety, insomnia, agitation,
they increase as dose increases, or they akathisia, or activation occur either upon
reemerge until tolerance re-develops) dosing initiation or discontinuation,
• Many side effects are time-dependent (i.e., consider the possibility of activated bipolar
they start immediately upon dosing and disorder and switch to a mood stabilizer or
upon each dose increase, but go away with an atypical antipsychotic
time)
• Activation and agitation may represent the Overdose
induction of a bipolar state, especially a • Rare fatalities have been reported, both in
mixed dysphoric bipolar II condition combination with other drugs and alone;
sometimes associated with suicidal sedation, dizziness, vomiting, diarrhea,
ideation, and require the addition of irregular heartbeat, seizures, coma,
lithium, a mood stabilizer or an atypical breathing difficulty
antipsychotic, and/or discontinuation of
fluvoxamine Long-Term Use
• Safe

Habit Forming
DOSING AND USE • No
Usual Dosage Range How to Stop
• 100–300 mg/day for OCD
• Taper to avoid withdrawal effects
• 100–200 mg/day for depression
(dizziness, nausea, stomach cramps,
Dosage Forms sweating, tingling, dysesthesias)
• Many patients tolerate 50% dose reduction
• Tablets 25 mg, 50 mg scored, 100 mg
for 3 days, then another 50% reduction for
scored
3 days, then discontinuation
How to Dose • If withdrawal symptoms emerge during
• Initial 50 mg/day; increase by 50 mg/day in discontinuation, raise dose to stop
4–7 days; usually wait a few weeks to symptoms and then restart withdrawal
assess drug effects before increasing dose much more slowly
further, but can increase by 50 mg/day
Pharmacokinetics
every 4–7 days until desired efficacy is
• Parent drug has 9–28 hour half-life
reached; maximum 300 mg/day
• Inhibits CYP450 3A4
• Doses below 100 mg/day usually given as
• Inhibits CYP450 1A2
a single dose at bedtime; doses above
• Inhibits CYP450 2C9/2C19
100 mg/day can be divided into two doses
to enhance tolerability, with the larger dose
administered at night, but can also be
given as a single dose at bedtime Drug Interactions
• Tramadol increases the risk of seizures in
patients taking an antidepressant
Dosing Tips • Can increase tricyclic antidepressant levels;
use with caution with tricyclic
• 50 mg and 100 mg tablets are scored, so
antidepressants
to save costs, give 25 mg as half of 50 mg
• Can cause a fatal “serotonin syndrome”
tablet, and give 50 mg as half of 100 mg
when combined with MAO inhibitors, so do
tablet
not use with MAO inhibitors or for at least
• To improve tolerability, dosing can either
14 days after MAOIs are stopped
be given once a day, usually all at night, or
• Do not start an MAO inhibitor for at least
split either symmetrically or
2 weeks after discontinuing fluvoxamine

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FLUVOXAMINE (continued)

• May displace highly protein bound drugs Do Not Use

(e.g., warfarin) • If patient is taking an MAO inhibitor
• Can rarely cause weakness, hyperreflexia, • If patient is taking thioridazine or pimozide
and incoordination when combined with • If there is a proven allergy to fluvoxamine
sumatriptan or possibly with other triptans,
requiring careful monitoring of patient
• Via CYP450 1A2 inhibition, fluvoxamine SPECIAL POPULATIONS
may reduce clearance of theophylline and
clozapine, thus raising their levels and Renal Impairment
requiring their dosing to be lowered • No dose adjustment
• Fluvoxamine administered with either
caffeine or theophylline can thus cause Hepatic Impairment
jitteriness, excessive stimulation, or rarely • Lower dose or give less frequently, perhaps
seizures, so concomitant use should by half; use slower titration
proceed cautiously
• Metabolism of fluvoxamine may be Cardiac Impairment
enhanced in smokers and thus its levels • Preliminary research suggests that
lowered, requiring higher dosing fluvoxamine is safe in these patients
• Via CYP450 3A4 inhibition, fluvoxamine • Treating depression with SSRIs in patients
may reduce clearance of carbamazepine with acute angina or following myocardial
and benzodiazepines such as alprazolam infarction may reduce cardiac events and
and triazolam, and thus require dosage improve survival as well as mood
reduction
• Via CYP450 3A4 inhibition, fluvoxamine Elderly
could theoretically increase concentrations • May require lower initial dose and slower
of certain cholesterol lowering HMG CoA titration
reductase inhibitors, especially simvastatin,
atorvastatin, and lovastatin, but not
pravastatin or fluvastatin, which would Children and Adolescents
increase the risk of rhabdomyolysis; thus, • Approved for ages 8–17 for OCD
coadministration of fluvoxamine with • 8–17: initial 25 mg/day at bedtime;
certain HMG CoA reductase inhibitors increase by 25 mg/day every 4–7 days;
should proceed with caution maximum 200 mg/day; doses above
• Via CYP450 3A4 inhibition, fluvoxamine 50 mg/day should be divided into 2 doses
could theoretically increase the with the larger dose administered at
concentrations of pimozide, and cause QTc bedtime
prolongation and dangerous cardiac • Preliminary evidence suggests efficacy for
arrhythmias other anxiety disorders and depression in
children and adolescents
Other Warnings/ • Use with caution, observing for activation
of known or unknown bipolar disorder
Precautions
and/or suicidal ideation, and strongly
• Add or initiate other antidepressants with
consider informing parents or guardian of
caution for up to two weeks after
this risk so they can help observe child or
discontinuing fluvoxamine
adolescent patients
• Use with caution in patients with history of
seizure
• Use with caution in patients with bipolar
disorder unless treated with concomitant Pregnancy
mood stabilizing agent • Risk Category C [some animal studies
• May cause photosensitivity show adverse effects, no controlled studies
• Monitor patients for activation of suicidal in humans]
ideation, especially children and • Not generally recommended for use during
adolescents pregnancy, especially during first trimester

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(continued) FLUVOXAMINE

• Nonetheless, continuous treatment during THE ART OF PSYCHOPHARMACOLOGY

pregnancy may be necessary and has not
been proven to be harmful to the fetus
Potential Advantages
• At delivery there may be more bleeding in • Patients with mixed anxiety/depression
the mother and transient irritability or • Generic is less expensive than brand name
sedation in the newborn where available
• Must weigh the risk of treatment (first
Potential Disadvantages
trimester fetal development, third trimester
• Patients with irritable bowel or multiple
newborn delivery) to the child against the
gastrointestinal complaints
risk of no treatment (recurrence of
• Can require dose titration and twice daily
depression, maternal health, infant
dosing
bonding) to the mother and child
• For many patients this may mean Primary Target Symptoms
continuing treatment during pregnancy • Depressed mood
• Neonates exposed to SSRIs or SNRIs late • Anxiety
in the third trimester have developed
complications requiring prolonged
hospitalization, respiratory support, and
tube feeding; reported symptoms are Pearls
consistent with either a direct toxic effect ✽ Often a preferred treatment of anxious
of SSRIs and SNRIs or, possibly, a drug depression as well as major depressive
discontinuation syndrome, and include disorder comorbid with anxiety disorders
respiratory distress, cyanosis, apnea, • Some withdrawal effects, especially
seizures, temperature instability, feeding gastrointestinal effects
difficulty, vomiting, hypoglycemia, • May have lower incidence of sexual
hypotonia, hypertonia, hyperreflexia, dysfunction than other SSRIs
tremor, jitteriness, irritability, and constant • Preliminary research suggests that
crying fluvoxamine is efficacious in obsessive-
compulsive symptoms in schizophrenia
Breast Feeding when combined with antipsychotics
• Some drug is found in mother’s breast milk • Not FDA approved for depression, but used
• Trace amounts may be present in nursing widely for depression in many countries
children whose mothers are on • SSRIs may be less effective in women over
fluvoxamine 50, especially if they are not taking
• If child becomes irritable or sedated, breast estrogen
feeding or drug may need to be • SSRIs may be useful for hot flushes in
discontinued perimenopausal women
• Immediate postpartum period is a high-risk ✽ Actions at sigma 1 receptors may explain
time for depression, especially in women in part fluvoxamine’s sometimes rapid
who have had prior depressive episodes, onset effects in anxiety disorders and
so drug may need to be reinstituted late in insomnia
the third trimester or shortly after ✽ Actions at sigma 1 receptors may explain
childbirth to prevent a recurrence during potential advantages of fluvoxamine for
the postpartum period psychotic depression and delusional
• Must weigh benefits of breast feeding with depression
risks and benefits of antidepressant ✽ For treatment-resistant OCD, consider
treatment versus non-treatment to both the cautious combination of fluvoxamine and
infant and the mother clomipramine by an expert
• For many patients this may mean • Normally, clomipramine (CMI), a potent
continuing treatment during breast feeding serotonin reuptake blocker, at steady state
is metabolized extensively to its active
metabolite desmethyl-clomipramine (de-
CMI), a potent noradrenergic reuptake
blocker

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FLUVOXAMINE (continued)

• Thus, at steady state, plasma drug activity powerfully enhance serotonergic activity,
is generally more noradrenergic (with not only due to the inherent serotonergic
higher de-CMI levels) than serotonergic activity of fluvoxamine, but also due to a
(with lower parent CMI levels) favorable pharmacokinetic interaction
• Addition of a CYP450 1A2 inhibitor, inhibiting CYP450 1A2 and thus converting
fluvoxamine, blocks this conversion and CMI’s metabolism to a more powerful
results in higher CMI levels than de-CMI serotonergic portfolio of parent drug
levels
• Thus, addition of the SSRI fluvoxamine to
CMI in treatment-resistant OCD can

Suggested Reading
Cheer SM, Figgitt DP. Spotlight on fluvoxamine Pigott TA, Seay SM. A review of the efficacy of
in anxiety disorders in children and selective serotonin reuptake inhibitors in
adolescents. CNS Drugs. 2002;16:139–44. obsessive-compulsive disorder. Journal of
Clinical Psychiatry. 1999;60:101–106.
Edwards JG, Anderson I. Systematic review
and guide to selection of selective serotonin Wares MR. Fluvoxamine: a review of the
reuptake inhibitors. Drugs. 1999;57:507–533. controlled trials in depression. Journal of
Clinical Psychiatry. 1997;58(suppl 5):15–23.
Figgitt DP, McClellan KJ. Fluvoxamine. An
updated review of its use in the management
of adults with anxiety disorders. Drugs.
2000;60:925–954.

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GABAPENTIN
THERAPEUTICS starting by 2 weeks although it may take
several weeks to months to optimize
Brands • Neurontin
see index for additional brand names If It Works
• The goal of treatment is complete
Generic? Not in U.S. or Europe remission of symptoms (e.g., seizures)
• The goal of treatment of chronic
neuropathic pain is to reduce symptoms as
Class much as possible, especially in
• Anticonvulsant, antineuralgic for chronic combination with other treatments
pain, alpha 2 delta ligand at voltage- • Treatment of chronic neuropathic pain
sensitive calcium channels most often reduces but does not eliminate
symptoms and is not a cure since
Commonly Prescribed For symptoms usually recur after medicine
(bold for FDA approved) stopped
• Partial seizures with or without secondary • Continue treatment until all symptoms are
generalization (adjunctive) gone or until improvement is stable and
• Postherpetic neuralgia then continue treating indefinitely as long
• Neuropathic pain/chronic pain as improvement persists
• Anxiety (adjunctive)
• Bipolar disorder (adjunctive) If It Doesn’t Work (for neuropathic
pain or bipolar disorder)
✽ May only be effective in a subset of
How The Drug Works bipolar patients, in some patients who fail
• Is a leucine analogue and is transported to respond to other mood stabilizers, or it
both into the blood from the gut and also may not work at all
across the blood-brain barrier into the • Many patients only have a partial response
brain from the blood by the system L where some symptoms are improved but
transport system others persist or continue to wax and wane
✽ Binds to the alpha 2 delta subunit of without stabilization of pain or mood
voltage-sensitive calcium channels • Other patients may be nonresponders,
• This closes N and P/Q presynaptic calcium sometimes called treatment-resistant or
channels, diminishing excessive neuronal treatment-refractory
activity and neurotransmitter release • Consider increasing dose, switching to
• Although structurally related to gamma- another agent or adding an appropriate
aminobutyric acid (GABA), no known direct augmenting agent
actions on GABA or its receptors • Consider biofeedback or hypnosis for pain
• Consider the presence of noncompliance
How Long Until It Works and counsel patient
• Should reduce seizures by 2 weeks • Switch to another agent with fewer side
• Should also reduce pain in postherpetic effects
neuralgia by 2 weeks; some patients • Consider evaluation for another diagnosis
respond earlier or for a comorbid condition (e.g., medical
• May reduce pain in other neuropathic pain illness, substance abuse, etc.)
syndromes within a few weeks
• If it is not reducing pain within 6–8 weeks, Best Augmenting Combos
it may require a dosage increase or it may for Partial Response or
not work at all Treatment-Resistance
• May reduce anxiety in a variety of disorders ✽ Gabapentin is itself an augmenting agent
within a few weeks to numerous other anticonvulsants in
• Not yet clear if it has mood stabilizing treating epilepsy; and to lithium, atypical
effects in bipolar disorder or antineuralgic antipsychotics and other anticonvulsants in
actions in chronic neuropathic pain, but the treatment of bipolar disorder
some patients may respond and if so, • For postherpetic neuralgia, gabapentin can
would be expected to show clinical effects decrease concomitant opiate use

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GABAPENTIN (continued)

✽ For neuropathic pain, gabapentin can • Dose-related; can be problematic at high

augment tricyclic antidepressants and doses
SNRIs as well as tiagabine, other • Can wear off with time, but may not wear
anticonvulsants and even opiates if done off at high doses
by experts while carefully monitoring in
difficult cases What To Do About Side Effects
• For anxiety, gabapentin is a second-line • Wait
treatment to augment SSRIs, SNRIs, or • Wait
benzodiazepines • Wait
• Take more of the dose at night to reduce
Tests daytime sedation
• None for healthy individuals • Lower the dose
• False positive readings with the Ames N- • Switch to another agent
Multistix SG® dipstick test for urinary
protein have been reported when Best Augmenting Agents for Side
gabapentin was administered with other Effects
anticonvulsants • Many side effects cannot be improved with
an augmenting agent

SIDE EFFECTS
DOSING AND USE
How Drug Causes Side Effects
• CNS side effects may be due to excessive Usual Dosage Range
blockade of voltage-sensitive calcium • 900–1800 mg/day in 3 divided doses
channels
Dosage Forms
Notable Side Effects • Capsule 100 mg, 300 mg, 400 mg
✽ Sedation, dizziness, ataxia, fatigue, • Tablet 600 mg, 800 mg
nystagmus, tremor • Liquid 250 mg/5 mL – 470 mL bottle
• Vomiting, dyspepsia, diarrhea, dry mouth,
constipation, weight gain How to Dose
• Blurred vision • Postherpetic neuralgia: 300 mg on day 1;
• Peripheral edema on day 2 increase to 600 mg in 2 doses; on
• Additional effects in children under age 12: day 3 increase to 900 mg in 3 doses;
hostility, emotional lability, hyperkinesia, maximum dose generally 1800 mg/day in
thought disorder, weight gain 3 doses
• Seizures (ages 12 and older): Initial
900 mg/day in 3 doses; recommended
Life Threatening or dose generally 1800 mg/day in 3 doses;
Dangerous Side Effects maximum dose generally 3600 mg/day;
• Sudden unexplained deaths have occurred time between any 2 doses should usually
in epilepsy (unknown if related to not exceed 12 hours
gabapentin use) • Seizures (under age 13): see Children and
Adolescents
Weight Gain

Dosing Tips
• Occurs in significant minority • Gabapentin should not be taken until 2
hours after administration of an antacid
Sedation • If gabapentin is added to a second
anticonvulsant, the titration period should
be at least a week to improve tolerance to
• Many experience and/or can be significant sedation
in amount

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(continued) GABAPENTIN

• Some patients need to take gabapentin

only twice daily in order to experience Other Warnings/
adequate symptomatic relief for pain or Precautions
anxiety • Depressive effects may be increased by
• At the high end of the dosing range, other CNS depressants (alcohol, MAOIs,
tolerability may be enhanced by splitting other anticonvulsants, etc.)
dose into more than 3 divided doses • Dizziness and sedation could increase the
• For intolerable sedation, can give most of chances of accidental injury (falls) in the
the dose at night and less during the day elderly
• To improve slow-wave sleep, may only • Pancreatic acinar adenocarcinomas have
need to take gabapentin at bedtime developed in male rats that were given
gabapentin, but clinical significance is
Overdose unknown
• No fatalities; slurred speech, sedation, • Development of new tumors or worsening
double vision, diarrhea of tumors has occurred in humans taking
gabapentin; it is unknown whether
Long-Term Use gabapentin affected the development or
• Safe worsening of tumors

Habit Forming Do Not Use

• No • If there is a proven allergy to gabapentin or
pregabalin
How to Stop
• Taper over a minimum of 1 week
• Epilepsy patients may seize upon SPECIAL POPULATIONS
withdrawal, especially if withdrawal is
abrupt Renal Impairment
✽ Rapid discontinuation may increase the • Gabapentin is renally excreted, so the dose
risk of relapse in bipolar disorder may need to be lowered
• Discontinuation symptoms uncommon • Dosing can be adjusted according to
creatinine clearance, such that patients
Pharmacokinetics with clearance below 16 mL/min should
• Gabapentin is not metabolized but excreted receive 100–300 mg/day in 1 dose,
intact renally patients with clearance between
• Not protein bound 16–29 mL/min should receive
• Elimination half-life approximately 5–7 200–700 mg/day in 1 dose, and patients
hours with clearance between 30–59 mL/min
should receive 400–1400 mg/day in 2 doses
• Can be removed by hemodialysis; patients
Drug Interactions receiving hemodialysis may require
• Antacids may reduce the bioavailability of supplemental doses of gabapentin
gabapentin, so gabapentin should be • Use in renal impairment has not been
administered approximately 2 hours before studied in children under age 12
antacid medication
• Naproxen may increase absorption of Hepatic Impairment
gabapentin • No available data but not metabolized by
• Morphine and hydrocodone may increase the liver and clinical experience suggests
plasma AUC (area under the curve) values normal dosing
of gabapentin and thus gabapentin plasma
levels over time Cardiac Impairment
• No specific recommendations

Elderly
• Some patients may tolerate lower doses
better

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GABAPENTIN (continued)

• Elderly patients may be more susceptible ✽ Recommended either to discontinue drug

to adverse effects or bottle feed
• If drug is continued while breast feeding,
infant should be monitored for possible
Children and Adolescents adverse effects
• Approved for use starting at age 3 as • If infant becomes irritable or sedated,
adjunct treatment for partial seizures breast feeding or drug may need to be
• Ages 5–12: initial 10–15 mg/kg/day in discontinued
3 doses; titrate over 3 days to ✽ Bipolar disorder may recur during the
25–35 mg/kg/day given in 3 doses; postpartum period, particularly if there is a
maximum dose generally 50 mg/kg/day; history of prior postpartum episodes of
time between any 2 doses should usually either depression or psychosis
not exceed 12 hours ✽ Relapse rates may be lower in women
• Ages 3–4: initial 10–15 mg/kg/day in 3 who receive prophylactic treatment for
doses; titrate over 3 days to 40 mg/kg/day; postpartum episodes of bipolar disorder
maximum dose generally 50 mg/kg/day; • Atypical antipsychotics and anticonvulsants
time between any 2 doses should usually such as valproate may be safer and more
not exceed 12 hours effective than gabapentin during the
postpartum period when treating a nursing
mother with bipolar disorder
Pregnancy
• Risk category C [some animal studies
show adverse effects, no controlled studies THE ART OF PSYCHOPHARMACOLOGY
in humans] Potential Advantages
• Use in women of childbearing potential
• Chronic neuropathic pain
requires weighing potential benefits to the
• Has relatively mild side effect profile
mother against the risks to the fetus
• Has few pharmacokinetic drug interactions
• Taper drug if discontinuing
• Treatment-resistant bipolar disorder
• Seizures, even mild seizures, may cause
harm to the embryo/fetus Potential Disadvantages
✽ Lack of convincing efficacy for treatment • Usually requires 3 times a day dosing
of bipolar disorder or psychosis suggests • Poor documentation of efficacy for many
risk/benefit ratio is in favor of off-label uses, especially bipolar disorder
discontinuing gabapentin during pregnancy
for these indications Primary Target Symptoms
✽ For bipolar patients, gabapentin should • Seizures
generally be discontinued before • Pain
anticipated pregnancies • Anxiety
✽ For bipolar patients, given the risk of
relapse in the postpartum period, mood
stabilizer treatment, especially with agents
with better evidence of efficacy than
Pearls
gabapentin, should generally be restarted • Gabapentin is generally well-tolerated, with
immediately after delivery if patient is only mild adverse effects
unmedicated during pregnancy • Well-studied in epilepsy and postherpetic
✽ Atypical antipsychotics may be preferable neuralgia
to gabapentin if treatment of bipolar ✽ Most use is off-label
disorder is required during pregnancy ✽ Off-label use for first-line treatment of
• Bipolar symptoms may recur or worsen neuropathic pain may be justified
during pregnancy and some form of ✽ Off-label use for second-line treatment of
treatment may be necessary anxiety may be justified
✽ Off-label use as an adjunct for bipolar
Breast Feeding disorder may not be justified
• Some drug is found in mother’s breast milk

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(continued) GABAPENTIN

✽ Misperceptions about gabapentin’s helpful in chronic neuropathic pain

efficacy in bipolar disorder have led to its syndromes
use in more patients than other agents with ✽ May be a useful adjunct for fibromyalgia
proven efficacy, such as lamotrigine • Drug absorption and clinical efficacy may
✽ Off-label use as an adjunct for not necessarily be proportionately
schizophrenia may not be justified increased at high doses, and thus response
• May be useful for some patients in alcohol to high doses may not be consistent
withdrawal
✽ One of the few agents that enhances
slow-wave delta sleep, which may be

Suggested Reading
Backonja NM. Use of anticonvulsants for Rose MA, Kam PC. Gabapentin: pharmacology
treatment of neuropathic pain. Neurology and its use in pain management. Anaesthesia.
2002;59(Suppl 2):S14–7. 2002;57:451–62.
MacDonald KJ, Young LT. Newer antiepileptic Stahl SM. Anticonvulsants and the relief of
drugs in bipolar disorder. CNS Drugs chronic pain: pregabalin and gabapentin as
2002;16:549–62. alpha(2)delta ligands at voltage-gated calcium
channels. J Clin Psychiatry. 2004;65:596–7.
Marson AG, Kadir ZA, Hutton JL, Chadwick
DW. Gabapentin for drug-resistant partial Stahl SM. Anticonvulsants as anxiolytics, part
epilepsy. Cochrane Database Syst Rev. 2: Pregabalin and gabapentin as alpha(2)delta
2000;(2):CD001415. ligands at voltage-gated calcium channels. J
Clin Psychiatry. 2004;65:460–1.

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GALANTAMINE
THERAPEUTICS If It Doesn’t Work
• Consider adjusting dose, switching to a
Brands • Reminyl
different cholinesterase inhibitor or adding
see index for additional brand names
an appropriate augmenting agent
Generic? No • Reconsider diagnosis and rule out other
conditions such as depression or a
dementia other than Alzheimer disease
Class Best Augmenting Combos
• Cholinesterase inhibitor for Partial Response or
(acetylcholinesterase inhibitor); also an Treatment-Resistance
allosteric nicotinic cholinergic modulator;
cognitive enhancer
✽ Atypical antipsychotics to reduce
behavioral disturbances
Commonly Prescribed For ✽ Antidepressants if concomitant
depression, apathy, or lack of interest
(bold for FDA approved)
• Alzheimer disease
✽ Memantine for moderate to severe
Alzheimer disease
• Memory disturbances in other dementias
• Divalproex, carbamazepine, or
• Memory disturbances in other conditions
oxcarbazepine for behavioral disturbances
• Mild cognitive impairment
• Not rational to combine with another
cholinesterase inhibitor

How The Drug Works Tests

✽ Reversibly and competitively inhibits • None for healthy individuals
centrally-active acetylcholinesterase
(AChE), making more acetylcholine
available SIDE EFFECTS
• Increased availability of acetylcholine
compensates in part for degenerating How Drug Causes Side Effects
cholinergic neurons in neocortex that • Peripheral inhibition of acetylcholinesterase
regulate memory can cause gastrointestinal side effects
✽ Modulates nicotinic receptors, which • Central inhibition of acetylcholinesterase
enhances actions of acetylcholine may contribute to nausea, vomiting, weight
• Nicotinic modulation may also enhance the loss, and sleep disturbances
actions of other neurotransmitters by
increasing the release of dopamine, Notable Side Effects
norepinephrine, serotonin, GABA, and ✽ Nausea, diarrhea, vomiting, appetite loss,
glutamate increased gastric acid secretion, weight
• Does not inhibit butyrylcholinesterase loss
• May release growth factors or interfere • Headache, dizziness
with amyloid deposition • Fatigue, depression

How Long Until It Works

• May take up to 6 weeks before any Life Threatening or
improvement in baseline memory or Dangerous Side Effects
behavior is evident • Rare seizures
• May take months before any stabilization in • Rare syncope
degenerative course is evident
Weight Gain
If It Works
• May improve symptoms and slow
progression of disease, but does not • Reported but not expected
reverse the degenerative process • Some patients may experience weight loss

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GALANTAMINE (continued)

Sedation Long-Term Use

• Drug may lose effectiveness in slowing
degenerative course of Alzheimer disease
after 6 months
• Reported but not expected
• Can be effective in some patients for
What To Do About Side Effects several years
• Wait
Habit Forming
• Wait
• No
• Wait
• Use slower dose titration How to Stop
• Consider lowering dose, switching to a
• Taper not necessary
different agent or adding an appropriate
• Discontinuation may lead to notable
augmenting agent
deterioration in memory and behavior,
Best Augmenting Agents for Side which may not be restored when drug is
restarted or another cholinesterase
Effects
inhibitor is initiated
• Many side effects cannot be improved with
an augmenting agent Pharmacokinetics
• Terminal elimination half-life approximately
7 hours
DOSING AND USE • Metabolized by CYP450 2D6 and 3A4

Usual Dosage Range

• 16–24 mg/day
Drug Interactions
Dosage Forms • Galantamine may increase the effects of
• Tablet 4 mg, 8 mg, 12 mg anesthetics and should be discontinued
• Liquid 4 mg/mL – 100 mL bottle prior to surgery
• Inhibitors of CYP450 2D6 and CYP450 3A4
How to Dose may inhibit galantamine metabolism and
• Initial 8 mg twice daily; after 4 weeks may raise galantamine plasma levels
increase dose to 16 mg twice daily; • Galantamine may interact with
maximum dose generally 32 mg/day anticholinergic agents and the combination
may decrease the efficacy of both
• Cimetidine may increase bioavailability of
galantamine
Dosing Tips • May have synergistic effect if administered
• Gastrointestinal side effects may be with cholinomimetics (e.g., bethanechol)
reduced if drug is administered with food • Bradycardia may occur if combined with
• Gastrointestinal side effects may also be beta blockers
reduced if dose is titrated slowly • Theoretically, could reduce the efficacy of
• Probably best to utilize highest tolerated levodopa in Parkinson’s disease
dose within the usual dosing range • Not rational to combine with another
✽ When switching to another cholinesterase cholinesterase inhibitor
inhibitor, probably best to cross-titrate
from one to the other to prevent
precipitous decline in function if the patient Other Warnings/
washes out of one drug entirely Precautions
• May exacerbate asthma or other pulmonary
Overdose disease
• Can be lethal; nausea, vomiting, excess • Increased gastric acid secretion may
salivation, sweating, hypotension, increase the risk of ulcers
bradycardia, collapse, convulsions, muscle • Bradycardia or heart block may occur in
weakness (weakness of respiratory patients with or without cardiac impairment
muscles can lead to death)

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(continued) GALANTAMINE

Do Not Use THE ART OF PSYCHOPHARMACOLOGY

• If there is a proven allergy to galantamine
Potential Advantages
• Alzheimer disease with cerebrovascular
disease
SPECIAL POPULATIONS • Theoretically, nicotinic modulation may
provide added therapeutic benefits for
Renal Impairment memory and behavior in some Alzheimer
• Should be used with caution patients
• Not recommended for use in patients with • Theoretically, nicotinic modulation may
severe renal impairment also provide efficacy for cognitive
Hepatic Impairment disorders other than Alzheimer disease
• Should be used with caution Potential Disadvantages
• Reduction of clearance may increase with • Patients who have difficulty taking a
the degree of hepatic impairment medication twice daily
• Not recommended for use in patients with
severe hepatic impairment Primary Target Symptoms
• Memory loss in Alzheimer disease
Cardiac Impairment • Behavioral symptoms in Alzheimer disease
• Should be used with caution • Memory loss in other dementias
• Syncopal episodes have been reported with
the use of galantamine

Elderly Pearls
• Clearance is reduced in elderly patients • Dramatic reversal of symptoms of
Alzheimer disease is not generally seen
with cholinesterase inhibitors
Children and Adolescents • Can lead to therapeutic nihilism among
prescribers and lack of an appropriate trial
• Safety and efficacy have not been
of a cholinesterase inhibitor
established
✽ Perhaps only 50% of Alzheimer patients
are diagnosed, and only 50% of those
diagnosed are treated, and only 50% of
Pregnancy those treated are given a cholinesterase
• Risk Category B [animal studies do not inhibitor, and then only for 200 days in a
show adverse effects, no controlled studies disease that lasts 7–10 years
in humans] • Must evaluate lack of efficacy and loss of
✽ Not recommended for use in pregnant efficacy over months, not weeks
women or in women of childbearing ✽ Treats behavioral and psychological
potential symptoms of Alzheimer dementia as well
as cognitive symptoms (i.e., especially
Breast Feeding apathy, disinhibition, delusions, anxiety,
• Unknown if galantamine is secreted in cooperation, pacing)
human breast milk, but all psychotropics • Patients who complain themselves of
assumed to be secreted in breast milk memory problems may have depression,
✽ Recommended either to discontinue drug whereas patients whose spouses or
or bottle feed children complain of the patient’s memory
• Galantamine is not recommended for use problems may have Alzheimer disease
in nursing women • Treat the patient but ask the caregiver
about efficacy
• What you see may depend upon how early
you treat
• The first symptoms of Alzheimer disease
are generally mood changes; thus,

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GALANTAMINE (continued)

Alzheimer disease may initially be ✽ Novel dual action uniquely combines

diagnosed as depression acetylcholinesterase inhibition with
• Women may experience cognitive allosteric nicotine modulation
symptoms in perimenopause as a result of ✽ Novel dual action should theoretically
hormonal changes that are not a sign of enhance cholinergic actions but
dementia or Alzheimer disease incremental clinical benefits have been
• Aggressively treat concomitant symptoms difficult to demonstrate
with augmentation (e.g., atypical ✽ Actions at nicotinic receptors enhance not
antipsychotics for agitation, only the release of acetylcholine but also
antidepressants for depression) that of other neurotransmitters, which may
• If treatment with antidepressants fails to boost attention and improve behaviors
improve apathy and depressed mood in the caused by deficiencies in those
elderly, it is possible that this represents neurotransmitters in Alzheimer disease
early Alzheimer disease and a • Some Alzheimer patients who fail to
cholinesterase inhibitor like galantamine respond to another cholinesterase inhibitor
may be helpful may respond when switched to
• What to expect from a cholinesterase galantamine
inhibitor: • Some Alzheimer patients who fail to
• Patients do not generally improve respond to galantamine may respond to
dramatically although this can be another cholinesterase inhibitor
observed in a significant minority of • To prevent potential clinical deterioration,
patients generally switch from long-term treatment
• Onset of behavioral problems and with one cholinesterase inhibitor to another
nursing home placement can be delayed without a washout period
• Functional outcomes, including activities ✽ Galantamine may slow the progression of
of daily living, can be preserved mild cognitive impairment to Alzheimer
• Caregiver burden and stress can be disease
reduced ✽ May be useful for dementia with Lewy
• Delay in progression in Alzheimer disease bodies (DLB, constituted by early loss of
is not evidence of disease-modifying attentiveness and visual perception with
actions of cholinesterase inhibition possible hallucinations, Parkinson-like
• Cholinesterase inhibitors like galantamine movement problems, fluctuating cognition
depend upon the presence of intact targets such as daytime drowsiness and lethargy,
for acetylcholine for maximum effectiveness staring into space for long periods,
and thus may be most effective in the early episodes of disorganized speech)
stages of Alzheimer disease • May decrease delusions, apathy, agitation,
• The most prominent side effects of and hallucinations in dementia with Lewy
galantamine are gastrointestinal effects, bodies
which are usually mild and transient ✽ May be useful for vascular dementia
• For patients with intolerable side effects, (e.g., acute onset with slow stepwise
generally allow a washout period with progression that has plateaus, often with
resolution of side effects prior to switching gait abnormalities, focal signs, imbalance,
to another cholinesterase inhibitor and urinary incontinence)
• Weight loss can be a problem in Alzheimer • May be helpful for dementia in Down’s
patients with debilitation and muscle wasting Syndrome
• Women over 85, particularly with low body • Suggestions of utility in some cases of
weights, may experience more adverse treatment-resistant bipolar disorder
effects • Theoretically, may be useful for ADHD, but
• Use with caution in underweight or frail not yet proven
patients • Theoretically, could be useful in any
• Cognitive improvement may be linked to memory condition characterized by
substantial (>65%) inhibition of cholinergic deficiency (e.g., some cases of
acetylcholinesterase brain injury, cancer chemotherapy-induced
✽ Galantamine is a natural product present cognitive changes, etc.)
in daffodils and snowdrops

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(continued) GALANTAMINE

Suggested Reading
Bentue-Ferrer D, Tribut O, Polard E, Allain H. Olin J, Schneider L. Galantamine for
Clinically significant drug interactions with Alzheimer’s disease. Cochrane Database Syst
cholinesterase inhibitors: a guide for Rev 2002;(3):CD001747.
neurologists. CNS Drugs 2003;17:947–63.
Stahl SM. Cholinesterase inhibitors for
Bonner LT, Peskind ER. Pharmacologic Alzheimer’s disease. Hosp Pract (Off Ed)
treatments of dementia. Med Clin North Am 1998;33:131–6.
2002;86:657–74.
Stahl SM. The new cholinesterase inhibitors
Coyle J, Kershaw P. Galantamine, a for Alzheimer’s disease, part 1. J Clin
cholinesterase inhibitor that allosterically Psychiatry 2000;61:710–11.
modulates nicotinic receptors: effects on the
course of Alzheimer’s disease. Biol Psychiatry Stahl SM. The new cholinesterase inhibitors
2001;49:289–99. for Alzheimer’s disease, part 2. J Clin
Psychiatry 2000;61:813–14.
Jones RW. Have cholinergic therapies reached
their clinical boundary in Alzheimer’s disease?
Int J Geriatr Psychiatry 2003;18(Suppl 1):
S7–S13.

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HALOPERIDOL
THERAPEUTICS • Continue treatment in schizophrenia until
reaching a plateau of improvement
Brands • Haldol • After reaching a satisfactory plateau,
see index for additional brand names continue treatment for at least a year after
first episode of psychosis in schizophrenia
Generic? Yes
• For second and subsequent episodes of
psychosis in schizophrenia, treatment may
need to be indefinite
Class • Reduces symptoms of acute psychotic
• Conventional antipsychotic (neuroleptic, mania but not proven as a mood stabilizer
butyrophenone, dopamine 2 antagonist) or as an effective maintenance treatment in
bipolar disorder
Commonly Prescribed For • After reducing acute psychotic symptoms
(bold for FDA approved) in mania, switch to a mood stabilizer
• Manifestations of psychotic disorders and/or an atypical antipsychotic for mood
(oral, immediate release injection) stabilization and maintenance
• Tics and vocal utterances in Tourette’s
Disorder (oral, immediate release If It Doesn’t Work
injection) • Consider trying one of the first-line atypical
• Second-line treatment of severe behavior antipsychotics (risperidone, olanzapine,
problems in children of combative, quetiapine, ziprasidone, aripiprazole,
explosive hyperexcitability (oral, amisulpride)
immediate release injection) • Consider trying another conventional
• Second-line short-term treatment of antipsychotic
hyperactive children (oral, immediate • If 2 or more antipsychotic monotherapies
release injection) do not work, consider clozapine
• Treatment of schizophrenic patients who
require prolonged parenteral Best Augmenting Combos
antipsychotic therapy (depot for Partial Response or
intramuscular decanoate) Treatment-Resistance
• Bipolar disorder • Augmentation of conventional
• Behavioral disturbances in dementias antipsychotics has not been systematically
studied
• Addition of a mood stabilizing
How The Drug Works anticonvulsant such as valproate,
• Blocks dopamine 2 receptors, reducing carbamazepine, or lamotrigine may be
positive symptoms of psychosis and helpful in both schizophrenia and bipolar
possibly combative, explosive, and mania
hyperactive behaviors • Augmentation with lithium in bipolar mania
• Blocks dopamine 2 receptors in the may be helpful
nigrostriatal pathway, improving tics and • Addition of a benzodiazepine, especially
other symptoms in Tourette’s syndrome short-term for agitation

How Long Until It Works Tests

• Psychotic symptoms can improve within 1 ✽ Since conventional antipsychotics are
week, but it may take several weeks for full frequently associated with weight gain,
effect on behavior before starting treatment, weigh all patients
and determine if the patient is already
If It Works overweight (BMI 25.0–29.9) or obese
• Most often reduces positive symptoms in (BMI ≥30)
schizophrenia but does not eliminate them • Before giving a drug that can cause weight
• Most schizophrenic patients do not have a gain to an overweight or obese patient,
total remission of symptoms but rather a consider determining whether the patient
reduction of symptoms by about a third already has pre-diabetes (fasting plasma
glucose 100–125 mg/dl), diabetes (fasting

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HALOPERIDOL (continued)

plasma glucose >126 mg/dl), or

dyslipidemia (increased total cholesterol, Life Threatening or
LDL cholesterol and triglycerides; Dangerous Side Effects
decreased HDL cholesterol), and treat or • Rare neuroleptic malignant syndrome
refer such patients for treatment, including • Rare seizures
nutrition and weight management, physical • Rare jaundice, agranulocytosis, leukopenia
activity counseling, smoking cessation, and
medical management Weight Gain
✽ Monitor weight and BMI during treatment
✽ While giving a drug to a patient who has
gained >5% of initial weight, consider • Occurs in significant minority
evaluating for the presence of pre-diabetes,
diabetes, or dyslipidemia, or consider Sedation
switching to a different antipsychotic
• Should check blood pressure in the elderly
before starting and for the first few weeks
of treatment • Sedation is usually transient
• Monitoring elevated prolactin levels of
What To Do About Side Effects
dubious clinical benefit
• Wait
• Wait
• Wait
SIDE EFFECTS • For motor symptoms, add an
anticholinergic agent
How Drug Causes Side Effects • Reduce the dose
• By blocking dopamine 2 receptors in the • For sedation, give at night
striatum, it can cause motor side effects • Switch to an atypical antipsychotic
• By blocking dopamine 2 receptors in the • Weight loss, exercise programs, and
pituitary, it can cause elevations in medical management for high BMIs,
prolactin diabetes, dyslipidemia
• By blocking dopamine 2 receptors
excessively in the mesocortical and Best Augmenting Agents for Side
mesolimbic dopamine pathways, especially Effects
at high doses, it can cause worsening of • Benztropine or trihexyphenidyl for motor
negative and cognitive symptoms side effects
(neuroleptic-induced deficit syndrome) • Sometimes amantadine can be helpful for
• By blocking alpha 1 adrenergic receptors, it motor side effects
can cause dizziness, sedation, and • Benzodiazepines may be helpful for
hypotension akathisia
• Mechanism of weight gain and any • Many side effects cannot be improved with
possible increased incidence of diabetes or an augmenting agent
dyslipidemia with conventional
antipsychotics is unknown

Notable Side Effects DOSING AND USE

✽ Neuroleptic-induced deficit syndrome Usual Dosage Range
✽ Akathisia
✽ Extrapyramidal symptoms, Parkinsonism, • 1–40 mg/day orally
• Immediate release injection 2–5 mg each
tardive dyskinesia, tardive dystonia
✽ Galactorrhea, amenorrhea dose
• Decanoate injection 10–20 times the
• Dizziness, sedation
• Dry mouth, constipation, urinary retention, previous daily dose of oral antipsychotic
blurred vision
• Decreased sweating
• Hypotension, tachycardia, hypertension
• Weight gain

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(continued) HALOPERIDOL

Dosage Forms Overdose

• Tablet 0.5 mg scored, 1 mg scored, 2 mg • Fatalities have been reported;
scored, 5 mg scored, 10 mg scored, 20 mg extrapyramidal symptoms, hypotension,
scored sedation, respiratory depression, shock-like
• Concentrate 2 mg/mL state
• Solution 1 mg/mL
• Injection 5 mg/mL (immediate release) Long-Term Use
• Decanoate injection 50 mg haloperidol as • Often used for long-term maintenance
70.5 mg/mL haloperidol decanoate, • Some side effects may be irreversible (e.g.,
100 mg haloperidol as 141.04 mg/mL tardive dyskinesia)
haloperidol decanoate
Habit Forming
How to Dose • No
• Oral: initial 1–15 mg/day; can give once
daily or in divided doses at the beginning How to Stop
of treatment during rapid dose escalation; • Slow down-titration of oral formulation
increase as needed; can be dosed up to (over 6 to 8 weeks), especially when
100 mg/day; safety not established for simultaneously beginning a new
doses over 100 mg/day antipsychotic while switching (i.e., cross-
• Immediate release injection: initial dose titration)
2–5 mg; subsequent doses may be given • Rapid oral discontinuation may lead to
as often as every hour; patient should be rebound psychosis and worsening of
switched to oral administration as soon as symptoms
possible • If antiparkinson agents are being used,
• Decanoate injection: initial dose 10–15 they should be continued for a few weeks
times the previous oral dose for patients after haloperidol is discontinued
maintained on low antipsychotic doses
(e.g., up to equivalent of 10 mg/day oral Pharmacokinetics
haloperidol); initial dose may be as high as • Decanoate half-life approximately 3 weeks
20 times the previous oral dose for • Oral half-life approximately 12–38 hours
patients maintained on higher antipsychotic
doses; maximum dose 100 mg, if higher
than 100 mg dose is required the Drug Interactions
remainder can be administered 3–7 days • May decrease the effects of levodopa,
later; administer total dose every 4 weeks dopamine agonists
• May increase the effects of
antihypertensive drugs except for
Dosing Tips guanethidine, whose antihypertensive
• Haloperidol is frequently dosed too high actions haloperidol may antagonize
• Some studies suggest that patients who • Additive effects may occur if used with
respond well to low doses of haloperidol CNS depressants; dose of other agent
(e.g., approximately 2 mg/day) may have should be reduced
efficacy similar to atypical antipsychotics • Some pressor agents (e.g., epinephrine)
for both positive and negative symptoms of may interact with haloperidol to lower
schizophrenia blood pressure
• Higher doses may actually induce or • Haloperidol and anticholinergic agents
worsen negative symptoms of together may increase intraocular pressure
schizophrenia • Reduces effects of anticoagulants
• Low doses, however, may not have • Plasma levels of haloperidol may be
beneficial actions on cognitive and affective lowered by rifampin
symptoms in schizophrenia • Some patients taking haloperidol and
• One of the only antipsychotics with a depot lithium have developed an encephalopathic
formulation lasting for up to a month syndrome similar to neuroleptic malignant
syndrome

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HALOPERIDOL (continued)

• May enhance effects of antihypertensive

drugs
Pregnancy
• Risk Category C [some animal studies
Other Warnings/ show adverse effects, no controlled studies
Precautions in humans]
• If signs of neuroleptic malignant syndrome • Reports of extrapyramidal symptoms,
develop, treatment should be immediately jaundice, hyperreflexia, hyporeflexia in
discontinued infants whose mothers took a conventional
• Use with caution in patients with antipsychotic during pregnancy
respiratory disorders • Reports of limb deformity in infants whose
• Avoid extreme heat exposure mothers took haloperidol during pregnancy
• If haloperidol is used to treat mania, • Haloperidol should generally not be used
patients may experience a rapid switch to during the first trimester
depression • Haloperidol should only be used during
• Patients with thyrotoxicosis may pregnancy if clearly needed
experience neurotoxicity • Psychotic symptoms may worsen during
• Use only with caution if at all in Parkison’s pregnancy and some form of treatment
disease on Lewy Body dementia may be necessary
• Atypical antipsychotics may be preferable
Do Not Use to conventional antipsychotics or
• If patient is in comatose state or has CNS anticonvulsant mood stabilizers if
depression treatment is required during pregnancy
• If patient has Parkinson’s disease
• If there is a proven allergy to haloperidol Breast Feeding
• Some drug is found in mother’s breast milk
✽ Recommended either to discontinue drug
SPECIAL POPULATIONS or bottle feed

Renal Impairment
• Use with caution THE ART OF PSYCHOPHARMACOLOGY
Hepatic Impairment Potential Advantages
• Use with caution • Intramuscular formulation for emergency
use
Cardiac Impairment • Depot formulation for noncompliance
• Use with caution because of risk of • Low dose responders may have
orthostatic hypertension comparable positive and negative symptom
efficacy to atypical antipsychotics
Elderly • Low cost, effective treatment
• Lower doses should be used and patient
should be monitored closely Potential Disadvantages
• Elderly may be more susceptible to • Patients with tardive dyskinesia or who
respiratory side effects and hypotension wish to avoid tardive dyskinesia and
extrapyramidal symptoms
• Vulnerable populations such as children or
Children and Adolescents elderly
• Safety and efficacy have not been • Patients with notable cognitive or mood
established; not intended for use under age 3 symptoms
• Oral: initial 0.5 mg/day; target dose
0.05–0.15 mg/kg/day for psychotic Primary Target Symptoms
disorders; 0.05–0.075 mg/kg/day for • Positive symptoms of psychosis
nonpsychotic disorders • Violent or aggressive behavior
• Generally consider second-line after
atypical antipsychotics

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(continued) HALOPERIDOL

antipsychotic, which is different from

atypical antipsychotics where antipsychotic
Pearls responses of individual patients can
• Prior to the introduction of atypical occasionally vary greatly from one atypical
antipsychotics, haloperidol was one of the antipsychotic to another
most preferred antipsychotics • Conventional antipsychotics are much less
• Haloperidol may still be a useful expensive than atypical antipsychotics
antipsychotic, especially at low doses for • Patients receiving atypical antipsychotics
those patients who require management may occasionally require a “top up” of a
with a conventional antipsychotic or who conventional antipsychotic such as
cannot afford an atypical antipsychotic haloperidol to control aggression or violent
• Low doses may not induce negative behavior
symptoms, but high doses may • Patients with inadequate responses to
• Not clearly effective for improving cognitive atypical antipsychotics may benefit from a
or affective symptoms of schizophrenia trial of augmentation with a conventional
• May be effective for bipolar maintenance, antipsychotic such as haloperidol or from
but there may be more tardive dyskinesia switching to a conventional antipsychotic
when affective disorders are treated with a such as haloperidol
conventional antipsychotic long-term • However, long-term polypharmacy with a
• Less sedating than many other combination of a conventional
conventional antipsychotics, especially antipsychotic such as haloperidol with an
“low potency” phenothiazines atypical antipsychotic may combine their
• Haloperidol’s long-acting intramuscular side effects without clearly augmenting the
formulation lasts up to 4 weeks, whereas efficacy of either
some other long-acting intramuscular • Although a frequent practice by some
antipsychotics may only last up to 2 weeks prescribers, adding 2 conventional
• Decanoate administration is intended for antipsychotics together has little rationale
patients with chronic schizophrenia who and may reduce tolerability without clearly
have been stabilized on oral antipsychotic enhancing efficacy
medication
• Patients have very similar antipsychotic
responses to any conventional

Suggested Reading
Csernansky JG, Mahmoud R, Brenner R, Joy CB, Adams CE, Lawrie SM. Haloperidol
Risperidone-USA-79 Study Group. A versus placebo for schizophrenia. Cochrane
comparison of risperidone and haloperidol for Database Syst Rev 2001;(2):CD003082.
the prevention of relapse in patients with
schizophrenia. N Engl J Med 2002;346:16–22. Kudo S, Ishizaki T. Pharmacokinetics of
haloperidol: an update. Clin Pharmacokinet
Davis JM, Chen N, Glick ID. A meta-analysis of 1999;37:435–56.
the efficacy of second-generation
antipsychotics. Arch Gen Psychiatry Quraishi S ,David A. Depot haloperidol
2003;60:553–64. decanoate for schizophrenia. Cochrane
Database Syst Rev 2000;(2):CD001361.
Geddes J, Freemantle N, Harrison P,
Bebbington P. Atypical antipsychotics in the
treatment of schizophrenia: systematic
overview and meta-regression analysis. BMJ
2000;321:1371–6.

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HYDROXYZINE
THERAPEUTICS • For chronic anxiety disorders, treatment
most often reduces or even eliminates
Brands • Atarax symptoms, but not a cure since symptoms
• Marax can recur after medicine stopped
• Vistaril • For long-term symptoms of anxiety,
see index for additional brand names consider switching to an SSRI or SNRI for
long-term maintenance
Generic? Yes
• If long-term maintenance is necessary,
continue treatment for 6 months after
Class symptoms resolve, and then taper dose
• Antihistamine (anxiolytic, hypnotic, slowly
antiemetic) • If symptoms reemerge, consider treatment
with an SSRI or SNRI, or consider
Commonly Prescribed For restarting hydroxyzine
(bold for FDA approved)
• Anxiety and tension associated with If It Doesn’t Work
psychoneurosis • Consider switching to another agent or
• Adjunct in organic disease states in adding an appropriate augmenting agent
which anxiety is manifested
• Pruritus due to allergic conditions Best Augmenting Combos
• Histamine-mediated pruritus for Partial Response or
• Premedication sedation Treatment-Resistance
• Sedation following general anesthesia • Hydroxyzine can be used as an adjunct to
• Acute disturbance/hysteria (injection) SSRIs or SNRIs in treating anxiety
• Anxiety withdrawal symptoms in disorders
alcoholics or patients with delirium
tremens (injection) Tests
• Adjunct in pre/postoperative and • None for healthy individuals
pre/postpartum patients to allay anxiety, • Hydroxyzine may cause falsely elevated
control emesis, and reduce narcotic dose urinary concentrations of
(injection) 17-hydroxycorticosteroids in certain lab
• Nausea and vomiting (injection) tests (e.g., Porter-Silber reaction, Glenn-
• Insomnia Nelson method)

How The Drug Works SIDE EFFECTS

• Blocks histamine 1 receptors
How Drug Causes Side Effects
How Long Until It Works • Blocking histamine 1 receptors can cause
• 15–20 minutes (oral administration) sedation
• Some immediate relief with first dosing is
common; can take several weeks with daily Notable Side Effects
dosing for maximal therapeutic benefit in • Dry mouth, sedation, tremor
chronic conditions
Life Threatening or
If It Works Dangerous Side Effects
• For short-term symptoms of anxiety – after
• Rare convulsions (generally at high doses)
a few weeks, discontinue use or use on an
• Rare cardiac arrest, death (intramuscular
“as-needed” basis
formulation combined with CNS
• For chronic anxiety disorders, the goal of
depressants)
treatment is complete remission of
• Bronchodilation
symptoms as well as prevention of future
• Respiratory depression
relapses

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HYDROXYZINE (continued)

Weight Gain
Dosing Tips
• Hydroxyzine may be administered
• Reported but not expected intramuscularly initially, but should be
changed to oral administration as soon as
Sedation possible
• Tolerance usually develops to sedation,
allowing higher dosing over time
• Many experience and/or can be significant
in amount Overdose
• Sedation is usually transient • Sedation, hypotension

What To Do About Side Effects Long-Term Use

• Wait • Evidence of efficacy for up to 16 weeks
• Wait
• Wait
Habit Forming
• Switch to another agent • No

Best Augmenting Agents for Side How to Stop

• Taper generally not necessary
Effects
• Many side effects cannot be improved with Pharmacokinetics
an augmenting agent • Rapidly absorbed from gastrointestinal
tract
• Mean elimination half-life approximately
DOSING AND USE 20 hours
Usual Dosage Range
• Anxiety: 50–100 mg 4 times a day
• Sedative: 50–100 mg oral, 25–100 mg
Drug Interactions
intramuscular injection • If hydroxyzine is taken in conjunction with
• Pruritus: 75 mg/day divided into 3–4 doses another CNS depressant, the dose of the
CNS depressant should be reduced by half
Dosage Forms • If hydroxyzine is used pre- or post-
• Tablet 10 mg, 25 mg, 50 mg, 100 mg operatively, the dose of narcotic can be
• Capsule 25 mg, 50 mg, 100 mg reduced
• Oral Liquid 10 mg/5 mL, 25 mg/5 mL • If anticholinergic agents are used with
• Intramuscular 25 mg/mL, 50 mg/mL, hydroxyzine, the anticholinergic effects
100 mg/2 mL may be enhanced
• Hydroxyzine may reverse the vasopressor
How to Dose effect of epinephrine; patients requiring a
• Oral dosing does not require titration vasopressor agent should use
• Emergency intramuscular injection: Initial norepinephrine or metaraminol instead
50–100 mg, repeat every 4–6 hours as
needed Other Warnings/
• Hydroxyzine intramuscular injection should
Precautions
not be given in the lower or mid-third of
• Hydroxyzine should not be administered
the arm and should only be given in the
subcutaneously, intra-arterially, or
deltoid area if it is well-developed
intravenously
• In adults, hydroxyzine intramuscular
injections may be given in the upper outer Do Not Use
quadrant of the buttock or in the mid- • If patient is in early stages of pregnancy
lateral thigh • If there is a proven allergy to hydroxyzine

220
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(continued) HYDROXYZINE

SPECIAL POPULATIONS Breast Feeding

• Unknown if hydroxyzine is secreted in
Renal Impairment
human breast milk, but all psychotropics
• Dosage adjustment may not be necessary
assumed to be secreted in breast milk
Hepatic Impairment ✽ Recommended either to discontinue drug
or bottle feed
• Dosage adjustment may not be necessary

Cardiac Impairment
• Hydroxyzine may be used to treat anxiety THE ART OF PSYCHOPHARMACOLOGY
associated with cardiac impairment
Potential Advantages
Elderly • Has multiple formulations, including oral
• Some patients may tolerate lower doses capsules, tablets, and liquid, as well as
better injectable
• Elderly patients may be more sensitive to • No abuse liability, dependence, or
sedative and anticholinergic effects withdrawal

Potential Disadvantages
• Patients with severe anxiety disorders
Children and Adolescents
• Anxiety, pruritus (6 and older): Primary Target Symptoms
50–100 mg/day in divided doses • Anxiety
• Anxiety, pruritus (under 6): 50 mg/day in • Skeletal muscle tension
divided doses • Itching
• Sedative: 0.6 mg/kg oral, 0.5 mg/lb • Nausea, vomiting
intramuscular injection
• Small children should not receive
hydroxyzine by intramuscular injection in
the periphery of the upper quadrant of the Pearls
buttock unless absolutely necessary ✽ A preferred anxiolytic for patients with
because of risk of damage to the sciatic dermatitis or skin symptoms such as
nerve pruritis
• Hyperactive children should be monitored • Anxiolytic actions may be proportional to
for paradoxical effects sedating actions
• Hydroxyzine tablets are made with 1,1,1-
trichloroethane, which destroys ozone
• Hydroxyzine by intramuscular injection
Pregnancy may be used to treat agitation during
✽ Hydroxyzine is contraindicated in early alcohol withdrawal
pregnancy • Hydroxyzine may not be as effective as
• Hydroxyzine intramuscular injection can be benzodiazepines or newer agents in the
used prepartum, reducing narcotic management of anxiety
requirements by up to 50%

Suggested Reading
Diehn F, Tefferi A. Pruritus in polycythaemia Paton DM, Webster DR. Clinical
vera: prevalence, laboratory correlates and pharmacokinetics of H1-receptor antagonists
management. Br J Haematol 2001;115:619–21. (the antihistamines). Clin Pharmacokinet
1985;10:477–97.
Ferreri M, Hantouche EG. Recent clinical trials
of hydroxyzine in generalized anxiety disorder.
Acta Psychiatr Scand Suppl 1998;393:102–8.

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0521011698s05.qxd 9/2/04 2:35 PM Page 223

IMIPRAMINE
THERAPEUTICS If It Works
• The goal of treatment of depression is
Brands • Tofranil
complete remission of current symptoms
see index for additional brand names
as well as prevention of future relapses
Generic? Yes • The goal of treatment of chronic
neuropathic pain is to reduce symptoms as
much as possible, especially in
combination with other treatments
Class • Treatment of depression most often
• Tricyclic antidepressant (TCA) reduces or even eliminates symptoms, but
• Serotonin and norepinephrine/ not a cure since symptoms can recur after
noradrenaline reuptake inhibitor medicine stopped
• Treatment of chronic neuropathic pain may
Commonly Prescribed For reduce symptoms, but rarely eliminates
(bold for FDA approved) them completely, and is not a cure since
• Depression symptoms can recur after medicine is
✽ Enuresis stopped
• Anxiety • Continue treatment of depression until all
• Insomnia symptoms are gone (remission)
• Neuropathic pain/chronic pain • Once symptoms of depression are gone,
• Treatment-resistant depression continue treating for 1 year for the first
• Cataplexy syndrome episode of depression
• For second and subsequent episodes of
depression, treatment may need to be
How The Drug Works indefinite
• Boosts neurotransmitters serotonin and • Use in anxiety disorders and chronic pain
norepinephrine/noradrenaline may also need to be indefinite, but long-
• Blocks serotonin reuptake pump (serotonin term treatment is not well studied in these
transporter), presumably increasing conditions
serotonergic neurotransmission
If It Doesn’t Work
• Blocks norepinephrine reuptake pump
• Many depressed patients only have a
(norepinephrine transporter), presumably
partial response where some symptoms
increasing noradrenergic
are improved but others persist (especially
neurotransmission
insomnia, fatigue, and problems
• Presumably desensitizes both serotonin 1A
concentrating)
receptors and beta adrenergic receptors
• Other depressed patients may be
• Since dopamine is inactivated by
nonresponders, sometimes called
norepinephrine reuptake in frontal cortex,
treatment-resistant or treatment-refractory
which largely lacks dopamine transporters,
• Consider increasing dose, switching to
imipramine can increase dopamine
another agent or adding an appropriate
neurotransmission in this part of the brain
augmenting agent
• May be effective in treating enuresis
• Consider psychotherapy
because of its anticholinergic properties
• Consider evaluation for another diagnosis
How Long Until It Works or for a comorbid condition (e.g., medical
• May have immediate effects in treating illness, substance abuse, etc.)
insomnia or anxiety • Some patients may experience apparent
• Onset of therapeutic actions usually not lack of consistent efficacy due to activation
immediate, but often delayed 2 to 4 weeks of latent or underlying bipolar disorder, and
• If it is not working within 6 to 8 weeks for require antidepressant discontinuation and
depression, it may require a dosage a switch to a mood stabilizer
increase or it may not work at all
• May continue to work for many years to
prevent relapse of symptoms

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IMIPRAMINE (continued)

Best Augmenting Combos SIDE EFFECTS

for Partial Response or How Drug Causes Side Effects
Treatment-Resistance • Anticholinergic activity may explain
• Lithium, buspirone, thyroid hormone (for sedative effects, dry mouth, constipation,
depression) and blurred vision
• Gabapentin, tiagabine, other • Sedative effects and weight gain may be
anticonvulsants, even opiates if done by due to antihistamine properties
experts while monitoring carefully in • Blockade of alpha adrenergic 1 receptors
difficult cases (for chronic pain) may explain dizziness, sedation, and
hypotension
Tests
• Cardiac arrhythmias and seizures,
• None for healthy individuals
especially in overdose, may be caused by
✽ Since tricyclic and tetracyclic blockade of ion channels
antidepressants are frequently associated
with weight gain, before starting treatment, Notable Side Effects
weigh all patients and determine if the • Blurred vision, constipation, urinary
patient is already overweight retention, increased appetite, dry mouth,
(BMI 25.0–29.9) or obese (BMI ≥30) nausea, diarrhea, heartburn, unusual taste
• Before giving a drug that can cause weight in mouth, weight gain
gain to an overweight or obese patient, • Fatigue, weakness, dizziness, sedation,
consider determining whether the patient headache, anxiety, nervousness, restlessness
already has pre-diabetes (fasting plasma • Sexual dysfunction, sweating
glucose 100–125 mg/dl), diabetes (fasting
plasma glucose >126 mg/dl), or
dyslipidemia (increased total cholesterol, Life Threatening or
LDL cholesterol and triglycerides; Dangerous Side Effects
decreased HDL cholesterol), and treat or • Paralytic ileus, hyperthermia (TCAs +
refer such patients for treatment, including anticholinergic agents)
nutrition and weight management, physical • Lowered seizure threshold and rare
activity counseling, smoking cessation, and seizures
medical management • Orthostatic hypotension, sudden death,
✽ Monitor weight and BMI during treatment arrhythmias, tachycardia
✽ While giving a drug to a patient who has • QTc prolongation
gained >5% of initial weight, consider • Hepatic failure, extrapyramidal symptoms
evaluating for the presence of pre-diabetes, • Increased intraocular pressure, increased
diabetes, or dyslipidemia, or consider psychotic symptoms
switching to a different antidepressant • Rare induction of mania and activation of
• EKGs may be useful for selected patients suicidal ideation
(e.g., those with personal or family history
of QTc prolongation; cardiac arrhythmia; Weight Gain
recent myocardial infarction;
uncompensated heart failure; or taking
agents that prolong QTc interval such as • Many experience and/or can be significant
pimozide, thioridazine, selected in amount
antiarrhythmics, moxifloxacin, sparfloxacin, • Can increase appetite and carbohydrate
etc.) craving
• Patients at risk for electrolyte disturbances
(e.g., patients on diuretic therapy) should Sedation
have baseline and periodic serum
potassium and magnesium measurements

• Many experience and/or can be significant

in amount
• Tolerance to sedative effects may develop
with long-term use

224
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(continued) IMIPRAMINE

What To Do About Side Effects disorder, and switch to a mood stabilizer or

• Wait an atypical antipsychotic
• Wait
• Wait Overdose
• Lower the dose • Death may occur; convulsions, cardiac
• Switch to an SSRI or newer antidepressant dysrhythmias, severe hypotension, CNS
depression, coma, changes in ECG
Best Augmenting Agents for Side
Effects Long-Term Use
• Many side effects cannot be improved with • Safe
an augmenting agent
Habit Forming
• No
DOSING AND USE How to Stop
• Taper to avoid withdrawal effects
Usual Dosage Range • Even with gradual dose reduction some
• 50–150 mg/day withdrawal symptoms may appear within
the first 2 weeks
Dosage Forms
• Many patients tolerate 50% dose reduction
• Capsule 75 mg, 100 mg, 125 mg, 150 mg
for 3 days, then another 50% reduction for
• Tablet 10 mg, 25 mg, 50 mg
3 days, then discontinuation
How to Dose • If withdrawal symptoms emerge during
• Initial 25 mg/day at bedtime; increase by discontinuation, raise dose to stop
25 mg every 3–7 days symptoms and then restart withdrawal
• 75–100 mg/day once daily or in divided much more slowly
doses; gradually increase daily dose to Pharmacokinetics
achieve desired therapeutic effects; dose at
• Substrate for CYP450 2D6 and 1A2
bedtime for daytime sedation and in
• Metabolized to an active metabolite,
morning for insomnia; maximum dose
desipramine, a predominantly
300 mg/day
norepinephrine reuptake inhibitor, by
demethylation via CYP450 1A2

Dosing Tips
• If given in a single dose, should generally Drug Interactions
be administered at bedtime because of its
• Tramadol increases the risk of seizures in
sedative properties
patients taking TCAs
• If given in split doses, largest dose should
• Use of TCAs with anticholinergic drugs
generally be given at bedtime because of
may result in paralytic ileus or
its sedative properties
hyperthermia
• If patients experience nightmares, split
• Fluoxetine, paroxetine, bupropion,
dose and do not give large dose at bedtime
duloxetine, and other CYP450 2D6
• Patients treated for chronic pain may only
inhibitors may increase TCA concentrations
require lower doses
• Fluvoxamine, a CYP450 1A2 inhibitor, can
• Tofranil-PM(r) (imipramine pamoate) 100-
decrease the conversion of imipramine to
and 125-mg capsules contain the dye
desmethylimipramine (desipramine) and
tartrazine (FD&C yellow No. 5), which may
increase imipramine plasma concentrations
cause allergic reactions in some patients;
• Cimetidine may increase plasma
this reaction is more likely in patients with
concentrations of TCAs and cause
sensitivity to aspirin
anticholinergic symptoms
• If intolerable anxiety, insomnia, agitation,
• Phenothiazines or haloperidol may raise
akathisia, or activation occur either upon
TCA blood concentrations
dosing initiation or discontinuation,
• May alter effects of antihypertensive drugs;
consider the possibility of activated bipolar
may inhibit hypotensive effects of clonidine

225
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IMIPRAMINE (continued)

• Use with sympathomimetic agents may pimozide, thioridazine, selected

increase sympathetic activity antiarrhythmics, moxifloxacin,
• Methylphenidate may inhibit metabolism of sparfloxacin)
TCAs • If there is a history of QTc prolongation or
• Activation and agitation, especially cardiac arrhythmia, recent acute
following switching or adding myocardial infarction, uncompensated
antidepressants, may represent the heart failure
induction of a bipolar state, especially a • If patient is taking drugs that inhibit TCA
mixed dysphoric bipolar II condition metabolism, including CYP450 2D6
sometimes associated with suicidal inhibitors, except by an expert
ideation, and require the addition of • If there is reduced CYP450 2D6 function,
lithium, a mood stabilizer or an atypical such as patients who are poor 2D6
antipsychotic, and/or discontinuation of metabolizers, except by an expert and at
imipramine low doses
• If there is a proven allergy to imipramine,
desipramine, or lofepramine
Other Warnings/
Precautions
• Add or initiate other antidepressants with
caution for up to 2 weeks after
SPECIAL POPULATIONS
discontinuing imipramine Renal Impairment
• Generally, do not use with MAO inhibitors,
• Cautious use; may need lower dose
including 14 days after MAOIs are stopped;
do not start an MAOI until 2 weeks after Hepatic Impairment
discontinuing imipramine, but see Pearls • Cautious use; may need lower dose
• Use with caution in patients with history of
seizure, urinary retention, narrow angle- Cardiac Impairment
closure glaucoma, hyperthyroidism • TCAs have been reported to cause
• TCAs can increase QTc interval, especially arrhythmias, prolongation of conduction
at toxic doses, which can be attained not time, orthostatic hypotension, sinus
only by overdose but also by combining tachycardia, and heart failure, especially in
with drugs that inhibit its metabolism via the diseased heart
CYP450 2D6, potentially causing torsade • Myocardial infarction and stroke have been
de pointes-type arrhythmia or sudden reported with TCAs
death • TCAs produce QTc prolongation, which
• Because TCAs can prolong QTc interval, may be enhanced by the existence of
use with caution in patients who have bradycardia, hypokalemia, congenital or
bradycardia or who are taking drugs that acquired long QTc interval, which should
can induce bradycardia (e.g., beta blockers, be evaluated prior to administering
calcium channel blockers, clonidine, imipramine
digitalis) • Use with caution if treating concomitantly
• Because TCAs can prolong QTc interval, with a medication likely to produce
use with caution in patients who have prolonged bradycardia, hypokalemia,
hypokalemia and/or hypomagnesemia or slowing of intracardiac conduction, or
who are taking drugs that can induce prolongation of the QTc interval
hypokalemia and/or magnesemia (e.g., • Avoid TCAs in patients with a known
diuretics, stimulant laxatives, intravenous history of QTc prolongation, recent acute
amphotericin B, glucocorticoids, myocardial infarction, and uncompensated
tetracosactide) heart failure
• TCAs may cause a sustained increase in
Do Not Use heart rate in patients with ischemic heart
• If patient is recovering from myocardial disease and may worsen (decrease) heart
infarction rate variability, an independent risk of
• If patient is taking agents capable of mortality in cardiac populations
significantly prolonging QTc interval (e.g.,

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(continued) IMIPRAMINE

• Since SSRIs may improve (increase) heart • Evaluate for treatment with an
rate variability in patients following a antidepressant with a better risk/benefit ratio
myocardial infarct and may improve
survival as well as mood in patients with Breast Feeding
acute angina or following a myocardial • Some drug is found in mother’s breast milk
infarction, these are more appropriate ✽ Recommended either to discontinue drug
agents for cardiac population than or bottle feed
tricyclic/tetracyclic antidepressants • Immediate postpartum period is a high-risk
✽ Risk/benefit ratio may not justify use of time for depression, especially in women
TCAs in cardiac impairment who have had prior depressive episodes,
so drug may need to be reinstituted late in
Elderly the third trimester or shortly after
• May be more sensitive to anticholinergic, childbirth to prevent a recurrence during
cardiovascular, hypotensive, and sedative the postpartum period
effects • Must weigh benefits of breast feeding with
• Initial 30–40 mg/day; maximum dose risks and benefits of antidepressant
100 mg/day treatment versus non-treatment to both the
infant and the mother
• For many patients this may mean
Children and Adolescents continuing treatment during breast feeding
• Use with caution, observing for activation
of known or unknown bipolar disorder
and/or suicidal ideation, and strongly THE ART OF PSYCHOPHARMACOLOGY
consider informing parents or guardian of
this risk so they can help observe child or Potential Advantages
adolescent patients • Patients with insomnia
• Used age 6 and older for enuresis; age 12 • Severe or treatment-resistant depression
and older for other disorders • Patients with enuresis
• Several studies show lack of efficacy of
TCAs for depression Potential Disadvantages
• May be used to treat hyperactive/impulsive • Pediatric and geriatric patients
behaviors • Patients concerned with weight gain
• Some cases of sudden death have • Cardiac patients
occurred in children taking TCAs
• Adolescents: initial 30–40 mg/day;
Primary Target Symptoms
maximum 100 mg/day • Depressed mood
• Children: initial 1.5 mg/kg/day; maximum • Chronic pain
5 mg/kg/day
• Functional enuresis: 50 mg/day (age 6–12)
or 75 mg/day (over 12) Pearls
• Was once one of the most widely
prescribed agents for depression
Pregnancy ✽ Probably the most preferred TCA for
• Risk Category D [positive evidence of risk treating enuresis in children
to human fetus; potential benefits may still ✽ Preference of some prescribers for
justify its use during pregnancy] imipramine over other TCAs for the
• Crosses the placenta treatment of enuresis is based more upon
• Should be used only if potential benefits art and anecdote and empiric clinical
outweigh potential risks experience than comparative clinical trials
• Adverse effects have been reported in with other TCAs
infants whose mothers took a TCA • Tricyclic antidepressants are no longer
(lethargy, withdrawal symptoms, fetal generally considered a first-line treatment
malformations) option for depression because of their side
effect profile

227
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IMIPRAMINE (continued)

• TCAs may aggravate psychotic symptoms common side effects of MAOI/tricyclic or

• Alcohol should be avoided because of tetracyclic combinations may be weight
additive CNS effects gain and orthostatic hypotension
• Underweight patients may be more • Patients on TCAs should be aware that they
susceptible to adverse cardiovascular may experience symptoms such as
effects photosensitivity or blue-green urine
• Children, patients with inadequate • SSRIs may be more effective than TCAs in
hydration, and patients with cardiac women, and TCAs may be more effective
disease may be more susceptible to TCA- than SSRIs in men
induced cardiotoxicity than healthy adults • Since tricyclic/tetracyclic antidepressants
• For the expert only: although generally are substrates for CYP450 2D6, and 7% of
prohibited, a heroic but potentially the population (especially Caucasians) may
dangerous treatment for severely have a genetic variant leading to reduced
treatment-resistant patients is to give a activity of 2D6, such patients may not
tricyclic/tetracyclic antidepressant other safely tolerate normal doses of
than clomipramine simultaneously with an tricyclic/tetracyclic antidepressants and
MAO inhibitor for patients who fail to may require dose reduction
respond to numerous other • Phenotypic testing may be necessary to
antidepressants detect this genetic variant prior to dosing
• If this option is elected, start the MAOI with with a tricyclic/tetracyclic antidepressant,
the tricyclic/tetracyclic antidepressant especially in vulnerable populations such
simultaneously at low doses after as children, elderly, cardiac populations,
appropriate drug washout, then alternately and those on concomitant medications
increase doses of these agents every few • Patients who seem to have extraordinarily
days to a week as tolerated severe side effects at normal or low doses
• Although very strict dietary and may have this phenotypic CYP450 2D6
concomitant drug restrictions must be variant and require low doses or switching
observed to prevent hypertensive crises to another antidepressant not metabolized
and serotonin syndrome, the most by 2D6

Suggested Reading
Anderson IM. Meta-analytical studies on new Preskorn SH. Comparison of the tolerability of
antidepressants. Br Med Bull 2001; bupropion, fluoxetine, imipramine,
57:161–178. nefazodone, paroxetine, sertraline, and
venlafaxine. J Clin Psychiatry 1995;56(Suppl
Anderson IM. Selective serotonin reuptake 6):12–21.
inhibitors versus tricyclic antidepressants: a
meta-analysis of efficacy and tolerability. J Aff Workman EA, Short DD. Atypical
Disorders 2000;58:19–36. antidepressants versus imipramine in the
treatment of major depression: a meta-
analysis. J Clin Psychiatry 1993;54:5–12.

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ISOCARBOXAZID
THERAPEUTICS If It Doesn’t Work
• Many patients only have a partial response
Brands • Marplan
where some symptoms are improved but
see index for additional brand names
others persist (especially insomnia, fatigue,
Generic? Not in U.S. and problems concentrating)
• Other patients may be nonresponders,
sometimes called treatment-resistant or
treatment-refractory
Class • Some patients who have an initial response
• Monoamine oxidase inhibitor (MAOI) may relapse even though they continue
treatment, sometimes called “poop-out”
Commonly Prescribed For • Consider increasing dose, switching to
(bold for FDA approved) another agent or adding an appropriate
• Depression augmenting agent
• Treatment-resistant depression • Consider psychotherapy
• Treatment-resistant panic disorder • Consider evaluation for another diagnosis
• Treatment-resistant social anxiety disorder or for a comorbid condition (e.g., medical
illness, substance abuse, etc.)
• Some patients may experience apparent
How The Drug Works lack of consistent efficacy due to activation
• Irreversibly blocks monoamine oxidase of latent or underlying bipolar disorder, and
(MAO) from breaking down require antidepressant discontinuation and
norepinephrine, serotonin, and dopamine a switch to a mood stabilizer
• This presumably boosts noradrenergic,
serotonergic, and dopaminergic Best Augmenting Combos
neurotransmission for Partial Response or
Treatment-Resistance
How Long Until It Works ✽ Augmentation of MAOIs has not been
• Onset of therapeutic actions usually not systematically studied, and this is
immediate, but often delayed 2 to 4 weeks something for the expert, to be done with
• If it is not working within 6 to 8 weeks, it caution and with careful monitoring
may require a dosage increase or it may ✽ A stimulant such as d-amphetamine or
not work at all methylphenidate (with caution; may
• May continue to work for many years to activate bipolar disorder and suicidal
prevent relapse of symptoms ideation; may elevate blood pressure)
• Lithium
If It Works • Mood stabilizing anticonvulsants
• The goal of treatment is complete • Atypical antipsychotics (with special
remission of current symptoms as well as caution for those agents with monoamine
prevention of future relapses reuptake blocking properties, such as
• Treatment most often reduces or even ziprasidone and zotepine)
eliminates symptoms, but not a cure since
symptoms can recur after medicine Tests
stopped • Patients should be monitored for changes
• Continue treatment until all symptoms are in blood pressure
gone (remission) • Patients receiving high doses or long-term
• Once symptoms gone, continue treating for treatment should have hepatic function
1 year for the first episode of depression evaluated periodically
• For second and subsequent episodes of ✽ Since MAO inhibitors are frequently
depression, treatment may need to be associated with weight gain, before starting
indefinite treatment, weigh all patients and determine
• Use in anxiety disorders may also need to if the patient is already overweight
be indefinite (BMI 25.0–29.9) or obese (BMI ≥30)

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ISOCARBOXAZID (continued)

• Before giving a drug that can cause weight • Seizures

gain to an overweight or obese patient, • Hepatotoxicity
consider determining whether the patient
already has pre-diabetes (fasting plasma Weight Gain
glucose 100–125 mg/dl), diabetes (fasting
plasma glucose >126 mg/dl), or
dyslipidemia (increased total cholesterol, • Many experience and/or can be significant
LDL cholesterol and triglycerides; in amount
decreased HDL cholesterol), and treat or
refer such patients for treatment, including Sedation
nutrition and weight management, physical
activity counseling, smoking cessation, and
medical management
✽ Monitor weight and BMI during treatment • Many experience and/or can be significant
✽ While giving a drug to a patient who has in amount
• Can also cause activation
gained >5% of initial weight, consider
evaluating for the presence of pre-diabetes,
What To Do About Side Effects
diabetes, or dyslipidemia, or consider
• Wait
switching to a different antidepressant
• Wait
• Wait
• Lower the dose
SIDE EFFECTS • Take at night if daytime sedation
• Switch after appropriate washout to an
How Drug Causes Side Effects SSRI or newer antidepressant
• Theoretically due to increases in
monoamines in parts of the brain and body Best Augmenting Agents for Side
and at receptors other than those that Effects
cause therapeutic actions (e.g., unwanted • Trazodone (with caution) for insomnia
actions of serotonin in sleep centers • Benzodiazepines for insomnia
causing insomnia, unwanted actions of
norepinephrine on vascular smooth muscle
✽ Single oral or sublingual dose of a
calcium channel blocker (e.g., nifedipine)
causing hypertension, etc.) for urgent treatment of hypertension due to
• Side effects are generally immediate, but drug interaction or dietary tyramine
immediate side effects often disappear in • Many side effects cannot be improved with
time an augmenting agent
Notable Side Effects
• Dizziness, sedation, headache, sleep
disturbances, fatigue, weakness, tremor, DOSING AND USE
movement problems, blurred vision,
increased sweating Usual Dosage Range
• Constipation, dry mouth, nausea, change in • 40–60 mg/day
appetite, weight gain
Dosage Forms
• Sexual dysfunction
• Tablet 10 mg
• Orthostatic hypotension (dose-related);
syncope may develop at high doses How to Dose
• Initial 10 mg twice a day; increase by 10
Life Threatening or mg/day every 2–4 days; dosed 2–4
Dangerous Side Effects times/day; maximum dose 60 mg/day
• Hypertensive crisis (especially when MAOIs
are used with certain tyramine-containing
foods or prohibited drugs)
• Induction of mania and activation of
suicidal ideation

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(continued) ISOCARBOXAZID

levodopa, L-tryptophan, L-tyrosine, and

phenylalanine)
Dosing Tips • Excitation, seizures, delirium, hyperpyrexia,
• Orthostatic hypotension, especially at high circulatory collapse, coma, and death may
doses, may require splitting into 3 or 4 result from combining MAO inhibitors with
daily doses mepiridine or dextromethorphan
• Patients receiving high doses may need to • Do not combine with another MAO
be evaluated periodically for effects on the inhibitor, alcohol, buspirone, bupropion, or
liver guanethidine
• Little evidence to support efficacy of • Adverse drug reactions can results from
isocarboxazid at doses below 30 mg/day combining MAO inhibitors with
tricyclic/tetracyclic antidepressants and
Overdose
related compounds, including
• Dizziness, sedation, ataxia, headache,
carbamazepine, cyclobenzaprine, and
insomnia, restlessness, anxiety, irritability;
mirtazapine, and should be avoided except
cardiovascular effects, confusion,
by experts to treat difficult cases (see
respiratory depression, or coma may also
Pearls)
occur
• MAO inhibitors in combination with spinal
Long-Term Use anesthesia may cause combined
hypotensive effects
• May require periodic evaluation of hepatic
• Combination of MAOIs and CNS
function
depressants may enhance sedation and
• MAOIs may lose some efficacy long-term
hypotension
Habit Forming
• Some patients have developed dependence Other Warnings/
to MAOIs Precautions
• Use requires low tyramine diet
How to Stop
• Patients taking MAO inhibitors should
• Generally no need to taper, as drug wears
avoid high protein food that has undergone
off slowly over 2–3 weeks
protein breakdown by aging, fermentation,
Pharmacokinetics pickling, smoking, or bacterial
• Clinical duration of action may be up to 21 contamination
days due to irreversible enzyme inhibition • Patients taking MAO inhibitors should
avoid cheeses (especially aged varieties),
pickled herring, beer, wine, liver, yeast
extract, dry sausage, hard salami,
Drug Interactions pepperoni, Lebanon bologna, pods of
• Tramadol may increase the risk of seizures broad beans (fava beans), yogurt, and
in patients taking an MAO inhibitor excessive use of caffeine and chocolate
• Can cause a fatal “serotonin syndrome” • Patient and prescriber must be vigilant to
when combined with drugs that block potential interactions with any drug,
serotonin reuptake (e.g., SSRIs, SNRIs, including antihypertensives and over-the-
sibutramine, tramadol, etc.), so do not use counter cough/cold preparations
with a serotonin reuptake inhibitor or for • Over-the-counter medications to avoid
up to 5 weeks after stopping the serotonin include cough and cold preparations,
reuptake inhibitor including those containing
• Hypertensive crisis with headache, dextromethorphan, nasal decongestants
intracranial bleeding, and death may result (tablets, drops, or spray), hay-fever
from combining MAO inhibitors with medications, sinus medications, asthma
sympathomimetic drugs (e.g., inhalant medications, anti-appetite
amphetamines, methylphenidate, cocaine, medications, weight reducing preparations,
dopamine, epinephrine, norepinephrine, “pep” pills
and related compounds methyldopa,

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ISOCARBOXAZID (continued)

• Use cautiously in patients receiving • Elderly patients may have greater

reserpine, anesthetics, disulfiram, sensitivity to adverse effects
metrizamide, anticholinergic agents
• Isocarboxazid is not recommended for use
in patients who cannot be monitored Children and Adolescents
closely • Not recommended for use under age 16
• Monitor patients for activation of suicidal • Use with caution, observing for activation
ideation, especially children and of known or unknown bipolar disorder
adolescents and/or suicidal ideation, and strongly
consider informing parents or guardian of
Do Not Use
this risk so they can help observe child or
• If patient is taking meperidine (pethidine)
adolescent patients
• If patient is taking a sympathomimetic
agent or taking guanethidine
• If patient is taking another MAOI
• If patient is taking any agent that can Pregnancy
inhibit serotonin reuptake (e.g., SSRIs, • Risk Category C [some animal studies
sibutramine, tramadol, milnacipran, show adverse effects, no controlled studies
duloxetine, venlafaxine, clomipramine, etc.) in humans]
• If patient is taking diuretics, • Not generally recommended for use during
dextromethorphan, buspirone, bupropion pregnancy, especially during first trimester
• If patient has pheochromocytoma • Should evaluate patient for treatment with
• If patient has cardiovascular or an antidepressant with a better risk/benefit
cerebrovascular disease ratio
• If patient has frequent or severe headaches
• If patient is undergoing elective surgery Breast Feeding
and requires general anesthesia • Some drug is found in mother’s breast milk
• If patient has a history of liver disease or • Immediate postpartum period is a high-risk
abnormal liver function tests time for depression, especially in women
• If patient is taking a prohibited drug who have had prior depressive episodes,
• If patient is not compliant with a low- so drug may need to be reinstituted late in
tyramine diet the third trimester or shortly after
• If there is a proven allergy to isocarboxazid childbirth to prevent a recurrence during
the postpartum period
• Should evaluate patient for treatment with
an antidepressant with a better risk/benefit
SPECIAL POPULATIONS ratio
Renal Impairment
• Use with caution – drug may accumulate in
plasma THE ART OF PSYCHOPHARMACOLOGY
• May require lower than usual adult dose
Potential Advantages
Hepatic Impairment • Atypical depression
• Not for use in hepatic impairment • Severe depression
• Treatment-resistant depression or anxiety
Cardiac Impairment disorders
• Contraindicated in patients with congestive
heart failure or hypertension Potential Disadvantages
• Any other cardiac impairment may require • Requires compliance to dietary restrictions,
lower than usual adult dose concomitant drug restrictions
• Patients with angina pectoris or coronary • Patients with cardiac problems or
artery disease should limit their exertion hypertension
• Multiple daily doses
Elderly
• Initial dose lower than usual adult dose

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(continued) ISOCARBOXAZID

Primary Target Symptoms prohibitions against concomitant drugs

• Depressed mood often not followed closely enough
• Somatic symptoms • Orthostatic hypotension, insomnia, and
• Sleep and eating disturbances sexual dysfunction are often the most
• Psychomotor retardation troublesome common side effects
• Morbid preoccupation ✽ MAOIs should be for the expert,
especially if combining with agents of
potential risk (e.g., stimulants, trazodone,
Pearls TCAs)
• MAOIs are generally reserved for second- ✽ MAOIs should not be neglected as
line use after SSRIs, SNRIs, and therapeutic agents for the treatment-
combinations of newer antidepressants resistant
have failed • Although generally prohibited, a heroic but
• Despite little utilization, some patients potentially dangerous treatment for
respond to isocarboxazid who do not severely treatment-resistant patients is for
respond to other antidepressants including an expert to give a tricyclic/tetracyclic
other MAOIs antidepressant other than clomipramine
• Patient should be advised not to take any simultaneously with an MAO inhibitor for
prescription or over-the-counter drugs patients who fail to respond to numerous
without consulting their doctor because of other antidepressants
possible drug interactions with the MAOI • Use of MAOIs with clomipramine is always
• Headache is often the first symptom of prohibited because of the risk of serotonin
hypertensive crisis syndrome and death
• Foods generally to avoid as they are • Amoxapine may be the preferred
usually high in tyramine content: dry trycyclic/tetracyclic antidepressant to
sausage, pickled herring, liver, broad bean combine with an MAOI in heroic cases due
pods, sauerkraut, cheese, yogurt, alcoholic to its theoretically protective 5HT2A
beverages, nonalcoholic beer and wine, antagonist properties
chocolate, caffeine, meat and fish • If this option is elected, start the MAOI with
• The rigid dietary restrictions may reduce the tricyclic/tetracyclic antidepressant
compliance simultaneously at low doses after
• Mood disorders can be associated with appropriate drug washout, then alternately
eating disorders (especially in adolescent increase doses of these agents every few
females), and isocarboxazid can be used to days to a week as tolerated
treat both depression and bulimia • Although very strict dietary and
• MAOIs are a viable second-line treatment concomitant drug restrictions must be
option in depression, but are not frequently observed to prevent hypertensive crises
used and serotonin syndrome, the most
✽ Myths about the danger of dietary common side effects of MAOI and
tricyclic/tetracyclic combinations may be
tyramine can be exaggerated, but
weight gain and orthostatic hypotension

Suggested Reading
Kennedy SH. Continuation and maintenance Larsen JK, Rafaelsen OJ. Long-term treatment
treatments in major depression: the neglected of depression with isocarboxazide. Acta
role of monoamine oxidase inhibitors. J Psychiatr Scand 1980;62(5):456–63.
Psychiatry Neurosci 1997;22:127–31.
Lippman SB, Nash K. Monoamine oxidase
inhibitor update. Potential adverse food and
drug interactions. Drug Saf 1990;5:195–204.

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0521011698s05.qxd 9/2/04 2:35 PM Page 235

LAMOTRIGINE
THERAPEUTICS • Continue treatment until all symptoms are
gone or until improvement is stable and
Brands • Lamictal then continue treating indefinitely as long
• Labileno as improvement persists
• Lamictin • Continue treatment indefinitely to avoid
see index for additional brand names recurrence of mania, depression, and/or
seizures
Generic? No
• Treatment of chronic neuropathic pain may
reduce but does not eliminate pain
symptoms and is not a cure since pain
Class usually recurs after medicine stopped
• Anticonvulsant, mood stabilizer, voltage-
sensitive sodium channel antagonist If It Doesn’t Work (for bipolar
disorder)
Commonly Prescribed For ✽ Many patients only have a partial
(bold for FDA approved) response where some symptoms are
• Maintenance treatment of bipolar I improved but others persist or continue to
disorder wax and wane without stabilization of
• Partial seizures (adjunctive; adults and mood
children over age 2) • Other patients may be nonresponders,
• Generalized seizures of Lennox-Gastaut sometimes called treatment-resistant or
syndrome (adjunctive; adults and children treatment-refractory
over age 2) • Consider increasing dose, switching to
• Conversion to monotherapy in adults with another agent or adding an appropriate
partial seizures who are receiving augmenting agent
treatment with a single enzyme-inducing • Consider adding psychotherapy
antiepileptic drug • Consider biofeedback or hypnosis for pain
• Bipolar depression • Consider the presence of noncompliance
• Bipolar mania (adjunctive and second-line) and counsel patient
• Psychosis, schizophrenia (adjunctive) • Switch to another mood stabilizer with
• Neuropathic pain/chronic pain fewer side effects
• Consider evaluation for another diagnosis
or for a comorbid condition (e.g., medical
How The Drug Works illness, substance abuse, etc.)
✽ Acts as a use-dependent blocker of
voltage-sensitive sodium channels Best Augmenting Combos
✽ Interacts with the open channel for Partial Response or
conformation of voltage-sensitive sodium Treatment-Resistance
channels (for bipolar disorder)
✽ Interacts at a specific site of the alpha • Lithium
pore-forming subunit of voltage-sensitive • Atypical antipsychotics (especially
sodium channels risperidone, olanzapine, quetiapine,
• Inhibits release of glutamate ziprasidone, and aripiprazole)
How Long Until It Works
✽ Valproate (with caution and at half dose
of lamotrigine in the presence of valproate,
• May take several weeks to improve bipolar because valproate can double lamotrigine
depression levels)
• May take several weeks to months to ✽ Antidepressants (with caution because
optimize an effect on mood stabilization antidepressants can destabilize mood in
• Should reduce seizures by 2 weeks some patients, including induction of rapid
cycling or suicidal ideation; in particular
If It Works consider bupropion; also SSRIs, SNRIs,
• The goal of treatment is complete others; generally avoid TCAs, MAOIs)
remission of symptoms (e.g., seizures,
depression, pain)

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LAMOTRIGINE (continued)

Tests ✽ If patient develops signs of a rash with

• Because lamotrigine binds to melanin- benign characteristics (i.e., a rash that
containing tissues, opthalmological checks peaks within days, settles in 10–14 days, is
may be considered spotty, nonconfluent, nontender, has no
systemic features, and laboratory tests are
normal):
SIDE EFFECTS • Reduce lamotrigine dose or stop dosage
increase
How Drug Causes Side Effects • Warn patient to stop drug and contact
• CNS side effects theoretically due to physician if rash worsens or new
excessive actions at voltage-sensitive symptoms emerge
sodium channels • Prescribe antihistamine and/or topical
• Rash hypothetically an allergic reaction corticosteroid for pruritis
• Monitor patient closely
Notable Side Effects ✽ If patient develops signs of a rash with
✽ Benign rash (approximately 10%) serious characteristics (i.e., a rash that is
• Sedation, blurred or double vision, confluent and widespread, or purpuric or
dizziness, ataxia, headache, tremor, tender; with any prominent involvement of
insomnia, poor coordination, fatigue neck or upper trunk; any involvement of
• Nausea, vomiting, dyspepsia, abdominal eyes, lips, mouth, etc.; any associated
pain, constipation, rhinitis fever, malaise, pharyngitis, anorexia, or
• Additional effects in pediatric patients: lymphadenopathy; abnormal laboratory
infection, flu syndrome, pharyngitis, tests for complete blood count, liver
asthenia function, urea, creatinine):
• Stop lamotrigine (and valproate if
administered)
Life Threatening or • Monitor and investigate organ
Dangerous Side Effects involvement (hepatic, renal,
✽ Rare serious rash (risk may be greater in hematologic)
pediatric patients but still rare) • Patient may require hospitalization
• Rare multi-organ failure associated with
Stevens Johnson syndrome, toxic Best Augmenting Agents for Side
epidermal necrolysis or drug Effects
hypersensitivity syndrome • Antihistamines and/or topical corticosteroid
• Rare blood dyscrasias for rash, pruritis
• Rare sudden unexplained deaths have • Many side effects cannot be improved with
occurred in epilepsy (unknown if related to an augmenting agent
lamotrigine use)

Weight Gain
DOSING AND USE
Usual Dosage Range
• Reported but not expected • Monotherapy for bipolar disorder:
100–200 mg/day
Sedation • Adjunctive treatment for bipolar disorder:
100 mg/day in combination with valproate;
400 mg/day in combination with enzyme-
• Reported but not expected inducing antiepileptic drugs such as
• Dose-related carbamazepine, phenobarbital, phenytoin,
• Can wear off with time and primidone
• Monotherapy for seizures:
What To Do About Side Effects 300–500 mg/day in 2 doses
• Wait • Adjunctive treatment for seizures:
• Take at night to reduce daytime sedation 100–400 mg/day for regimens containing

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(continued) LAMOTRIGINE

valproate; 100–200 mg/day for valproate • Seizures (under age 12): see Children and
alone; 300–500 mg/day in 2 doses for Adolescents
regimens not containing valproate

Dosage Forms Dosing Tips

• Tablet 25 mg scored, 100 mg scored,
150 mg scored, 200 mg scored
✽ Very slow dose titration may reduce the
incidence of skin rash
• Chewable tablet 2 mg, 5 mg, 25 mg
• Therefore, dose should not be titrated
How to Dose faster than recommended because of
possible risk of increased side effects,
✽ Bipolar disorder (monotherapy): for the including rash
first 2 weeks administer 25 mg/day; at
• If patient stops taking lamotrigine for
week 3 increase to 50 mg/day; at week 5
5 days or more it may be necessary to
increase to 100 mg/day; at week 6 increase
restart the drug with the initial dose
to 200 mg/day; maximum dose generally
titration, as rashes have been reported on
200 mg/day
re-exposure
✽ Bipolar disorder (adjunct to valproate): • Advise patient to avoid new medications,
for the first 2 weeks administer 25 mg
foods, or products during the first
every other day; at week 3 increase to
3 months of lamotrigine treatment in order
25 mg/day; at week 5 increase to
to decrease the risk of unrelated rash;
50 mg/day; at week 6 increase to
patient should also not start lamotrigine
100 mg/day; maximum dose generally
within 2 weeks of a viral infection, rash, or
100 mg/day
vaccination
• Bipolar disorder (adjunct to enzyme-
inducing antiepileptic drugs): for the first ✽ If lamotrigine is added to patients taking
valproate, remember that valproate inhibits
2 weeks administer 50 mg/day; at week
lamotrigine metabolism and therefore
3 increase to 100 mg/day in divided doses;
titration rate and ultimate dose of
starting at week 5 increase by 100 mg/day
lamotrigine should be reduced by 50% to
each week; maximum dose generally
reduce the risk of rash
400 mg/day in divided doses
• When lamotrigine is added to epilepsy ✽ Thus, if concomitant valproate is
discontinued after lamotrigine dose is
treatment that includes valproate (ages 12
stabilized, then the lamotrigine dose should
and older): for the first 2 weeks administer
be cautiously doubled over at least 2 weeks
25 mg every other day; at week 3 increase
in equal increments each week following
to 25 mg/day; every 1–2 weeks can
discontinuation of valproate
increase by 25–50 mg/day; usual
• Also, if concomitant enzyme-inducing
maintenance dose 100–400 mg/day in
antiepileptic drugs such as carbamazepine,
1–2 doses or 100–200 mg/day if
phenobarbital, phenytoin, and primidone
lamotrigine is added to valproate alone
are discontinued after lamotrigine dose is
• When lamotrigine is added to epilepsy
stabilized, then the lamotrigine dose should
treatment that does not include valproate
be maintained for 1 week following
(ages 12 and older): for the first 2 weeks
discontinuation of the other drug and then
administer 50 mg/day; at week 3 increase
reduced by half over 2 weeks in equal
to 100 mg/day in 2 doses; every 1–2 weeks
decrements each week
can increase by 100 mg/day; usual
• Chewable dispersible tablets should only
maintenance dose 300–500 mg/day in
be administered as whole tablets; dose
2 doses
should be rounded down to the nearest
• When converting from a single enzyme-
whole tablet
inducing antiepileptic drug to lamotrigine
• Chewable dispersible tablets can be
monotherapy for epilepsy: titrate as
dispersed by adding the tablet to liquid
described above to 500 mg/day in 2 doses
(enough to cover the drug); after
while maintaining dose of previous
approximately 1 minute the solution should
medication; decrease first drug in 20%
be stirred and then consumed immediately
decrements each week over the next
in its entirety
4 weeks

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LAMOTRIGINE (continued)

Overdose • Enzyme-inducing antiepileptic drugs (e.g.,

• Some fatalities have occurred; ataxia, carbamazepine, phenobarbital, phenytoin,
nystagmus, seizures, coma, intraventricular primidone) may increase the clearance of
conduction delay lamotrigine and lower its plasma levels
• Oral contraceptives may decrease plasma
Long-Term Use levels of lamotrigine
• Safe • No likely pharmacokinetic interactions of
• Because lamotrigine binds to melanin- lamotrigine with lithium, atypical
containing tissues, opthalmological checks antipsychotics, or antidepressants
may be considered

Habit Forming Other Warnings/

• No Precautions
✽ Life-threatening rashes have developed in
How to Stop association with lamotrigine use;
• Taper lamotrigine should generally be
✽ Rapid discontinuation can increase the discontinued at the first sign of serious
risk of relapse in bipolar disorder rash
• Patients with epilepsy may seize upon ✽ Risk of rash may be increased with
withdrawal, especially if withdrawal is higher doses, faster dose escalation,
abrupt concomitant use of valproate, or in children
• Discontinuation symptoms uncommon under age 12
• Patient should be instructed to report any
Pharmacokinetics symptoms of hypersensitivity immediately
• Elimination half-life in healthy volunteers (fever; flu-like symptoms; rash; blisters on
approximately 33 hours after a single dose skin or in eyes, mouth, ears, nose, or
of lamotrigine genital areas; swelling of eyelids,
• Elimination half-life in patients receiving conjunctivitis, lymphadenopathy)
concomitant valproate treatment • Depressive effects may be increased by
approximately 59 hours after a single dose other CNS depressants (alcohol, MAOIs,
of lamotrigine other anticonvulsants, etc.)
• Elimination half-life in patients receiving • A small number of people may experience
concomitant enzyme-inducing antiepileptic a worsening of seizures
drugs (such as carbamazepine, • May cause photosensitivity
phenobarbital, phenytoin, and primidone) • Lamotrigine binds to tissue that contains
approximately 14 hours after a single dose melanin, so for long-term treatment
of lamotrigine ophthalmological checks may be
• Metabolized in the liver but not through the considered
CYP450 enzyme system
• Inactive metabolite Do Not Use
• Renally excreted • If there is a proven allergy to lamotrigine
• Lamotrigine inhibits dihydrofolate
reductase and may therefore reduce folate
concentrations SPECIAL POPULATIONS
Renal Impairment
Drug Interactions • Lamotrigine is renally excreted, so the dose
✽ Valproate increases plasma may need to be lowered
concentrations and half-life of lamotrigine, • Can be removed by hemodialysis; patients
requiring lower doses of lamotrigine (half receiving hemodialysis may require
or less) supplemental doses of lamotrigine
✽ Use of lamotrigine with valproate may be Hepatic Impairment
associated with an increased incidence of
rash • Dose may need to be reduced and titration
may need to be slower, perhaps by 50% in

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(continued) LAMOTRIGINE

patients with moderate impairment and

75% in patients with severe impairment
Pregnancy
Cardiac Impairment • Risk category C [some animal studies
• Drug should be used with caution show adverse effects, no controlled studies
in humans]
Elderly • Use in women of childbearing potential
• Some patients may tolerate lower doses requires weighing potential benefits to the
better mother against the risks to the fetus
• Elderly patients may be more susceptible ✽ If treatment with lamotrigine is continued,
to adverse effects plasma concentrations of lamotrigine may
be reduced during pregnancy, possibly
requiring increased doses with dose
Children and Adolescents reduction following delivery
• Ages 2 and older: approved as add-on for • Taper drug if discontinuing
Lennox-Gastaut syndrome • Seizures, even mild seizures, may cause
• Ages 2 and older: approved as add-on for harm to the embryo/fetus
partial seizures • Recurrent bipolar illness during pregnancy
• No other use of lamotrigine is approved for can be quite disruptive
patients under 16 years of age ✽ For bipolar patients, lamotrigine should
✽ Risk of rash is increased in pediatric generally be discontinued before
anticipated pregnancies
patients, especially in children under 12
and in children taking valproate ✽ For bipolar patients in whom treatment is
• When lamotrigine is added to treatment discontinued, given the risk of relapse in
that includes valproate (ages 2–12): for the the postpartum period, lamotrigine should
first 2 weeks administer 0.15 mg/kg/day in generally be restarted immediately after
1–2 doses rounded down to the nearest delivery
whole tablet; at week 3 increase to ✽ Atypical antipsychotics may be preferable
0.3 mg/kg/day in 1–2 doses rounded down to lithium or anticonvulsants such as
to the nearest whole tablet; every lamotrigine if treatment of bipolar disorder
1–2 weeks can increase by 0.3 mg/kg/day is required during pregnancy, but
rounded down to the nearest whole tablet; lamotrigine may be preferable to other
usual maintenance dose 1–5 mg/kg/day in anticonvulsants such as valproate if
1–2 doses (maximum generally anticonvulsant treatment is required during
200 mg/day) or 1–3 mg/kg/day in pregnancy
1–2 doses if lamotrigine is added to • Bipolar symptoms may recur or worsen
valproate alone during pregnancy and some form of
• When lamotrigine is added to treatment treatment may be necessary
that does not include valproate (ages
Breast Feeding
2–12): for the first 2 weeks administer
• Some drug is found in mother’s breast milk
0.6 mg/kg/day in 2 doses rounded down to
the nearest whole tablet; at week 3 increase ✽ Generally recommended either to
discontinue drug or bottle feed
to 1.2 mg/kg/day in 2 doses rounded down
• If drug is continued while breast feeding,
to the nearest whole tablet; every
infant should be monitored for possible
1–2 weeks can increase by 1.2 mg/kg/day
adverse effects
rounded down to the nearest whole tablet;
• If infant shows signs of irritability or
usual maintenance dose 5–15 mg/kg/day in
sedation, drug may need to be
2 doses (maximum dose generally
discontinued
400 mg/day)
• Clearance of lamotrigine may be influenced ✽ Bipolar disorder may recur during the
postpartum period, particularly if there is a
by weight, such that patients weighing less
history of prior postpartum episodes of
than 30 kg may require an increase of up
either depression or psychosis
to 50% for maintenance doses

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LAMOTRIGINE (continued)

✽ Relapse rates may be lower in women • Actual risk of serious skin rash comparable
who receive prophylactic treatment for to agents erroneously considered “safer”
postpartum episodes of bipolar disorder including carbamazepine, phenytoin, and
• Atypical antipsychotics and anticonvulsants phenobarbital
such as valproate may be preferable to • Rashes are common even in placebo-
lithium or lamotrigine during the treated patients in clinical trials of bipolar
postpartum period when breast feeding patients (5–10%) due to non-drug related
causes including eczema, irritant, and
allergic contact dermatitis, such as poison
THE ART OF PSYCHOPHARMACOLOGY ivy and insect bite reactions
✽ To manage rashes in bipolar patients
Potential Advantages receiving lamotrigine, realize that rashes
• Depressive stages of bipolar disorder that occur within the first 5 days or after
(bipolar depression) 8–12 weeks of treatment are rarely drug-
• To prevent recurrences of both depression related, and learn the clinical distinctions
and mania in bipolar disorder between a benign rash and a serious rash
(see What to Do About Side Effects above)
Potential Disadvantages • Rash, including serious rash, appears
• May not be as effective in the manic stage riskiest in patients with epilepsy, in
of bipolar disorder younger children, in those who are
receiving concomitant valproate, and/or in
Primary Target Symptoms those receiving rapid lamotrigine titration
• Incidence of seizures and/or high dosing
• Unstable mood, especially depression, in • Risk of serious rash is less than 1% and
bipolar disorder has been declining since slower titration,
• Pain lower dosing, adjustments to use of
concomitant valproate administration, and
limitations on use in children under 12
Pearls have been implemented
✽ Lamotrigine is a first-line treatment • Incidence of serious rash is very low
option that may be best for patients with (approaching zero) in recent studies of
bipolar depression bipolar patients
✽ Seems to be more effective in treating • Benign rashes related to lamotrigine may
depressive episodes than manic episodes affect up to 10% of patients and resolve
in bipolar disorder (treats from below rapidly with drug discontinuation
better than it treats from above) ✽ Given the limited treatment options for
✽ Seems to be effective in preventing both bipolar depression, patients with benign
manic relapses as well as depressive rashes can even be re-challenged with
relapses (stabilizes both from above and lamotrigine 5–12 mg/day with very slow
from below) although it may be even better titration after risk-benefit analysis if they
for preventing depressive relapses than for are informed, reliable, closely monitored,
preventing manic relapses and warned to stop lamotrigine and contact
✽ Despite convincing evidence of efficacy in their physician if signs of hypersensitivity
bipolar disorder, is often used far less occur
frequently than anticonvulsants without • Only a third of bipolar patients experience
convincing evidence of efficacy in bipolar adequate relief with a monotherapy, so
disorder (e.g., gabapentin or topiramate) most patients need multiple medications
✽ Low levels of use may be based upon for best control
exaggerated fears of skin rashes or lack of • Lamotrigine is useful in combination with
knowledge about how to manage skin atypical antipsychotics and/or lithium for
rashes if they occur acute mania
✽ May actually be one of the best tolerated • Usefulness for bipolar disorder in
mood stabilizers with little weight gain or combination with anticonvulsants other
sedation than valproate is not well demonstrated;

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(continued) LAMOTRIGINE

such combinations can be expensive and • Early studies suggest possible utility for
are possibly ineffective or even irrational patients with neuropathic pain such as
• May be useful as an adjunct to atypical diabetic peripheral neuropathy, HIV-
antipsychotics for rapid onset of action in associated neuropathy, and other pain
schizophrenia conditions including migraine

Suggested Reading
Calabrese JR, Vieta E, Shelton MD. Latest Culy CR, Goa KL. Lamotrigine. A review of its
maintenance data on lamotrigine in bipolar use in childhood epilepsy. Paediatr Drugs.
disorder. Eur Neuropsychopharmacol. 2000; 2: 299–330.
2003;13(Suppl 2):S57–66.
Green B. Lamotrigine in mood disorders. Curr
Calabrese JR, Sullivan JR, Bowden CL, Med Res Opin. 2003;19:272–7.
Suppes T, Goldberg JF, Sachs GS, Shelton MD,
Goodwin FK, Frye MA, Kusumakar V. Rash in
multicenter trials of lamotrigine in mood
disorders: clinical relevance and management.
J Clin Psychiatry. 2002;63:1012–1019

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0521011698s05.qxd 9/2/04 2:35 PM Page 243

LEVETIRACETAM
THERAPEUTICS continue treating indefinitely as long as
improvement persists
Brands • Keppra • Continue treatment indefinitely to avoid
see index for additional brand names recurrence of seizures, mania, and pain
Generic? Not in U.S. If It Doesn’t Work (for bipolar
disorder or neuropathic pain)
✽ May only be effective in a subset of
Class bipolar patients, in some patients who fail
• Anticonvulsant, synaptic vesicle protein to respond to other mood stabilizers, or it
SV2A modulator may not work at all
• Many patients only have a partial response
Commonly Prescribed For where some symptoms are improved but
(bold for FDA approved) others persist or continue to wax and wane
• Adjunct therapy for partial seizures in without stabilization of pain or mood
adults with epilepsy • Other patients may be nonresponders,
• Neuropathic pain/chronic pain sometimes called treatment-resistant or
• Mania treatment-refractory
• Consider increasing dose or switching to
another agent with better demonstrated
How The Drug Works efficacy in bipolar disorder or neuropathic
✽ Binds to synaptic vesicle protein SV2A, pain
which is involved in synaptic vesicle
exocytosis Best Augmenting Combos
• No apparent effects on GABA for Partial Response or
neurotransmission or inhibition of voltage- Treatment-Resistance
sensitive sodium channels or voltage- • Levetiracetam is itself a second-line
sensitive calcium channels augmenting agent to numerous other
anticonvulsants, lithium, and atypical
How Long Until It Works antipsychotics for bipolar disorder and to
• Should reduce seizures by 2 weeks gabapentin, tiagabine, other
• Not yet clear if it has mood stabilizing anticonvulsants, SNRIs, and tricyclic
effects in bipolar disorder or antineuralgic antidepressants for neuropathic pain
actions in chronic neuropathic pain, but
some patients may respond and if so, Tests
would be expected to show clinical effects • None for healthy individuals
starting by 2 weeks although it may take
several weeks to months to optimize
clinical effects SIDE EFFECTS
If It Works How Drug Causes Side Effects
• The goal of treatment is complete • CNS side effects may be due to excessive
remission of symptoms (e.g., seizures, actions on SV2A synaptic vesicle proteins
mania, pain) or to actions on various voltage-sensitive
• The goal of treatment of chronic ion channels
neuropathic pain is to reduce symptoms as
much as possible, especially in Notable Side Effects
combination with other treatments ✽ Sedation, dizziness, ataxia, asthenia
• Treatment of chronic neuropathic pain • Hematologic abnormalities (decrease in red
most often reduces but does not eliminate blood cell count and hemoglobin)
symptoms and is not a cure since
symptoms usually recur after medicine
stopped
• Continue treatment until all symptoms are
gone or until mood is stable and then

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LEVETIRACETAM (continued)

Overdose
Life Threatening or • No fatalities; sedation, agitation,
Dangerous Side Effects aggression, respiratory depression, coma
• Activation of suicidal ideation and acts
(rare) Long-Term Use
• Safe
Weight Gain
Habit Forming
• No
• Reported but not expected
How to Stop
Sedation • Taper
• Epilepsy patients may seize upon
withdrawal, especially if withdrawal is
abrupt
• Many experience and/or can be significant ✽ Rapid discontinuation can increase the
in amount risk of relapse in bipolar disorder
• Discontinuation symptoms uncommon
What To Do About Side Effects
• Wait Pharmacokinetics
• Wait • Elimination half-life approximately
• Wait 6–8 hours
• Take more of the dose at night to reduce • Inactive metabolites
daytime sedation • Not metabolized by CYP450 enzymes
• Lower the dose • Does not inhibit/induce CYP450 enzymes
• Switch to another agent • Renally excreted
Best Augmenting Agents for Side
Effects
Drug Interactions
• Many side effects cannot be improved with
• Because levetiracetam is not metabolized
an augmenting agent
by CYP450 enzymes and does not inhibit
or induce CYP450 enzymes, it is unlikely to
have significant pharmacokinetic drug
DOSING AND USE interactions
Usual Dosage Range
• 1000–3000 mg/day in 2 doses Other Warnings/
Precautions
Dosage Forms • Depressive effects may be increased by
• Tablet 250 mg, 500 mg, 750 mg other CNS depressants (alcohol, MAOIs,
• Oral solution 100 mg/mL other anticonvulsants, etc.)
How to Dose Do Not Use
• Initial 1000 mg/day in 2 divided doses; • If there is a proven allergy to levetiracetam
after 2 weeks can increase by 1000 mg/day
every 2 weeks; maximum dose generally
3000 mg/day SPECIAL POPULATIONS
Renal Impairment
Dosing Tips • Recommended dose for patients with mild
• For intolerable sedation, can give most of impairment may be between 500 mg and
the dose at night and less during the day 1500 mg twice a day
• Some patients may tolerate and respond to • Recommended dose for patients with
doses greater than 3000 mg/day moderate impairment may be between
250 mg and 750 mg twice a day

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(continued) LEVETIRACETAM

• Recommended dose for patients with ✽ Atypical antipsychotics may be preferable

severe impairment may be between to levetiracetam if treatment of bipolar
250 mg and 500 mg twice a day disorder is required during pregnancy
• Patients on dialysis may require doses • Bipolar symptoms may recur or worsen
between 500 mg and 1000 mg once a day, during pregnancy and some form of
with a supplemental dose of 250–500 mg treatment may be necessary
following dialysis
Breast Feeding
Hepatic Impairment • Some drug is found in mother’s breast milk
• Dose adjustment usually not necessary ✽ Recommended either to discontinue drug
or bottle feed
Cardiac Impairment • If drug is continued while breast feeding,
• No specific recommendations infant should be monitored for possible
adverse effects
Elderly • If infant becomes irritable or sedated,
• Some patients may tolerate lower doses breast feeding or drug may need to be
better discontinued
• Elderly patients may be more susceptible ✽ Bipolar disorder may recur during the
to adverse effects postpartum period, particularly if there is a
history of prior postpartum episodes of
either depression or psychosis
Children and Adolescents ✽ Relapse rates may be lower in women
• Safety and efficacy not established under who receive prophylactic treatment for
age 16 postpartum episodes of bipolar disorder
• Children may require higher doses than • Atypical antipsychotics and anticonvulsants
adults; dosing should be adjusted such as valproate may be safer than
according to weight levetiracetam during the postpartum period
when breast feeding

Pregnancy
• Risk category C [some animal studies THE ART OF PSYCHOPHARMACOLOGY
show adverse effects, no controlled studies
in humans] Potential Advantages
• Use in women of childbearing potential • Patients on concomitant drugs (lack of
requires weighing potential benefits to the drug interactions)
mother against the risks to the fetus • Treatment-refractory bipolar disorder
• Taper drug if discontinuing • Treatment-refractory neuropathic pain
• Seizures, even mild seizures, may cause
harm to the embryo/fetus
Potential Disadvantages
• Lack of convincing efficacy for treatment of • Patients noncompliant with twice daily
bipolar disorder or chronic neuropathic dosing
pain suggests risk/benefit ratio is in favor • Efficacy for bipolar disorder or neuropathic
of discontinuing levetiracetam during pain not well documented
pregnancy for these indications Primary Target Symptoms
✽ For bipolar patients, given the risk of • Seizures
relapse in the postpartum period, mood
• Pain
stabilizer treatment, especially with agents
• Mania
with better evidence of efficacy than
levetiracetam, should generally be restarted
immediately after delivery if patient is
unmedicated during pregnancy Pearls
✽ For bipolar patients, levetiracetam should • Well studied in epilepsy
generally be discontinued before ✽ Off-label use second-line and as an
anticipated pregnancies augmenting agent may be justified for

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LEVETIRACETAM (continued)

bipolar disorder and neuropathic pain suggests theoretical utility for clinical
unresponsive to other treatments conditions that are hypothetically linked to
✽ Unique mechanism of action suggests excessively activated neuronal circuits,
utility where other anticonvulsants fail to such as anxiety disorders and neuropathic
work pain as well as epilepsy
✽ Unique mechanism of action as
modulator of synaptic vesicle release

Suggested Reading
Ben-Menachem E. Levetiracetam: treatment in Lynch BA, Lambeng N, Nocka K, Kensel-
epilepsy. Expert Opin Pharmacother. Hammes P, Bajjalieh SM, Matagne A, Fuks B..
2003;4(11):2079–88. The synaptic vesicle protein SV2A is the
binding site for the antiepileptic drug
French J. Use of levetiracetam in special levetiracetam. Proc Natl Acad Sci U S A.
populations. Epilepsia. 2001;42 Suppl 4:40–3. 2004;101:9861–6.
Leppik IE. Three new drugs for epilepsy: Pinto A, Sander JW. Levetiracetam: a new
levetiracetam, oxcarbazepine, and zonisamide. therapeutic option for refractory epilepsy. Int J
J Child Neurol. 2002;17 Suppl 1:S53–7. Clin Pract. 2003;57(7):616–21.

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LITHIUM
THERAPEUTICS If It Works
• The goal of treatment is complete
Brands • Eskalith
remission of symptoms (i.e., mania and/or
• Eskalith CR
depression)
• Lithobid slow release tablets
• Continue treatment until all symptoms are
• Lithostat tablets
gone or until improvement is stable and
• Lithium carbonate tablets
then continue treating indefinitely as long
• Lithium citrate syrup
as improvement persists
see index for additional brand names
• Continue treatment indefinitely to avoid
Generic? Yes recurrence of mania or depression

If It Doesn’t Work
✽ Many patients only have a partial
Class response where some symptoms are
• Mood stabilizer improved but others persist or continue to
wax and wane without stabilization of
Commonly Prescribed For mood
(bold for FDA approved) • Other patients may be nonresponders,
• Manic episodes of manic depressive sometimes called treatment-resistant or
illness treatment-refractory
• Maintenance treatment for manic • Consider checking plasma drug level,
depressive patients with a history of increasing dose, switching to another agent
mania or adding an appropriate augmenting agent
• Bipolar depression • Consider adding psychotherapy
• Major depressive disorder (adjunctive) • Consider the presence of noncompliance
• Vascular headache and counsel patient
• Neutropenia • Switch to another mood stabilizer with
fewer side effects
• Consider evaluation for another diagnosis
How The Drug Works or for a comorbid condition (e.g., medical
• Unknown and complex illness, substance abuse, etc.)
• Alters sodium transport across cell
membranes in nerve and muscle cells Best Augmenting Combos
• Alters metabolism of neurotransmitters for Partial Response or
including catecholamines and serotonin Treatment-Resistance
✽ May alter intracellular signaling through • Valproate
actions on second messenger systems • Atypical antipsychotics (especially
• Specifically, inhibits inositol risperidone, olanzapine, quetiapine,
monophosphatase, possibly affecting ziprasidone, and aripiprazole)
neurotransmission via phosphatidyl inositol • Lamotrigine
second messenger system ✽ Antidepressants (with caution because
• Also reduces protein kinase C activity, antidepressants can destabilize mood in
possibly affecting genomic expression some patients, including induction of rapid
associated with neurotransmission cycling or suicidal ideation; in particular
• Increases cytoprotective proteins, activates consider bupropion; also SSRIs, SNRIs,
signaling cascade utilized by endogenous others; generally avoid TCAs, MAOIs)
growth factors, and increases gray matter
content, possibly by activating Tests
neurogenesis and enhancing trophic ✽ Before initiating treatment, kidney
actions that maintain synapses function tests (including creatinine and
urine specific gravity) and thyroid function
How Long Until It Works tests; electrocardiogram for patients over
• 1–3 weeks 50
• Repeat kidney function tests 1–2
times/year

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LITHIUM (continued)

✽ Frequent tests to monitor trough lithium

plasma levels (should generally be between Life Threatening or
1.0 and 1.5 mEq/L for acute treatment, 0.6 Dangerous Side Effects
and 1.2 mEq/l for chronic treatment) • Lithium toxicity
✽ Since lithium is frequently associated • Renal impairment (interstitial nephritis)
with weight gain, before starting treatment, • Nephrogenic diabetes insipidus
weigh all patients and determine if the • Arrhythmia, cardiovascular changes, sick
patient is already overweight sinus syndrome, bradycardia, hypotension
(BMI 25.0–29.9) or obese (BMI ≥30) • T wave flattening and inversion
• Before giving a drug that can cause weight • Rare pseudotumor cerebri
gain to an overweight or obese patient, • Rare seizures
consider determining whether the patient
already has pre-diabetes (fasting plasma Weight Gain
glucose 100–125 mg/dl), diabetes (fasting
plasma glucose >126 mg/dl), or
dyslipidemia (increased total cholesterol, • Many experience and/or can be significant
LDL cholesterol and triglycerides; in amount
decreased HDL cholesterol), and treat or • Can become a health problem in some
refer such patients for treatment, including • May be associated with increased appetite
nutrition and weight management, physical
activity counseling, smoking cessation, and Sedation
medical management
✽ Monitor weight and BMI during treatment
✽ While giving a drug to a patient who has • Many experience and/or can be significant
gained >5% of initial weight, consider
in amount
evaluating for the presence of pre-diabetes,
• May wear off with time
diabetes, or dyslipidemia, or consider
switching to a different agent What To Do About Side Effects
• Wait
• Wait
SIDE EFFECTS • Wait
• Lower the dose
How Drug Causes Side Effects ✽ Take entire dose at night as long as
• Unknown and complex efficacy persists all day long with this
• CNS side effects theoretically due to administration
excessive actions at the same or similar ✽ Change to a different lithium preparation
sites that mediate its therapeutic actions (e.g., controlled release)
• Some renal side effects theoretically due to ✽ Reduce dosing from 3 times/day to
lithium’s actions on ion transport 2 times/day
• If signs of lithium toxicity occur,
Notable Side Effects discontinue immediately
✽ Ataxia, dysarthria, delirium, tremor, • For stomach upset, take with food
memory problems • For tremor, avoid caffeine
✽ Polyuria, polydipsia (nephrogenic • Switch to another agent
diabetes insipidus)
✽ Diarrhea, nausea Best Augmenting Agents for Side
✽ Weight gain Effects
• Euthyroid goiter or hypothyroid goiter,
possibly with increased TSH and reduced
✽ Propranolol 20–30 mg 2–3 times/day
may reduce tremor
thyroxine levels • For the expert, cautious addition of a
• Acne, rash, alopecia diuretic (e.g., chlorothiazide 50 mg/day)
• Leukocytosis while reducing lithium dose by 50% and
monitoring plasma lithium levels may

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(continued) LITHIUM

reduce polydipsia and polyuria that does tapered slowly over 3 months if it is to be
not go away with time alone discontinued after long-term maintenance
• Many side effects cannot be improved with
an augmenting agent Overdose
• Fatalities have occurred; tremor, dysarthria,
delirium, coma, seizures, autonomic
DOSING AND USE instability

Usual Dosage Range Long-Term Use

• 1800 mg/day in divided doses (acute) • Indicated for long-term prevention of
• 900–1200 mg/day in divided doses relapse
(maintenance) • May cause reduced kidney function
• Liquid: 10 mL three times/day (acute • Requires regular therapeutic monitoring of
mania); 5 mL 3–4 times/day (long-term) lithium levels as well as of kidney function
and thyroid function
Dosage Forms
• Tablet 300 mg (slow release), 450 mg Habit Forming
(controlled release) • No
• Capsule 150 mg, 300 mg, 600 mg
How to Stop
• Liquid 8 mEq/5 mL
• Taper gradually over 3 months to avoid
How to Dose relapse
• Start 300 mg 2–3 times/day and adjust • Rapid discontinuation increases the risk of
dosage upward as indicated by plasma relapse
lithium levels • Discontinuation symptoms uncommon

Pharmacokinetics
• Half life 18–30 hours
Dosing Tips
✽ Sustained release formulation may reduce
gastric irritation, lower peak lithium plasma
Drug Interactions
levels, and diminish peak dose side effects
(i.e., side effects occurring 1–2 hours after ✽ Non-steroidal anti-inflammatory agents,
including ibuprofen and selective Cox-2
each dose of standard lithium carbonate
inhibitors (cyclo-oxygenase 2), can
may be improved by sustained release
increase plasma lithium concentrations;
formulation)
add with caution to patients stabilized on
• Lithium sulfate and other dosage strengths
lithium
for lithium are available in Europe
• Check therapeutic blood levels as “trough” ✽ Diuretics, especially thiazides, can
increase plasma lithium concentrations;
levels about 12 hours after the last dose
add with caution to patients stabilized on
• After stabilization, some patients may do
lithium
best with a once daily dose at night
• Angiotensin-converting enzyme inhibitors
• Responses in acute mania may take 7–14
can increase plasma lithium
days even with adequate plasma lithium
concentrations; add with caution to
levels
patients stabilized on lithium
✽ Some patients apparently respond to • Metronidazole can lead to lithium toxicity
doses as low as 300 mg twice a day, even
through decreased renal clearance
with plasma lithium levels below 0.5 mEq/L
• Acetazolamide, alkalizing agents, xanthine
• Use the lowest dose of lithium associated
preparations, and urea may lower lithium
with adequate therapeutic response
plasma concentrations
• Lower doses and lower plasma lithium
• Methyldopa, carbamazepine, and phenytoin
levels (<0.6 mEq/L) are often adequate and
may interact with lithium to increase its
advisable in the elderly
toxicity
✽ Rapid discontinuation increases the risk
of relapse, so lithium may need to be

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LITHIUM (continued)

• Use lithium cautiously with calcium ✽ Neurotoxicity, including delirium and

channel blockers, which may also increase other mental status changes, may occur
lithium toxicity even at therapeutic doses in elderly and
• Use of lithium with an SSRI may raise risk organically compromised patients
of dizziness, confusion, diarrhea, agitation, • Lower doses and lower plasma lithium
tremor levels (<0.6 mEg/L) are often adequate and
• Some patients taking haloperidol and advisable in the elderly
lithium have developed an encephalopathic
syndrome similar to neuroleptic malignant
syndrome Children and Adolescents
• Lithium may prolong effects of • Safety and efficacy not established under
neuromuscular blocking agents age 12
• No likely pharmacokinetic interactions of • Use only with caution
lithium with mood stabilizing • Younger children tend to have more
anticonvulsants or atypical antipsychotics frequent and severe side effects
• Children should be monitored more
Other Warnings/ frequently
Precautions
✽ Toxic levels are near therapeutic levels;
signs of toxicity include tremor, ataxia, Pregnancy
diarrhea, vomiting, sedation • Risk category D [positive evidence of risk
• Monitor for dehydration; lower dose if to human fetus; potential benefits may still
patient exhibits signs of infection, justify its use during pregnancy]
excessive sweating, diarrhea ✽ Evidence of increased risk of major birth
• Closely monitor patients with thyroid defects (perhaps 2–3 times the general
disorders population), but probably lower than with
some other mood stabilizers (e.g.,
Do Not Use valproate)
• If patient has severe kidney disease • Evidence of increase in cardiac anomalies
• If patient has severe cardiovascular disease (especially Ebstein’s anomaly) in infants
• If patient has severe dehydration whose mothers took lithium during
• If patient has sodium depletion pregnancy
• If there is a proven allergy to lithium • Lithium administration during delivery may
be associated with hypotonia in the infant
• Use in women of childbearing potential
SPECIAL POPULATIONS requires weighing potential benefits to the
mother against the risks to the fetus
Renal Impairment • Taper drug if discontinuing
• Not recommended for use in patients with ✽ For bipolar patients, lithium should
severe impairment generally be discontinued before
anticipated pregnancies
Hepatic Impairment • Recurrent bipolar illness during pregnancy
• No special indications can be quite disruptive
✽ For bipolar patients, given the risk of
Cardiac Impairment relapse in the postpartum period, lithium
• Not recommended for use in patients with should generally be restarted immediately
severe impairment after delivery, but this generally means no
breast feeding
Elderly ✽ Atypical antipsychotics may be preferable
• Likely that elderly patients will require to lithium or anticonvulsants if treatment of
lower doses to achieve therapeutic serum bipolar disorder is required during
levels pregnancy
• Elderly patients may be more sensitive to
adverse effects

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(continued) LITHIUM

• Bipolar symptoms may recur or worsen bipolar disorder generally do less well on
during pregnancy and some form of lithium
treatment may be necessary ✽ Seems to be more effective in treating
manic episodes than depressive episodes
Breast Feeding in bipolar disorder (treats from above
• Some drug is found in mother’s breast better than it treats from below)
milk, possibly at full therapeutic levels ✽ May also be more effective in preventing
since lithium is soluble in breast milk manic relapses than in preventing
✽ Recommended either to discontinue drug depressive episodes (stabilizes from above
or bottle feed better than it stabilizes from below)
✽ Bipolar disorder may recur during the ✽ May decrease suicide and suicide
postpartum period, particularly if there is a attempts not only in bipolar I disorder but
history of prior postpartum episodes of also in bipolar II disorder and in unipolar
either depression or psychosis depression
✽ Relapse rates may be lower in women ✽ Due to its narrow therapeutic index,
who receive prophylactic treatment for lithium’s toxic side effects occur at doses
postpartum episodes of bipolar disorder close to its therapeutic effects
• Atypical antipsychotics and anticonvulsants • Close therapeutic monitoring of plasma
such as valproate may be safer than drug levels is required during lithium
lithium during the postpartum period when treatment; lithium is the first psychiatric
breast feeding drug that required blood level monitoring
• Probably less effective than atypical
antipsychotics for severe, excited,
THE ART OF PSYCHOPHARMACOLOGY disturbed, hyperactive, or psychotic
patients with mania
Potential Advantages • Due to delayed onset of action, lithium
• Euphoric mania monotherapy may not be the first choice in
• Treatment-resistant depression acute mania, but rather may be used as an
• Reduces suicide risk adjunct to atypical antipsychotics,
• Works well in combination with atypical benzodiazepines, and/or valproate loading
antipsychotics and/or mood stabilizing • After acute symptoms of mania are
anticonvulsants such as valproate controlled, some patients can be
maintained on lithium monotherapy
Potential Disadvantages • However, only a third of bipolar patients
• Dysphoric mania experience adequate relief with a
• Mixed mania, rapid-cycling mania monotherapy, so most patients need
• Depressed phase of bipolar disorder multiple medications for best control
• Patients unable to tolerate weight gain, • Lithium is not a convincing augmentation
sedation, gastrointestinal effects, renal agent to atypical antipsychotics for the
effects, and other side effects treatment of schizophrenia
• Lithium is one of the most useful
Primary Target Symptoms adjunctive agents to augment
• Unstable mood antidepressants for treatment-resistant
• Mania unipolar depression
• Lithium may be useful for a number of
patients with episodic, recurrent symptoms
Pearls with or without affective illness, including
✽ Lithium was the original mood stabilizer episodic rage, anger or violence, and self-
and is still a first-line treatment option but destructive behavior; such symptoms may
may be underutilized since it is an older be associated with psychotic or
agent and is less promoted for use in nonpsychotic illnesses, personality
bipolar disorder than newer agents disorders, organic disorders, or mental
✽ May be best for euphoric mania; patients retardation
with rapid-cycling and mixed state types of

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LITHIUM (continued)

• Lithium is better tolerated during acute disease, dehydration, or sodium depletion,

manic phases than when manic symptoms lithium can be administered cautiously in a
have abated hospital setting to such patients, with
• Adverse effects generally increase in lithium serum levels determined daily
incidence and severity as lithium serum • Lithium-induced weight gain may be more
levels increase common in women than in men
• Although not recommended for use in
patients with severe renal or cardiovascular

Suggested Reading
Delva NJ, Hawken ER. Preventing lithium Maj M. The effect of lithium in bipolar
intoxication. Guide for physicians. Can Fam disorder: a review of recent research evidence.
Physician. 2001;47:1595–600. Bipolar Disord. 2003;5:180–8.
Goodwin FK. Rationale for using lithium in Tueth MJ, Murphy TK, Evans DL. Special
combination with other mood stabilizers in the considerations: use of lithium in children,
management of bipolar disorder. J Clin adolescents, and elderly populations. J Clin
Psychiatry. 2003;64(Suppl 5):18–24. Psychiatry. 1998;59 (Suppl 6):66–73.
Goodwin GM, Geddes GR. Latest maintenance
data on lithium in bipolar disorder. Eur
Neuropsychopharmacol. 2003;13(Suppl
2):S51–5.

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LOFEPRAMINE
THERAPEUTICS If It Works
• The goal of treatment of depression is
Brands • Deprimyl
complete remission of current symptoms
• Gamanil
as well as prevention of future relapses
see index for additional brand names
• The goal of treatment of chronic
Generic? Yes neuropathic pain is to reduce symptoms as
much as possible, especially in
combination with other treatments
• Treatment of depression most often
Class reduces or even eliminates symptoms, but
• Tricyclic antidepressant (TCA) not a cure since symptoms can recur after
• Predominantly a norepinephrine/ medicine stopped
noradrenaline reuptake inhibitor • Treatment of chronic neuropathic pain may
reduce symptoms, but rarely eliminates
Commonly Prescribed For them completely, and is not a cure since
(bold for FDA approved) symptoms can recur after medicine is
• Major depressive disorder stopped
• Anxiety • Continue treatment of depression until all
• Insomnia symptoms are gone (remission)
• Neuropathic pain/chronic pain • Once symptoms of depression are gone,
• Treatment-resistant depression continue treating for 1 year for the first
episode of depression
• For second and subsequent episodes of
How The Drug Works depression, treatment may need to be
• Boosts neurotransmitter indefinite
norepinephrine/noradrenaline • Use in anxiety disorders and chronic pain
• Blocks norepinephrine reuptake pump may also need to be indefinite, but long-
(norepinephrine transporter), presumably term treatment is not well studied in these
increasing noradrenergic conditions
neurotransmission
If It Doesn’t Work
• Since dopamine is inactivated by
• Many depressed patients only have a
norepinephrine reuptake in frontal cortex,
partial response where some symptoms
which largely lacks dopamine transporters,
are improved but others persist (especially
lofepramine can increase dopamine
insomnia, fatigue, and problems
neurotransmission in this part of the brain
concentrating)
• A more potent inhibitor of norepinephrine
• Other depressed patients may be
reuptake pump than serotonin reuptake
nonresponders, sometimes called
pump (serotonin transporter)
treatment-resistant or treatment-refractory
• At high doses may also boost
• Consider increasing dose, switching to
neurotransmitter serotonin and presumably
another agent or adding an appropriate
increase serotonergic neurotransmission
augmenting agent
How Long Until It Works • Consider psychotherapy
• May have immediate effects in treating • Consider evaluation for another diagnosis
insomnia or anxiety or for a comorbid condition (e.g, medical
• Onset of therapeutic actions usually not illness, substance abuse, etc.)
immediate, but often delayed 2 to 4 weeks • Some patients may experience apparent
• If it is not working within 6 to 8 weeks for lack of consistent efficacy due to activation
depression, it may require a dosage of latent or underlying bipolar disorder, and
increase or it may not work at all require antidepressant discontinuation and
• May continue to work for many years to a switch to a mood stabilizer
prevent relapse of symptoms

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LOFEPRAMINE (continued)

Best Augmenting Combos SIDE EFFECTS

for Partial Response or How Drug Causes Side Effects
Treatment-Resistance • Anticholinergic activity may explain
• Lithium, buspirone, thyroid hormone (for sedative effects, dry mouth, constipation,
depression) and blurred vision
• Gabapentin, tiagabine, other • Sedative effects and weight gain may be
anticonvulsants, even opiates if done by due to antihistamine properties
experts while monitoring carefully in • Blockade of alpha adrenergic 1 receptors
difficult cases (for chronic pain) may explain dizziness, sedation, and
hypotension
Tests
• Cardiac arrhythmias and seizures,
• None for healthy individuals
especially in overdose, may be caused by
✽ Since tricyclic and tetracyclic blockade of ion channels
antidepressants are frequently associated
with weight gain, before starting treatment, Notable Side Effects
weigh all patients and determine if the • Blurred vision, constipation, urinary
patient is already overweight retention, increased appetite, dry mouth,
(BMI 25.0–29.9) or obese (BMI ≥30) nausea, diarrhea, heartburn, unusual taste
• Before giving a drug that can cause weight in mouth, weight gain
gain to an overweight or obese patient, • Fatigue, weakness, dizziness, sedation,
consider determining whether the patient headache, anxiety, nervousness,
already has pre-diabetes (fasting plasma restlessness
glucose 100–125 mg/dl), diabetes (fasting • Sexual dysfunction, sweating
plasma glucose >126 mg/dl), or
dyslipidemia (increased total cholesterol,
LDL cholesterol and triglycerides; Life Threatening or
decreased HDL cholesterol), and treat or Dangerous Side Effects
refer such patients for treatment, including • Paralytic ileus, hyperthermia (TCAs +
nutrition and weight management, physical anticholinergic agents)
activity counseling, smoking cessation, and • Lowered seizure threshold and rare
medical management seizures
✽ Monitor weight and BMI during treatment • Orthostatic hypotension, sudden death,
✽ While giving a drug to a patient who has arrhythmias, tachycardia
gained >5% of initial weight, consider • QTc prolongation
evaluating for the presence of pre-diabetes, • Hepatic failure, extrapyramidal symptoms
diabetes, or dyslipidemia, or consider • Increased intraocular pressure
switching to a different antidepressant • Rare induction of mania and activation of
• EKGs may be useful for selected patients suicidal ideation
(e.g., those with personal or family history
of QTc prolongation; cardiac arrhythmia; Weight Gain
recent myocardial infarction;
uncompensated heart failure; or taking
agents that prolong QTc interval such as • Many experience and/or can be significant
pimozide, thioridazine, selected in amount
antiarrhythmics, moxifloxacin, sparfloxacin, • Can increase appetite and carbohydrate
etc.) craving
• Patients at risk for electrolyte disturbances
(e.g., patients on diuretic therapy) should Sedation
have baseline and periodic serum
potassium and magnesium measurements

• Many experience and/or can be significant

in amount
• Tolerance to sedative effect may develop
with long-term use

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(continued) LOFEPRAMINE

What To Do About Side Effects Overdose

• Wait • Death may occur; convulsions, cardiac
• Wait dysrhythmias, severe hypotension, CNS
• Wait depression, coma, changes in ECG
• Lower the dose
• Switch to an SSRI or newer antidepressant Long-Term Use
• Safe
Best Augmenting Agents for Side
Effects Habit Forming
• Many side effects cannot be improved with • No
an augmenting agent
How to Stop
• Taper to avoid withdrawal effects
• Even with gradual dose reduction some
DOSING AND USE withdrawal symptoms may appear within
Usual Dosage Range the first 2 weeks
• Many patients tolerate 50% dose reduction
• 140–210 mg/day
for 3 days, then another 50% reduction for
Dosage Forms 3 days, then discontinuation
• Tablet 70 mg multiscored • If withdrawal symptoms emerge during
• Liquid 70 mg/5mL discontinuation, raise dose to stop
symptoms and then restart withdrawal
How to Dose much more slowly
• Initial 70 mg/day once daily or in divided
doses; gradually increase daily dose to Pharmacokinetics
achieve desired therapeutic effects; dose at • Substrate for CYP450 2D6
bedtime for daytime sedation and in • Half-life of parent compound approximately
morning for insomnia; maximum dose 1.5–6 hours
280 mg/day for inpatients, 210 mg/day for ✽ Major metabolite is the antidepressant
outpatients desipramine, with a half-life of
approximately 24 hours

Dosing Tips
• If given in a single dose, should generally Drug Interactions
be administered at bedtime because of its • Tramadol increases the risk of seizures in
sedative properties patients taking TCAs
• If given in split doses, largest dose should • Use of TCAs with anticholinergic drugs
generally be given at bedtime because of may result in paralytic ileus or
its sedative properties hyperthermia
• If patients experience nightmares, split • Fluoxetine, paroxetine, bupropion,
dose and do not give large dose at bedtime duloxetine, and other CYP450 2D6
• Unusual dose compared to most TCAs inhibitors may increase TCA concentrations
• Patients treated for chronic pain may only • Cimetidine may increase plasma
require lower doses concentrations of TCAs and cause
• If intolerable anxiety, insomnia, agitation, anticholinergic symptoms
akathisia, or activation occur either upon • Phenothiazines or haloperidol may raise
dosing initiation or discontinuation, TCA blood concentrations
consider the possibility of activated bipolar • May alter effects of antihypertensive drugs;
disorder, and switch to a mood stabilizer or may inhibit hypotensive effects of clonidine
an atypical antipsychotic • Use with sympathomimetic agents may
increase sympathetic activity
• Methylphenidate may inhibit metabolism of
TCAs
• Activation and agitation, especially
following switching or adding

255
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LOFEPRAMINE (continued)

antidepressants, may represent the myocardial infarction, uncompensated

induction of a bipolar state, especially a heart failure
mixed dysphoric bipolar II condition • If patient is taking drugs that inhibit TCA
sometimes associated with suicidal metabolism, including CYP450 2D6
ideation, and require the addition of inhibitors, except by an expert
lithium, a mood stabilizer or an atypical • If there is reduced CYP450 2D6 function,
antipsychotic, and/or discontinuation of such as patients who are poor 2D6
lofepramine metabolizers, except by an expert and at
low doses
• If there is a proven allergy to lofepramine,
Other Warnings/ desipramine, or imipramine
Precautions
• Add or initiate other antidepressants with
caution for up to 2 weeks after
discontinuing lofepramine
SPECIAL POPULATIONS
• Generally, do not use with MAO inhibitors, Renal Impairment
including 14 days after MAOIs are stopped; • Use with caution
do not start an MAOI until 2 weeks after
discontinuing lofepramine, but see Pearls Hepatic Impairment
• Use with caution in patients with history of • Use with caution
seizure, urinary retention, narrow angle-
closure glaucoma, hyperthyroidism Cardiac Impairment
• TCAs can increase QTc interval, especially • TCAs have been reported to cause
at toxic doses, which can be attained not arrhythmias, prolongation of conduction
only by overdose but also by combining time, orthostatic hypotension, sinus
with drugs that inhibit its metabolism via tachycardia, and heart failure, especially in
CYP450 2D6, potentially causing torsade the diseased heart
de pointes-type arrhythmia or sudden • Myocardial infarction and stroke have been
death reported with TCAs
• Because TCAs can prolong QTc interval, • TCAs produce QTc prolongation, which
use with caution in patients who have may be enhanced by the existence of
bradycardia or who are taking drugs that bradycardia, hypokalemia, congenital or
can induce bradycardia (e.g., beta blockers, acquired long QTc interval, which should
calcium channel blockers, clonidine, be evaluated prior to administering
digitalis) lofepramine
• Because TCAs can prolong QTc interval, • Use with caution if treating concomitantly
use with caution in patients who have with a medication likely to produce
hypokalemia and/or hypomagnesemia or prolonged bradycardia, hypokalemia,
who are taking drugs that can induce slowing of intracardiac conduction, or
hypokalemia and/or magnesemia (e.g., prolongation of the QTc interval
diuretics, stimulant laxatives, intravenous • Avoid TCAs in patients with a known
amphotericin B, glucocorticoids, history of QTc prolongation, recent acute
tetracosactide) myocardial infarction, and uncompensated
heart failure
Do Not Use • TCAs may cause a sustained increase in
• If patient is recovering from myocardial heart rate in patients with ischemic heart
infarction disease and may worsen (decrease) heart
• If patient is taking agents capable of rate variability, an independent risk of
significantly prolonging QTc interval (e.g., mortality in cardiac populations
pimozide, thioridazine, selected • Since SSRIs may improve (increase) heart
antiarrhythmics, moxifloxacin, rate variability in patients following a
sparfloxacin) myocardial infarct and may improve
• If there is a history of QTc prolongation or survival as well as mood in patients with
cardiac arrhythmia, recent acute acute angina or following a myocardial
infarction, these are more appropriate

256
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(continued) LOFEPRAMINE

agents for cardiac population than so drug may need to be reinstituted late in
tricyclic/tetracyclic antidepressants the third trimester or shortly after
✽ Risk/benefit ratio may not justify use of childbirth to prevent a recurrence during
TCAs in cardiac impairment the postpartum period
• Must weigh benefits of breast feeding with
Elderly risks and benefits of antidepressant
• May be more sensitive to anticholinergic, treatment versus non-treatment to both the
cardiovascular, hypotensive, and sedative infant and the mother
effects • For many patients this may mean
continuing treatment during breast feeding

Children and Adolescents

• Use with caution, observing for activation THE ART OF PSYCHOPHARMACOLOGY
of known or unknown bipolar disorder
and/or suicidal ideation, and strongly Potential Advantages
consider informing parents or guardian of • Patients with insomnia
this risk so they can help observe child or • Severe or treatment-resistant depression
adolescent patients • Anxious depression
• Not recommended for use under age 18
• Several studies show lack of efficacy of Potential Disadvantages
TCAs for depression • Pediatric and geriatric patients
• May be used to treat enuresis or • Patients concerned with weight gain
hyperactive/impulsive behaviors • Cardiac patients
• Some cases of sudden death have
occurred in children taking TCAs Primary Target Symptoms
• Depressed mood

Pregnancy
• Risk Category C [some animal studies Pearls
show adverse effects, no controlled studies • Tricyclic antidepressants are often a first-
in humans] line treatment option for chronic pain
• Crosses the placenta • Tricyclic antidepressants are no longer
• Adverse effects have been reported in generally considered a first-line option for
infants whose mothers took a TCA depression because of their side effect
(lethargy, withdrawal symptoms, fetal profile
malformations) • Tricyclic antidepressants continue to be
• Not generally recommended for use during useful for severe or treatment-resistant
pregnancy, especially during first trimester depression
• Must weigh the risk of treatment (first • Noradrenergic reuptake inhibitors such as
trimester fetal development, third trimester lofepramine can be used as a second-line
newborn delivery) to the child against the treatment for smoking cessation, cocaine
risk of no treatment (recurrence of dependence, and attention deficit disorder
depression, maternal health, infant ✽ Lofepramine is a short acting prodrug of
bonding) to the mother and child the TCA desipramine
• For many patients this may mean ✽ Fewer anticholinergic side effects,
continuing treatment during pregnancy particularly sedation, than some other
tricyclics
Breast Feeding • Once a popular TCA in the UK, but not
• Some drug is found in mother’s breast milk widely marketed throughout the world
✽ Recommended either to discontinue drug • TCAs may aggravate psychotic symptoms
or bottle feed • Alcohol should be avoided because of
• Immediate postpartum period is a high-risk additive CNS effects
time for depression, especially in women
who have had prior depressive episodes,

257
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LOFEPRAMINE (continued)

• Underweight patients may be more tetracyclic combinations may be weight

susceptible to adverse cardiovascular gain and orthostatic hypotension
effects • Patients on TCAs should be aware that they
• Children, patients with inadequate may experience symptoms such as
hydration, and patients with cardiac photosensitivity or blue-green urine
disease may be more susceptible to TCA- • SSRIs may be more effective than TCAs in
induced cardiotoxicity than healthy adults women, and TCAs may be more effective
• For the expert only: although generally than SSRIs in men
prohibited, a heroic treatment (but • Since tricyclic/tetracyclic antidepressants
potentially dangerous) for severely are substrates for CYP450 2D6, and 7% of
treatment-resistant patients is to give a the population (especially Caucasians) may
tricyclic/tetracyclic antidepressant other have a genetic variant leading to reduced
than clomipramine simultaneously with an activity of 2D6, such patients may not
MAO inhibitor for patients who fail to safely tolerate normal doses of
respond to numerous other tricyclic/tetracyclic antidepressants and
antidepressants may require dose reduction
• If this option is elected, start the MAOI with • Phenotypic testing may be necessary to
the tricyclic/tetracyclic antidepressant detect this genetic variant prior to dosing
simultaneously at low doses after with a tricyclic/tetracyclic antidepressant,
appropriate drug washout, then alternately especially in vulnerable populations such
increase doses of these agents every few as children, elderly, cardiac populations,
days to a week as tolerated and those on concomitant medications
• Although very strict dietary and • Patients who seem to have extraordinarily
concomitant drug restrictions must be severe side effects at normal or low doses
observed to prevent hypertensive crises may have this phenotypic CYP450 2D6
and serotonin syndrome, the most variant and require low doses or switching
common side effects of MAOI/tricyclic or to another antidepressant not metabolized
by 2D6

Suggested Reading
Anderson IM. Meta-analytical studies on new Lancaster SG, Gonzales JP. Lofepramine. A
antidepressants. Br Med Bull. 2001; review of its pharmacodynamic and
57:161–178. pharmacokinetic properties, and therapeutic
efficacy in depressive illness. Drugs. 1989;
Anderson IM. Selective serotonin reuptake 37:123–40.
inhibitors versus tricyclic antidepressants: a
meta-analysis of efficacy and tolerability. J Aff
Disorders. 2000;58:19–36.
Kerihuel JC, Dreyfus JF. Meta-analyses of the
efficacy and tolerability of the tricyclic
antidepressant lofepramine. J Int Med Res.
1991;19:183–201.

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LOFLAZEPATE
THERAPEUTICS • If symptoms reemerge, consider treatment
with an SSRI or SNRI, or consider
Brands • Meilax restarting the benzodiazepine; sometimes
see index for additional brand names benzodiazepines have to be used in
combination with SSRIs or SNRIs for best
Generic? No
results

If It Doesn’t Work
Class • Consider switching to another agent or
• Benzodiazepine (anxiolytic) adding an appropriate augmenting agent
• Consider psychotherapy, especially
Commonly Prescribed For cognitive behavioral psychotherapy
(bold for FDA approved) • Consider presence of concomitant
• Anxiety, tension, depression, or sleep substance abuse
disorder in patients with neurosis • Consider presence of loflazepate abuse
• Anxiety, tension, depression, or sleep • Consider another diagnosis, such as a
disorder in patients with psychosomatic comorbid medical condition
disease
Best Augmenting Combos
for Partial Response or
How The Drug Works Treatment-Resistance
• Binds to benzodiazepine receptors at the • Benzodiazepines are frequently used as
GABA-A ligand-gated chloride channel augmenting agents for antipsychotics and
complex mood stabilizers in the treatment of
• Enhances the inhibitory effects of GABA psychotic and bipolar disorders
• Boosts chloride conductance through • Benzodiazepines are frequently used as
GABA-regulated channels augmenting agents for SSRIs and SNRIs in
• Inhibits neuronal activity presumably in the treatment of anxiety disorders
amygdala-centered fear circuits to provide • Not generally rational to combine with
therapeutic benefits in anxiety disorders other benzodiazepines
• Caution if using as an anxiolytic
How Long Until It Works concomitantly with other sedative
• Some immediate relief with first dosing is hypnotics for sleep
common; can take several weeks with daily
dosing for maximal therapeutic benefit Tests
• In patients with seizure disorders,
If It Works concomitant medical illness, and/or those
• For short-term symptoms of anxiety – after with multiple concomitant long-term
a few weeks, discontinue use or use on an medications, periodic liver tests and blood
“as-needed” basis counts may be prudent
• For chronic anxiety disorders, the goal of
treatment is complete remission of
symptoms as well as prevention of future SIDE EFFECTS
relapses
• For chronic anxiety disorders, treatment How Drug Causes Side Effects
most often reduces or even eliminates • Same mechanism for side effects as for
symptoms, but not a cure since symptoms therapeutic effects – namely due to
can recur after medicine stopped excessive actions at benzodiazepine
• For long-term symptoms of anxiety, receptors
consider switching to an SSRI or SNRI for • Long-term adaptations in benzodiazepine
long-term maintenance receptors may explain the development of
• If long-term maintenance with a dependence, tolerance, and withdrawal
benzodiazepine is necessary, continue • Side effects are generally immediate, but
treatment for 6 months after symptoms immediate side effects often disappear in
resolve, and then taper dose slowly time

259
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LOFLAZEPATE (continued)

Notable Side Effects Dosage Forms

✽ Sedation, fatigue, depression • Tablet 1 mg, 2 mg
✽ Dizziness, ataxia, slurred speech,
weakness How to Dose
✽ Forgetfulness, confusion • Start at 1 mg, increase to 1mg twice/day or
✽ Hyper-excitability, nervousness 2 mg once a day in a few days if necessary
• Rare hallucinations, mania
• Rare hypotension
• Hypersalivation, dry mouth Dosing Tips
✽ Because of its long half-life, patients who
Life Threatening or require chronic treatment may need dose
Dangerous Side Effects reduction after a few weeks due to drug
accumulation
• Respiratory depression, especially when
taken with CNS depressants in overdose ✽ Because of its long half-life, once daily
dosing is the most frequent dosing
• Rare hepatic dysfunction, renal
generally necessary
dysfunction, blood dyscrasias
✽ Because of its long half-life, some patients
Weight Gain may have sustained benefits even if dosing
is intermittently skipped on some days
• Use lowest possible effective dose for the
shortest possible period of time (a
• Reported but not expected benzodiazepine-sparing strategy)
• Assess need for continued treatment
Sedation regularly
• Risk of dependence may increase with
dose and duration of treatment
• Occurs in significant minority • For inter-dose symptoms of anxiety, can
• Especially at initiation of treatment or when either increase dose or maintain same total
dose increases daily dose but divide into more frequent
• Tolerance often develops over time doses
• Can also use an as-needed occasional “top
What To Do About Side Effects up” dose for inter-dose anxiety
• Wait • Because panic disorder can require doses
• Wait higher than 2 mg/day, the risk of
• Wait dependence may be greater in these
• Lower the dose patients
• Take largest dose at bedtime to avoid • Some severely ill patients may require
sedative effects during the day more than 2 mg/day
• Switch to another agent • Frequency of dosing in practice is often
• Administer flumazenil if side effects are greater than predicted from half-life, as
severe or life-threatening duration of biological activity is often
shorter than pharmacokinetic terminal half-
Best Augmenting Agents for Side life, which is why once daily dosing is
Effects usually the favored option despite the long
• Many side effects cannot be improved with half-life
an augmenting agent
Overdose
• Sedation, confusion, poor coordination,
DOSING AND USE diminished reflexes, coma

Usual Dosage Range Long-Term Use

• 1mg once or twice a day • Risk of dependence, particularly for
treatment periods longer than 12 weeks
and especially in patients with past or
current polysubstance abuse

260
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(continued) LOFLAZEPATE

Habit Forming Other Warnings/

• Patients may develop dependence and/or
Precautions
tolerance with long-term use
• Dosage changes should be made in
How to Stop collaboration with prescriber
• Patients with history of seizures may seize • Use with caution in patients with
upon withdrawal, especially if withdrawal is pulmonary disease; rare reports of death
abrupt after initiation of benzodiazepines in
• Taper by 0.5 mg every 3–7 days to reduce patients with severe pulmonary impairment
chances of withdrawal effects • History of drug or alcohol abuse often
• For difficult to taper cases, consider creates greater risk for dependency
reducing dose much more slowly after • Hypomania and mania have occurred in
reaching 3 mg/day, perhaps by as little as depressed patients taking loflazepate
0.25 mg every 7–10 days or slower • Use only with extreme caution if patient
• For other patients with severe problems has obstructive sleep apnea
discontinuing a benzodiazepine, dosing • Some depressed patients may experience a
may need to be tapered over many months worsening of suicidal ideation
(i.e., reduce dose by 1% every 3 days by • Some patients may exhibit abnormal
crushing tablet and suspending or thinking or behavioral changes similar to
dissolving in 100 ml of fruit juice and then those caused by other CNS depressants
disposing of 1 ml while drinking the rest; (i.e., either depressant actions or
3–7 days later, dispose of 2 ml, and so on). disinhibiting actions)
This is both a form of very slow biological
Do Not Use
tapering and a form of behavioral
• If patient has narrow angle-closure
desensitization
glaucoma
• Be sure to differentiate reemergence of
• If patient has myasthenia gravis
symptoms requiring reinstitution of
• If there is a proven allergy to loflazepate or
treatment from withdrawal symptoms
any benzodiazepine
• Benzodiazepine-dependent anxiety patients
and insulin-dependent diabetics are not
addicted to their medications. When
benzodiazepine-dependent patients stop SPECIAL POPULATIONS
their medication, disease symptoms can
reemerge, disease symptoms can worsen Renal Impairment
(rebound), and/or withdrawal symptoms • Drug should be used with caution
can emerge
Hepatic Impairment
Pharmacokinetics • Drug should be used with caution
• Elimination half-life approximately 122
hours (ultra-long half-life)
Cardiac Impairment
• Benzodiazepines have been used to treat
anxiety associated with acute myocardial
infarction
Drug Interactions
• Increased depressive effects when taken Elderly
with other CNS depressants • Drug should be used with caution
• Cimetidine raises loflazepate plasma levels • Should begin with lower starting dose
• Rapid dose reduction or discontinuation of
loflazepate during concomitant use with
tetracyclic antidepressants such as Children and Adolescents
maprotiline may result in convulsive
• Safety and efficacy have not been
seizures, possibly due to the loss of
established
anticonvulsant actions that suppress the
• Benzodiazepines are often used in children
pro-convulsant actions of tetracyclic
and adolescents, especially short-term and
antidepressants
at the lower end of the dosing scale

261
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LOFLAZEPATE (continued)

• Long-term effects of loflazepate in Potential Disadvantages

children/adolescents are unknown • Drug may accumulate in long-term users
• Should generally receive lower doses and and require dosage reduction
be more closely monitored
Primary Target Symptoms
• Anxiety
Pregnancy • Tension
• Possible increased risk of birth defects
when benzodiazepines taken during
pregnancy Pearls
• Because of the potential risks, loflazepate is ✽ Is the only “ultra-long half-life”
not generally recommended as treatment benzodiazepine with a half-life much longer
for anxiety during pregnancy, especially than 24 hours
during the first trimester ✽ Less inter-dose anxiety than other
• Drug should be tapered if discontinued benzodiazepines
• Infants whose mothers received a ✽ Long half-life could theoretically reduce
benzodiazepine late in pregnancy may abuse and withdrawal symptoms
experience withdrawal effects • Is a very useful adjunct to SSRIs and
• Neonatal flaccidity has been reported in SNRIs in the treatment of numerous
infants whose mothers took a anxiety disorders
benzodiazepine during pregnancy • Not effective for treating psychosis as a
• Seizures, even mild seizures, may cause monotherapy, but can be used as an
harm to the embryo/fetus adjunct to antipsychotics
• Not effective for treating bipolar disorder
Breast Feeding as a monotherapy, but can be used as an
• Some drug is found in mother’s breast milk adjunct to mood stabilizers and
✽ Recommended either to discontinue drug antipsychotics
or bottle feed • May both cause depression and treat
• Effects on infant have been observed and depression in different patients
include feeding difficulties, sedation, and • Risk of seizure is greatest during the first
weight loss 3 days after discontinuation of loflazepate,
especially in those with prior seizures, head
injuries or withdrawal from drugs of abuse
THE ART OF PSYCHOPHARMACOLOGY • Clinical duration of action may be shorter
than plasma half-life, leading to dosing
Potential Advantages more frequently than 2–3 times daily in
• Patients who have inter-dose anxiety on some patients
shorter-acting benzodiazepines • When using to treat insomnia, remember
• Patients who wish to take drug only once that insomnia may be a symptom of some
daily other primary disorder itself, and thus
• Patients who occasionally forget to take warrant evaluation for comorbid psychiatric
their dose and/or medical conditions

262
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(continued) LOFLAZEPATE

Suggested Reading
Ba BB, Iliadis A, Cano JP. Pharmacokinetic Murasaki M, Mori A, Noguchi T, Hada Y,
modeling of ethyl loflazepate (Victan) and its Hasegawa K, Jinbo S, Kamijima K.
main active metabolites. Ann Biomed Eng. Comparison of therapeutic efficacy of
1989;17(6):633–46. neuroses between CM6912 (ethyl loflazepate)
and diazepam in a double-blind trial. Prog
Chambon JP, Perio A, Demarne H, Hallot A, Neuropsychopharmacol Biol Psychiatry.
Dantzer R, Roncucci R, Biziere K. Ethyl 1989;13(1–2):145–54.
loflazepate: a prodrug from the benzodiazepine
series designed to dissociate anxiolytic and
sedative activities. Arzneimittelforschung.
1985;35(10):1573–7.

263
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0521011698s05.qxd 9/2/04 2:35 PM Page 265

LORAZEPAM
THERAPEUTICS symptoms as well as prevention of future
relapses
Brands • Ativan • For chronic anxiety disorders, treatment
see index for additional brand names most often reduces or even eliminates
symptoms, but not a cure since symptoms
Generic? Yes
can recur after medicine stopped
• For long-term symptoms of anxiety,
consider switching to an SSRI or SNRI for
Class long-term maintenance
• Benzodiazepine (anxiolytic, anticonvulsant) • If long-term maintenance with a
benzodiazepine is necessary, continue
Commonly Prescribed For treatment for 6 months after symptoms
(bold for FDA approved) resolve, and then taper dose slowly
• Anxiety disorder (oral) • If symptoms reemerge, consider treatment
• Anxiety associated with depressive with an SSRI or SNRI, or consider
symptoms (oral) restarting the benzodiazepine; sometimes
• Initial treatment of status epilepticus benzodiazepines have to be used in
(injection) combination with SSRIs or SNRIs for best
• Preanesthetic (injection) results
• Insomnia
• Muscle spasm If It Doesn’t Work
• Alcohol withdrawal psychosis • Consider switching to another agent or
• Headache adding an appropriate augmenting agent
• Panic disorder • Consider psychotherapy, especially
• Acute mania (adjunctive) cognitive behavioral psychotherapy
• Acute psychosis (adjunctive) • Consider presence of concomitant
substance abuse
• Consider presence of lorazepam abuse
How The Drug Works • Consider another diagnosis such as a
• Binds to benzodiazepine receptors at the comorbid medical condition
GABA-A ligand-gated chloride channel
complex Best Augmenting Combos
• Enhances the inhibitory effects of GABA for Partial Response or
• Boosts chloride conductance through Treatment-Resistance
GABA-regulated channels • Benzodiazepines are frequently used as
• Inhibits neuronal activity presumably in augmenting agents for antipsychotics and
amygdala-centered fear circuits to provide mood stabilizers in the treatment of
therapeutic benefits in anxiety disorders psychotic and bipolar disorders
• Inhibitory actions in cerebral cortex may • Benzodiazepines are frequently used as
provide therapeutic benefits in seizure augmenting agents for SSRIs and SNRIs in
disorders the treatment of anxiety disorders
• Not generally rational to combine with
How Long Until It Works other benzodiazepines
• Some immediate relief with first dosing is • Caution if using as an anxiolytic
common; can take several weeks for concomitantly with other sedative
maximal therapeutic benefit with daily hypnotics for sleep
dosing
Tests
If It Works • In patients with seizure disorders,
• For short-term symptoms of anxiety – after concomitant medical illness, and/or those
a few weeks, discontinue use or use on an with multiple concomitant long-term
“as-needed” basis medications, periodic liver tests and blood
• For chronic anxiety disorders, the goal of counts may be prudent
treatment is complete remission of

265
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LORAZEPAM (continued)

SIDE EFFECTS • Administer flumazenil if side effects are

severe or life-threatening
How Drug Causes Side Effects
• Same mechanism for side effects as for Best Augmenting Agents for Side
therapeutic effects – namely due to Effects
excessive actions at benzodiazepine • Many side effects cannot be improved with
receptors an augmenting agent
• Long-term adaptations in benzodiazepine
receptors may explain the development of
dependence, tolerance, and withdrawal
• Side effects are generally immediate, but DOSING AND USE
immediate side effects often disappear in
Usual Dosage Range
time
• Oral: 2–6 mg/day in divided doses, largest
Notable Side Effects dose at bedtime
✽ Sedation, fatigue, depression • Injection: 4 mg administered slowly
✽ Dizziness, ataxia, slurred speech, Dosage Forms
weakness
• Tablet 0.5 mg, 1 mg, 2 mg
✽ Forgetfulness, confusion • Liquid 0.5 mg/5mL, 2 mg/mL
✽ Hyper-excitability, nervousness • Injection 1 mg/0.5mL, 2 mg/mL, 4 mg/mL
✽ Pain at injection site
• Rare hallucinations, mania How to Dose
• Rare hypotension • Oral: Initial 2–3 mg/day in 2–3 doses;
• Hypersalivation, dry mouth increase as needed, starting with evening
dose; maximum generally 10 mg/day
Life Threatening or • Injection: Initial 4 mg administered slowly;
Dangerous Side Effects after 10–15 minutes may administer again
• Respiratory depression, especially when • Take liquid formulation with water, soda,
taken with CNS depressants in overdose applesauce or pudding
• Rare hepatic dysfunction, renal
dysfunction, blood dyscrasias
Dosing Tips
Weight Gain ✽ One of the few benzodiazepines available
in an oral liquid formulation
✽ One of the few benzodiazepines available
• Reported but not expected in an injectable formulation
• Lorazepam injection is intended for acute
Sedation use; patients who require long-term
treatment should be switched to the oral
formulation
• Use lowest possible effective dose for the
• Many experience and/or can be significant shortest possible period of time (a
in amount benzodiazepine-sparing strategy)
• Especially at initiation of treatment or when • Assess need for continued treatment
dose increases regularly
• Tolerance often develops over time • Risk of dependence may increase with
dose and duration of treatment
What To Do About Side Effects
• For inter-dose symptoms of anxiety, can
• Wait
either increase dose or maintain same total
• Wait
daily dose but divide into more frequent
• Wait
doses
• Lower the dose
• Can also use an as-needed occasional “top
• Take largest dose at bedtime to avoid
up” dose for inter-dose anxiety
sedative effects during the day
• Switch to another agent

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(continued) LORAZEPAM

• Because panic disorder can require doses benzodiazepine-dependent patients stop

higher than 6 mg/day, the risk of their medication, disease symptoms can
dependence may be greater in these reemerge, disease symptoms can worsen
patients (rebound), and/or withdrawal symptoms
• Some severely ill patients may require can emerge
10 mg/day or more
• Frequency of dosing in practice is often Pharmacokinetics
greater than predicted from half-life, as • Elimination half-life 10–20 hours
duration of biological activity is often • No active metabolites
shorter than pharmacokinetic terminal half-
life
Drug Interactions
Overdose • Increased depressive effects when taken
• Fatalities can occur; hypotension, with other CNS depressants
tiredness, ataxia, confusion, coma • Valproate and probenecid may reduce
clearance and raise plasma concentrations
Long-Term Use
of lorazepam
• Evidence of efficacy up to 16 weeks
• Oral contraceptives may increase clearance
• Risk of dependence, particularly for
and lower plasma concentrations of
treatment periods longer than 12 weeks
lorazepam
and especially in patients with past or
• Flumazenil (used to reverse the effects of
current polysubstance abuse
benzodiazepines) may precipitate seizures
Habit Forming and should not be used in patients treated
for seizure disorders with lorazepam
• Lorazepam is a Schedule IV drug
• Patients may develop dependence and/or
tolerance with long-term use Other Warnings/
Precautions
How to Stop • Dosage changes should be made in
• Patients with history of seizure may seize collaboration with prescriber
upon withdrawal, especially if withdrawal is • Use with caution in patients with
abrupt pulmonary disease; rare reports of death
• Taper by 0.5 mg every 3 days to reduce after initiation of benzodiazepines in
chances of withdrawal effects patients with severe pulmonary impairment
• For difficult to taper cases, consider • History of drug or alcohol abuse often
reducing dose much more slowly once creates greater risk for dependency
reaching 3 mg/day, perhaps by as little as • Use oral formulation only with extreme
0.25 mg per week or less caution if patient has obstructive sleep
• For other patients with severe problems apnea; injection is contraindicated in
discontinuing a benzodiazepine, dosing patients with sleep apnea
may need to be tapered over many months • Some depressed patients may experience a
(i.e., reduce dose by 1% every 3 days by worsening of suicidal ideation
crushing tablet and suspending or • Some patients may exhibit abnormal
dissolving in 100 ml of fruit juice and then thinking or behavioral changes similar to
disposing of 1 ml while drinking the rest; those caused by other CNS depressants
3–7 days later, dispose of 2 ml, and so on). (i.e., either depressant actions or
This is both a form of very slow biological disinhibiting actions)
tapering and a form of behavioral
desensitization Do Not Use
• Be sure to differentiate reemergence of • If patient has narrow angle-closure
symptoms requiring reinstitution of glaucoma
treatment from withdrawal symptoms • If patient has sleep apnea (injection)
• Benzodiazepine-dependent anxiety patients • Must not be given intra-arterially because it
and insulin-dependent diabetics are not may cause arteriospasm and result in
addicted to their medications. When gangrene

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LORAZEPAM (continued)

• If there is a proven allergy to lorazepam or • Infants whose mothers received a

any benzodiazepine benzodiazepine late in pregnancy may
experience withdrawal effects
• Neonatal flaccidity has been reported in
SPECIAL POPULATIONS infants whose mothers took a
benzodiazepine during pregnancy
Renal Impairment • Seizures, even mild seizures, may cause
• 1–2 mg/day in 2–3 doses harm to the embryo/fetus

Hepatic Impairment Breast Feeding

• 1–2 mg/day in 2–3 doses • Some drug is found in mother’s breast milk
• Because of its short half-life and inactive ✽ Recommended either to discontinue drug
metabolites, lorazepam may be a preferred or bottle feed
benzodiazepine in some patients with liver • Effects on infant have been observed and
disease include feeding difficulties, sedation, and
weight loss
Cardiac Impairment
• Benzodiazepines have been used to treat
anxiety associated with acute myocardial THE ART OF PSYCHOPHARMACOLOGY
infarction
• Lorazepam may be used as an adjunct to Potential Advantages
control drug-induced cardiovascular • Rapid onset of action
emergencies • Availability of oral liquid as well as
injectable dosage formulations
Elderly
• 1–2 mg/day in 2–3 doses Potential Disadvantages
• May be more sensitive to sedative or • Euphoria may lead to abuse
respiratory effects • Abuse especially risky in past or present
substance abusers
• Possibly more sedation than some other
Children and Adolescents benzodiazepines commonly used to treat
• Oral: safety and efficacy not established anxiety
under age 12
• Injection: safety and efficacy not Primary Target Symptoms
established under age 18 • Panic attacks
• Long-term effects of lorazepam in • Anxiety
children/adolescents are unknown • Muscle spasms
• Should generally receive lower doses and • Incidence of seizures (adjunct)
be more closely monitored

Pearls
Pregnancy ✽ One of the most popular and useful
• Risk Category D [positive evidence of risk benzodiazepines for treatment of agitation
to human fetus; potential benefits may still associated with psychosis, bipolar disorder,
justify its use] and other disorders, especially in the
• Possible increased risk of birth defects inpatient setting; this is due in part to
when benzodiazepines taken during useful sedative properties and flexibility of
pregnancy administration with oral tablets, oral liquid,
• Because of the potential risks, lorazepam is or injectable formulations, which is often
not generally recommended as treatment useful in treating uncooperative patients
for anxiety during pregnancy, especially • Is a very useful adjunct to SSRIs and
during the first trimester SNRIs in the treatment of numerous
• Drug should be tapered if discontinued anxiety disorders

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(continued) LORAZEPAM

• Not effective for treating psychosis as a ✽ Lorazepam is often used to induce pre-
monotherapy, but can be used as an operative anterograde amnesia to assist in
adjunct to antipsychotics anesthesiology
• Not effective for treating bipolar disorder • May both cause depression and treat
as a monotherapy, but can be used as an depression in different patients
adjunct to mood stabilizers and • Clinical duration of action may be shorter
antipsychotics than plasma half-life, leading to dosing
• Because of its short half-life and inactive more frequently than 2–3 times daily in
metabolites, lorazepam may be preferred some patients
over some benzodiazepines for patients • When using to treat insomnia, remember
with liver disease that insomnia may be a symptom of some
✽ Lorazepam may be preferred over other other primary disorder itself, and thus
benzodiazepines for the treatment of warrant evaluation for comorbid psychiatric
delirium and/or medical conditions

Suggested Reading
Bonnet MH, Arand DL. The use of lorazepam Starreveld E, Starreveld AA. Status epilepticus.
TID for chronic insomnia. Int Clin Current concepts and management. Can Fam
Psychopharmacol 1999;14:81–9. Physician 2000;46:1817–23.
Greenblatt DJ. Clinical pharmacokinetics of Wagner BK, O’Hara DA, Hammond JS. Drugs
oxazepam and lorazepam. Clin Pharmacokinet for amnesia in the ICU. Am J Crit Care 1997;
1981;6:89–105. 6:192–201.

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LOXAPINE
THERAPEUTICS and/or an atypical antipsychotic for mood
stabilization and maintenance
Brands • Loxitane
see index for additional brand names If It Doesn’t Work
• Consider trying one of the first-line atypical
Generic? Yes antipsychotics (risperidone, olanzapine,
quetiapine, ziprasidone, aripiprazole,
amisulpride)
Class • Consider trying another conventional
• Conventional antipsychotic (neuroleptic, antipsychotic
dopamine 2 antagonist, serotonin • If 2 or more antipsychotic monotherapies
dopamine antagonist) do not work, consider clozapine

Commonly Prescribed For Best Augmenting Combos

(bold for FDA approved) for Partial Response or
• Schizophrenia Treatment-Resistance
• Other psychotic disorders • Augmentation of conventional
• Bipolar disorder antipsychotics has not been systematically
studied
• Addition of a mood stabilizing
How The Drug Works anticonvulsant such as valproate,
• Blocks dopamine 2 receptors, reducing carbamazepine, or lamotrigine may be
positive symptoms of psychosis helpful in both schizophrenia and bipolar
✽ Although classified as a conventional mania
antipsychotic, loxapine is a potent • Augmentation with lithium in bipolar mania
serotonin 2A antagonist may be helpful
• Serotonin 2A antagonist properties might • Addition of a benzodiazepine, especially
be relevant at low doses, but generally are short-term for agitation
overwhelmed by high dosing
Tests
How Long Until It Works ✽ Since conventional antipsychotics are
• Psychotic symptoms can improve within frequently associated with weight gain,
1 week, but it may take several weeks for before starting treatment, weigh all patients
full effect on behavior and determine if the patient is already
overweight (BMI 25.0–29.9) or obese
If It Works (BMI ≥30)
• Most often reduces positive symptoms in • Before giving a drug that can cause weight
schizophrenia but does not eliminate them gain to an overweight or obese patient,
• Most schizophrenic patients do not have a consider determining whether the patient
total remission of symptoms but rather a already has pre-diabetes (fasting plasma
reduction of symptoms by about a third glucose 100–125 mg/dl), diabetes (fasting
• Continue treatment in schizophrenia until plasma glucose >126 mg/dl), or
reaching a plateau of improvement dyslipidemia (increased total cholesterol,
• After reaching a satisfactory plateau, LDL cholesterol and triglycerides;
continue treatment for at least a year after decreased HDL cholesterol), and treat or
first episode of psychosis in schizophrenia refer such patients for treatment, including
• For second and subsequent episodes of nutrition and weight management, physical
psychosis in schizophrenia, treatment may activity counseling, smoking cessation, and
need to be indefinite medical management
• Reduces symptoms of acute psychotic ✽ Monitor weight and BMI during treatment
mania but not proven as a mood stabilizer ✽ While giving a drug to a patient who has
or as an effective maintenance treatment in gained >5% of initial weight, consider
bipolar disorder evaluating for the presence of pre-diabetes,
• After reducing acute psychotic symptoms diabetes, or dyslipidemia, or consider
in mania, switch to a mood stabilizer switching to a different antipsychotic

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LOXAPINE (continued)

• Should check blood pressure in the elderly Weight Gain

before starting and for the first few weeks
of treatment
• Monitoring elevated prolactin levels of
• Reported but not expected
dubious clinical benefit
Sedation
SIDE EFFECTS
How Drug Causes Side Effects • Many experience and/or can be significant
• By blocking dopamine 2 receptors in the in amount
striatum, it can cause motor side effects • Sedation is usually transient
• By blocking dopamine 2 receptors in the • Sedation is usually dose-dependent and
pituitary, it can cause elevations in may not be experienced at low doses
prolactin where loxapine may function as an atypical
• By blocking dopamine 2 receptors antipsychotic (e.g., <50 mg/day; especially
excessively in the mesocortical and 5–25 mg/day)
mesolimbic dopamine pathways, especially
at high doses, it can cause worsening of
What To Do About Side Effects
negative and cognitive symptoms • Wait
(neuroleptic-induced deficit syndrome) • Wait
• Anticholinergic actions may cause • Wait
sedation, blurred vision, constipation, dry • For motor symptoms, add an
mouth anticholinergic agent
• Antihistaminic actions may cause sedation, • Reduce the dose
weight gain • For sedation, give at night
• By blocking alpha 1 adrenergic receptors, it • Switch to an atypical antipsychotic
can cause dizziness, sedation, and • Weight loss, exercise programs, and
hypotension medical management for high BMIs,
• Mechanism of weight gain and any diabetes, dyslipidemia
possible increased incidence of diabetes or
Best Augmenting Agents for Side
dyslipidemia with conventional
antipsychotics is unknown
Effects
• Benztropine or trihexyphenidyl for motor
Notable Side Effects side effects
✽ Neuroleptic-induced deficit syndrome • Sometimes amantadine can be helpful for
✽ Akathisia motor side effects
✽ Extrapyramidal symptoms, Parkinsonism, • Benzodiazepines may be helpful for
tardive dyskinesia akathisia
✽ Galactorrhea, amenorrhea • Many side effects cannot be improved with
• Sedation an augmenting agent
• Dry mouth, constipation, vision
disturbance, urninary retention
• Hypotension, tachycardia DOSING AND USE
Usual Dosage Range
Life Threatening or • 60–100 mg/day in divided doses
Dangerous Side Effects
• Rare neuroleptic malignant syndrome Dosage Forms
• Rare agranulocytosis • Capsule 6.8 mg loxapine succinate
• Rare hepatocellular injury equivalent to 5 mg loxapine, 13.6 mg
• Rare seizures loxapine succinate equivalent to 10 mg
loxapine, 34.0 mg loxapine succinate
equivalent to 25 mg loxapine, 68.1 mg

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(continued) LOXAPINE

loxapine succinate equivalent to 50 mg antipsychotic with 25–50 mg loxapine

loxapine 2–3 times a day intramuscularly to achieve
• Oral liquid 25 mg/mL antipsychotic effects without
• Injection 50 mg/mL extrapyramidal symptoms and sedation
• When using loxapine to “top-up”
How to Dose previously stabilized patients now
• Initial 20 mg/day in 2 doses; titrate over decompensating, may use loxapine as
7–10 days to 60–100 mg/day in 2–4 doses; single 25–50 mg doses as needed
maximum generally 250 mg/day intramuscularly or as oral liquid or tablets
• Take liquid formulation in orange or • Patients receiving atypical antipsychotics
grapefruit juice may occasionally require a “top up” of a
conventional antipsychotic to control
aggression or violent behavior
Dosing Tips
• Has conventional antipsychotic properties Overdose
at originally recommended doses (i.e., • Deaths have occurred; extrapyramidal
starting at 10 mg twice a day, maintenance symptoms, CNS depression, cardiovascular
60–100 mg/day, maximum 250 mg/day effects, hypotension, seizures, respiratory
given in 2 divided doses) depression, renal failure, coma
✽ Binding studies, PET studies, and Long-Term Use
anecdotal clinical observations suggest that
• Some side effects may be irreversible (e.g.,
loxapine may be atypical at lower doses
tardive dyskinesia)
(perhaps 5–30 mg/day) but further studies
needed Habit Forming
• Anecdotal evidence that many patients can
• No
be maintained at 20–60 mg/day as
monotherapy How to Stop
• To augment partial responders to an • Slow down-titration of oral formulation
atypical antipsychotic, consider doses of (over 6 to 8 weeks), especially when
loxapine as low as 5–60 mg/day, but use simultaneously beginning a new
full doses if necessary antipsychotic while switching (i.e., cross-
• No formal studies, but some patients may titration)
do well on once-daily dosing, especially at • Rapid oral discontinuation may lead to
night, rather than twice-daily dosing rebound psychosis and worsening of
• Available as 5 mg and 10 mg capsules for symptoms
low dose use and as 25 mg and 50 mg • If antiparkinson agents are being used,
capsules for routine use they should be continued for a few weeks
• Available as a liquid dosage formulation after loxapine is discontinued
• Available for acute intramuscular
administration (50 mg/ml) Pharmacokinetics
• Intramuscular loxapine may have faster • Half-life approximately 4 hours for oral
onset of action and superior efficacy for formulation
agitated/excited and aggressive behavior in • Half-life approximately 12 hours for
some patients than intramuscular intramuscular formulation
haloperidol • Multiple active metabolites with longer
• In the acute situation, give 25–50 mg half-lives than parent drug
intramuscularly (0.5–1.0 ml of 50 mg/ml ✽ N-desmethyl loxapine is amoxapine, an
solution) with onset of action within antidepressant
60 minutes • 8-hydroxyloxapine and 7-hydroxyloxapine
• When initiating therapy with an atypical are also serotonin-dopamine antagonists
antipsychotic in an acute situation, • 8-hydroxyamoxapine and
consider short-term intramuscular loxapine 7-hydroxyamoxapine are also serotonin-
to “lead in” to orally administered atypical; dopamine antagonists
e.g., initiate oral dosing of an atypical

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LOXAPINE (continued)

SPECIAL POPULATIONS
Drug Interactions Renal Impairment
• Respiratory depression may occur when • Use with caution
loxapine is combined with lorazepam
• Additive effects may occur if used with Hepatic Impairment
CNS depressants • Use with caution
• May decrease the effects of levodopa,
dopamine agonists Cardiac Impairment
• Some patients taking a neuroleptic and • Use with caution
lithium have developed an encephalopathic
syndrome similar to neuroleptic malignant
Elderly
syndrome • Some patients may tolerate lower doses
• Combined use with epinephrine may lower better
blood pressure
• May increase the effects of
antihypertensive drugs except for Children and Adolescents
guanethidine, whose antihypertensive • Safety and efficacy not established
actions loxapine may antagonize • Generally, consider second-line after
atypical antipsychotics
Other Warnings/
Precautions
• If signs of neuroleptic malignant syndrome
Pregnancy
develop, treatment should be immediately • Renal papillary abnormalities have been
discontinued seen in rats during pregnancy
• Use cautiously in patients with alcohol • No studies in pregnant women
withdrawal or convulsive disorders • Psychotic symptoms may worsen during
because of possible lowering of seizure pregnancy and some form of treatment
threshold may be necessary
• Antiemetic effect can mask signs of other • Atypical antipsychotics may be preferable
disorders or overdose to conventional antipsychotics or
• Do not use epinephrine in event of anticonvulsant mood stabilizers if
overdose, as interaction with some pressor treatment is required during pregnancy
agents may lower blood pressure Breast Feeding
• Use cautiously in patients with glaucoma,
• Unknown if loxapine is secreted in human
urinary retention
breast milk, but all psychotropics assumed
• Observe for signs of ocular toxicity
to be secreted in breast milk
(pigmentary retinopathy, lenticular
pigmentation) ✽ Recommended either to discontinue drug
or bottle feed
• Avoid extreme heat exposure
• Use only with caution if at all in
Parkinson’s disease or Lewy Body
dementia THE ART OF PSYCHOPHARMACOLOGY

Do Not Use Potential Advantages

• If patient is in a comatose state or has CNS • Intramuscular formulation for emergency
depression use
• If there is a proven allergy to loxapine
• If there is a known sensitivity to any
Potential Disadvantages
dibenzoxazepine • Patients with tardive dyskinesia

Primary Target Symptoms

• Positive symptoms of psychosis
• Motor and autonomic hyperactivity
• Violent or aggressive behavior

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(continued) LOXAPINE

✽ Enhances efficacy in clozapine partial

responders when given concomitantly with
Pearls clozapine
✽ Recently discovered to be a serotonin • For previously stabilized patients with
dopamine antagonist (binding studies and “breakthrough” agitation or incipient
PET scans) decompensation, “top-up” the atypical
✽ Active metabolites are also serotonin antipsychotic with as-needed intramuscular
dopamine antagonists with longer half-lives or oral single doses of loxapine
than parent drug, thus possibly allowing • Patients have very similar antipsychotic
once-daily treatment responses to any conventional
✽ One active metabolite is an antipsychotic, which is different from
antidepressant (amoxapine, also known as atypical antipsychotics where antipsychotic
N-desmethyl-loxapine) responses of individual patients can
• Theoretically, loxapine should have occasionally vary greatly from one atypical
antidepressant actions, especially at high antipsychotic to another
doses, but no controlled studies • Patients with inadequate responses to
• Theoretically, loxapine may have atypical antipsychotics may benefit from a
advantages for short-term use in some trial of augmentation with a conventional
patients with psychotic depression antipsychotic such as loxapine or from
• Developed as a conventional antipsychotic; switching to a conventional antipsychotic
i.e., reduces positive symptoms, but such as loxapine
causes extrapyramidal symptoms and • However, long-term polypharmacy with a
prolactin elevations combination of a conventional
• Lower extrapyramidal symptoms than antipsychotic such as loxapine with an
haloperidol in some studies, but not fixed atypical antipsychotic may combine their
dose studies and no low dose studies side effects without clearly augmenting the
✽ Causes less weight gain than other efficacy of either
antipsychotics, both atypical and • Although a frequent practice by some
conventional, and may even be associated prescribers, adding 2 conventional
with weight loss antipsychotics together has little rationale
• No formal studies of negative symptoms, and may reduce tolerability without clearly
but some studies show superiority to enhancing efficacy
conventional antipsychotics for emotional
withdrawal and social competence
• Best use may be as low-cost augmentation
agent to atypical antipsychotics

Suggested Reading
Fenton M, Murphy B, Wood J, Bagnall A, Chue Zisook S, Click MA Jr. Evaluations of loxapine
P, Leitner M. Loxapine for schizophrenia. succinate in the ambulatory treatment of acute
Cochrane Database Syst Rev 2000; (2): schizophrenic episodes. Int
CD001943. Pharmacopsychiatry 1980; 15 (6): 365–78.
Heel RC, Brogden RN, Speight TM, Avery GS.
Loxapine: a review of its pharmacological
properties and therapeutic efficacy as an
antipsychotic agent. Drugs 1978; 15 (3):
198–217.

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MAPROTILINE
THERAPEUTICS If It Works
• The goal of treatment of depression is
Brands • Ludiomil
complete remission of current symptoms
see index for additional brand names
as well as prevention of future relapses
Generic? Yes • The goal of treatment of chronic
neuropathic pain is to reduce symptoms as
much as possible, especially in
combination with other treatments
Class • Treatment of depression most often
• Tricyclic antidepressant (TCA), sometimes reduces or even eliminates symptoms, but
classified as a tetracyclic antidepressant not a cure since symptoms can recur after
(tetra) medicine stopped
• Predominantly a norepinephrine/ • Treatment of chronic neuropathic pain may
noradrenaline reuptake inhibitor reduce symptoms, but rarely eliminates
them completely, and is not a cure since
Commonly Prescribed For symptoms can recur after medicine is
(bold for FDA approved) stopped
• Depression • Continue treatment of depression until all
• Anxiety symptoms are gone (remission)
• Insomnia • Once symptoms of depression are gone,
• Neuropathic pain/chronic pain continue treating for 1 year for the first
• Treatment-resistant depression episode of depression
• For second and subsequent episodes of
depression, treatment may need to be
How The Drug Works indefinite
• Boosts neurotransmitter • Use in anxiety disorders and chronic pain
norepinephrine/noradrenaline may also need to be indefinite, but long-
• Blocks norepinephrine reuptake pump term treatment is not well-studied in these
(norepinephrine transporter), presumably conditions
increasing noradrenergic
If It Doesn’t Work
neurotransmission
• Many depressed patients only have a
• Since dopamine is inactivated by
partial response where some symptoms
norepinephrine reuptake in frontal cortex,
are improved but others persist (especially
which largely lacks dopamine transporters,
insomnia, fatigue, and problems
maprotiline can thus increase dopamine
concentrating)
neurotransmission in this part of the brain
• Other depressed patients may be
• A more potent inhibitor of norepinephrine
nonresponders, sometimes called
reuptake pump than serotonin reuptake
treatment-resistant or treatment-refractory
pump (serotonin transporter)
• Consider increasing dose, switching to
• At high doses may also boost
another agent or adding an appropriate
neurotransmitter serotonin and presumably
augmenting agent
increase serotonergic neurotransmission
• Consider psychotherapy
How Long Until It Works • Consider evaluation for another diagnosis
• Onset of therapeutic actions usually not or for a comorbid condition (e.g., medical
immediate, but often delayed 2 to 4 weeks illness, substance abuse, etc.)
• If it is not working within 6 to 8 weeks for • Some patients may experience apparent
depression, it may require a dosage lack of consistent efficacy due to activation
increase or it may not work at all of latent or underlying bipolar disorder, and
• May continue to work for many years to require antidepressant discontinuation and
prevent relapse of symptoms a switch to a mood stabilizer

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MAPROTILINE (continued)

Best Augmenting Combos SIDE EFFECTS

for Partial Response or How Drug Causes Side Effects
Treatment-Resistance • Anticholinergic activity may explain
• Lithium, buspirone, thyroid hormone (for sedative effects, dry mouth, constipation,
depression) and blurred vision
• Gabapentin, tiagabine, other • Sedative effects and weight gain may be
anticonvulsants, even opiates if done by due to antihistamine properties
experts while monitoring carefully in • Blockade of alpha adrenergic 1 receptors
difficult cases (for chronic pain) may explain dizziness, sedation, and
hypotension
Tests
• Cardiac arrhythmias and seizures,
• None for healthy individuals
especially in overdose, may be caused by
✽ Since tricyclic and tetracyclic blockade of ion channels
antidepressants are frequently associated
with weight gain, before starting treatment, Notable Side Effects
weigh all patients and determine if the • Blurred vision, constipation, urinary
patient is already overweight retention, increased appetite, dry mouth,
(BMI 25.0–29.9) or obese (BMI ≥30) nausea, diarrhea, heartburn, unusual taste
• Before giving a drug that can cause weight in mouth, weight gain
gain to an overweight or obese patient, • Fatigue, weakness, dizziness, sedation,
consider determining whether the patient headache, anxiety, nervousness,
already has pre-diabetes (fasting plasma restlessness
glucose 100–125 mg/dl), diabetes (fasting • Sexual dysfunction (impotence, change in
plasma glucose >126 mg/dl), or libido)
dyslipidemia (increased total cholesterol, • Sweating, rash, itching
LDL cholesterol and triglycerides;
decreased HDL cholesterol), and treat or
refer such patients for treatment, including Life Threatening or
nutrition and weight management, physical Dangerous Side Effects
activity counseling, smoking cessation, and • Paralytic ileus, hyperthermia (TCAs/
medical management tetracylics + anticholinergic agents)
✽ Monitor weight and BMI during treatment • Lowered seizure threshold and rare
✽ While giving a drug to a patient who has seizures
gained >5% of initial weight, consider • Orthostatic hypotension, sudden death,
evaluating for the presence of pre-diabetes, arrhythmias, tachycardia
diabetes, or dyslipidemia, or consider • QTc prolongation
switching to a different antidepressant • Hepatic failure, extrapyramidal symptoms
• EKGs may be useful for selected patients • Increased intraocular pressure
(e.g., those with personal or family history • Rare induction of mania and activation of
of QTc prolongation; cardiac arrhythmia; suicidal ideation
recent myocardial infarction;
uncompensated heart failure; or taking Weight Gain
agents that prolong QTc interval such as
pimozide, thioridazine, selected
antiarrhythmics, moxifloxacin, sparfloxacin, • Many experience and/or can be significant
etc.) in amount
• Patients at risk for electrolyte disturbances • Can increase appetite and carbohydrate
(e.g., patients on diuretic therapy) should craving
have baseline and periodic serum
potassium and magnesium measurements Sedation

• Many experience and/or can be significant

in amount

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(continued) MAPROTILINE

• Tolerance to sedative effect may develop Overdose

with long-term use • Death may occur; convulsions, cardiac
dysrhythmias, severe hypotension, CNS
What To Do About Side Effects depression, coma, changes in ECG
• Wait
• Wait Long-Term Use
• Wait • Safe
• Lower the dose
• Switch to an SSRI or newer antidepressant Habit Forming
• No
Best Augmenting Agents for Side
Effects How to Stop
• Many side effects cannot be improved with • Taper to avoid withdrawal effects
an augmenting agent • Even with gradual dose reduction some
withdrawal symptoms may appear within
the first 2 weeks
DOSING AND USE • Many patients tolerate 50% dose reduction
for 3 days, then another 50% reduction for
Usual Dosage Range 3 days, then discontinuation
• 75–150 mg/day (for depression) • If withdrawal symptoms emerge during
• 50–150 mg/day (for chronic pain) discontinuation, raise dose to stop
symptoms and then restart withdrawal
Dosage Forms much more slowly
• Tablet 25 mg, 50 mg, 75 mg
Pharmacokinetics
How to Dose • Substrate for CYP450 2D6
• Initial 25 mg/day at bedtime; increase by • Mean half-life approximately 51 hours
25 mg every 3–7 days • Peak plasma concentration 8–24 hours
• 75 mg/day; after 2 weeks increase dose
gradually by 25 mg/day; maximum dose
generally 225 mg/day Drug Interactions
• Tramadol increases the risk of seizures in
patients taking TCAs
Dosing Tips • Use of TCAs/tetracyclics with
• If given in a single dose, should generally anticholinergic drugs may result in
be administered at bedtime because of its paralytic ileus or hyperthermia
sedative properties • Fluoxetine, paroxetine, bupropion,
• If given in split doses, largest dose should duloxetine, and other CYP450 2D6
generally be given at bedtime because of inhibitors may increase TCA/tetracyclic
its sedative properties concentrations
• If patients experience nightmares, split • Cimetidine may increase plasma
dose and do not give large dose at bedtime concentrations of TCAs/tetracyclics and
• Patients treated for chronic pain may only cause anticholinergic symptoms
require lower doses • Phenothiazines or haloperidol may raise
✽ Risk of seizures increases with dose, TCA/tetracyclic blood concentrations
especially with maprotiline above 200 • May alter effects of antihypertensive drugs;
mg/day may inhibit hypotensive effects of clonidine
• If intolerable anxiety, insomnia, agitation, • Use with sympathomimetic agents may
akathisia, or activation occur either upon increase sympathetic activity
dosing initiation or discontinuation, • Methylphenidate may inhibit metabolism of
consider the possibility of activated bipolar TCAs/tetracyclics
disorder, and switch to a mood stabilizer or • Activation and agitation, especially
an atypical antipsychotic following switching or adding
antidepressants, may represent the
induction of a bipolar state, especially a

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MAPROTILINE (continued)

mixed dysphoric bipolar II condition • If patient is taking drugs that inhibit

sometimes associated with suicidal TCA/tetracyclic metabolism, including
ideation, and require the addition of CYP450 2D6 inhibitors, except by an expert
lithium, a mood stabilizer or an atypical • If there is reduced CYP450 2D6 function,
antipsychotic, and/or discontinuation of such as patients who are poor 2D6
maprotiline metabolizers, except by an expert and at
low doses
• If there is a proven allergy to maprotiline
Other Warnings/
Precautions
• Add or initiate other antidepressants with
caution for up to 2 weeks after
SPECIAL POPULATIONS
discontinuing maprotiline Renal Impairment
• Generally, do not use with MAO inhibitors,
• Use with caution
including 14 days after MAOIs are stopped;
do not start an MAOI until 2 weeks after Hepatic Impairment
discontinuing maprotiline, but see Pearls • Use with caution
• Use with caution in patients with history of
seizures, urinary retention, narrow angle- Cardiac Impairment
closure glaucoma, hyperthyroidism • TCAs/tetracyclics have been reported to
• TCAs/tetracyclics can increase QTc interval, cause arrhythmias, prolongation of
especially at toxic doses, which can be conduction time, orthostatic hypotension,
attained not only by overdose but also by sinus tachycardia, and heart failure,
combining with drugs that inhibit TCA/ especially in the diseased heart
tetracyclic metabolism via CYP450 2D6, • Myocardial infarction and stroke have been
potentially causing torsade de pointes-type reported with TCAs/tetracyclics
arrhythmia or sudden death • TCAs/tetracyclics produce QTc
• Because TCAs/tetracyclics can prolong QTc prolongation, which may be enhanced by
interval, use with caution in patients who the existence of bradycardia, hypokalemia,
have bradycardia or who are taking drugs congenital or acquired long QTc interval,
that can induce bradycardia (e.g., beta which should be evaluated prior to
blockers, calcium channel blockers, administering maprotiline
clonidine, digitalis) • Use with caution if treating concomitantly
• Because TCAs/tetracyclics can prolong QTc with a medication likely to produce
interval, use with caution in patients who prolonged bradycardia, hypokalemia,
have hypokalemia and/or hypomagnesemia slowing of intracardiac conduction, or
or who are taking drugs that can induce prolongation of the QTc interval
hypokalemia and/or magnesemia (e.g., • Avoid TCAs/tetracyclics in patients with a
diuretics, stimulant laxatives, intravenous known history of QTc prolongation, recent
amphotericin B, glucocorticoids, acute myocardial infarction, and
tetracosactide) uncompensated heart failure
• TCAs/tetracyclics may cause a sustained
Do Not Use increase in heart rate in patients with
• If patient is recovering from myocardial ischemic heart disease and may worsen
infarction (decrease) heart rate variability, an
• If patient is taking agents capable of independent risk of mortality in cardiac
significantly prolonging QTc interval (e.g., populations
pimozide, thioridazine, selected • Since SSRIs may improve (increase) heart
antiarrhythmics, moxifloxacin, rate variability in patients following a
sparfloxacin) myocardial infarct and may improve
• If there is a history of QTc prolongation or survival as well as mood in patients with
cardiac arrhythmia, recent acute acute angina or following a myocardial
myocardial infarction, uncompensated infarction, these are more appropriate
heart failure agents for cardiac population than
tricyclic/tetracyclic antidepressants

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(continued) MAPROTILINE

✽ Risk/benefit ratio may not justify use of the third trimester or shortly after
TCAs/tetracyclics in cardiac impairment childbirth to prevent a recurrence during
the postpartum period
Elderly • Must weigh benefits of breast feeding with
• May be more sensitive to anticholinergic, risks and benefits of antidepressant
cardiovascular, hypotensive, and sedative treatment versus non-treatment to both the
effects infant and the mother
• Usual dose generally 50–75 mg/day • For many patients this may mean
continuing treatment during breast feeding

Children and Adolescents

• Use with caution, observing for activation THE ART OF PSYCHOPHARMACOLOGY
of known or unknown bipolar disorder
and/or suicidal ideation, and strongly Potential Advantages
consider informing parents or guardian of • Patients with insomnia
this risk so they can help observe child or • Severe or treatment-resistant depression
adolescent patients
• Not recommended for use under age 18 Potential Disadvantages
• Several studies show lack of efficacy of • Pediatric and geriatric patients
TCAs/tetracyclics for depression • Patients concerned with weight gain
• May be used to treat enuresis or • Cardiac patients
hyperactive/impulsive behaviors • Patients with seizure disorders
• Some cases of sudden death have
occurred in children taking Primary Target Symptoms
TCAs/tetracyclics • Depressed mood
• Maximum dose for children and • Chronic pain
adolescents is 75 mg/day

Pearls
Pregnancy • Tricyclic/tetracyclic antidepressants are
• Risk Category B [animal studies do not often a first-line treatment option for
show adverse effects, no controlled studies chronic pain
in humans] • Tricyclic/tetracyclic antidepressants are no
• Adverse effects have been reported in longer generally considered a first-line
infants whose mothers took a treatment option for depression because of
TCA/tetracyclic (lethargy, withdrawal their side effect profile
symptoms, fetal malformations) • Tricyclic/tetracyclic antidepressants
• Must weigh the risk of treatment (first continue to be useful for severe or
trimester fetal development, third trimester treatment-resistant depression
newborn delivery) to the child against the ✽ May have somewhat increased risk of
risk of no treatment (recurrence of seizures compared to some other TCAs,
depression, maternal health, infant especially at higher doses
bonding) to the mother and child • TCAs/tetracyclics may aggravate psychotic
• For many patients this may mean symptoms
continuing treatment during pregnancy • Alcohol should be avoided because of
additive CNS effects
Breast Feeding • Underweight patients may be more
• Some drug is found in mother’s breast milk susceptible to adverse cardiovascular
✽ Recommended either to discontinue drug effects
or bottle feed • Children, patients with inadequate
• Immediate postpartum period is a high-risk hydration, and patients with cardiac
time for depression, especially in women disease may be more susceptible to
who have had prior depressive episodes, TCA/tetracyclic-induced cardiotoxicity than
so drug may need to be reinstituted late in healthy adults

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MAPROTILINE (continued)

• For the expert only: a heroic treatment (but TCAs/tetracyclics may be more effective
potentially dangerous) for severely than SSRIs in men
treatment-resistant patients is to give ✽ May have a more rapid onset of action
simultaneously with monoamine oxidase than some other TCAs/tetracyclics
inhibitors for patients who fail to respond • Since tricyclic/tetracyclic antidepressants
to numerous other antidepressants are substrates for CYP450 2D6, and 7% of
• If this option is elected, start the MAOI with the population (especially Caucasians) may
the tricyclic/tetracyclic antidepressant have a genetic variant leading to reduced
simultaneously at low doses after activity of 2D6, such patients may not
appropriate drug washout, then alternately safely tolerate normal doses of
increase doses of these agents every few tricyclic/tetracyclic antidepressants and
days to a week as tolerated may require dose reduction
• Although very strict dietary and • Phenotypic testing may be necessary to
concomitant drug restrictions must be detect this genetic variant prior to dosing
observed to prevent hypertensive crises with a tricyclic/tetracyclic antidepressant,
and serotonin syndrome, the most especially in vulnerable populations such
common side effects of MAOI/ tricyclic or as children, elderly, cardiac populations,
tetracyclic combinations may be weight and those on concomitant medications
gain and orthostatic hypotension • Patients who seem to have extraordinarily
• Patients on tricyclics/tetracyclics should be severe side effects at normal or low doses
aware that they may experience symptoms may have this phenotypic CYP450 2D6
such as photosensitivity or blue-green variant and require low doses or switching
urine to another antidepressant not metabolized
• SSRIs may be more effective than by 2D6
TCAs/tetracyclics in women, and

Suggested Reading
Anderson IM. Meta-analytical studies on new Kane JM, Lieberman J. The efficacy of
antidepressants. Br Med Bull. 2001; amoxapine, maprotiline, and trazodone in
57:161–178. comparison to imipramine and amitriptyline: a
review of the literature. Psychopharmacol Bull.
Anderson IM. Selective serotonin reuptake 1984;20:240–9.
inhibitors versus tricyclic antidepressants: a
meta-analysis of efficacy and tolerability. J Aff
Disorders. 2000;58:19–36.

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MEMANTINE
THERAPEUTICS Best Augmenting Combos
Brands • Namenda for Partial Response or
see index for additional brand names Treatment-Resistance
✽ Atypical antipsychotics to reduce
Generic? No behavioral disturbances
✽ Antidepressants if concomitant
depression, apathy, or lack of interest
Class ✽ May be combined with cholinesterase
inhibitors
• NMDA receptor antagonist; N-methyl-
• Divalproex, carbamazepine, or
d-aspartate (NMDA) subtype of glutamate
oxcarbazepine for behavioral disturbances
receptor antagonist; cognitive enhancer
Tests
Commonly Prescribed For
• None for healthy individuals
(bold for FDA approved)
• Moderate to severe dementia of the
Alzheimer type
• Mild to moderate Alzheimer dementia SIDE EFFECTS
• Memory disorders in other conditions
How Drug Causes Side Effects
• Mild cognitive impairment
• Presumably due to excessive actions at
• Chronic pain
NMDA receptors

Notable Side Effects

How The Drug Works • Dizziness, headache
✽ Is a low to moderate affinity • Constipation
noncompetitive (open-channel) NMDA
receptor antagonist, which binds
preferentially to the NMDA receptor- Life Threatening or
operated cation channels Dangerous Side Effects
• Presumably interferes with the postulated • Seizures (rare)
persistent activation of NMDA receptors by
excessive glutamate release in Alzheimer Weight Gain
disease

How Long Until It Works • Reported but not expected

• Memory improvement is not expected and
it may take months before any stabilization Sedation
in degenerative course is evident

If It Works
• May slow progression of disease, but does • Reported but not expected
not reverse the degenerative process • Fatigue may occur

If It Doesn’t Work What To Do About Side Effects

• Consider adjusting dose, switching to a • Wait
cholinesterase inhibitor or adding a • Wait
cholinesterase inhibitor • Wait
• Reconsider diagnosis and rule out other • Consider lowering dose or switching to a
conditions such as depression or a different agent
dementia other than Alzheimer disease
Best Augmenting Agents for Side
Effects
• Many side effects cannot be improved with
an augmenting agent

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MEMANTINE (continued)

DOSING AND USE

Usual Dosage Range Drug Interactions
• 20 mg twice daily • No interactions with drugs metabolized by
CYP450 enzymes
Dosage Forms • Drugs that raise the urine pH (e.g.,
• Tablet 5 mg, 10 mg carbonic anhydrase inhibitors, sodium
bicarbonate) may reduce elimination of
How to Dose memantine and raise plasma levels of
• Initial 5 mg/day; can increase by 5 mg each memantine
week; doses over 5 mg should be divided; ✽ No interactions with cholinesterase
maximum dose 20 mg twice daily inhibitors

Dosing Tips Other Warnings/

Precautions
✽ Despite very long half-life, is generally
dosed twice daily ✽ Use cautiously if co-administering with
• Both the patient and the patient’s caregiver other NMDA antagonists such as
should be instructed on how to dose amantadine, ketamine, and
memantine since patients themselves have dextromethorphan
moderate to severe dementia and may
Do Not Use
require assistance
• If there is a proven allergy to memantine
✽ Memantine is unlikely to affect
pharmacokinetics of acetylcholinesterase
inhibitors
• Absorption not affected by food SPECIAL POPULATIONS

Overdose Renal Impairment

• No fatalities have been reported; • Use with caution; dose may need to be
restlessness, psychosis, visual reduced
hallucinations, sedation, stupor, loss of • Not recommended for use in severe renal
consciousness impairment

Long-Term Use Hepatic Impairment

• Drug may lose effectiveness in slowing • Not likely to require dosage adjustment
degenerative course of Alzheimer disease
after 6 months Cardiac Impairment
• Not likely to require dosage adjustment
Habit Forming
• No Elderly
• Pharmacokinetics similar to younger adults
How to Stop
• No known withdrawal symptoms
• Theoretically, discontinuation could lead to Children and Adolescents
notable deterioration in memory and • Memantine use has not been studied in
behavior which may not be restored when children or adolescents
drug is restarted or a cholinesterase
inhibitor is initiated

Pharmacokinetics Pregnancy
• Risk Category B [animal studies do not
• Little metabolism; mostly excreted
show adverse effects; no controlled studies
unchanged in the urine
in humans]
• Terminal elimination half-life approximately
60–80 hours ✽ Not recommended for use in pregnant
women or women of childbearing potential
• Minimal inhibition of CYP450 enzymes

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(continued) MEMANTINE

Breast Feeding magnesium, and thus memantine is a sort

• Unknown if memantine is secreted in of “artificial magnesium”
human breast milk, but all psychotropics • Theoretically, NMDA antagonism of
assumed to be secreted in breast milk memantine is strong enough to block
✽ Recommended either to discontinue drug chronic low level over-excitation of
or bottle feed glutamate receptors associated with
• Memantine is not recommended for use in Alzheimer disease, but not strong enough
nursing women to interfere with periodic high level
utilization of glutamate for plasticity,
learning, and memory
THE ART OF PSYCHOPHARMACOLOGY • Structurally related to the antiparkinsonian
and anti-influenza agent amantadine, which
Potential Advantages is also a weak NMDA antagonist
• In patients with more advanced Alzheimer ✽ Memantine is well-tolerated with a low
disease incidence of adverse effects
• Antagonist actions at 5HT3 receptors have
Potential Disadvantages unknown clinical consequences but may
• Unproven to be effective in mild to contribute to low incidence of
moderate Alzheimer disease gastrointestinal side effects
• Patients who have difficulty taking a • Treat the patient but ask the caregiver
medication twice daily about efficacy
• Delay in progression of Alzheimer disease
Primary Target Symptoms is not evidence of disease-modifying
• Memory loss in Alzheimer disease actions of NMDA antagonism
• Behavioral symptoms in Alzheimer disease • May or may not be effective in vascular
• Memory loss in other dementias dementia
• Under investigation for dementia
associated with HIV/AIDS
Pearls • May or may not be effective in chronic
✽ In contrast to cholinesterase inhibitors, neuropathic pain
which are indicated for mild to moderate ✽ Theoretically, could be useful for any
Alzheimer disease, memantine is indicated condition characterized by moderate over-
for moderate to severe Alzheimer disease activation of NMDA glutamate receptors
• Recently approved in the U.S. but available (possibly neurodegenerative conditions or
for many years in other countries (e.g., even bipolar disorder, anxiety disorders, or
Germany) chronic neuropathic pain), but this is not
✽ Memantine’s actions are somewhat like proven
the natural inhibition of NMDA receptors by

Suggested Reading
Areosa SA, Sherriff F. Memantine for Mobius HJ. Memantine: update on the current
dementia. Cochrane Database Syst Rev evidence. Int J Geriatr Psychiatry
2003;(3):CD003154. 2003;18(Suppl 1):S47–54.
Doggrell S. Is memantine a breakthrough in Tariot PN, Federoff HJ. Current treatment for
the treatment of moderate-to-severe Alzheimer disease and future prospects.
Alzheimer’s disease? Expert Opin Alzheimer Dis Assoc Disord 2003;17 Suppl 4:
Pharmacother 2003;4:1857–60. S105–13.

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MESORIDAZINE
THERAPEUTICS Tests
Brands • Serentil ✽ Baseline ECG and serum potassium levels
should be determined
• Lidanil
see index for additional brand names
✽ Periodic evaluation of ECG and serum
potassium levels
Generic? Yes • Serum magnesium levels may also need to
be monitored
✽ Since conventional antipsychotics are
frequently associated with weight gain,
Class before starting treatment, weigh all patients
• Conventional antipsychotic (neuroleptic, and determine if the patient is already
phenothiazine, dopamine 2 antagonist) overweight (BMI 25.0–29.9) or obese
(BMI ≥30)
Commonly Prescribed For • Before giving a drug that can cause weight
(bold for FDA approved) gain to an overweight or obese patient,
• Management of schizophrenic patients consider determining whether the patient
who fail to respond adequately to already has pre-diabetes (fasting plasma
treatment with other antipsychotic drugs glucose 100–125 mg/dl), diabetes (fasting
plasma glucose >126 mg/dl), or
dyslipidemia (increased total cholesterol,
How The Drug Works LDL cholesterol and triglycerides;
• Blocks dopamine 2 receptors, reducing decreased HDL cholesterol), and treat or
positive symptoms of psychosis refer such patients for treatment, including
nutrition and weight management, physical
How Long Until It Works activity counseling, smoking cessation, and
• Psychotic symptoms can improve within 1 medical management
week, but it may take several weeks for full ✽ Monitor weight and BMI during treatment
effect on behavior ✽ While giving a drug to a patient who has
gained >5% of initial weight, consider
If It Works evaluating for the presence of pre-diabetes,
• Is a second-line treatment option diabetes, or dyslipidemia, or consider
✽ Should evaluate for switching to an switching to a different antipsychotic
antipsychotic with a better risk/benefit ratio • Should check blood pressure in the elderly
before starting and for the first few weeks
If It Doesn’t Work of treatment
• Consider trying one of the first-line atypical • Monitoring elevated prolactin levels of
antipsychotics (risperidone, olanzapine, dubious clinical benefit
quetiapine, ziprasidone, aripiprazole, • Phenothiazines may cause false-positive
amisulpride) phenylketonuria results
• Consider trying another conventional
antipsychotic
• If 2 or more antipsychotic monotherapies
do not work, consider clozapine
SIDE EFFECTS

Best Augmenting Combos How Drug Causes Side Effects

• By blocking dopamine 2 receptors in the
for Partial Response or
striatum, it can cause motor side effects
Treatment-Resistance • By blocking dopamine 2 receptors in the
• Augmentation of mesoridazine has not pituitary, it can cause elevations in
been systematically studied and can be prolactin
dangerous, especially with drugs that can • By blocking dopamine 2 receptors
prolong QTc interval excessively in the mesocortical and
mesolimbic dopamine pathways, especially
at high doses, it can cause worsening of

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MESORIDAZINE (continued)

negative and cognitive symptoms What To Do About Side Effects

(neuroleptic-induced deficit syndrome) • Wait
• Anticholinergic actions may cause • Wait
sedation, blurred vision, constipation, dry • Wait
mouth • For motor symptoms, add an
• Antihistaminic actions may cause sedation, anticholinergic agent
weight gain • Reduce the dose
• By blocking alpha 1 adrenergic receptors, it • For sedation, give at night
can cause dizziness, sedation, and • Switch to an atypical antipsychotic
hypotension • Weight loss, exercise programs, and
• Mechanism of weight gain and any medical management for high BMIs,
possible increased incidence of diabetes or diabetes, dyslipidemia
dyslipidemia with conventional
antipsychotics is unknown Best Augmenting Agents for Side
✽ Mechanism of potentially dangerous QTc Effects
prolongation may be related to actions at • Augmentation of mesoridazine has not
ion channels been systematically studied and can be
dangerous
Notable Side Effects
✽ Neuroleptic-induced deficit syndrome
✽ Akathisia DOSING AND USE
✽ Priapism
✽ Extrapyramidal symptoms, Parkinsonism, Usual Dosage Range
tardive dyskinesia • Oral: 100–400 mg/day
✽ Galactorrhea, amenorrhea • Injection: 25–200 mg/day
✽ Pigmentary retinopathy at high doses
• Dizziness, sedation Dosage Forms
• Dry mouth, constipation, blurred vision • Tablet 10 mg, 25 mg, 50 mg, 100 mg
• Decreased sweating • Ampul 25 mg/mL, 1 mL
• Sexual dysfunction • Concentrate 25 mg/mL
• Hypotension
• Weight gain How to Dose
• Oral: initial 50 mg 3 times a day; increase
dose cautiously as needed
Life Threatening or
• Injection: initial 25 mg; repeat after 30–60
Dangerous Side Effects minutes if needed
• Rare neuroleptic malignant syndrome • Take liquid formulation in water, orange
• Rare jaundice, agranulocytosis juice, or grapefruit juice
• Rare seizures
✽ Dose-dependent QTc prolongation
• Ventricular arrhythmias and sudden death
Dosing Tips
Weight Gain ✽ The effects of mesoridazine on the QTc
interval are dose-dependent, so start low
and go slow while carefully monitoring QTc
interval
• Occurs in significant minority
Overdose
Sedation • Deaths have occurred; sedation, confusion,
agitation, respiratory depression, cardiac
disturbances, coma
• Many experience and/or can be significant
in amount Long-Term Use
• Sedation is usually transient • Some side effects may be irreversible (e.g.,
tardive dyskinesia)

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(continued) MESORIDAZINE

Habit Forming • Antiemetic effect can mask signs of other

• No disorders or overdose
• Do not use epinephrine in event of
How to Stop overdose as interaction with some pressor
• Slow down-titration of oral formulation agents may lower blood pressure
(over 6 to 8 weeks), especially when • Because mesoridazine may dose-
simultaneously beginning a new dependently prolong QTc interval, use with
antipsychotic while switching (i.e., cross- caution in patients who have bradycardia
titration) or who are taking drugs that can induce
• Rapid oral discontinuation may lead to bradycardia (e.g., beta blockers, calcium
rebound psychosis and worsening of channel blockers, clonidine, digitalis)
symptoms • Because mesoridazine may dose-
• If antiparkinson agents are being used, dependently prolong QTc interval, use with
they should be continued for a few weeks caution in patients who have hypokalemia
after mesoridazine is discontinued and/or hypomagnesemia or who are taking
drugs that can induce hypokalemia and/or
Pharmacokinetics magnesemia (e.g., diuretics, stimulant
• Half-life approximately 2–9 hours laxatives, intravenous amphotericin B,
glucocorticoids, tetracosactide)
• Mesoridazine can increase the QTc interval,
Drug Interactions potentially causing torsades de pointes-
• May decrease the effects of levodopa, type arrhythmia or sudden death
dopamine agonists
• May increase the effects of Do Not Use
antihypertensive drugs • If there is a history of QTc prolongation or
• May enhance QTc prolongation of other cardiac arrhythmia, recent acute
drugs capable of prolonging QTc interval myocardial infarction, uncompensated
• Additive effects may occur if used with heart failure
CNS depressants ✽ If QTc interval greater than 450 msec or if
• Respiratory depression or respiratory taking an agent capable of prolonging the
arrest may occur if mesoridazine is used QTc interval
with a barbiturate • If patient is in a comatose state or has CNS
• Some patients taking a neuroleptic and depression
lithium have developed an encephalopathic • If there is a proven allergy to mesoridazine
syndrome similar to neuroleptic malignant • If there is a known sensitivity to any
syndrome phenothiazine
• Combined use with epinephrine may lower
blood pressure
SPECIAL POPULATIONS
Other Warnings/ Renal Impairment
Precautions • Use with caution
• If signs of neuroleptic malignant syndrome
develop, treatment should be immediately Hepatic Impairment
discontinued • Use with caution
• Use with caution in patients with
respiratory disorders, glaucoma, or urinary Cardiac Impairment
retention • Mesoridazine produces a dose-dependent
• Use cautiously in patients with alcohol prolongation of QTc interval, which may be
withdrawal or convulsive disorders enhanced by the existence of bradycardia,
because of possible lowering of seizure hypokalemia, congenital or acquired long
threshold QTc interval, which should be evaluated
• Use with caution if at all in Parkinson’s prior to administering mesoridazine
disease or Lewy Body dementia • Use with caution if treating concomitantly
• Avoid extreme heat exposure with a medication likely to produce

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MESORIDAZINE (continued)

prolonged bradycardia, hypokalemia, • Effects on infant have been observed

slowing of intracardiac conduction, or (dystonia, tardive dyskinesia, sedation)
prolongation of the QTc interval ✽ Recommended either to discontinue drug
• Avoid mesoridazine in patients with a or bottle feed
known history of QTc prolongation, recent
acute myocardial infarction, and
uncompensated heart failure THE ART OF PSYCHOPHARMACOLOGY
✽ Risk/benefit ratio may not justify use in
cardiac impairment Potential Advantages
• Only for patients who respond to this agent
Elderly and not other antipsychotics
• Lower doses should be used and patient
should be monitored closely Potential Disadvantages
• Vulnerable populations such as children or
elderly
Children and Adolescents • Patients on other drugs
• Safety and efficacy not established
Primary Target Symptoms
• Positive symptoms of psychosis in patients
who fail to respond to treatment with other
Pregnancy antipsychotics
• Risk Category C [some animal studies • Motor and autonomic hyperactivity in
show adverse effects, no controlled studies patients who fail to respond to treatment
in humans] with other antipsychotics
• Reports of extrapyramidal symptoms, • Violent or aggressive behavior in patients
jaundice, hyperreflexia, hyporeflexia in who fail to respond to treatment with other
infants whose mothers took a antipsychotics
phenothiazine during pregnancy
• Psychotic symptoms may worsen during
pregnancy and some form of treatment
may be necessary Pearls
• Atypical antipsychotics may be preferable ✽ Generally, the benefits of mesoridazine do
to conventional antipsychotics or not outweigh its risks for most patients
anticonvulsant mood stabilizers if ✽ Because of its effects on the QTc interval,
treatment is required during pregnancy mesoridazine is not intended for use unless
• Mesoridazine should generally not be used other options (at least 2 antipsychotics)
during the first trimester have failed
• Should evaluate for an antipsychotic with a • Mesoridazine has not been systematically
better risk/benefit ratio if treatment is studied in treatment-refractory
required during pregnancy schizophrenia
• Conventional antipsychotics are much less
Breast Feeding expensive than atypical antipsychotics
• Some drug is found in mother’s breast milk

Suggested Reading
Frankenburg FR. Choices in antipsychotic Potential predictors of drug response. Compr
therapy in schizophrenia. Harv Rev Psychiatry Psychiatry 1978; 19: 527–32.
1999; 6: 241–9.
Gershon S, Sakalis G, Bowers PA.
Gardos G, Tecce JJ, Hartmann E, Bowers P, Mesoridazine — a pharmacodynamic and
Cole JO. Treatment with mesoridazine and pharmacokinetic profile. J Clin Psychiatry
thioridazine in chronic schizophrenia: II. 1981; 42: 463–9.

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MIDAZOLAM
THERAPEUTICS SIDE EFFECTS
Brands • Versed How Drug Causes Side Effects
see index for additional brand names • Actions at benzodiazepine receptors that
carry over to next day can cause daytime
Generic? No sedation, amnesia, and ataxia

Notable Side Effects

Class • Over-sedation, impaired recall, agitation,
• Benzodiazepine (hypnotic) involuntary movements, headache
• Nausea, vomiting
Commonly Prescribed For • Hiccups, fluctuation in vital signs,
(bold for FDA approved) irritation/pain at site of injection
• Sedation in pediatric patients • Hypotension
• Sedation (adjunct to anesthesia)
• Pre-operative anxiolytic Life Threatening or
• Drug-induced amnesia Dangerous Side Effects
• Respiratory depression, apnea, respiratory
arrest
How The Drug Works • Cardiac arrest
• Binds to benzodiazepine receptors at the
GABA-A ligand-gated chloride channel Weight Gain
complex
• Enhances the inhibitory effects of GABA
• Boosts chloride conductance through
• Reported but not expected
GABA-regulated channels
• Inhibitory actions in sleep centers may Sedation
provide sedative hypnotic effects

How Long Until It Works

• Intravenous injection: onset 3–5 minutes • Many experience and/or can be significant
• Intramuscular injection: onset 15 minutes, in amount
peak 30–60 minutes
What To Do About Side Effects
If It Works • Wait
• Patients generally recover 2–6 hours after • Switch to another agent
awakening • Administer flumazenil if side effects are
severe or life-threatening
If It Doesn’t Work
• Increase the dose Best Augmenting Agents for Side
• Switch to another agent Effects
• Many side effects cannot be improved with
Best Augmenting Combos an augmenting agent
for Partial Response or
Treatment-Resistance
• Augmenting agents have not been DOSING AND USE
adequately studied
Usual Dosage Range
Tests • Intravenous (adults): 1–2.5 mg
• None for healthy individuals • Liquid (age 16 and under): 0.25–1.0 mg/kg

Dosage Forms
• Intravenous: 5 mg/mL – 1 mL vial, 2 mL
vial, 5 mL vial, 10 mL vial
• Liquid: 2 mg/mL – 118 mL bottle

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MIDAZOLAM (continued)

How to Dose Other Warnings/

• Liquid single dose: 0.25–1.0 mg/kg;
Precautions
maximum dose generally 20 mg
• Midazolam should only be used in an
• Intravenous (adults): administer over 2
environment in which the patient can be
minutes; monitor patient over the next 2 or
closely monitored (e.g., hospital) because
more minutes to determine effects; allow
of the risk of respiratory depression and
3–5 minutes between administrations;
respiratory arrest
maximum 2.5 mg within 2 minutes
• Sedated pediatric patients should be
monitored throughout the procedure
• Patients with chronic obstructive
Dosing Tips pulmonary disease should receive lower
• Better to underdose, observe for effects, doses
and then prudently raise dose while • Use with caution in patients with impaired
monitoring carefully respiratory function
Overdose Do Not Use
• Sedation, confusion, poor coordination, • If patient has narrow angle-closure
respiratory depression, coma glaucoma
• If there is a proven allergy to midazolam or
Long-Term Use any benzodiazepine
• Not generally intended for long-term use

Habit Forming
• Some patients may develop dependence SPECIAL POPULATIONS
and/or tolerance; risk may be greater with
Renal Impairment
higher doses
• May have longer elimination half-life,
• History of drug addiction may increase risk
prolonging time to recovery
of dependence

How to Stop Hepatic Impairment

• Longer elimination half-life; clearance is
• If administration was prolonged, do not
reduced
stop abruptly

Pharmacokinetics Cardiac Impairment

• Longer elimination half-life; clearance is
• Elimination half-life 1.8–6.4 hours
reduced
• Active metabolite
Elderly
• Longer elimination half-life; clearance is
Drug Interactions reduced
• If CNS depressants are used concomitantly, • Intravenous: 1–3.5 mg; maximum 1.5 mg
midazolam dose should be reduced by half within 2 minutes
or more
• Increased depressive effects when taken
with other CNS depressants Children and Adolescents
• Drugs that inhibit CYP450 3A4, such as
• In most pediatric populations,
nefazodone and fluvoxamine, may reduce
pharmacokinetic properties are similar to
midazolam clearance and thus raise
those in adults
midazolam levels
• Seriously ill neonates have reduced
• Midazolam decreases the minimum
clearance and longer elimination half-life
alveolar concentration of halothane needed
• Hypotension has occurred in neonates
for general anesthesia
given midazolam and fentanyl
• Intravenous dose: dependent on age,
weight, route, procedure

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(continued) MIDAZOLAM

THE ART OF PSYCHOPHARMACOLOGY

Pregnancy Potential Advantages
• Risk Category D [positive evidence of risk • Fast onset
to human fetus; potential benefits may still • Parenteral dosage forms
justify its use during pregnancy]
• Midazolam crosses the placenta Potential Disadvantages
• Neonatal flaccidity has been reported in • Can be oversedating
infants whose mother took a
benzodiazepine during pregnancy Primary Target Symptoms
• Anxiety
Breast Feeding
• Some drug is found in mother’s breast milk
• Effects on infant have been observed and Pearls
include feeding difficulties, sedation, and • Recovery (e.g., ability to stand/walk)
weight loss generally takes from 2–6 hours after
• Midazolam can be used to relieve wakening
postoperative pain after cesarean section • Half-life may be longer in obese patients
• Patients with premenstrual syndrome may
be less sensitive to midazolam than healthy
women throughout the cycle
• Midazolam clearance may be reduced in
postmenopausal women compared to
premenopausal women

Suggested Reading
Blumer JL. Clinical pharmacology of Yuan R, Flockhart DA, Balian JD.
midazolam in infants and children. Clin Pharmacokinetic and pharmacodynamic
Pharmacokinet 1998;35:37–47. consequences of metabolism-based drug
interactions with alprazolam, midazolam, and
Fountain NB, Adams RE. Midazolam treatment triazolam. J Clin Pharmacol 1999;39:1109–25.
of acute and refractory status epilepticus. Clin
Neuropharmacol 1999;22:261–7.
Shafer A. Complications of sedation with
midazolam in the intensive care unit and a
comparison with other sedative regimens. Crit
Care Med 1998;26:947–56.

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MILNACIPRAN
THERAPEUTICS If It Works
• The goal of treatment of depression is
Brands • Toledomin
complete remission of current symptoms
• Ixel
as well as prevention of future relapses
see index for additional brand names
• The goal of treatment of fibromyalgia and
Generic? No chronic neuropathic pain is to reduce
symptoms as much as possible, especially
in combination with other treatments
• Treatment of depression most often
Class reduces or even eliminates symptoms, but
• SNRI (dual serotonin and norepinephrine is not a cure since symptoms can recur
reuptake inhibitor); antidepressant; chronic after medicine stopped
pain treatment • Treatment of fibromyalgia and chronic
neuropathic pain may reduce symptoms,
Commonly Prescribed For but rarely eliminates them completely, and
(bold for FDA approved) is not a cure since symptoms can recur
• Major depressive disorder after medicine is stopped
• Fibromyalgia • Continue treatment of depression until all
• Neuropathic pain/chronic pain symptoms are gone (remission)
• Once symptoms of depression are gone,
continue treating for 1 year for the first
How The Drug Works episode of depression
• Boosts neurotransmitters serotonin, • For second and subsequent episodes of
norepinephrine/noradrenaline, and depression, treatment may need to be
dopamine indefinite
• Blocks serotonin reuptake pump (serotonin • Use in fibromyalgia and chronic
transporter), presumably increasing neuropathic pain may also need to be
serotonergic neurotransmission indefinite, but long-term treatment is not
• Blocks norepinephrine reuptake pump well-studied in these conditions
(norepinephrine transporter), presumably
increasing noradrenergic If It Doesn’t Work
neurotransmission • Many depressed patients only have a
• Presumably desensitizes both serotonin 1A partial response where some symptoms
receptors and beta adrenergic receptors are improved but others persist (especially
✽ Weak noncompetitive NMDA-receptor insomnia, fatigue, and problems
antagonist (high doses), which may concentrating)
contribute to actions in chronic pain • Other depressed patients may be
• Since dopamine is inactivated by nonresponders, sometimes called
norepinephrine reuptake in frontal cortex, treatment-resistant or treatment-refractory
which largely lacks dopamine transporters, • Some depressed patients who have an
milnacipran can increase dopamine initial response may relapse even though
neurotransmission in this part of the brain they continue treatment, sometimes called
“poop-out”
How Long Until It Works • Consider increasing dose, switching to
• Onset of therapeutic actions usually not another agent or adding an appropriate
immediate, but often delayed 2 to 4 weeks augmenting agent
• If it is not working within 6 to 8 weeks, it • Consider psychotherapy
may require a dosage increase or it may • Consider evaluation for another diagnosis
not work at all or for a comorbid condition (e.g., medical
• May continue to work for many years to illness, substance abuse, etc.)
prevent relapse of symptoms in depression • Some patients may experience apparent
lack of consistent efficacy due to activation
of latent or underlying bipolar disorder, and
require antidepressant discontinuation and
switch to a mood stabilizer

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MILNACIPRAN (continued)

Best Augmenting Combos Notable Side Effects

for Partial Response or • Most side effects increase with higher
Treatment-Resistance doses, at least transiently
• Augmentation experience is limited • Headache, nervousness, insomnia,
compared to other antidepressants sedation
• Benzodiazepines can reduce insomnia and • Nausea, diarrhea, decreased appetite
anxiety • Sexual dysfunction (abnormal
• Adding other agents to milnacipran for ejaculation/orgasm, impotence)
treating depression could follow the same • Asthenia, sweating
practice for augmenting SSRIs or other • SIADH (syndrome of inappropriate
SNRIs if done by experts while monitoring antidiuretic hormone secretion)
carefully in difficult cases • Dose-dependent increased blood pressure
• Although no controlled studies and little • Dry mouth, constipation
clinical experience, adding other agents for • Dysuria, urological complaints, urinary
treating fibromyalgia and chronic hesitancy, urinary retention
neuropathic pain could theoretically include • Increase in heart rate
gabapentin, tiagabine, other • Palpitations
anticonvulsants, or even opiates if done by
experts while monitoring carefully in Life Threatening or
difficult cases
Dangerous Side Effects
• Mirtazapine, bupropion, reboxetine,
• Rare induction of mania and activation of
atomoxetine (use combinations of
suicidal ideation
antidepressants with caution as this may
• Rare seizures
activate bipolar disorder and suicidal
ideation) Weight Gain
• Modafinil, especially for fatigue, sleepiness,
and lack of concentration
• Mood stabilizers or atypical antipsychotics
for bipolar depression, psychotic • Reported but not expected
depression or treatment-resistant
depression Sedation
• Hypnotics or trazodone for insomnia
• Classically, lithium, buspirone, or thyroid
hormone • Many experience and/or can be significant
in amount
Tests
• Check blood pressure before initiating What To Do About Side Effects
treatment and regularly during treatment • Wait
• Wait
• Wait
SIDE EFFECTS • Lower the dose
• In a few weeks, switch or add other drugs
How Drug Causes Side Effects
• Theoretically due to increases in serotonin Best Augmenting Agents for Side
and norepinephrine concentrations at Effects
receptors in parts of the brain and body ✽ For urinary hesitancy, give an alpha 1
other than those that cause therapeutic blocker such as tamsulosin or naftopidil
actions (e.g., unwanted actions of • Often best to try another antidepressant
serotonin in sleep centers causing monotherapy prior to resorting to
insomnia, unwanted actions of augmentation strategies to treat side
norepinephrine on acetylcholine release effects
causing urinary retention or constipation) • Trazodone or a hypnotic for insomnia
• Most side effects are immediate but often • Bupropion, sildenafil, vardenafil, or tadalafil
go away with time for sexual dysfunction

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(continued) MILNACIPRAN

• Benzodiazepines for anxiety, agitation • Preferred dose for depression in the elderly
• Mirtazapine for insomnia, agitation, and may be 15 mg twice daily to 25 mg twice
gastrointestinal side effects daily in Japan
• Many side effects are dose-dependent (i.e., • Preferred dosing for depression in other
they increase as dose increases, or they adults may be 25 mg twice daily to 50 mg
reemerge until tolerance re-develops) twice daily in Japan
• Many side effects are time-dependent (i.e., • Preferred dose for fibromyalgia may be
they start immediately upon dosing and 100 mg twice daily
upon each dose increase, but go away with ✽ Thus, clinicians must be aware that
time) titration of twice daily dosing across a 10-
• Activation and agitation may represent the fold range (30 mg – 300 mg total daily
induction of a bipolar state, especially a dose) can optimize milnacipran’s efficacy in
mixed dysphoric bipolar II condition broad clinical use
sometimes associated with suicidal • Patients with agitation or anxiety may
ideation, and require the addition of require slower titration to optimize
lithium, a mood stabilizer or an atypical tolerability
antipsychotic, and/or discontinuation of • Higher doses usually well tolerated in
milnacipran fibromyalgia patients
• No pharmacokinetic drug interactions (not
an inhibitor of CYP450 2D6 or 3A4)
DOSING AND USE • As milnacipran is a more potent
norepinephrine reuptake inhibitor than a
Usual Dosage Range serotonin reuptake inhibitor, some patients
• 30–200 mg/day in 2 doses may require dosing at the higher end of the
dosing range to obtain robust dual SNRI
Dosage Forms actions
• Capsule 25 mg, 50 mg (France, other • At high doses, NMDA glutamate antagonist
European countries, and worldwide actions may be a factor
markets)
• Capsule 15 mg, 25 mg, 50 mg (Japan) Overdose
• Vomiting, hypertension, sedation,
How to Dose tachycardia
• Should be administered in 2 divided doses • The emetic effect of high doses of
• Begin at 25 mg twice daily and increase as milnacipran may reduce the risk of serious
necessary and as tolerated up to 100 mg adverse effects
twice daily; maximum dose 300 mg/day
Long-Term Use
• Safe
Dosing Tips Habit Forming
✽ Once daily dosing has far less consistent • No
efficacy, so only give as twice daily
• Higher doses (>200 mg/day) not How to Stop
consistently effective in all studies of • Taper is prudent, but usually not necessary
depression
• Nevertheless, some patients respond better Pharmacokinetics
to higher doses (200–300 mg/day) than to • Half-life 8 hours
lower doses • No active metabolite
• Different doses in different countries
• Different doses in different indications and
different populations
Drug Interactions
• Preferred dose for depression may be
• Tramadol increases the risk of seizures in
50 mg twice daily to 100 mg twice daily in
patients taking an antidepressant
France
• Can cause a fatal “serotonin syndrome”
when combined with MAO inhibitors, so do

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MILNACIPRAN (continued)

not use with MAO inhibitors or for at least consider informing parents or guardian of
14 days after MAOIs are stopped this risk so they can help observe child or
• Do not start an MAO inhibitor for at least adolescent patients
2 weeks after discontinuing milnacipran • Not well-studied
• Switching from or addition of other
norepinephrine reuptake inhibitors should
be done with caution, as the additive pro- Pregnancy
noradrenergic effects may enhance • Not generally recommended for use during
therapeutic actions in depression, but also pregnancy, especially during first trimester
enhance noradrenergically-mediated side • Nonetheless, continuous treatment during
effects pregnancy may be necessary and has not
• Few known adverse pharmacokinetic drug been proven to be harmful to the fetus
interactions • Must weigh the risk of treatment (first
trimester fetal development, third trimester
Other Warnings/ newborn delivery) to the child against the
Precautions risk of no treatment (recurrence of
• Use with caution in patients with history of depression, maternal health, infant
seizures bonding) to the mother and child
• Use with caution in patients with bipolar • For many patients this may mean
disorder unless treated with concomitant continuing treatment during pregnancy
mood stabilizing agent • Neonates exposed to SSRIs or SNRIs late
• Monitor patients for activation of suicidal in the third trimester have developed
ideation, especially children and complications requiring prolonged
adolescents hospitalization, respiratory support, and
tube feeding; reported symptoms are
Do Not Use consistent with either a direct toxic effect
• If patient has uncontrolled narrow angle- of SSRIs and SNRIs or, possibly, a drug
closure glaucoma discontinuation syndrome, and include
• If patient is taking an MAO inhibitor respiratory distress, cyanosis, apnea,
• If there is a proven allergy to milnacipran seizures, temperature instability, feeding
difficulty, vomiting, hypoglycemia,
hypotonia, hypertonia, hyperreflexia,
tremor, jitteriness, irritability, and constant
SPECIAL POPULATIONS crying
Renal Impairment Breast Feeding
• Should receive lower doses; amount of
• Unknown if milnacipran is secreted in
dose adjustment related to degree of
human breast milk, but all psychotropics
impairment
assumed to be secreted in breast milk
Hepatic Impairment • Immediate postpartum period is a high-risk
• No dose adjustment necessary time for depression, especially in women
who have had prior depressive episodes,
Cardiac Impairment so drug may need to be reinstituted late in
• Drug should be used with caution the third trimester or shortly after
childbirth to prevent a recurrence during
Elderly the postpartum period
• Some patients may tolerate lower doses • Must weigh benefits of breast feeding with
better risks and benefits of antidepressant
treatment versus non-treatment to both the
infant and the mother
• For many patients, this may mean
Children and Adolescents
continuing treatment during breast feeding
• Use with caution, observing for activation
of known or unknown bipolar disorder
and/or suicidal ideation, and strongly

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(continued) MILNACIPRAN

THE ART OF PSYCHOPHARMACOLOGY clinical significance as a differentiating

feature from other SNRIs, although it might
Potential Advantages contribute to its therapeutic activity in
• Patients with retarded depression fibromyalgia and chronic pain
• Patients with hypersomnia
• Patients with atypical depression
✽ Onset of action in fibromyalgia may be
somewhat faster than depression (i.e.,
• Patients with depression may have higher 2 weeks rather than 2–8 weeks)
remission rates on SNRIs than on SSRIs • Therapeutic actions in fibromyalgia are
• Depressed patients with somatic partial, with symptom reduction but not
symptoms, fatigue, and pain necessarily remission of painful symptoms
• Fibromyalgia, chronic pain syndrome in many patients
Potential Disadvantages ✽ Potent noradrenergic actions may
account for possibly higher incidence of
• Patients with urologic disorders, prostate
sweating and urinary hesitancy than other
disorders
SNRIs
• Patients with borderline or uncontrolled
• Urinary hesitancy more common in men
hypertension
than women and in older men than in
• Patients with agitation and anxiety (short-
younger men
term)
• Alpha 1 antagonists such as tamsulosin or
Primary Target Symptoms naftopidil can reverse urinary hesitancy or
• Depressed mood retention
• Energy, motivation, and interest • Alpha 1 antagonists given prophylactically
• Sleep disturbance may prevent urinary hesitancy or retention
• Physical symptoms in patients at higher risk, such as elderly
• Pain men with borderline urine flow
• May be better tolerated than tricyclic or
tetracyclic antidepressants in the treatment
of fibromyalgia or other chronic pain
Pearls syndromes
• Not studied in stress urinary incontinence • No pharmacokinetic interactions or
• Not well studied in ADHD or anxiety elevations in plasma drug levels of tricyclic
disorders, but may be effective or tetracyclic antidepressants when adding
✽ Has greater potency for norepinephrine or switching to or from milnacipran
reuptake blockade than for serotonin
reuptake blockade, but this is of unclear

Suggested Reading
Bisserbe JC. Clinical utility of milnacipran in Puozzo C, Panconi E, Deprez D. Pharmacology
comparison with other antidepressants. Int and pharmacokinetics of milnacipran. Int Clin
Clin Psychopharmacol 2002;17 Suppl Psychopharmacol 2002;17 Suppl 1:S25–35.
1:S43–50.
Spencer CM, Wilde MI. Milnacipran. A review
Montgomery SA, Prost JF, Solles A, Briley M. of its use in depression. Drugs 1998;
Efficacy and tolerability of milnacipran: an 56:405–27.
overview. Int Clin Psychopharmacol 1996;11
Suppl 4:47–51.

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MIRTAZAPINE
THERAPEUTICS If It Works
• The goal of treatment is complete
Brands • Remeron
remission of current symptoms as well as
see index for additional brand names
prevention of future relapses
Generic? Yes • Treatment most often reduces or even
eliminates symptoms, but not a cure since
symptoms can recur after medicine
stopped
Class • Continue treatment until all symptoms are
• Alpha 2 antagonist; NaSSA (noradrenaline gone (remission)
and specific serotonergic agent); dual • Once symptoms gone, continue treating for
serotonin and norepinephrine agent; 1 year for the first episode of depression
antidepressant • For second and subsequent episodes of
depression, treatment may need to be
Commonly Prescribed For indefinite
(bold for FDA approved) • Use in anxiety disorders may also need to
• Major depressive disorder be indefinite
• Panic disorder
• Generalized anxiety disorder If It Doesn’t Work
• Posttraumatic stress disorder • Many patients only have a partial response
where some symptoms are improved but
others persist (especially insomnia, fatigue,
How The Drug Works and problems concentrating)
• Boost neurotransmitters serotonin and • Other patients may be nonresponders,
norepinephrine/noradrenaline sometimes called treatment-resistant or
• Blocks alpha 2 adrenergic presynaptic treatment-refractory
receptor, thereby increasing norepinephrine • Consider increasing dose, switching to
neurotransmission another agent or adding an appropriate
• Blocks alpha 2 adrenergic presynaptic augmenting agent
receptor on serotonin neurons • Consider psychotherapy
(heteroreceptors), thereby increasing • Consider evaluation for another diagnosis
serotonin neurotransmission or for a comorbid condition (e.g., medical
• This is a novel mechanism independent of illness, substance abuse, etc.)
norepinephrine and serotonin reuptake • Some patients may experience apparent
blockade lack of consistent efficacy due to activation
• Blocks 5HT2A, 5HT2C, and 5HT3 serotonin of latent or underlying bipolar disorder, and
receptors require antidepressant discontinuation and
• Blocks H1 histamine receptors a switch to a mood stabilizer

How Long Until It Works Best Augmenting Combos

✽ Actions on insomnia and anxiety can start for Partial Response or
shortly after initiation of dosing Treatment-Resistance
• Onset of therapeutic actions in depression, • SSRIs, bupropion, reboxetine, atomoxetine
however, is usually not immediate, but (use combinations of antidepressants with
often delayed 2 to 4 weeks caution as this may activate bipolar
• If it is not working within 6 to 8 weeks for disorder and suicidal ideation)
depression, it may require a dosage ✽ Venlafaxine (“California rocket fuel”; a
increase or it may not work at all potentially powerful dual serotonin and
• May continue to work for many years to norepinephrine combination, but observe
prevent relapse of symptoms for activation of bipolar disorder and
suicidal ideation)
• Modafinil, especially for fatigue, sleepiness,
and lack of concentration

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MIRTAZAPINE (continued)

• Mood stabilizers or atypical antipsychotics Notable Side Effects

for bipolar depression, psychotic • Dry mouth, constipation, increased
depression or treatment-resistant appetite, weight gain
depression • Sedation, dizziness, abnormal dreams,
• Benzodiazepines confusion
• Hypnotics or trazodone for insomnia • Flu-like symptoms (may indicate low white
blood cell or granulocyte count)
Tests • Change in urinary function
• None for healthy individuals • Hypotension
• May need liver function tests for those with
hepatic abnormalities before initiating
treatment Life Threatening or
• May need to monitor blood count during Dangerous Side Effects
treatment for those with blood dyscrasias, • Rare seizures
leucopenia, or granulocytopenia • Rare induction of mania and activation of
• Since some antidepressants such as suicidal ideation
mirtazapine can be associated with
significant weight gain, before starting Weight Gain
treatment, weigh all patients and determine
if the patient is already overweight
(BMI>25.0–29.9) or obese (BMI>30) • Many experience and/or can be significant
• Before giving a drug that can cause weight in amount
gain to an overweight or obese patient,
consider determining whether the patient Sedation
already has pre-diabetes (fasting plasma
glucose 100–125 mg/dl), diabetes (fasting
plasma glucose >126 mg/dl), or
• Many experience and/or can be significant
dyslipidemia (increased total cholesterol,
in amount
LDL cholesterol and triglycerides;
decreased HDL cholesterol), and treat or What To Do About Side Effects
refer such patients for treatment, including
• Wait
nutrition and weight management, physical
• Wait
activity counseling, smoking cessation, and
• Wait
medical management
• Switch to another drug
✽ Monitor weight and BMI during treatment
✽ While giving a drug to a patient who has Best Augmenting Agents for Side
gained >5% of initial weight, consider Effects
evaluating for the presence of pre-diabetes,
• Often best to try another antidepressant
diabetes, or dyslipidemia, or consider
monotherapy prior to resorting to
switching to a different antipsychotic
augmentation strategies to treat side
effects
• Many side effects are dose-dependent (i.e.,
SIDE EFFECTS they increase as dose increases, or they
reemerge until tolerance re-develops)
How Drug Causes Side Effects • Many side effects are time-dependent (i.e.,
• Most side effects are immediate but often they start immediately upon dosing and
go away with time upon each dose increase, but go away with
✽ Histamine 1 receptor antagonism may time)
explain sedative effects • Trazodone or a hypnotic for insomnia
✽ Histamine 1 receptor antagonism plus • Many side effects cannot be improved with
5HT2C antagonism may explain some an augmenting agent
aspects of weight gain • Activation and agitation may represent the
induction of a bipolar state, especially a
mixed dysphoric bipolar II condition

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(continued) MIRTAZAPINE

sometimes associated with suicidal Pharmacokinetics

ideation, and require the addition of • Half-life 20–40 hours
lithium, a mood stabilizer or an atypical
antipsychotic, and/or discontinuation of
mirtazapine Drug Interactions
• Tramadol increases the risk of seizures in
patients taking an antidepressant
DOSING AND USE • No significant pharmacokinetic drug
interactions
Usual Dosage Range • Can cause a fatal “serotonin syndrome”
• 15–45 mg at night when combined with MAO inhibitors, so do
not use with MAO inhibitors or for at least
Dosage Forms 14 days after MAOIs are stopped
• Tablet 15 mg scored, 30 mg scored, 45 mg • Do not start an MAO inhibitor for at least
• SolTab disintegrating tablet 15 mg, 30 mg, 2 weeks after discontinuing mirtazapine
45 mg

How to Dose Other Warnings/

• Initial 15 mg/day in the evening; increase Precautions
every 1–2 weeks until desired efficacy is • Drug may lower white blood cell count
reached; maximum generally 45 mg/day (rare; may not be increased compared to
other antidepressants but controlled
studies lacking; not a common problem
Dosing Tips reported in post marketing surveillance)
• Sedation may not worsen as dose • Drug may increase cholesterol
increases • May cause photosensitivity
✽ Breaking a 15 mg tablet in half and • Avoid alcohol, which may increase sedation
administering 7.5 mg dose may actually and cognitive and motor effects
increase sedation • Use with caution in patients with history of
• Some patients require more than 45 mg seizures
daily, including up to 90 mg in difficult • Use with caution in patients with bipolar
patients who tolerate these doses disorder unless treated with concomitant
• If intolerable anxiety, insomnia, agitation, mood stabilizing agent
akathisia, or activation occur either upon • Monitor patients for activation of suicidal
dosing initiation or discontinuation, ideation, especially children and
consider the possibility of activated bipolar adolescents
disorder and switch to a mood stabilizer or
an atypical antipsychotic Do Not Use
• If patient is taking an MAO inhibitor
Overdose • If there is a proven allergy to mirtazapine
• Rarely lethal; all fatalities have involved
other medications; symptoms include
sedation, disorientation, memory SPECIAL POPULATIONS
impairment, rapid heartbeat
Renal Impairment
Long-Term Use • Drug should be used with caution
• Safe
Hepatic Impairment
Habit Forming • Drug should be used with caution
• Not expected • May require lower dose

How to Stop Cardiac Impairment

• Taper is prudent to avoid withdrawal • Drug should be used with caution
effects, but tolerance, dependence, and • The potential risk of hypotension should be
withdrawal effects not reliably reported considered

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MIRTAZAPINE (continued)

Elderly THE ART OF PSYCHOPHARMACOLOGY

• Some patients may tolerate lower doses
Potential Advantages
better
• Patients particularly concerned about
sexual side effects
• Patients with symptoms of anxiety
Children and Adolescents • Patients on concomitant medications
• Use with caution, observing for activation • As an augmenting agent to boost the
of known or unknown bipolar disorder efficacy of other antidepressants
and/or suicidal ideation, and strongly
consider informing parents or guardian of Potential Disadvantages
this risk so they can help observe child or • Patients particularly concerned about
adolescent patients gaining weight
• Safety and efficacy have not been • Patients with low energy
established
Primary Target Symptoms
• Depressed mood
Pregnancy • Sleep disturbance
• Risk Category C [some animal studies • Anxiety
show adverse effects; no controlled studies
in humans]
• Not generally recommended for use during Pearls
pregnancy, especially during first trimester ✽ Adding alpha 2 antagonism to agents that
• Must weigh the risk of treatment (first block serotonin and/or norepinephrine
trimester fetal development, third trimester reuptake may be synergistic for severe
newborn delivery) to the child against the depression
risk of no treatment (recurrence of • Adding mirtazapine to venlafaxine or SSRIs
depression, maternal health, infant may reverse drug-induced anxiety and
bonding) to the mother and child insomnia
• For many patients this may mean • Adding mirtazapine’s 5HT3 antagonism to
continuing treatment during pregnancy venlafaxine or SSRIs may reverse drug-
induced nausea, diarrhea, stomach cramps,
Breast Feeding and gastrointestinal side effects
• Unknown if mirtazapine is secreted in • SSRIs, venlafaxine, bupropion,
human breast milk, but all psychotropics phentermine, or stimulants may mitigate
assumed to be secreted in breast milk mirtazapine-induced weight gain
• If child becomes irritable or sedated, breast • If weight gain has not occurred by week 6
feeding or drug may need to be of treatment, it is less likely for there to be
discontinued significant weight gain
• Immediate postpartum period is a high-risk • Has been demonstrated to have an earlier
time for depression, especially in women onset of action than SSRIs
who have had prior depressive episodes, ✽ Does not affect the CYP450 system, and
so drug may need to be reinstituted late in so may be preferable in patients requiring
the third trimester or shortly after concomitant medications
childbirth to prevent a recurrence during • Preliminary evidence suggests efficacy as
the postpartum period an augmenting agent to haloperidol in
• Must weigh benefits of breast feeding with treating negative symptoms of
risks and benefits of antidepressant schizophrenia
treatment versus non-treatment to both the • Anecdotal reports of efficacy in recurrent
infant and the mother brief depression
• For many patients, this may mean • Weight gain as a result of mirtazapine
continuing treatment during breast feeding treatment is more likely in women than in
men, and before menopause rather than
after

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(continued) MIRTAZAPINE

✽ May cause sexual dysfunction only

infrequently
• Patients can have carryover sedation and
intoxicated-like feeling if particularly
sensitive to sedative side effects when
initiating dosing
• Rarely, patients may complain of visual
“trails” or after-images on mirtazapine

Suggested Reading
Anttila SA, Leinonen EV. A review of the trials of mirtazapine for the treatment of
pharmacological and clinical profile of patients with major depression and symptoms
mirtazapine. CNS Drug Rev 2001;7(3):249–64. of anxiety. J Clin Psychiatry. 1998;
59:123–127.
Benkert O, Muller M, Szegedi A. An overview
of the clinical efficacy of mirtazapine. Hum Masand PS, Gupta S. Long-term side effects
Psychopharmacol. 2002;17 Suppl 1:S23–6. of newer-generation antidepressants: SSRIS,
venlafaxine, nefazodone, bupropion, and
Falkai P. Mirtazapine: other indications. J Clin mirtazapine. Ann Clin Psychiatry 2002;
Psychiatry 1999;60(suppl 17):36–40. 14:175–82.
Fawcett J, Barkin RL. A meta-analysis of eight
randomized, double-blind, controlled clinical

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MOCLOBEMIDE
THERAPEUTICS • For second and subsequent episodes of
depression, treatment may need to be
Brands • Aurorix indefinite
• Arima • Use in anxiety disorders may also need to
• Manerix be indefinite
see index for additional brand names
If It Doesn’t Work
Generic? No • Many patients only have a partial response
where some symptoms are improved but
others persist (especially insomnia, fatigue,
Class and problems concentrating)
• Reversible inhibitor of monoamine oxidase • Other patients may be nonresponders,
A (MAO-A) (RIMA) sometimes called treatment-resistant or
treatment-refractory
Commonly Prescribed For • Consider increasing dose, switching to
(bold for FDA approved) another agent or adding an appropriate
• Depression augmenting agent
• Social anxiety disorder • Consider psychotherapy
• Consider evaluation for another diagnosis
or for a comorbid condition (e.g., medical
How The Drug Works illness, substance abuse, etc.)
• Reversibly blocks MAO-A from breaking • Some patients may experience apparent
down norepinephrine, dopamine, and lack of consistent efficacy due to activation
serotonin of latent or underlying bipolar disorder, and
• This presumably boosts noradrenergic, require antidepressant discontinuation and
serotonergic, and dopaminergic a switch to a mood stabilizer
neurotransmission
• MAO-A inhibition predominates unless Best Augmenting Combos
significant concentrations of monoamines for Partial Response or
build up (e.g., due to dietary tyramine), in Treatment-Resistance
which case MAO-A inhibition is ✽ Augmentation of MAOIs has not been
theoretically reversed systematically studied, and this is
something for the expert, to be done with
How Long Until It Works caution and with careful monitoring, but
• Onset of therapeutic actions usually not may be somewhat less risky with
immediate, but often delayed 2 to 4 weeks moclobemide than with other MAO
• If it is not working within 6 to 8 weeks, it inhibitors
may require a dosage increase or it may ✽ A stimulant such as d-amphetamine or
not work at all methylphenidate (with caution; may
• May continue to work for many years to activate bipolar disorder and suicidal
prevent relapse of symptoms ideation)
• Lithium
If It Works • Mood stabilizing anticonvulsants
• The goal of treatment is complete • Atypical antipsychotics (with special
remission of current symptoms as well as caution for those agents with monoamine
prevention of future relapses reuptake blocking properties, such as
• Treatment most often reduces or even ziprasidone and zotepine)
eliminates symptoms, but not a cure since
symptoms can recur after medicine Tests
stopped • Patients should be monitored for changes
• Continue treatment until all symptoms are in blood pressure
gone (remission)
• Once symptoms gone, continue treating for
1 year for the first episode of depression

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MOCLOBEMIDE (continued)

SIDE EFFECTS ✽ Single oral or sublingual dose of a

calcium channel blocker (e.g., nifedipine)
How Drug Causes Side Effects for urgent treatment of hypertension due to
• Theoretically due to increases in drug interaction or dietary tyramine
monoamines in parts of the brain and body • Many side effects cannot be improved with
and at receptors other than those that an augmenting agent
cause therapeutic actions (e.g., unwanted
actions of serotonin in sleep centers
causing insomnia, unwanted actions of
norepinephrine on vascular smooth muscle DOSING AND USE
causing changes in blood pressure)
Usual Dosage Range
• Side effects are generally immediate, but
• 300–600 mg/day
immediate side effects often disappear in
time Dosage Forms
Notable Side Effects • Tablet 100 mg scored, 150 mg scored
• Insomnia, dizziness, agitation, anxiety, How to Dose
restlessness • Initial 300 mg/day in 3 divided doses after
• Dry mouth, diarrhea, constipation, nausea, a meal; increase dose gradually; maximum
vomiting dose generally 600 mg/day; minimum dose
• Galactorrhea generally 150 mg/day
• Rare hypertension

Life Threatening or Dosing Tips

Dangerous Side Effects ✽ At higher doses, moclobemide also
• Hypertensive crisis (especially when MAOIs inhibits MAO-B and thereby loses its
are used with certain tyramine containing selectivity for MAO-A, with uncertain
foods – reduced risk compared to clinical consequences
irreversible MAOIs) ✽ Taking moclobemide after meals as
• Induction of mania and activation of opposed to before may minimize the
suicidal ideation chances of interactions with tyramine
• Seizures • May be less toxic in overdose than tricyclic
antidepressants and older MAOIs
Weight Gain • Clinical duration of action may be longer
than biological half-life and allow twice
daily dosing in some patients, or even once
• Reported but not expected daily dosing, especially at lower doses

Sedation Overdose
• Agitation, aggression, behavioral
disturbances, gastrointestinal irritation

• Occurs in significant minority Long-Term Use

• MAOIs may lose efficacy long-term
What To Do About Side Effects
• Wait Habit Forming
• Wait • Some patients have developed dependence
• Wait to MAOIs
• Lower the dose
• Switch to an SSRI or newer antidepressant How to Stop
• Taper not generally necessary
Best Augmenting Agents for Side
Effects Pharmacokinetics
• Trazodone (with caution) for insomnia • Partially metabolized by CYP450 2C19 and
• Benzodiazepines for insomnia 2D6

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(continued) MOCLOBEMIDE

• Inactive metabolites
• Elimination half-life approximately 1–4
Other Warnings/
hours Precautions
• Clinical duration of action at least 24 hours • Use still requires low tyramine diet,
although more tyramine may be tolerated
with moclobemide than with other MAO
inhibitors before eliciting a hypertensive
Drug Interactions reaction
• Tramadol may increase the risk of seizures • Patients taking MAO inhibitors should
in patients taking an MAO inhibitor avoid high protein food that has undergone
• Can cause a fatal “serotonin syndrome” protein breakdown by aging, fermentation,
when combined with drugs that block pickling, smoking, or bacterial
serotonin reuptake (e.g., SSRIs, SNRIs, contamination
sibutramine, tramadol, etc.), so do not use • Patients taking MAO inhibitors should
with a serotonin reuptake inhibitor or for avoid cheeses (especially aged varieties),
up to 5 weeks after stopping the serotonin pickled herring, beer, wine, liver, yeast
reuptake inhibitor extract, dry sausage, hard salami,
• Hypertensive crisis with headache, pepperoni, Lebanon bologna, pods of
intracranial bleeding, and death may result broad beans (fava beans), yogurt, and
from combining MAO inhibitors with excessive use of caffeine and chocolate
sympathomimetic drugs (e.g., • Patient and prescriber must be vigilant to
amphetamines, methylphenidate, cocaine, potential interactions with any drug,
dopamine, epinephrine, norepinephrine, including antihypertensives and over-the-
and related compounds methyldopa, counter cough/cold preparations
levodopa, L-tryptophan, L-tyrosine, and • Over-the-counter medications to avoid
phenylalanine) include cough and cold preparations,
• Excitation, seizures, delirium, hyperpyrexia, including those containing
circulatory collapse, coma, and death may dextromethorphan, nasal decongestants
result from combining MAO inhibitors with (tablets, drops, or spray), hay-fever
mepiridine or dextromethorphan medications, sinus medications, asthma
• Do not combine with another MAO inhalant medications, anti-appetite
inhibitor, alcohol, buspirone, bupropion, or medications, weight reducing preparations,
guanethidine “pep” pills
• Adverse drug reactions can result from • Use cautiously in hypertensive patients
combining MAO inhibitors with • Moclobemide is not recommended for use
tricyclic/tetracyclic antidepressants and in patients who cannot be monitored
related compounds, including closely
carbamazepine, cyclobenzaprine, and • Monitor patients for activation of suicidal
mirtazapine, and should be avoided except ideation, especially children and
by experts to treat difficult cases adolescents
• MAO inhibitors in combination with spinal
anesthesia may cause combined Do Not Use
hypotensive effects • If patient is taking meperidine (pethidine)
• Combination of MAOIs and CNS • If patient is taking a sympathomimetic
depressants may enhance sedation and agent or taking guanethidine
hypotension • If patient is taking another MAOI
• Cimetidine may increase plasma • If patient is taking any agent that can
concentrations of moclobemide inhibit serotonin reuptake (e.g., SSRIs,
• Moclobemide may enhance the effects of sibutramine, tramadol, milnacipran,
non-steroidal anti-inflammatory drugs such duloxetine, venlafaxine, clomipramine, etc.)
as ibuprofen • If patient is in an acute confusional state
• Risk of hypertensive crisis may be • If patient has pheochromocytoma or
increased if moclobemide is used thyrotoxicosis
concurrently with levodopa or other • If patient has frequent or severe headaches
dopaminergic agents

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MOCLOBEMIDE (continued)

• If patient is undergoing elective surgery • Should evaluate patient for treatment with
and requires general anesthesia an antidepressant with a better risk/benefit
• If there is a proven allergy to moclobemide ratio

SPECIAL POPULATIONS THE ART OF PSYCHOPHARMACOLOGY

Renal Impairment Potential Advantages
• Use with caution • Atypical depression
• Severe depression
Hepatic Impairment • Treatment-resistant depression or anxiety
• Plasma concentrations are increased disorders
• May require one-half to one-third of usual
adult dose Potential Disadvantages
• Patients noncompliant with dietary
Cardiac Impairment restrictions, concomitant drug restrictions,
• Cardiac impairment may require lower than and twice daily dosing after meals
usual adult dose
• Patients with angina pectoris or coronary Primary Target Symptoms
artery disease should limit their exertion • Depressed mood

Elderly
• Elderly patients may have greater Pearls
sensitivity to adverse effects
• MAOIs are generally reserved for second-
line use after SSRIs, SNRIs, and
combinations of newer antidepressants
Children and Adolescents have failed
• Not recommended for use under age 18 • Patient should be advised not to take any
• Use with caution, observing for activation prescription or over-the-counter drugs
of known or unknown bipolar disorder without consulting their doctor because of
and/or suicidal ideation, and strongly possible drug interactions with the MAOI
consider informing parents or guardian of • Headache is often the first symptom of
this risk so they can help observe child or hypertensive crisis
adolescent patients • Moclobemide has a much reduced risk of
interactions with tyramine than
nonselective MAOIs
Pregnancy • Especially at higher doses of moclobemide,
• Not generally recommended for use during foods with high tyramine need to be
pregnancy, especially during first trimester avoided: dry sausage, pickled herring, liver,
• Should evaluate patient for treatment with broad bean pods, sauerkraut, cheese,
an antidepressant with a better risk/benefit yogurt, alcoholic beverages, nonalcoholic
ratio beer and wine, chocolate, caffeine, meat
and fish
Breast Feeding • The rigid dietary restrictions may reduce
• Some drug is found in mother’s breast milk compliance
• Effects on infant are unknown ✽ May be a safer alternative to classical
• Immediate postpartum period is a high-risk irreversible nonselective MAO-A and MAO-
time for depression, especially in women B inhibitors with less propensity for
who have had prior depressive episodes, tyramine and drug interactions and
so drug may need to be reinstituted late in hepatotoxicity (although not entirely free of
the third trimester or shortly after interactions)
childbirth to prevent a recurrence during • May not be as effective at low doses, and
the postpartum period may have more side effects at higher doses

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(continued) MOCLOBEMIDE

• Moclobemide’s profile at higher doses may patients who fail to respond to numerous
be more similar to classical MAOIs other antidepressants
• MAOIs are a viable second-line treatment • Use of MAOIs with clomipramine is always
option in depression, but are not frequently prohibited because of the risk of serotonin
used syndrome and death
✽ Myths about the danger of dietary • Amoxapine may be the preferred
tyramine can be exaggerated, but trycyclic/tetracyclic antidepressant to
prohibitions against concomitant drugs combine with an MAOI in heroic cases due
often not followed closely enough to its theoretically protective 5HT2A
• Orthostatic hypotension, insomnia, and antagonist properties
sexual dysfunction are often the most • If this option is elected, start the MAOI with
troublesome common side effects the tricyclic/tetracyclic antidepressant
✽ MAOIs should be for the expert, simultaneously at low doses after
especially if combining with agents of appropriate drug washout, then alternately
potential risk (e.g., stimulants, trazodone, increase doses of these agents every few
TCAs) days to a week as tolerated
✽ MAOIs should not be neglected as • Although very strict dietary and
therapeutic agents for the treatment- concomitant drug restrictions must be
resistant observed to prevent hypertensive crises
• Although generally prohibited, a heroic but and serotonin syndrome, the most
potentially dangerous treatment for common side effects of MAOI and
severely treatment-resistant patients is for tricyclic/tetracyclic combinations may be
an expert to give a tricyclic/tetracyclic weight gain and orthostatic hypotension
antidepressant other than clomipramine
simultaneously with an MAO inhibitor for

Suggested Reading
Amrein R, Martin JR, Cameron AM. Lippman SB, Nash K. Monoamine oxidase
Moclobemide in patients with dementia and inhibitor update. Potential adverse food and
depression. Adv Neurol 1999;80:509–19. drug interactions. Drug Saf 1990;5:195–204
Fulton B, Benfield P. Moclobemide. An update Nutt D, Montgomery SA. Moclobemide in the
of its pharmacological properties and treatment of social phobia. Int Clin
therapeutic use. Drugs 1996;52:450–74. Psychopharmacol 1996;11 (Suppl 3):77–82.
Kennedy SH. Continuation and maintenance
treatments in major depression: the neglected
role of monoamine oxidase inhibitors. J
Psychiatry Neurosci 1997;22:127–31.

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0521011698s06.qxd 9/2/04 2:42 PM Page 313

MODAFINIL
THERAPEUTICS ✽ Does not prevent one from falling asleep
when needed
Brands • Provigil • May not completely normalize wakefulness
• Alertec • Treat until improvement stabilizes and then
• Modiodal continue treatment indefinitely as long as
see index for additional brand names improvement persists
Generic? No If It Doesn’t Work
✽ Change dose; some patients do better
with an increased dose but some actually
Class do better with a decreased dose
• Wake-promoting • Augment or consider an alternative
treatment for daytime sleepiness, fatigue,
Commonly Prescribed For or ADHD
(bold for FDA approved)
• Reducing excessive sleepiness in Best Augmenting Combos
patients with narcolepsy and shift work for Partial Response or
sleep disorder Treatment-Resistance
• Reducing excessive sleepiness in ✽ Modafinil is itself an adjunct to standard
patients with obstructive sleep treatments for obstructive sleep
apnea/hypopnea syndrome (OSAHS) apnea/hypopnea syndrome (OSAHS); if
(adjunct to standard treatment for continuous positive airway pressure
underlying airway obstruction) (CPAP) is the treatment of choice, a
• Fatigue and sleepiness in depression maximal effort to treat first with CPAP
• Fatigue in multiple sclerosis should be made prior to initiating modafinil
• Attention deficit hyperactivity disorder and CPAP should be continued after
initiation of modafinil
✽ Modafinil is itself an augmenting therapy
How The Drug Works to antidepressants for residual sleepiness
• Unknown, but clearly different from and fatigue in major depressive disorder
classical stimulants such as • Best to attempt another monotherapy prior
methylphenidate and amphetamine to augmenting with other drugs in the
• Increases neuronal activity selectively in treatment of sleepiness associated with
the hypothalamus sleep disorders or problems concentrating
✽ Presumably enhances activity in in ADHD
hypothalamic wakefulness center (TMN, • Combination of modafinil with stimulants
tuberomammillary nucleus) within the such as methylphenidate or amphetamine
hypothalamic sleep wake switch by an or with atomoxetine for ADHD has not
unknown mechanism been systematically studied
✽ Activates tuberomammillary nucleus • However, such combinations may be useful
neurons that release histamine options for experts, with close monitoring,
✽ Activates other hypothalamic neurons when numerous monotherapies for
that release orexin/hypocretin sleepiness or ADHD have failed

How Long Until It Works Tests

• Can immediately reduce daytime sleepiness • None for healthy individuals
and improve cognitive task performance
within 2 hours of first dosing
• Can take several days to optimize dosing SIDE EFFECTS
and clinical improvement
How Drug Causes Side Effects
If It Works • Unknown
✽ Improves daytime sleepiness and may • CNS side effects presumably due to
improve attention as well as fatigue excessive CNS actions on various
neurotransmitter systems

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MODAFINIL (continued)

Notable Side Effects How to Dose

✽ Headache • Titration up or down only necessary if not
• Anxiety, nervousness, insomnia optimally efficacious at the standard
• Dry mouth, diarrhea, nausea, anorexia starting dose of 200 mg once a day in the
• Pharyngitis, rhinitis, infection morning
• Hypertension
• Palpitations
Dosing Tips
Life Threatening or ✽ For sleepiness, more may be more:
Dangerous Side Effects higher doses (200–800 mg/day) may be
• Transient EKG ischemic changes in patients better than lower doses (50–200 mg/day)
with mitral valve prolapse or left ventricular in patients with daytime sleepiness in sleep
hypertrophy have been reported (rare) disorders
• Theoretically, could activate hypomania or ✽ For problems concentrating and fatigue,
mania less may be more: lower doses (50–200
mg/day) may be paradoxically better than
Weight Gain higher doses (200–800 mg/day) in some
patients
• At high doses, may slightly induce its own
metabolism, possibly by actions of
• Reported but not expected inducing CYP450 3A4
• Dose may creep upward in some patients
Sedation with long-term treatment due to
autoinduction; drug holiday may restore
efficacy at original dose
• Reported but not expected
• Patients are usually awakened and some Overdose
may be activated • No fatalities; agitation, insomnia, increase
in hemodynamic parameters
What To Do About Side Effects
• Wait Long-Term Use
• Lower the dose • Efficacy in reducing excessive sleepiness in
• Give only once daily sleep disorders has been demonstrated in
• Give smaller split doses 2 or more times 9 to 12 week trials
daily • Unpublished data show safety for up to
• For activation or insomnia, do not give in 136 weeks
the evening • The need for continued treatment should
• If unacceptable side effects persist, be reevaluated periodically
discontinue use
Habit Forming
Best Augmenting Agents for Side • Schedule IV; may have some potential for
Effects abuse but unusual in clinical practice
• Many side effects cannot be improved with
an augmenting agent
How to Stop
• Taper not necessary; patients may have
sleepiness on discontinuation
DOSING AND USE Pharmacokinetics
• Metabolized by the liver
Usual Dosage Range • Excreted renally
• 200 mg/day in the morning • Elimination half-life 10–12 hours
• Inhibits CYP450 2C19 (and perhaps 2C9)
Dosage Forms
• Induces CYP450 3A4 (and slightly 1A2 and
• Tablet 100 mg, 200 mg (scored)
2B6)

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(continued) MODAFINIL

• Modafinil should be used in patients with

sleep disorders that have been completely
Drug Interactions evaluated for narcolepsy, obstructive sleep
• May increase plasma levels of drugs apnea/hypopnea syndrome (OSAHS), and
metabolized by CYP450 2C19 (e.g., shift work sleep disorder
diazepam, phenytoin, propranolol) • In OSAHS patients for whom continuous
• Modafinil may increase plasma levels of positive airway pressure (CPAP) is the
CYP450 2D6 substrates such as tricyclic treatment of choice, a maximal effort to
antidepressants and SSRIs, perhaps treat first with CPAP should be made prior
requiring downward dose adjustments of to initiating modafinil, and then CPAP
these agents should be continued after initiating
• Modafinil may decrease plasma levels of modafinil
CYP450 3A4 substrates such as ethinyl • The effectiveness of steroidal
estradiol and triazolam contraceptives may be reduced when used
• Due to induction of CYP450 3A4, with modafinil and for 1 month after
effectiveness of steroidal contraceptives discontinuation of modafinil
may be reduced by modafinil, including • Modafinil is not a replacement for sleep
1 month after discontinuation
• Inducers or inhibitors of CYP450 3A4 may Do Not Use
affect levels of modafinil (e.g., • If patient has severe hypertension
carbamazepine may lower modafinil • If patient has cardiac arrhythmias
plasma levels; fluvoxamine and fluoxetine • If there is a proven allergy to modafinil
may raise modafinil plasma levels)
• Modafinil may slightly reduce its own
levels by autoinduction of CYP450 3A4
SPECIAL POPULATIONS
• Modafinil may increase clearance of drugs
dependent on CYP450 1A2 and reduce Renal Impairment
their plasma levels • Use with caution; dose reduction is
• Patients on modafinil and warfarin should recommended
have prothrombin times monitored
• Methylphenidate may delay absorption of Hepatic Impairment
modafinil by an hour • Reduce dose by half in severely impaired
✽ However, co-administration with patients
methylphenidate does not significantly
change the pharmacokinetics of either Cardiac Impairment
modafinil or methylphenidate • Use with caution
✽ Co-administration with • Not recommended for use in patients with
dextroamphetamine also does not a history of left ventricular hypertrophy,
significantly change the pharmacokinetics ischemic ECG changes, chest pain,
of either modafinil or dextroamphetamine arrhythmias, or recent myocardial
• Interaction studies with MAO inhibitors infarction
have not been performed, but MAOIs can
be given with modafinil by experts with Elderly
cautious monitoring • Limited experience in patients over 65
• Clearance of modafinil may be reduced in
elderly patients
Other Warnings/
Precautions
• Patients with history of drug abuse should
be monitored closely Children and Adolescents
• Modafinil may cause CNS effects similar to • Safety and efficacy not established under
those caused by other CNS agents (e.g., age 16
changes in mood and, theoretically, • Can be used cautiously by experts for
activation of psychosis, mania, or suicidal children and adolescents
ideation)

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MODAFINIL (continued)

✽ Anecdotal usefulness for jet lag short-

term (off-label)
Pregnancy ✽ Modafinil is not a replacement for sleep
• Risk Category C [some animal studies ✽ The treatment for sleep deprivation is
show adverse effects, no controlled studies sleep, not modafinil
in humans] • Controlled studies suggest modafinil
• Animal studies were conducted at doses improves attention in OSAHS, shift work
lower than necessary to elucidate the sleep disorder, and ADHD (both children
effects of modafinil on the developing fetus and adults), but controlled studies of
• Use in women of childbearing potential attention have not been performed in major
requires weighing potential benefits to the depressive disorder
mother against potential risks to the fetus ✽ May be useful to treat fatigue in patients
✽ Generally, modafinil should be with depression as well as other disorders,
discontinued prior to anticipated such as multiple sclerosis, myotonic
pregnancies dystrophy, HIV/AIDS
• In depression, modafinil’s actions on
Breast Feeding fatigue appear to be independent of actions
• Unknown if modafinil is secreted in human (if any) on mood
breast milk, but all psychotropics assumed • In depression, modafinil’s actions on
to be secreted in breast milk sleepiness also appear to be independent
✽ Recommended either to discontinue drug of actions (if any) on mood but may be
or bottle feed linked to actions on fatigue or on global
functioning
• Several controlled studies in depression
THE ART OF PSYCHOPHARMACOLOGY show improvement in sleepiness or global
functioning, especially for depressed
Potential Advantages patients with sleepiness and fatigue
• Selective for areas of brain involved in • May be useful in treating sleepiness
sleep/wake promotion associated with opioid analgesia,
• Less activating and less abuse potential particularly in end-of-life management
than stimulants • Subjective sensation associated with
modafinil is usually one of normal
Potential Disadvantages wakefulness, not of stimulation, although
• May not work as well as stimulants in jitteriness can rarely occur
some patients • Anecdotally, some patients may experience
wearing off of efficacy over time, especially
Primary Target Symptoms
for off-label uses, with restoration of
• Sleepiness
efficacy after a drug holiday; such wearing
• Concentration
off is less likely with intermittent dosing
• Physical and mental fatigue
✽ Compared to stimulants, modafinil has a
novel mechanism of action, novel
therapeutic uses, and less abuse potential,
Pearls but is often inaccurately classified as a
✽ Only agent approved for treating stimulant
sleepiness associated with obstructive • Alpha 1 antagonists such as prazosin may
sleep apnea/hypopnea syndrome (OSAHS) block the therapeutic actions of modafinil
✽ Only agent approved for treating • The active R-enantiomer of modafinil, also
sleepiness associated with shift work sleep called armodafinil, is in development
disorder

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(continued) MODAFINIL

Suggested Reading
Batejat DM, Lagarde DP. Naps and modafinil Jasinski DR, Koyacevic-Ristanovic. Evaluation
as countermeasures for the effects of sleep of the abuse liability of modafinil and other
deprivation on cognitive performance. Aviat drugs for excessive daytime sleepiness
Space Environ Med 1999;70:493–8. associated with narcolepsy. Clin
Neuropharmacol 2000;23:149–56.
Bourdon L, Jacobs I, Bateman WA, Vallerand
AL. Effect of modafinil on heat production and Wesensten NJ, Belenky G, Kautz MA, Thorne
regulation of body temperatures in cold- DR, Reichardt RM, Balkin TJ. Maintaining
exposed humans. Aviat Space Environ Med alertness and performance during sleep
1994;65:999–1004. deprivation: modafinil versus caffeine.
Psychopharmacology (Berl) 2002;159:238–47.
Cox JM, Pappagallo M. Modafinil: a gift to
portmanteau. Am J Hosp Palliat Care
2001;18:408–10.

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0521011698s06.qxd 9/2/04 2:42 PM Page 319

MOLINDONE
THERAPEUTICS quetiapine, ziprasidone, aripiprazole,
amisulpride)
Brands • Moban • Consider trying another conventional
see index for additional brand names antipsychotic
• If 2 or more antipsychotic monotherapies
Generic? Yes
do not work, consider clozapine

Best Augmenting Combos

Class for Partial Response or
• Conventional antipsychotic (neuroleptic, Treatment-Resistance
dopamine 2 antagonist) • Augmentation of conventional
antipsychotics has not been systematically
Commonly Prescribed For studied
(bold for FDA approved) • Addition of a mood stabilizing
• Schizophrenia anticonvulsant such as valproate,
• Other psychotic disorders carbamazepine, or lamotrigine may be
• Bipolar disorder helpful in both schizophrenia and bipolar
mania
• Augmentation with lithium in bipolar mania
How The Drug Works may be helpful
• Blocks dopamine 2 receptors, reducing • Addition of a benzodiazepine, especially
positive symptoms of psychosis short-term for agitation

How Long Until It Works Tests

• Psychotic symptoms can improve within ✽ Since conventional antipsychotics are
1 week, but it may take several weeks for frequently associated with weight gain,
full effect on behavior before starting treatment, weigh all patients
and determine if the patient is already
If It Works overweight (BMI 25.0–29.9) or obese
• Most often reduces positive symptoms in (BMI ≥30)
schizophrenia but does not eliminate them • Before giving a drug that can cause weight
• Most schizophrenic patients do not have a gain to an overweight or obese patient,
total remission of symptoms but rather a consider determining whether the patient
reduction of symptoms by about a third already has pre-diabetes (fasting plasma
• Continue treatment in schizophrenia until glucose 100–125 mg/dl), diabetes (fasting
reaching a plateau of improvement plasma glucose >126 mg/dl), or
• After reaching a satisfactory plateau, dyslipidemia (increased total cholesterol,
continue treatment for at least a year after LDL cholesterol and triglycerides;
first episode of psychosis in schizophrenia decreased HDL cholesterol), and treat or
• For second and subsequent episodes of refer such patients for treatment, including
psychosis in schizophrenia, treatment may nutrition and weight management, physical
need to be indefinite activity counseling, smoking cessation, and
• Reduces symptoms of acute psychotic medical management
mania but not proven as a mood stabilizer ✽ Monitor weight and BMI during treatment
or as an effective maintenance treatment in ✽ While giving a drug to a patient who has
bipolar disorder gained >5% of initial weight, consider
• After reducing acute psychotic symptoms evaluating for the presence of pre-diabetes,
in mania, switch to a mood stabilizer diabetes, or dyslipidemia, or consider
and/or an atypical antipsychotic for mood switching to a different antipsychotic
stabilization and maintenance • Should check blood pressure in the elderly
before starting and for the first few weeks
If It Doesn’t Work of treatment
• Consider trying one of the first-line atypical • Monitoring elevated prolactin levels of
antipsychotics (risperidone, olanzapine, dubious clinical benefit

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MOLINDONE (continued)

SIDE EFFECTS • Sedation is usually transient

How Drug Causes Side Effects What To Do About Side Effects
• By blocking dopamine 2 receptors in the • Wait
striatum, it can cause motor side effects • Wait
• By blocking dopamine 2 receptors in the • Wait
pituitary, it can cause elevations in • For motor symptoms, add an
prolactin anticholinergic agent
• By blocking dopamine 2 receptors • Reduce the dose
excessively in the mesocortical and • For sedation, give at night
mesolimbic dopamine pathways, especially • Switch to an atypical antipsychotic
at high doses, it can cause worsening of • Weight loss, exercise programs, and
negative and cognitive symptoms medical management for high BMIs,
(neuroleptic-induced deficit syndrome) diabetes, dyslipidemia
• Anticholinergic actions may cause
sedation, blurred vision, constipation, dry Best Augmenting Agents for Side
mouth Effects
• Antihistaminic actions may cause sedation, • Benztropine or trihexyphenidyl for motor
weight gain side effects
• By blocking alpha 1 adrenergic receptors, it • Sometimes amantadine can be helpful for
can cause dizziness, sedation, and motor side effects
hypotension • Benzodiazepines may be helpful for
• Mechanism of weight gain and any akathisia
possible increased incidence of diabetes or • Many side effects cannot be improved with
dyslipidemia with conventional an augmenting agent
antipsychotics is unknown

Notable Side Effects

DOSING AND USE
✽ Neuroleptic-induced deficit syndrome
✽ Akathisia Usual Dosage Range
✽ Extrapyramidal symptoms, Parkinsonism, • 40–100 mg/day in divided doses
tardive dyskinesia
✽ Galactorrhea, amenorrhea Dosage Forms
• Sedation • Tablet 5 mg, 10 mg, 25 mg scored, 50 mg
• Dry mouth, constipation, vision scored, 100 mg scored
disturbance, urninary retention • Liquid 20 mg/mL
• Hypotension, tachycardia
How to Dose
Life Threatening or • Initial 50–75 mg/day; increase to
Dangerous Side Effects 100 mg/day after 3–4 days; maximum
225 mg/day
• Rare neuroleptic malignant syndrome
• Rare leukopenia
• Rare seizures
Dosing Tips
Weight Gain • Very short half-life, but some patients may
only require once daily dosing
• Other patients may do better with 3 or
4 divided doses daily
✽ Reported but not expected • Patients receiving atypical antipsychotics
Sedation may occasionally require a “top up” of a
conventional antipsychotic to control
aggression or violent behavior

• Many experience and/or can be significant

in amount

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(continued) MOLINDONE

Overdose because of possible lowering of seizure

• Deaths have occurred; extrapyramidal threshold
symptoms, sedation, hypotension, • Antiemetic effect can mask signs of other
respiratory depression, coma disorders or overdose
• Do not use epinephrine in event of
Long-Term Use overdose as interaction with some pressor
• Some side effects may be irreversible (e.g., agents may lower blood pressure
tardive dyskinesia) • Use cautiously in patients with glaucoma,
urinary retention
Habit Forming • Observe for signs of ocular toxicity
• No (pigmentary retinopathy, lenticular
pigmentation)
How to Stop • Use only with caution if at all in
• Slow down-titration (over 6 to 8 weeks), Parkinson’s disease or Lewy Body
especially when simultaneously beginning dementia
a new antipsychotic while switching (i.e.,
cross-titration) Do Not Use
• Rapid discontinuation may lead to rebound • If patient is in a comatose state or has CNS
psychosis and worsening of symptoms depression
• If antiparkinson agents are being used, • If there is a proven allergy to molindone
they should be continued for a few weeks
after molindone is discontinued

Pharmacokinetics SPECIAL POPULATIONS

• Half-life approximately 1.5 hours Renal Impairment
• Should receive initial lower dose

Drug Interactions Hepatic Impairment

• Additive effects may occur if used with • Should receive initial lower dose
CNS depressants
• Some patients taking a neuroleptic and Cardiac Impairment
lithium have developed an encephalopathic • Use with caution
syndrome similar to neuroleptic malignant
syndrome Elderly
• Molindone tablets contain calcium sulfate, • Should receive initial lower dose
which may interfere with absorption of
phenytoin sodium or tetracyclines
• Combined use with epinephrine may lower Children and Adolescents
blood pressure • Safety and efficacy not well established
• May increase the effects of • Generally consider second-line after
antihypertensive drugs atypical antipsychotics

Other Warnings/
Precautions Pregnancy
• If signs of neuroleptic malignant syndrome • Animal studies have not shown adverse
develop, treatment should be immediately effects
discontinued • No studies in pregnant women
• Liquid molindone contains sodium • Psychotic symptoms may worsen during
metabisulfite, which may cause allergic pregnancy and some form of treatment
reactions in some people, especially in may be necessary
asthmatic people • Atypical antipsychotics may be preferable
• Use cautiously in patients with alcohol to conventional antipsychotics or
withdrawal or convulsive disorders anticonvulsant mood stabilizers if
treatment is required during pregnancy

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MOLINDONE (continued)

Breast Feeding • Not shown to be effective for behavioral

• Unknown if molindone is secreted in problems in mental retardation
human breast milk, but all psychotropics • Patients have very similar antipsychotic
assumed to be secreted in breast milk responses to any conventional
✽ Recommended either to discontinue drug antipsychotic, which is different from
or bottle feed atypical antipsychotics where antipsychotic
responses of individual patients can
occasionally vary greatly from one atypical
THE ART OF PSYCHOPHARMACOLOGY antipsychotic to another
• Patients with inadequate responses to
Potential Advantages atypical antipsychotics may benefit from a
• Some patients benefit from molindone’s trial of augmentation with a conventional
sedative properties antipsychotic such as molindone or from
switching to a conventional antipsychotic
Potential Disadvantages such as molindone
• Patients with tardive dyskinesia • However, long-term polypharmacy with a
combination of a conventional
Primary Target Symptoms antipsychotic such as molindone with an
• Positive symptoms of psychosis atypical antipsychotic may combine their
• Motor and autonomic hyperactivity side effects without clearly augmenting the
• Violent or aggressive behavior efficacy of either
• Although a frequent practice by some
prescribers, adding two conventional
Pearls antipsychotics together has little rationale
✽ May have less weight gain than some and may reduce tolerability without clearly
enhancing efficacy
other antipsychotics
• Conventional antipsychotics are much less
expensive than atypical antipsychotics

Suggested Reading
Bagnall A, Fenton M, Lewis R, Leitner ML, Owen RR Jr, Cole JO. Molindone
Kleijnen J. Molindone for schizophrenia and hydrochloride: a review of laboratory and
severe mental illness. Cochrane Database Syst clinical findings. J Clin Psychopharmacol
Rev 2000; (2): CD002083. 1989; 9 (4): 268–76.

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NEFAZODONE
THERAPEUTICS If It Doesn’t Work
• Many patients only have a partial response
Brands • Serzone
where some symptoms are improved but
see index for additional brand names
others persist (especially insomnia, fatigue,
Generic? Yes and problems concentrating)
• Other patients may be nonresponders,
sometimes called treatment-resistant or
treatment-refractory
Class • Some patients who have an initial response
• SARI (serotonin 2 antagonist/reuptake may relapse even though they continue
inhibitor); antidepressant treatment, sometimes called “poop-out”
• Consider increasing dose, switching to
Commonly Prescribed For another agent or adding an appropriate
(bold for FDA approved) augmenting agent
• Depression • Consider psychotherapy, especially
• Relapse prevention in MDD cognitive-behavioral psychotherapies,
• Panic disorder which have been specifically shown to
• Posttraumatic stress disorder enhance nefazodone’s antidepressant
actions
• Consider evaluation for another diagnosis
How The Drug Works or for a comorbid condition (e.g., medical
• Blocks serotonin 2A receptors potently illness, substance abuse, etc.)
• Blocks serotonin reuptake pump (serotonin • Some patients may experience apparent
transporter) and norepinephrine reuptake lack of consistent efficacy due to activation
pump (norepinephrine transporter) less of latent or underlying bipolar disorder, and
potently require antidepressant discontinuation and
a switch to a mood stabilizer
How Long Until It Works
• Can improve insomnia and anxiety early Best Augmenting Combos
after initiating dosing for Partial Response or
• Onset of therapeutic actions usually not Treatment-Resistance
immediate, but often delayed 2 to 4 weeks ✽ Venlafaxine and escitalopram may be the
• If it is not working within 6 to 8 weeks for best tolerated when switching or
depression, it may require a dosage augmenting with a serotonin reuptake
increase or it may not work at all inhibitor, as neither is a potent CYP450
• May continue to work for many years to 2D6 inhibitor (use combinations of
prevent relapse of symptoms antidepressants with caution as this may
activate bipolar disorder and suicidal
If It Works ideation)
• The goal of treatment is complete • Modafinil, especially for fatigue, sleepiness,
remission of current symptoms as well as and lack of concentration
prevention of future relapses • Mood stabilizers or atypical antipsychotics
• Treatment most often reduces or even for bipolar depression, psychotic
eliminates symptoms, but not a cure since depression or treatment-resistant
symptoms can recur after medicine depression
stopped • Benzodiazepines for anxiety, but give
• Continue treatment until all symptoms are alprazolam cautiously with nefazodone as
gone (remission) alprazolam levels can be much higher in
• Once symptoms gone, continue treating for the presence of nefazodone
1 year for the first episode of depression • Classically, lithium, buspirone, or thyroid
• For second and subsequent episodes of hormone
depression, treatment may need to be
indefinite
• Use in anxiety disorders may also need to
be indefinite

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NEFAZODONE (continued)

Tests Sedation
✽ Liver function testing is not required but
is often prudent given the small but finite
risk of serious hepatoxicity
• Many experience and/or can be significant
✽ However, to date no clinical strategy, in amount
including routine liver function tests, has
been identified to reduce the risk of What To Do About Side Effects
irreversible liver failure • Wait
• Wait
• Wait
SIDE EFFECTS • Take once-daily at night to reduce daytime
sedation
How Drug Causes Side Effects • Lower the dose and try titrating again more
• Blockade of alpha adrenergic 1 receptors slowly as tolerated
may explain dizziness, sedation, and • Switch to another agent
hypotension
• A metabolite of nefazodone, mCPP (meta- Best Augmenting Agents for Side
chloro-phenyl-piperazine), can cause side Effects
effects if its levels rise significantly • Often best to try another antidepressant
✽ If CYP450 2D6 is absent (7% of monotherapy prior to resorting to
Caucasians lack CYP450 2D6) or inhibited augmentation strategies to treat side
(concomitant treatment with CYP450 2D6 effects
inhibitors such as fluoxetine or paroxetine), • Many side effects cannot be improved with
increased levels of mCPP can form, leading an augmenting agent
to stimulation of 5HT2C receptors and • Many side effects are dose-dependent (i.e.,
causing dizziness, insomnia, and agitation they increase as dose increases, or they
• Most side effects are immediate but often reemerge until tolerance re-develops)
go away with time • Many side effects are time-dependent (i.e.,
they start immediately upon dosing and
Notable Side Effects upon each dose increase, but go away with
• Nausea, dry mouth, constipation, time)
dyspepsia, increased appetite • Activation and agitation may represent the
• Headache, dizziness, vision changes, induction of a bipolar state, especially a
sedation, insomnia, agitation, confusion, mixed dysphoric bipolar II condition
memory impairment sometimes associated with suicidal
• Ataxia, paresthesia, asthenia ideation, and require the addition of
• Cough increased lithium, a mood stabilizer or an atypical
• Rare postural hypotension antipsychotic, and/or discontinuation of
nefazodone
Life Threatening or
Dangerous Side Effects
• Rare seizures DOSING AND USE
• Rare induction of mania and activation of
suicidal ideation Usual Dosage Range
• Rare priapism (no causal relationship • 300–600 mg/day
established)
• Hepatic failure requiring liver transplant
Dosage Forms
and/or fatal • Tablet 50 mg, 100 mg scored, 150 mg
scored, 200 mg, 250 mg
Weight Gain
How to Dose
• Initial dose 100 mg twice a day; increase
by 100–200 mg/day each week until
• Reported but not expected

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(continued) NEFAZODONE

desired efficacy is reached; maximum dose • Can cause a fatal “serotonin syndrome”
600 mg twice a day when combined with MAO inhibitors, so do
not use with MAO inhibitors or for at least
14 days after MAOIs are stopped
Dosing Tips • Do not start an MAO inhibitor for at least
• Take care switching from or adding to 2 weeks after discontinuing nefazodone
SSRIs (especially fluoxetine or paroxetine) • Via CYP450 3A4 inhibition, nefazodone
because of side effects due to the drug may increase the half-life of alprazolam and
interaction triazolam, so their dosing may need to be
• Do not underdose the elderly reduced by half or more
• Normally twice daily dosing, especially • Via CYP450 3A4, nefazodone may increase
when initiating treatment plasma concentrations of buspirone, so
• Patients may tolerate all dosing once daily buspirone dose may need to be reduced
at night once titrated • Via CYP450 3A4 inhibition, nefazodone
• Often much more effective at could theoretically increase concentrations
400–600 mg/day than at lower doses if of certain cholesterol lowering HMG CoA
tolerated reductase inhibitors, especially simvastatin,
• Slow titration can enhance tolerability when atorvastatin, and lovastatin, but not
initiating dosing pravastatin or fluvastatin, which would
increase the risk of rhabdomyolysis; thus,
Overdose coadministration of nefazodone with
• Rarely lethal; sedation, nausea, vomiting, certain HMG CoA reductase inhibitors
low blood pressure should proceed with caution
• Via CYP450 3A4 inhibition, nefazodone
Long-Term Use could theoretically increase the
• Safe concentrations of pimozide, and cause QTc
prolongation and dangerous cardiac
Habit Forming arrhythmias
• No • Nefazodone may reduce clearance of
haloperidol, so haloperidol dose may need
How to Stop to be reduced
• Taper is prudent to avoid withdrawal • It is recommended to discontinue
effects, but problems in withdrawal not nefazodone prior to elective surgery
common because of the potential for interaction with
general anesthetics
Pharmacokinetics
• Half-life of parent compound is 2–4 hours
• Half-life of active mebatolites up to 12 Other Warnings/
hours Precautions
• Inhibits CYP450 3A4 ✽ Hepatotoxicity, sometimes requiring liver
transplant and/or fatal, has occurred with
nefazodone use. Risk may be one in every
Drug Interactions 250,000 to 300,000 patient years. Patients
• Tramadol increases the risk of seizures in should be advised to report symptoms
patients taking an antidepressant such as jaundice, dark urine, loss of
• May interact with SSRIs such as appetite, nausea, and abdominal pain to
paroxetine, fluoxetine, and others that prescriber immediately. If patient develops
inhibit CYP450 2D6 signs of hepatocellular injury, such as
increased serum AST or serum ALPT levels
✽ Since a metabolite of nefazodone, mCPP, >3 times the upper limit of normal,
is a substrate of CYP450 2D6, combination
of 2D6 inhibitors with nefazodone will raise nefazodone treatment should be
mCPP levels, leading to stimulation of discontinued.
5HT2C receptors and causing dizziness and ✽ No risk factor yet predicts who will
agitation develop irreversible liver failure with
nefazodone and no clinical strategy,

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NEFAZODONE (continued)

including routine monitoring of liver consider informing parents or guardian of

function tests, is known to reduce the risk this risk so they can help observe child or
of liver failure adolescent patients
• Use with caution in patients with history of • Safety and efficacy have not been
seizures established
• Use with caution in patients with bipolar • Preliminary research indicates efficacy and
disorder unless treated with concomitant tolerability of nefazodone in children and
mood stabilizing agent adolescents with depression
• Monitor patients for activation of suicidal
ideation, especially children and
adolescents Pregnancy
• Risk Category C [some animal studies
Do Not Use
show adverse effects; no controlled studies
• If patient is taking an MAO inhibitor
in humans]
• If patient has acute hepatic impairment or
• Not generally recommended for use during
elevated baseline serum transaminases
pregnancy, especially during first trimester
• If patient was previously withdrawn from
• Must weigh the risk of treatment (first
nefazodone treatment due to hepatic injury
trimester fetal development, third trimester
• If patient is taking pimozide, as nefazodone
newborn delivery) to the child against the
could raise pimozide levels and increase
risk of no treatment (recurrence of
QTc interval, perhaps causing dangerous
depression, maternal health, infant
arrhythmia
bonding) to the mother and child
• If patient is taking carbamazepine, as this
• For many patients this may mean
agent can dramatically reduce nefazodone
continuing treatment during pregnancy
levels and thus interfere with its
antidepressant actions Breast Feeding
• If there is a proven allergy to nefazodone • Unknown if nefazodone is secreted in
human breast milk, but all psychotropics
assumed to be secreted in breast milk
SPECIAL POPULATIONS • Trace amounts may be present in nursing
children whose mothers are on nefazodone
Renal Impairment • If child becomes irritable or sedated, breast
• No dose adjustment necessary feeding or drug may need to be
discontinued
Hepatic Impairment • Immediate postpartum period is a high-risk
• Contraindicated in patients with known time for depression, especially in women
hepatic impairment who have had prior depressive episodes,
so drug may need to be reinstituted late in
Cardiac Impairment the third trimester or shortly after
• Use in patients with cardiac impairment childbirth to prevent a recurrence during
has not been studied, so use with caution the postpartum period
because of risk of orthostatic hypotension • Must weigh benefits of breast feeding with
risks and benefits of antidepressant
Elderly
treatment versus non-treatment to both the
• Recommended to initiate treatment at half
infant and the mother
the usual adult dose, but to follow the
• For many patients, this may mean
same titration schedule as with younger
continuing treatment during breast feeding
patients, including same ultimate dose

Children and Adolescents

• Use with caution, observing for activation
of known or unknown bipolar disorder
and/or suicidal ideation, and strongly

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(continued) NEFAZODONE

THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages Pearls
• Depressed patients with anxiety or • Preliminary data for efficacy in panic
insomnia who do not respond to other disorder and PTSD
antidepressants • Fluoxetine and paroxetine may not be
• Patients with SSRI-induced sexual tolerated when switching or augmenting
dysfunction • For elderly patients with early dementia and
agitated depression, consider nefazodone
Potential Disadvantages in the morning and additional trazodone at
• Patients who have difficulty with a long night
titration period or twice-daily dosing • Anecdotal reports suggest that nefazodone
• Patients with hepatic impairment may be effective in treating PMDD
Primary Target Symptoms ✽ Studies suggest that cognitive-behavioral
psychotherapy enhances the efficacy of
• Depressed mood nefazodone in chronic depression
• Sleep disturbance
• Anxiety
✽ Risk of hepatotoxicity makes this agent a
second-line choice and has led to its
withdrawal from some markets
• Rarely, patients may complain of visual
“trails” or after-images on nefazodone

Suggested Reading
DeVane CL, Grothe DR, Smith SL. Masand PS, Gupta S. Long-term side effects
Pharmacology of antidepressants: focus on of newer-generation antidepressants: SSRIS,
nefazodone. J Clin Psychiatry 2002; venlafaxine, nefazodone, bupropion, and
63(1):10–7. mirtazapine. Ann Clin Psychiatry 2002;
14:175–82.
Dunner DL, Laird LK, Zajecka J, Bailey L,
Sussman N, Seabolt JL. Six-year perspectives Schatzberg AF, Prather MR, Keller MB, Rush
on the safety and tolerability of nefazodone. J AJ, Laird LK, Wright CW. Clinical use of
Clin Psychiatry 2002;63(1):32–41. nefazodone in major depression: a 6-year
perspective. J Clin Psychiatry 2002;
Khouzam HR. The antidepressant nefazodone. 63(1):18–31.
A review of its pharmacology, clinical efficacy,
adverse effects, dosage, and administration.
Journal of Psychosocial Nursing and Mental
Health Services 2000;38:20–25.

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NORTRIPTYLINE
THERAPEUTICS • The goal of treatment of chronic
neuropathic pain is to reduce symptoms as
Brands • Pamelor much as possible, especially in
see index for additional brand names combination with other treatments
• Treatment of depression most often
Generic? Yes
reduces or even eliminates symptoms, but
not a cure since symptoms can recur after
medicine stopped
Class • Treatment of chronic neuropathic pain may
• Tricyclic antidepressant (TCA) reduce symptoms, but rarely eliminates
• Predominantly a norepinephrine/ them completely, and is not a cure since
noradrenaline reuptake inhibitor symptoms can recur after medicine is
stopped
Commonly Prescribed For • Continue treatment of depression until all
(bold for FDA approved) symptoms are gone (remission)
• Major depressive disorder • Once symptoms of depression are gone,
• Anxiety continue treating for 1 year for the first
• Insomnia episode of depression
• Neuropathic pain/chronic pain • For second and subsequent episodes of
• Treatment-resistant depression depression, treatment may need to be
indefinite
• Use in anxiety disorders and chronic pain
How The Drug Works may also need to be indefinite, but long-
• Boosts neurotransmitter norepinephrine/ term treatment is not well studied in these
noradrenaline conditions
• Blocks norepinephrine reuptake pump If It Doesn’t Work
(norepinephrine transporter), presumably
• Many depressed patients only have a
increasing noradrenergic neurotransmission
partial response where some symptoms
• Since dopamine is inactivated by
are improved but others persist (especially
norepinephrine reuptake in frontal cortex,
insomnia, fatigue, and problems
which largely lacks dopamine transporters,
concentrating)
nortriptyline can increase dopamine
• Other depressed patients may be
neurotransmission in this part of the brain
nonresponders, sometimes called
• A more potent inhibitor of norepinephrine
treatment-resistant or treatment-refractory
reuptake pump than serotonin reuptake
• Consider increasing dose, switching to
pump (serotonin transporter)
another agent or adding an appropriate
• At high doses may also boost
augmenting agent
neurotransmitter serotonin and presumably
• Consider psychotherapy
increase serotonergic neurotransmission
• Consider evaluation for another diagnosis
How Long Until It Works or for a comorbid condition (e.g., medical
• May have immediate effects in treating illness, substance abuse, etc.)
insomnia or anxiety • Some patients may experience apparent
• Onset of therapeutic actions usually not lack of consistent efficacy due to activation
immediate, but often delayed 2 to 4 weeks of latent or underlying bipolar disorder, and
• If it is not working within 6 to 8 weeks for require antidepressant discontinuation and
depression, it may require a dosage a switch to a mood stabilizer
increase or it may not work at all Best Augmenting Combos
• May continue to work for many years to
for Partial Response or
prevent relapse of symptoms
Treatment-Resistance
If It Works • Lithium, buspirone, thyroid hormone (for
• The goal of treatment of depression is depression)
complete remission of current symptoms • Gabapentin, tiagabine, other
as well as prevention of future relapses anticonvulsants, even opiates if done by

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NORTRIPTYLINE (continued)

experts while monitoring carefully in • Blockade of alpha adrenergic 1 receptors

difficult cases (for chronic pain) may explain dizziness, sedation, and
hypotension
Tests • Cardiac arrhythmias and seizures,
✽ None for healthy individuals, although especially in overdose, may be caused by
monitoring of plasma drug levels is blockade of ion channels
available
✽ Since tricyclic and tetracyclic Notable Side Effects
antidepressants are frequently associated • Blurred vision, constipation, urinary
with weight gain, before starting treatment, retention, increased appetite, dry mouth,
weigh all patients and determine if the nausea, diarrhea, heartburn, unusual taste
patient is already overweight in mouth, weight gain
(BMI 25.0–29.9) or obese (BMI ≥30) • Fatigue, weakness, dizziness, sedation,
• Before giving a drug that can cause weight headache, anxiety, nervousness,
gain to an overweight or obese patient, restlessness
consider determining whether the patient • Sexual dysfunction (impotence, change in
already has pre-diabetes (fasting plasma libido)
glucose 100–125 mg/dl), diabetes (fasting • Sweating, rash, itching
plasma glucose >126 mg/dl), or
dyslipidemia (increased total cholesterol,
LDL cholesterol and triglycerides;
Life Threatening or
decreased HDL cholesterol), and treat or Dangerous Side Effects
refer such patients for treatment, including • Paralytic ileus, hyperthermia (TCAs +
nutrition and weight management, physical anticholinergic agents)
activity counseling, smoking cessation, and • Lowered seizure threshold and rare
medical management seizures
✽ Monitor weight and BMI during treatment • Orthostatic hypotension, sudden death,
✽ While giving a drug to a patient who has arrhythmias, tachycardia
gained >5% of initial weight, consider • QTc prolongation
evaluating for the presence of pre-diabetes, • Hepatic failure, extrapyramidal symptoms
diabetes, or dyslipidemia, or consider • Increased intraocular pressure
switching to a different antidepressant • Rare induction of mania and activation of
• EKGs may be useful for selected patients suicidal ideation
(e.g., those with personal or family history of
QTc prolongation; cardiac arrhythmia; recent
Weight Gain
myocardial infarction; uncompensated
heart failure; or taking agents that prolong
QTc interval such as pimozide, thioridazine, • Many experience and/or can be significant
selected antiarrhythmics, moxifloxacin, in amount
sparfloxacin, etc.) • Can increase appetite and carbohydrate
• Patients at risk for electrolyte disturbances craving
(e.g., patients on diuretic therapy) should
have baseline and periodic serum Sedation
potassium and magnesium measurements

• Many experience and/or can be significant

SIDE EFFECTS in amount
• Tolerance to sedative effect may develop
How Drug Causes Side Effects with long-term use
• Anticholinergic activity may explain
sedative effects, dry mouth, constipation, What To Do About Side Effects
and blurred vision • Wait
• Sedative effects and weight gain may be • Wait
due to antihistamine properties • Wait

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(continued) NORTRIPTYLINE

• Lower the dose consider the possibility of activated bipolar

• Switch to an SSRI or newer antidepressant disorder, and switch to a mood stabilizer or
an atypical antipsychotic
Best Augmenting Agents for Side
Effects Overdose
• Many side effects cannot be improved with • Death may occur; CNS depression,
an augmenting agent convulsions, cardiac dysrhythmias, severe
hypotension, ECG changes, coma

Long-Term Use
DOSING AND USE
• Safe
Usual Dosage Range
Habit Forming
• 75–150 mg/day once daily or in up to
• No
4 divided doses (for depression)
• 50–150 mg/day (for chronic pain) How to Stop
Dosage Forms • Taper to avoid withdrawal effects
• Even with gradual dose reduction some
• Capsule 10 mg, 25 mg, 50 mg, 75 mg
withdrawal symptoms may appear within
• Liquid 10 mg/5mL
the first two weeks
How to Dose • Many patients tolerate 50% dose reduction
• Initial 10–25 mg/day at bedtime; increase for 3 days, then another 50% reduction for
by 25 mg every 3–7 days; can be dosed 3 days, then discontinuation
once daily or in divided doses; maximum • If withdrawal symptoms emerge during
dose 300 mg/day discontinuation, raise dose to stop
• When treating nicotine dependence, symptoms and then restart withdrawal
nortriptyline should be initiated 10–28 days much more slowly
before cessation of smoking to achieve
Pharmacokinetics
steady drug states
• Substrate for CYP450 2D6
• Nortriptyline is the active metabolite of
amitriptyline, formed by demethylation via
Dosing Tips CYP450 1A2
• If given in a single dose, should generally • Half-life approximately 36 hours
be administered at bedtime because of its
sedative properties
• If given in split doses, largest dose should
Drug Interactions
generally be given at bedtime because of
• Tramadol increases the risk of seizures in
its sedative properties
patients taking TCAs
• If patients experience nightmares, split
• Use of TCAs with anticholinergic drugs
dose and do not give large dose at bedtime
may result in paralytic ileus or
• Patients treated for chronic pain may only
hyperthermia
require lower doses
• Fluoxetine, paroxetine, bupropion,
• Risk of seizure increases with dose
duloxetine and other CYP450 2D6
✽ Monitoring plasma levels of nortriptyline inhibitors may increase TCA concentrations
is recommended in patients who do not
and cause side effects including dangerous
respond to the usual dose or whose
arrhythmias
treatment is regarded as urgent
• Cimetidine may increase plasma
• Some formulations of nortriptyline contain
concentrations of TCAs and cause
sodium bisulphate, which may cause
anticholinergic symptoms
allergic reactions in some patients, perhaps
• Phenothiazines or haloperidol may raise
more frequently in asthmatics
TCA blood concentrations
• If intolerable anxiety, insomnia, agitation,
• May alter effects of antihypertensive drugs;
akathisia, or activation occur either upon
may inhibit hypotensive effects of clonidine
dosing initiation or discontinuation,

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NORTRIPTYLINE (continued)

• Use of TCAs with sympathomimetic agents • If patient is taking agents capable of

may increase sympathetic activity significantly prolonging QTc interval (e.g.,
• Methylphenidate may inhibit metabolism of pimozide, thioridazine, selected
TCAs antiarrhythmics, moxifloxacin,
• Nortriptyline may raise plasma levels of sparfloxacin)
dicumarol • If there is a history of QTc prolongation or
• Activation and agitation, especially cardiac arrhythmia, recent acute
following switching or adding myocardial infarction, uncompensated
antidepressants, may represent the heart failure
induction of a bipolar state, especially a • If patient is taking drugs that inhibit TCA
mixed dysphoric bipolar II condition metabolism, including CYP450 2D6
sometimes associated with suicidal inhibitors, except by an expert
ideation, and require the addition of • If there is reduced CYP450 2D6 function,
lithium, a mood stabilizer or an atypical such as patients who are poor 2D6
antipsychotic, and/or discontinuation of metabolizers, except by an expert and at
nortriptyline low doses
• If there is a proven allergy to nortriptyline
or amitriptyline
Other Warnings/
Precautions
• Add or initiate other antidepressants with
caution for up to 2 weeks after
SPECIAL POPULATIONS
discontinuing nortriptyline Renal Impairment
• Generally, do not use with MAO inhibitors, • Use with caution; may need to lower dose
including 14 days after MAOIs are stopped; • May need to monitor plasma levels
do not start an MAOI until 2 weeks after
discontinuing nortriptyline, but see Pearls Hepatic Impairment
• Use with caution in patients with history of • Use with caution
seizures, urinary retention, narrow angle- • May need to monitor plasma levels
closure glaucoma, hyperthyroidism • May require a lower dose with slower
• TCAs can increase QTc interval, especially titration
at toxic doses, which can be attained not
only by overdose but also by combining Cardiac Impairment
with drugs that inhibit TCA metabolism via • TCAs have been reported to cause
CYP450 2D6, potentially causing torsade arrhythmias, prolongation of conduction
de pointes-type arrhythmia or sudden time, orthostatic hypotension, sinus
death tachycardia, and heart failure, especially in
• Because TCAs can prolong QTc interval, the diseased heart
use with caution in patients who have • Myocardial infarction and stroke have been
bradycardia or who are taking drugs that reported with TCAs
can induce bradycardia (e.g., beta blockers, • TCAs produce QTc prolongation, which
calcium channel blockers, clonidine, may be enhanced by the existence of
digitalis) bradycardia, hypokalemia, congenital or
• Because TCAs can prolong QTc interval, acquired long QTc interval, which should
use with caution in patients who have be evaluated prior to administering
hypokalemia and/or hypomagnesemia or nortriptyline
who are taking drugs that can induce • Use with caution if treating concomitantly
hypokalemia and/or magnesemia (e.g., with a medication likely to produce
diuretics, stimulant laxatives, intravenous prolonged bradycardia, hypokalemia,
amphotericin B, glucocorticoids, slowing of intracardiac conduction, or
tetracosactide) prolongation of the QTc interval
• Avoid TCAs in patients with a known
Do Not Use history of QTc prolongation, recent acute
• If patient is recovering from myocardial myocardial infarction, and uncompensated
infarction heart failure

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(continued) NORTRIPTYLINE

• TCAs may cause a sustained increase in • Adverse effects have been reported in
heart rate in patients with ischemic heart infants whose mothers took a TCA
disease and may worsen (decrease) heart (lethargy, withdrawal symptoms, fetal
rate variability, an independent risk of malformations)
mortality in cardiac populations • Evaluate for treatment with an antidepressant
• Since SSRIs may improve (increase) heart with a better risk/benefit ratio
rate variability in patients following a
myocardial infarct and may improve Breast Feeding
survival as well as mood in patients with • Some drug is found in mother’s breast milk
acute angina or following a myocardial ✽ Recommended either to discontinue drug
infarction, these are more appropriate or bottle feed
agents for cardiac population than • Immediate postpartum period is a high-risk
tricyclic/tetracyclic antidepressants time for depression, especially in women
✽ Risk/benefit ratio may not justify use of who have had prior depressive episodes,
TCAs in cardiac impairment so drug may need to be reinstituted late in
the third trimester or shortly after
Elderly childbirth to prevent a recurrence during
• May be more sensitive to anticholinergic, the postpartum period
cardiovascular, hypotensive, and sedative • Must weigh benefits of breast feeding with
effects risks and benefits of antidepressant
• May require lower dose; it may be useful to treatment versus non-treatment to both the
monitor plasma levels in elderly patients infant and the mother
• For many patients this may mean
continuing treatment during breast feeding
Children and Adolescents
• Use with caution, observing for activation
of known or unknown bipolar disorder THE ART OF PSYCHOPHARMACOLOGY
and/or suicidal ideation, and strongly
consider informing parents or guardian of Potential Advantages
this risk so they can help observe child or • Patients with insomnia
adolescent patients • Severe or treatment-resistant depression
• Not recommended for use under age 12 • Patients for whom therapeutic drug
• Not intended for use under age 6 monitoring is desirable
• Several studies show lack of efficacy of
TCAs for depression Potential Disadvantages
• May be used to treat enuresis or • Pediatric and geriatric patients
hyperactive/impulsive behaviors • Patients concerned with weight gain
• Some cases of sudden death have • Cardiac patients
occurred in children taking TCAs
• Plasma levels may need to be monitored
Primary Target Symptoms
• Dose in children generally less than • Depressed mood
50 mg/day • Chronic pain
• May be useful to monitor plasma levels in
children and adolescents
Pearls
• Tricyclic antidepressants are often a first-
Pregnancy line treatment option for chronic pain
• Risk Category D [positive evidence of risk • Tricyclic antidepressants are no longer
to human fetus; potential benefits may still generally considered a first-line option for
justify its use during pregnancy] depression because of their side effect
• Crosses the placenta profile
• Should be used only if potential benefits • Tricyclic antidepressants continue to be
outweigh potential risks useful for severe or treatment-resistant
depression

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NORTRIPTYLINE (continued)

• Noradrenergic reuptake inhibitors such as • Patients on TCAs should be aware that they
nortriptyline can be used as a second-line may experience symptoms such as
treatment for smoking cessation, cocaine photosensitivity or blue-green urine
dependence, and attention deficit disorder • SSRIs may be more effective than TCAs in
• TCAs may aggravate psychotic symptoms women, and TCAs may be more effective
• Alcohol should be avoided because of than SSRIs in men
additive CNS effects • Not recommended for first-line use in
• Underweight patients may be more children with ADHD because of the
susceptible to adverse cardiovascular availability of safer treatments with better
effects documented efficacy and because of
• Children, patients with inadequate nortriptyline’s potential for sudden death in
hydration, and patients with cardiac children
disease may be more susceptible to TCA- ✽ Nortriptyline is one of the few TCAs
induced cardiotoxicity than healthy adults where monitoring of plasma drug levels
• For the expert only: although generally has been well studied
prohibited, a heroic but potentially • Since tricyclic/tetracyclic antidepressants
dangerous treatment for severely are substrates for CYP450 2D6, and 7% of
treatment-resistant patients is for an expert the population (especially Caucasians) may
to give a tricyclic/tetracyclic antidepressant have a genetic variant leading to reduced
other than clomipramine simultaneously activity of 2D6, such patients may not
with an MAO inhibitor for patients who fail safely tolerate normal doses of
to respond to numerous other tricyclic/tetracyclic antidepressants and
antidepressants may require dose reduction
• If this option is elected, start the MAOI with • Phenotypic testing may be necessary to
the tricyclic/tetracyclic antidepressant detect this genetic variant prior to dosing
simultaneously at low doses after with a tricyclic/tetracyclic antidepressant,
appropriate drug washout, then alternately especially in vulnerable populations such
increase doses of these agents every few as children, elderly, cardiac populations,
days to a week as tolerated and those on concomitant medications
• Although very strict dietary and • Patients who seem to have extraordinarily
concomitant drug restrictions must be severe side effects at normal or low doses
observed to prevent hypertensive crises may have this phenotypic CYP450 2D6
and serotonin syndrome, the most variant and require low doses or switching
common side effects of MAOI and to another antidepressant not metabolized
tricyclic/tetracyclic antidepressant by 2D6
combinations may be weight gain and
orthostatic hypotension

Suggested Reading
Anderson IM. Meta-analytical studies on new Wilens TE, Biederman J, Baldessarini RJ,
antidepressants. Br Med Bull 2001; Geller B, Schleifer D, Spencer TJ, Birmajer B,
57:161–178. Goldblatt A. Cardiovascular effects of
therapeutic doses of tricyclic antidepressants
Anderson IM. Selective serotonin reuptake in children and adolescents. J Am Acad Child
inhibitors versus tricyclic antidepressants: a Adolesc Psychiatry 1996;35(11):1491–501.
meta-analysis of efficacy and tolerability. J Aff
Disorders 2000;58:19–36.
Hughes JR, Stead LF, Lancaster T.
Antidepressants for smoking cessation.
Cochrane Database Syst Rev
2000;4:CD000031.

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OLANZAPINE
THERAPEUTICS cognitive and affective symptoms in some
patients
Brands • Zyprexa
• Olasek
✽ 5HT2C antagonist actions plus serotonin
reuptake blockade of fluoxetine add to the
• Ziprexa actions of olanzapine when given as
• Symbyax (olanzapine-fluoxetine Symbyax (olanzapine-fluoxetine
combination) combination)
see index for additional brand names
How Long Until It Works
Generic? Not in U.S., Europe, or Japan • Psychotic symptoms can improve within
1 week, but it may take several weeks for
full effect on behavior as well as on
Class cognition and affective stabilization
• Atypical antipsychotic (serotonin-dopamine • Classically recommended to wait at least
antagonist; second generation 4–6 weeks to determine efficacy of drug,
antipsychotic; also a mood stabilizer) but in practice some patients require up to
16–20 weeks to show a good response,
Commonly Prescribed For especially on cognitive symptoms
(bold for FDA approved)
• Schizophrenia If It Works
• Maintaining response in schizophrenia • Most often reduces positive symptoms in
• Acute agitation associated with schizophrenia but does not eliminate them
schizophrenia (intramuscular) • Can improve negative symptoms, as well
• Acute mania (monotherapy and adjunct to as aggressive, cognitive, and affective
lithium or valproate) symptoms in schizophrenia
• Bipolar maintenance • Most schizophrenic patients do not have a
• Acute agitation associated with bipolar I total remission of symptoms but rather a
mania (intramuscular) reduction of symptoms by about a third
• Bipolar depression [in combination with • Perhaps 5–15% of schizophrenic patients
fluoxetine (Symbyax)] can experience an overall improvement of
• Other psychotic disorders greater than 50–60%, especially when
• Unipolar depression unresponsive to receiving stable treatment for more than a
antidepressants year
• Behavioral disturbances in dementias • Such patients are considered super-
• Behavioral disturbances in children and responders or “awakeners” since they may
adolescents be well enough to be employed, live
• Disorders associated with problems with independently, and sustain long-term
impulse control relationships
• Many bipolar patients may experience a
reduction of symptoms by half or more
How The Drug Works • Continue treatment until reaching a plateau
• Blocks dopamine 2 receptors, reducing of improvement
positive symptoms of psychosis and • After reaching a satisfactory plateau,
stabilizing affective symptoms continue treatment for at least a year after
• Blocks serotonin 2A receptors, causing first episode of psychosis
enhancement of dopamine release in • For second and subsequent episodes of
certain brain regions and thus reducing psychosis, treatment may need to be
motor side effects and possibly improving indefinite
cognitive and affective symptoms • Even for first episodes of psychosis, it may
• Interactions at a myriad of other be preferable to continue treatment
neurotransmitter receptors may contribute indefinitely to avoid subsequent episodes
to olanzapine’s efficacy • Treatment may not only reduce mania but
✽ Specifically, antagonist actions at 5HT2C also prevent recurrences of mania in
receptors may contribute to efficacy for bipolar disorder

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OLANZAPINE (continued)

If It Doesn’t Work • has diabetes (fasting plasma glucose

• Try one of the other atypical antipsychotics >126 mg/dl)
(risperidone, quetiapine, ziprasidone, • has hypertension (BP >140/90 mm Hg)
aripiprazole, amisulpride) • has dyslipidemia (increased total
• If 2 or more antipsychotic monotherapies cholesterol, LDL cholesterol, and
do not work, consider clozapine triglycerides; decreased HDL cholesterol)
• If no first-line atypical antipsychotic is • Treat or refer such patients for treatment,
effective, consider higher doses or including nutrition and weight
augmentation with valproate or lamotrigine management, physical activity counseling,
• Some patients may require treatment with smoking cessation, and medical
a conventional antipsychotic management
• Consider noncompliance and switch to Monitoring after starting an atypical
another antipsychotic with fewer side antipsychotic
effects or to an antipsychotic that can be ✽ BMI monthly for 3 months, then quarterly
given by depot injection ✽ Blood pressure, fasting plasma glucose,
• Consider initiating rehabilitation and fasting lipids within 3 months and then
psychotherapy annually, but earlier and more frequently
• Consider presence of concomitant drug for patients with diabetes or who have
abuse gained >5% of initial weight
• Treat or refer for treatment and consider
Best Augmenting Combos switching to another atypical antipsychotic
for Partial Response or for patients who become overweight,
Treatment-Resistance obese, pre-diabetic, diabetic, hypertensive,
• Valproic acid (valproate, divalproex, or dyslipidemic while receiving an atypical
divalproex ER) antipsychotic
• Other mood stabilizing anticonvulsants ✽ Even in patients without known diabetes,
(carbamazepine, oxcarbazepine, be vigilant for the rare but life threatening
lamotrigine) onset of diabetic ketoacidosis, which
• Lithium always requires immediate treatment, by
• Benzodiazepines monitoring for the rapid onset of polyuria,
• Fluoxetine and other antidepressants may polydipsia, weight loss, nausea, vomiting,
be effective augmenting agents to dehydration, rapid respiration, weakness
olanzapine for bipolar depression, and clouding of sensorium, even coma
psychotic depression, and for unipolar • Patients with liver disease should have
depression not responsive to blood tests a few times a year
antidepressants alone (e.g., olanzapine-
fluoxetine combination)

Tests SIDE EFFECTS

Before starting an atypical antipsychotic How Drug Causes Side Effects
✽ Weigh all patients and track BMI during • By blocking histamine 1 receptors in the
treatment brain, it can cause sedation and possibly
• Get baseline personal and family history of weight gain
obesity, dyslipidemia, hypertension, and • By blocking alpha 1 adrenergic receptors, it
cardiovascular disease can cause dizziness, sedation, and
✽ Get waist circumference (at umbilicus), hypotension
blood pressure, fasting plasma glucose, • By blocking muscarinic 1 receptors, it can
and fasting lipid profile cause dry mouth, constipation, and
• Determine if the patient is sedation
• overweight (BMI 25.0–29.9) • By blocking dopamine 2 receptors in the
• obese (BMI ≥30) striatum, it can cause motor side effects
• has pre-diabetes (fasting plasma glucose (unusual)
100–125 mg/dl)

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(continued) OLANZAPINE

• Mechanism of weight gain and increased • May be less than for some antipsychotics,
incidence of diabetes and dyslipidemia with more than for others
atypical antipsychotics is unknown
What To Do About Side Effects
Notable Side Effects • Wait
✽ Probably increases risk for diabetes • Wait
mellitus and dyslipidemia • Wait
• Dizziness, sedation • Take at bedtime to help reduce daytime
• Dry mouth, constipation, dyspepsia, weight sedation
gain • Anticholinergics may reduce motor side
• Joint pain, back pain, chest pain, extremity effects such as akathisia when present, but
pain, abnormal gait, ecchymosis, peripheral rarely necessary
edema • Weight loss, exercise programs, and
• Tachycardia medical management for high BMIs,
• Rare orthostatic hypotension, usually diabetes, dyslipidemia
during initial dose titration • Switch to another atypical antipsychotic
• Rare tardive dyskinesia (much reduced risk
compared to conventional antipsychotics) Best Augmenting Agents for Side
• Rare rash on exposure to sunlight Effects
• Benztropine or trihexyphenidyl for motor
side effects
Life Threatening or • Many side effects cannot be improved with
Dangerous Side Effects an augmenting agent
• Hyperglycemia, in some cases extreme and
associated with ketoacidosis or
hyperosmolar coma or death, has been
reported in patients taking atypical
DOSING AND USE
antipsychotics Usual Dosage Range
• Increased incidence of cerebrovascular
• 10–20 mg/day (oral or intramuscular)
events, including stoke, transient ischemic
• 6–12 mg olanzapine / 25–50 mg fluoxetine
attacks, and fatalities, in elderly patients
(olanzapine-fluoxetine combination)
with dementia
• Increased incidence of mortality in elderly Dosage Forms
patients with dementia-related psychosis • Tablets 2.5 mg, 5 mg, 7.5 mg, 10 mg,
• Rare neuroleptic malignant syndrome 15 mg, 20 mg
(much reduced risk compared to • Orally disintegrating tablets 5 mg, 10 mg,
conventional antipsychotics) 15 mg, 20 mg
• Rare seizures • Intramuscular formulation 5 mg/mL, each
vial contains 10 mg (available in some
Weight Gain
countries)
• Olanzapine-fluoxetine combination capsule
(mg equivalent olanzapine/mg equivalent
• Frequent and can be significant in amount fluoxetine) 6 mg/25 mg, 6 mg/50 mg,
• Can become a health problem in some 12 mg/25 mg, 12 mg/50 mg
• More than for some other antipsychotics,
but never say always as not a problem in How to Dose
everyone • Initial 5–10 mg once daily orally; increase
by 5 mg/day once a week until desired
Sedation efficacy is reached; maximum approved
dose is 20 mg/day
• For intramuscular formulation,
recommended initial dose 10 mg; second
• Many patients experience and/or can be
injection of 5–10 mg may be administered
significant in amount
2 hours after first injection; maximum daily
• Usually transient

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OLANZAPINE (continued)

dose of olanzapine is 20 mg, with no more • Often used for long-term maintenance in
than 3 injections per 24 hours various behavioral disorders
• For olanzapine-fluoxetine combination,
recommended initial dose 6 mg/25 mg Habit Forming
once daily in evening; increase dose based • No
on efficacy and tolerability; maximum
generally 18 mg/75 mg How to Stop
• Slow down-titration of oral formulation
(over 6 to 8 weeks), especially when
simultaneously beginning a new
Dosing Tips
antipsychotic while switching (i.e., cross-
✽ More may be more: raising usual dose titration)
above 15 mg/day can be useful for acutely
• Rapid oral discontinuation may lead to
ill and agitated patients and some
rebound psychosis and worsening of
treatment-resistant patients, gaining
symptoms
efficacy without many more side effects
✽ Some heroic uses for patients who do not Pharmacokinetics
respond to other antipsychotics can • Metabolites are inactive
occasionally justify dosing over 30 mg/day • Parent drug has 21–54 hour half-life
• Usual doses (>15 mg/day range) can be
among the most costly among atypical
antipsychotics, and dosing >30 mg/day can
be very expensive Drug Interactions
• Rather than raise the dose above these • May increase effect of anti-hypertensive
levels in acutely agitated patients requiring agents
acute antipsychotic actions, consider • May antagonize levodopa, dopamine
augmentation with a benzodiazepine or agonists
conventional antipsychotic, either orally or • Dose may need to be lowered if given with
intramuscularly CYP450 1A2 inhibitors (e.g., fluvoxamine);
• Rather than raise the dose above these raised if given in conjunction with CYP450
levels in partial responders, consider 1A2 inducers (e.g., cigarette smoke,
augmentation with a mood stabilizing carbamazepine)
anticonvulsant, such as valproate or
lamotrigine Other Warnings/
• Clearance of olanzapine is reduced in Precautions
women compared to men, so women may • Use with caution in patients with
need lower doses than men conditions that predispose to hypotension
• Children and elderly should generally be (dehydration, overheating)
dosed at the lower end of the dosage • Use with caution in patients with prostatic
spectrum hypertrophy, narrow angle-closure
✽ Olanzapine intramuscularly can be given glaucoma, paralytic ileus
short-term, both to initiate dosing with oral • Patients receiving the intramuscular
olanzapine or another oral antipsychotic formulation of olanzapine should be
and to treat breakthrough agitation in observed closely for hypotension
patients maintained on oral antipsychotics • Intramuscular formulation is not generally
recommended to be administered with
Overdose
parenteral benzodiazepines; if patient
• Rarely lethal in monotherapy overdose;
requires a parenteral benzodiazepine it
sedation, slurred speech
should be given at least 1 hour after
Long-Term Use intramuscular olanzapine
• Approved to maintain response in long- • Olanzapine should be used cautiously in
term treatment of schizophrenia patients at risk for aspiration pneumonia,
• Approved for long-term maintenance in as dysphagia has been reported
bipolar disorder

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(continued) OLANZAPINE

Do Not Use for behavioral disturbances in children and

• If there is a known risk of narrow adolescents
angle-closure glaucoma (intramuscular • Children and adolescents using olanzapine
formulation) may need to be monitored more often than
• If patient has unstable medical condition adults
(e.g., acute myocardial infarction, unstable • Intramuscular formulation has not been
angina pectoris, severe hypotension and/or studied in patients under 18 and is not
bradycardia, sick sinus syndrome, recent recommended for use in this population
heart surgery) (intramuscular formulation)
• If there is a proven allergy to olanzapine
Pregnancy
• Risk Category C [some animal studies
SPECIAL POPULATIONS show adverse effects, no controlled studies
in humans]
Renal Impairment • Psychotic symptoms may worsen during
• No dose adjustment required for oral pregnancy, and some form of treatment
formulation may be necessary
• Not removed by hemodialysis • Early findings of infants exposed to
• For intramuscular formulation, consider olanzapine in utero currently do not show
lower starting dose (5 mg) adverse consequences
• Olanzapine may be preferable to
Hepatic Impairment anticonvulsant mood stabilizers if
• May need to lower dose treatment is required during pregnancy
• Patients with liver disease should have liver
function tests a few times a year Breast Feeding
• For moderate to severe hepatic impairment, • Unknown if olanzapine is secreted in
starting oral dose 5 mg; increase with human breast milk, but all psychotropics
caution assumed to be secreted in breast milk
• For intramuscuar formulation, consider ✽ Recommended either to discontinue drug
lower starting dose (5 mg) or bottle feed
• Infants of women who choose to breast
Cardiac Impairment feed while on olanzapine should be
• Drug should be used with caution because monitored for possible adverse effects
of risk of orthostatic hypotension

Elderly
• Some patients may tolerate lower doses
THE ART OF PSYCHOPHARMACOLOGY
better Potential Advantages
• Increased incidence of stroke
• For intramuscular formulation,
✽ Some cases of psychosis and bipolar
disorder refractory to treatment with other
recommended starting dose is 2.5–5 mg; a
antipsychotics
second injection of 2.5–5 mg may be
administered 2 hours after first injection;
✽ Often a preferred augmenting agent in
bipolar depression or treatment-resistant
no more than 3 injections should be
unipolar depression
administered within 24 hours
✽ Patients needing rapid onset of
antipsychotic action without drug titration
• Patients switching from intramuscular
Children and Adolescents olanzapine to an oral preparation
• Not officially recommended under age 18;
however, olanzapine is often used for Potential Disadvantages
patients under 18 • Patients concerned about gaining weight
• Clinical experience and early data suggest ✽ Patients with diabetes mellitus
olanzapine is probably safe and effective

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OLANZAPINE (continued)

Primary Target Symptoms • More weight gain than other antipsychotics

• Positive symptoms of psychosis —does not mean every patient gains weight
• Negative symptoms of psychosis • Motor side effects unusual at low- to
• Cognitive symptoms mid-doses
• Unstable mood (both depressed mood and • Less sedation than for some other
mania) antipsychotics, more than for others
• Aggressive symptoms ✽ Controversial as to whether olanzapine
has more risk of diabetes and dyslipidemia
than other antipsychotics
Pearls • One of the most expensive atypical
• Well accepted for use in schizophrenia and antipsychotics within the usual therapeutic
bipolar disorder, including difficult cases dosing range
• Cigarette smoke can decrease olanzapine
✽ Documented utility in treatment- levels and patients may require a dose
refractory cases, especially at higher doses
increase if they begin or increase smoking
✽ Documented efficacy as augmenting ✽ One of only two atypical antipsychotics
agent to SSRIs (especially fluoxetine) in
nonpsychotic treatment-resistant major with a short-acting intramuscular dosage
depressive disorder formulation
✽ Documented efficacy in bipolar
depression, especially in combination with
fluoxetine

Suggested Reading
Duggan L, Fenton M, Dardennes RM, El- Tandon R, Jibson MD. Efficacy of newer
Dosoky A, Indran S. Olanzapine for generation antipsychotics in the treatment of
schizophrenia. Cochrane Database Syst Rev schizophrenia. Psychoneuroendocrinology
2003;(1):CD001359. 2003;28:9–26.
Kapur S, Remington G. Atypical Yatham LN. Efficacy of atypical antipsychotics
antipsychotics: new directions and new in mood disorders. J Clin Psychopharmacol
challenges in the treatment of schizophrenia. 2003;23(3 Suppl 1):S9–14.
Annu Rev Med 2001;52:503–17.
Tandon R. Safety and tolerability: how do new
generation “atypical” antipsychotics compare?
Psychiatric Quarterly 2002;73:297–311.

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OXAZEPAM
THERAPEUTICS restarting the benzodiazepine; sometimes
benzodiazepines have to be used in
Brands • Serax combination with SSRIs or SNRIs for best
see index for additional brand names results
Generic? Yes If It Doesn’t Work
• Consider switching to another agent or
adding an appropriate augmenting agent
Class • Consider psychotherapy, especially
• Benzodiazepine (anxiolytic) cognitive behavioral psychotherapy
• Consider presence of concomitant
Commonly Prescribed For substance abuse
(bold for FDA approved) • Consider presence of oxazepam abuse
• Anxiety • Consider another diagnosis, such as a
• Anxiety associated with depression comorbid medical condition
• Alcohol withdrawal
Best Augmenting Combos
for Partial Response or
How The Drug Works Treatment-Resistance
• Binds to benzodiazepine receptors at the • Benzodiazepines are frequently used as
GABA-A ligand-gated chloride channel augmenting agents for antipsychotics and
complex mood stabilizers in the treatment of
• Enhances the inhibitory effects of GABA psychotic and bipolar disorders
• Boosts chloride conductance through • Benzodiazepines are frequently used as
GABA-regulated channels augmenting agents for SSRIs and SNRIs in
• Inhibits neuronal activity presumably in the treatment of anxiety disorders
amygdala-centered fear circuits to provide • Not generally rational to combine with
therapeutic benefits in anxiety disorders other benzodiazepines
• Caution if using as an anxiolytic
How Long Until It Works concomitantly with other sedative
• Some immediate relief with first dosing is hypnotics for sleep
common; can take several weeks with daily
dosing for maximal therapeutic benefit Tests
• In patients with seizure disorders,
If It Works concomitant medical illness, and/or those
• For short-term symptoms of anxiety – after with multiple concomitant long-term
a few weeks, discontinue use or use on an medications, periodic liver tests and blood
“as-needed” basis counts may be prudent
• For chronic anxiety disorders, the goal of
treatment is complete remission of
symptoms as well as prevention of future SIDE EFFECTS
relapses
• For chronic anxiety disorders, treatment How Drug Causes Side Effects
most often reduces or even eliminates • Same mechanism for side effects as for
symptoms, but not a cure since symptoms therapeutic effects – namely due to
can recur after medicine stopped excessive actions at benzodiazepine
• For long-term symptoms of anxiety, receptors
consider switching to an SSRI or SNRI for • Long-term adaptations in benzodiazepine
long-term maintenance receptors may explain the development of
• If long-term maintenance with a dependence, tolerance, and withdrawal
benzodiazepine is necessary, continue • Side effects are generally immediate, but
treatment for 6 months after symptoms immediate side effects often disappear in
resolve, and then taper dose slowly time
• If symptoms reemerge, consider treatment
with an SSRI or SNRI, or consider

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OXAZEPAM (continued)

Notable Side Effects • Severe anxiety, anxiety associated with

✽ Sedation, fatigue, depression alcohol withdrawal: 45–120 mg/day in
✽ Dizziness, ataxia, slurred speech, 3–4 divided doses
weakness
✽ Forgetfulness, confusion Dosage Forms
✽ Hyper-excitability, nervousness • Capsule 10 mg, 15 mg, 30 mg
• Rare hallucinations, mania • Tablet 15 mg
• Rare hypotension
• Hypersalivation, dry mouth How to Dose
• Titration generally not necessary

Life Threatening or
Dangerous Side Effects Dosing Tips
• Respiratory depression, especially when • Use lowest possible effective dose for the
taken with CNS depressants in overdose shortest possible period of time (a
• Rare hepatic dysfunction, renal benzodiazepine-sparing strategy)
dysfunction, blood dyscrasias • 15 mg tablet contains tartrazine, which
may cause allergic reactions in certain
Weight Gain
patients, particularly those who are
sensitive to aspirin
• For inter-dose symptoms of anxiety, can
• Reported but not expected either increase dose or maintain same total
daily dose but divide into more frequent
Sedation doses
• Can also use an as-needed occasional “top
up” dose for inter-dose anxiety
• Many experience and/or can be significant • Because anxiety disorders can require
in amount higher doses, the risk of dependence may
• Especially at initiation of treatment or when be greater in these patients
dose increases • Some severely ill patients may require
• Tolerance often develops over time doses higher than the generally
recommended maximum dose
What To Do About Side Effects • Frequency of dosing in practice is often
• Wait greater than predicted from half-life, as
• Wait duration of biological activity is often
• Wait shorter than pharmacokinetic terminal half-
• Lower the dose life
• Take largest dose at bedtime to avoid
sedative effects during the day Overdose
• Switch to another agent • Fatalities can occur; hypotension,
• Administer flumazenil if side effects are tiredness, ataxia, confusion, coma
severe or life-threatening
Long-Term Use
Best Augmenting Agents for Side • Risk of dependence, particularly for
Effects treatment periods longer than 12 weeks
and especially in patients with past or
• Many side effects cannot be improved with
current polysubstance abuse
an augmenting agent
Habit Forming
• Oxazepam is a Schedule IV drug
DOSING AND USE • Patients may develop dependence and/or
tolerance with long-term use
Usual Dosage Range
• Mild to moderate anxiety: 30–60 mg/day in
3–4 divided doses

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(continued) OXAZEPAM

How to Stop • Some depressed patients may experience a

• Patients with history of seizure may seize worsening of suicidal ideation
upon withdrawal, especially if withdrawal is • Some patients may exhibit abnormal
abrupt thinking or behavioral changes similar to
• Taper by 15 mg every 3 days to reduce those caused by other CNS depressants
chances of withdrawal effects (i.e., either depressant actions or
• For difficult to taper cases, consider disinhibiting actions)
reducing dose much more slowly once
reaching 45 mg/day, perhaps by as little as Do Not Use
10 mg per week or less • If patient has narrow angle-closure
• For other patients with severe problems glaucoma
discontinuing a benzodiazepine, dosing • If there is a proven allergy to oxazepam or
may need to be tapered over many months any benzodiazepine
(i.e., reduce dose by 1% every 3 days by
crushing tablet and suspending or
dissolving in 100 ml of fruit juice and then SPECIAL POPULATIONS
disposing of 1 ml while drinking the rest;
3–7 days later, dispose of 2 ml, and so on). Renal Impairment
This is both a form of very slow biological • Use with caution; oxazepam levels may be
tapering and a form of behavioral increased
desensitization
• Be sure to differentiate reemergence of Hepatic Impairment
symptoms requiring reinstitution of • Use with caution; oxazepam levels may be
treatment from withdrawal symptoms increased
• Benzodiazepine-dependent anxiety patients • Because of its short half-life and inactive
and insulin-dependent diabetics are not metabolites, oxazepam may be a preferred
addicted to their medications. When benzodiazepine in some patients with liver
benzodiazepine-dependent patients stop disease
their medication, disease symptoms can
reemerge, disease symptoms can worsen Cardiac Impairment
(rebound), and/or withdrawal symptoms • Benzodiazepines have been used to treat
can emerge anxiety associated with acute myocardial
infarction
Pharmacokinetics
• Elimination half-life 3–21 hours Elderly
• No active metabolites • Initial 30 mg in 3 divided doses; can be
increased to 30–60 mg/day in 3–4 divided
doses
Drug Interactions
• Increased depressive effects when taken
with other CNS depressants Children and Adolescents
• Safety and efficacy not established under
age 6
Other Warnings/ • No clear dosing guidelines for children
Precautions ages 6–12
• Dosage changes should be made in • Long-term effects of oxazepam in
collaboration with prescriber children/adolescents are unknown
• Use with caution in patients with • Should generally receive lower doses and
pulmonary disease; rare reports of death be more closely monitored
after initiation of benzodiazepines in
patients with severe pulmonary impairment
• History of drug or alcohol abuse often
creates greater risk for dependency

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OXAZEPAM (continued)

Potential Disadvantages
• Euphoria may lead to abuse
Pregnancy • Abuse especially risky in past or present
• Risk Category D [positive evidence of risk substance abusers
to human fetus; potential benefits may still
justify its use during pregnancy] Primary Target Symptoms
• Possible increased risk of birth defects • Panic attacks
when benzodiazepines taken during • Anxiety
pregnancy • Agitation
• Because of the potential risks, oxazepam is
not generally recommended as treatment
for anxiety during pregnancy, especially
Pearls
during the first trimester
• Can be a very useful adjunct to SSRIs and
• Drug should be tapered if discontinued
SNRIs in the treatment of numerous
• Infants whose mothers received a
anxiety disorders
benzodiazepine late in pregnancy may
• Not effective for treating psychosis as a
experience withdrawal effects
monotherapy, but can be used as an
• Neonatal flaccidity has been reported in
adjunct to antipsychotics
infants whose mothers took a
• Not effective for treating bipolar disorder
benzodiazepine during pregnancy
as a monotherapy, but can be used as an
• Seizures, even mild seizures, may cause
adjunct to mood stabilizers and
harm to the embryo/fetus
antipsychotics
Breast Feeding ✽ Because of its short half-life and inactive
• Some drug is found in mother’s breast milk metabolites, oxazepam may be preferred
✽ Recommended either to discontinue drug over some benzodiazepines for patients
with liver disease
or bottle feed
• Effects on infant have been observed and • Oxazepam may be preferred over some
include feeding difficulties, sedation, and other benzodiazepines for the treatment of
weight loss delirium
• Can both cause and treat depression in
different patients
• When using to treat insomnia, remember
THE ART OF PSYCHOPHARMACOLOGY that insomnia may be a symptom of some
Potential Advantages other primary disorder itself, and thus
warrant evaluation for comorbid psychiatric
• Rapid onset of action
and/or medical conditions

Suggested Reading
Ayd FJ Jr. Oxazepam: update 1989. Int Clin Greenblatt DJ. Clinical pharmacokinetics of
Psychopharmacol 1990;5:1–15. oxazepam and lorazepam. Clin Pharmacokinet
1981;6:89–105.
Garattini S. Biochemical and pharmacological
properties of oxazepam. Acta Psychiatr Scand
Suppl 1978;274:9–18.

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OXCARBAZEPINE
THERAPEUTICS improved but others persist or continue to
wax and wane without stabilization of
Brands • Trileptal mood
see index for additional brand names • Other patients may be nonresponders,
sometimes called treatment-resistant or
Generic? No
treatment-refractory
• Consider increasing dose, switching to
another agent or adding an appropriate
Class augmenting agent
• Anticonvulsant, voltage-sensitive sodium • Consider adding psychotherapy
channel antagonist • For bipolar disorder, consider the presence
of noncompliance and counsel patient
Commonly Prescribed For • Switch to another mood stabilizer with
(bold for FDA approved) fewer side effects
• Partial seizures in adults with epilepsy • Consider evaluation for another diagnosis
(monotherapy or adjunctive) or for a comorbid condition (e.g., medical
• Partial seizures in children ages 4–16 illness, substance abuse, etc.)
with epilepsy (monotherapy or
adjunctive) Best Augmenting Combos
• Bipolar disorder for Partial Response or
Treatment-Resistance
• Oxcarbazepine is itself a second-line
How The Drug Works augmenting agent for numerous other
✽ Acts as a use-dependent blocker of anticonvulsants, lithium, and atypical
voltage-sensitive sodium channels antipsychotics in treating bipolar disorder,
✽ Interacts with the open channel although its use in bipolar disorder is not
conformation of voltage-sensitive sodium yet well-studied
channels • Oxcarbazepine may be a second or third-
✽ Interacts at a specific site of the alpha line augmenting agent for antipsychotics in
pore-forming subunit of voltage-sensitive treating schizophrenia, although its use in
sodium channels schizophrenia is also not yet well-studied
• Inhibits release of glutamate
Tests
How Long Until It Works • Consider monitoring sodium levels
• For acute mania, effects should occur because of possibility of hyponatremia,
within a few weeks especially during the first 3 months
• May take several weeks to months to
optimize an effect on mood stabilization
• Should reduce seizures by 2 weeks SIDE EFFECTS
If It Works How Drug Causes Side Effects
• The goal of treatment is complete • CNS side effects theoretically due to
remission of symptoms (e.g., seizures, excessive actions at voltage-sensitive
mania) sodium channels
• Continue treatment until all symptoms are
gone or until improvement is stable and Notable Side Effects
then continue treating indefinitely as long ✽ Sedation, dizziness, headache, ataxia,
as improvement persists nystagmus, abnormal gait, confusion,
• Continue treatment indefinitely to avoid nervousness, fatigue
recurrence of mania and seizures ✽ Nausea, vomiting, abdominal pain,
dyspepsia
If It Doesn’t Work (for bipolar • Diplopia, vertigo, abnormal vision
disorder) ✽ Rash
✽ Many patients only have a partial
response where some symptoms are

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OXCARBAZEPINE (continued)

• When converting from adjunctive to

Life Threatening or monotherapy in the treatment of epilepsy,
Dangerous Side Effects titrate concomitant drug down over 3–6
• Hyponatremia weeks while titrating oxcarbazepine up over
2–4 weeks, with an initial daily
Weight Gain oxcarbazepine dose of 600 mg divided in
2 doses

• Occurs in significant minority

• Some patients experience increased Dosing Tips
appetite ✽ Doses of oxcarbazepine need to be about
one-third higher than those of
Sedation carbamazepine for similar results
• Usually administered as adjunctive
medication to other anticonvulsants,
• Occurs in significant minority lithium, or atypical antipsychotics for
• Dose-related bipolar disorder
• Less than carbamazepine • Side effects may increase with dose
• More when combined with other • Although increased efficacy for seizures is
anticonvulsants seen at 2400 mg/day compared to
• Can wear off with time, but may not wear 1200 mg/day, CNS side effects may be
off at high doses intolerable at the higher dose
• Liquid formulation can be administered
What To Do About Side Effects mixed in a glass of water or directly from
• Wait the oral dosing syringe supplied
• Wait • Slow dose titration may delay onset of
• Wait therapeutic action but enhance tolerability
• Switch to another agent to sedating side effects
• Should titrate slowly in the presence of
Best Augmenting Agents for Side other sedating agents, such as other
Effects anticonvulsants, in order to best tolerate
• Many side effects cannot be improved with additive sedative side effects
an augmenting agent
Overdose
• No fatalities reported
DOSING AND USE Long-Term Use
Usual Dosage Range • Safe
• Monitoring of sodium may be required,
• 1200–2400 mg/day
especially during the first 3 months
Dosage Forms
Habit Forming
• Tablet 150 mg, 300 mg, 600 mg
• No
• Liquid 300 mg/5 mL

How to Dose How to Stop

• Taper
• Monotherapy for seizures or bipolar
• Epilepsy patients may seize upon
disorder: initial 600 mg/day in 2 doses;
withdrawal, especially if withdrawal is
increase every 3 days by 300 mg/day;
abrupt
maximum dose generally 2400 mg/day
• Adjunctive: initial 600 mg/day in 2 doses; ✽ Rapid discontinuation may increase the
risk of relapse in bipolar disorder
each week can increase by 600 mg/day;
• Discontinuation symptoms uncommon
recommended dose 1200 mg/day;
maximum dose generally 2400 mg/day Pharmacokinetics
• Metabolized in the liver

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(continued) OXCARBAZEPINE

• Renally excreted • If there is a proven allergy to any tricyclic

• Inhibits CYP450 2C19 compound
✽ Oxcarbazepine is a prodrug for • If there is a proven allergy to
10-hydroxy carbazepine oxcarbazepine
✽ This main active metabolite is sometimes
called the monohydroxy derivative or MHD,
and is also known as licarbazepine SPECIAL POPULATIONS
✽ Half-life of parent drug is approximately 2
hours; half-life of MHD is approximately 9 Renal Impairment
hours; thus oxcarbazepine is essentially a • Oxcarbazepine is renally excreted
prodrug rapidly converted to its MHD, • Elimination half-life of active metabolite
licarbazepine MHD is increased
• A mild inducer of CYP450 3A4 • Reduce initial dose by half; may need to
use slower titration

Drug Interactions Hepatic Impairment

• Depressive effects may be increased by • No dose adjustment recommended for mild
other CNS depressants (alcohol, MAOIs, to moderate hepatic impairment
other anticonvulsants, etc.)
• Strong inducers of CYP450 cytochromes
Cardiac Impairment
(e.g., carbamazepine, phenobarbital, • No dose adjustment recommended
phenytoin, and primidone) can decrease Elderly
plasma levels of the active metabolite MHD
• Older patients may have reduced creatinine
• Verapamil may decrease plasma levels of
clearance and require reduced dosing
the active metabolite MHD
• Elderly patients may be more susceptible
• Oxcarbazepine can decrease plasma levels
to adverse effects
of hormonal contraceptives and
• Some patients may tolerate lower doses
dihydropyridine calcium antagonists
better
• Oxcarbazepine at doses greater than 1200
mg/day may increase plasma levels of
phenytoin, possibly requiring dose
reduction of phenytoin Children and Adolescents
• Approved as adjunctive therapy or
monotherapy for partial seizures in children
Other Warnings/ 4 and older
Precautions • Ages 4–16 (adjunctive): initial
• Because oxcarbazepine has a tricyclic 8–10 mg/kg/day or less than 600 mg/day
chemical structure, it is not recommended in 2 doses; increase over 2 weeks to
to be taken with MAOIs, including 14 days 900 mg/day (20–29 kg), 1200 mg/day
after MAOIs are stopped; do not start an (29.1–39 kg), or 1800 mg/day (>39 kg)
MAOI until 2 weeks after discontinuing • When converting from adjunctive to
oxcarbazepine monotherapy, titrate concomitant drug
• Because oxcarbazepine can lower plasma down over 3–6 weeks while titrating
levels of hormonal contraceptives, it may oxcarbazepine up by no more than
also reduce their effectiveness 10 mg/kg/day each week, with an initial
• May exacerbate narrow angle-closure daily oxcarbazepine dose of
glaucoma 8–10 mg/kg/day divided in 2 doses
• May need to restrict fluids and/or monitor • Monotherapy: Initial 8–10 mg/kg/day in
sodium because of risk of hyponatremia 2 doses; increase every 3 days by
• Use cautiously in patients who have 5 mg/kg/day; recommended maintenance
demonstrated hypersensitivity to dose dependent on weight
carbamazepine • 0–20 kg (600–900 mg/day);
21–30 kg (900–1200 mg/day);
Do Not Use 31–40 kg (900–1500 mg/day);
• If patient is taking an MAOI

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OXCARBAZEPINE (continued)

41–45 kg (1200–1500 mg/day); • If drug is continued while breast feeding,

46–55 kg (1200–1800 mg/day); infant should be monitored for possible
56–65 kg (1200–2100 mg/day); adverse effects
over 65 kg (1500–2100 mg) • If infant shows signs of irritability or
• Children below age 8 may have increased sedation, drug may need to be
clearance compared to adults discontinued
• Bipolar disorder may recur during the
postpartum period, particularly if there is a
Pregnancy history of prior postpartum episodes of
• Risk category C [some animal studies either depression or psychosis
show adverse effects, no controlled studies ✽ Relapse rates may be lower in women
in humans] who receive prophylactic treatment for
✽ Oxcarbazepine is structurally similar to postpartum episodes of bipolar disorder
• Atypical antipsychotics and anticonvulsants
carbamazepine, which is thought to be
teratogenic in humans such as valproate may be safer than
✽ Use during first trimester may raise risk oxcarbazepine during the postpartum
period when breast feeding
of neural tube defects (e.g., spina bifida) or
other congenital anomalies
• Use in women of childbearing potential
requires weighing potential benefits to the THE ART OF PSYCHOPHARMACOLOGY
mother against the risks to the fetus
✽ If drug is continued, perform tests to Potential Advantages
detect birth defects • Treatment-resistant bipolar and psychotic
✽ If drug is continued, start on folate disorders
1 mg/day to reduce risk of neural tube • Those unable to tolerate carbamazepine but
defects who respond to carbamazepine
• Taper drug if discontinuing
✽ For bipolar patients, oxcarbazepine Potential Disadvantages
should generally be discontinued before • Patients at risk for hyponatremia
anticipated pregnancies
• Seizures, even mild seizures, may cause
Primary Target Symptoms
harm to the embryo/fetus • Incidence of seizures
• Recurrent bipolar illness during pregnancy • Severity of seizures
can be quite disruptive • Unstable mood, especially mania
✽ For bipolar patients, given the risk of
relapse in the postpartum period, some
form of mood stabilizer treatment may Pearls
need to be restarted immediately after ✽ Some evidence of effectiveness in
delivery if patient is unmedicated during treating acute mania; included in American
pregnancy Psychiatric Association’s bipolar treatment
✽ Atypical antipsychotics may be preferable guidelines as an option for acute treatment
to lithium or anticonvulsants such as and maintenance treatment of bipolar
oxcarbazepine if treatment of bipolar disorder
disorder is required during pregnancy • Some evidence of effectiveness as
• Bipolar symptoms may recur or worsen adjunctive treatment in schizophrenia and
during pregnancy and some form of schizoaffective disorders
treatment may be necessary • Oxcarbazepine is the 10-keto analog of
carbamazepine, but not a metabolite of
Breast Feeding carbamazepine
• Some drug is found in mother’s breast milk ✽ Oxcarbazepine seems to have the same
✽ Recommended either to discontinue drug mechanism of therapeutic action as
or bottle feed carbamazepine but with fewer side effects
✽ Specifically, risk of leukopenia, aplastic
anemia, agranulocytosis, elevated liver

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(continued) OXCARBAZEPINE

enzymes, or Stevens Johnson syndrome • The active S enantiomer of licarbazepine is

and serious rash associated with another related compound in development
carbamazepine does not seem to be as yet another novel mood stabilizer
associated with oxcarbazepine ✽ Most significant risk of oxcarbazepine
• Skin rash reactions to carbamazepine may may be clinically significant hyponatremia
resolve in 75% of patients with epilepsy (sodium level <125 m mol/L), most likely
when switched to oxcarbazepine; thus, occurring within the first 3 months of
25% of patients who experience rash with treatment, and occurring in 2–3% of
carbamazepine may also experience it with patients
oxcarbazepine • Unknown if this risk is higher than for
• Oxcarbazepine has much less prominent carbamazepine
actions on CYP 450 enzyme systems than ✽ Since SSRIs can sometimes also reduce
carbamazepine, and thus fewer drug-drug sodium due to SIADH (syndrome of
interactions inappropriate antidiuretic hormone
• Specifically, oxcarbazepine and its active production), patients treated with
metabolite, the monohydroxy derivative combinations of oxcarbazepine and SSRIs
(MHD), cause less enzyme induction of should be carefully monitored, especially in
CYP450 3A4 than the structurally-related the early stages of treatment
carbamazepine • By analogy with carbamazepine, could
• The active metabolite MHD, also called theoretically be useful in chronic
licarbazepine, is a racemic mixture of 80% neuropathic pain
S-MHD (active) and 20% R-MHD (inactive)
• R, S-licarbazepine is also in clinical
development as a novel mood stabilizer

Suggested Reading
Beydoun A. Safety and efficacy of Dietrich DE, Kropp S, Emrich HM.
oxcarbazepine: results of randomized, double- Oxcarbazepine in affective and schizoaffective
blind trials. Pharmacotherapy. 2000; 20(8 Pt disorders. Pharmacopsychiatry.
2):152S–158S. 2001;34:242–50.
Centorrino F, Albert MJ, Berry JM, Kelleher JP, Glauser TA. Oxcarbazepine in the treatment of
Fellman V, Line G, Koukopoulos AE, Kidwell epilepsy. Pharmacotherapy. 2001;21:904–19.
JE, Fogarty KV, Baldessarini RJ.
Oxcarbazepine: clinical experience with Hellewell JS. Oxcarbazepine (Trileptal) in the
hospitalized psychiatric patients. Bipolar treatment of bipolar disorders: a review of
Disord. 2003;5:370–4. efficacy and tolerability. J Affect Disord.
2002;72(Suppl 1):S23–34.

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PAROXETINE
THERAPEUTICS treatment and for up to 6 months after
initiating dosing
Brands • Paxil • May continue to work for many years to
• Paxil CR prevent relapse of symptoms
see index for additional brand names
If It Works
Generic? Yes (not for paroxetine CR) • The goal of treatment is complete
remission of current symptoms as well as
prevention of future relapses
Class • Treatment most often reduces or even
• SSRI (selective serotonin reuptake eliminates symptoms, but not a cure since
inhibitor); often classified as an symptoms can recur after medicine
antidepressant, but it is not just an stopped
antidepressant • Continue treatment until all symptoms are
gone (remission) or significantly reduced
Commonly Prescribed For (e.g., OCD, PTSD)
(bold for FDA approved) • Once symptoms are gone, continue
• Major depressive disorder (paroxetine treating for 1 year for the first episode of
and paroxetine CR) depression
• Obsessive-compulsive disorder (OCD) • For second and subsequent episodes of
• Panic disorder (paroxetine and paroxetine depression, treatment may need to be
CR) indefinite
• Social anxiety disorder (social phobia) • Use in anxiety disorders may also need to
(paroxetine and paroxetine CR) be indefinite
• Posttraumatic stress disorder (PTSD)
• Generalized anxiety disorder (GAD) If It Doesn’t Work
• Premenstrual dysphoric disorder (PMDD) • Many patients only have a partial response
(paroxetine CR) where some symptoms are improved but
others persist (especially insomnia, fatigue,
and problems concentrating in depression)
How The Drug Works • Other patients may be nonresponders,
• Boosts neurotransmitter serotonin sometimes called treatment-resistant or
• Blocks serotonin reuptake pump (serotonin treatment-refractory
transporter) • Some patients who have an initial response
• Desensitizes serotonin receptors, especially may relapse even though they continue
serotonin 1A autoreceptors treatment, sometimes called “poop-out”
• Presumably increases serotonergic • Consider increasing dose, switching to
neurotransmission another agent or adding an appropriate
• Paroxetine also has mild anticholinergic augmenting agent
actions • Consider psychotherapy
• Paroxetine may have mild norepinephrine • Consider evaluation for another diagnosis
reuptake blocking actions or for a comorbid condition (e.g., medical
illness, substance abuse, etc.)
How Long Until It Works • Some patients may experience apparent
✽ Some patients may experience relief of lack of consistent efficacy due to activation
insomnia or anxiety early after initiation of of latent or underlying bipolar disorder, and
treatment require antidepressant discontinuation and
• Onset of therapeutic actions usually not a switch to a mood stabilizer
immediate, but often delayed 2 to 4 weeks
• If it is not working within 6 to 8 weeks for Best Augmenting Combos
depression, it may require a dosage for Partial Response or
increase or it may not work at all Treatment-Resistance
• By contrast, for generalized anxiety, onset • Trazodone, especially for insomnia
of response and increases in remission • Bupropion, mirtazapine, reboxetine, or
rates may still occur after 8 weeks of atomoxetine (add with caution and at lower

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PAROXETINE (continued)

doses since paroxetine could theoretically • Note: patients with diagnosed or

raise atomoxetine levels); use undiagnosed bipolar or psychotic disorders
combinations of antidepressants with may be more vulnerable to CNS-activating
caution as this may activate bipolar actions of SSRIs
disorder and suicidal ideation • Autonomic (sweating)
• Modafinil, especially for fatigue, sleepiness, • Bruising and rare bleeding
and lack of concentration • Rare hyponatremia (mostly in elderly
• Mood stabilizers or atypical antipsychotics patients and generally reversible on
for bipolar depression, psychotic discontinuation of paroxetine)
depression, treatment-resistant depression,
or treatment-resistant anxiety disorders
• Benzodiazepines
Life Threatening or
• If all else fails for anxiety disorders, Dangerous Side Effects
consider gabapentin or tiagabine • Rare seizures
• Hypnotics for insomnia • Rare induction of mania and activation of
• Classically, lithium, buspirone, or thyroid suicidal ideation
hormone
Weight Gain
Tests
• None for healthy individuals
• Occurs in significant minority

SIDE EFFECTS Sedation

How Drug Causes Side Effects

• Theoretically due to increases in serotonin • Many experience and/or can be significant
concentrations at serotonin receptors in in amount
parts of the brain and body other than • Generally transient
those that cause therapeutic actions (e.g.,
unwanted actions of serotonin in sleep What To Do About Side Effects
centers causing insomnia, unwanted • Wait
actions of serotonin in the gut causing • Wait
diarrhea, etc.) • Wait
• Increasing serotonin can cause diminished • If paroxetine is sedating, take at night to
dopamine release and might contribute to reduce daytime drowsiness
emotional flattening, cognitive slowing, and • Reduce dose to 5–10 mg (12.5 mg for CR)
apathy in some patients until side effects abate, then increase as
• Most side effects are immediate but often tolerated, usually to at least 20 mg (25 mg
go away with time, in contrast to most CR)
therapeutic effects which are delayed and • In a few weeks, switch or add other drugs
are enhanced over time
✽ Paroxetine’s weak antimuscarinic Best Augmenting Agents for Side
properties can cause constipation, dry Effects
mouth, sedation • Often best to try another SSRI or another
antidepressant monotherapy prior to
Notable Side Effects resorting to augmentation strategies to
• Sexual dysfunction (men: delayed treat side effects
ejaculation, erectile dysfunction; men and • Trazodone or a hypnotic for insomnia
women: decreased sexual desire, • Bupropion, sildenafil, vardenafil, or tadalafil
anorgasmia) for sexual dysfunction
• Gastrointestinal (decreased appetite, • Bupropion for emotional flattening,
nausea, diarrhea, constipation, dry mouth) cognitive slowing, or apathy
• Mostly central nervous system (insomnia • Mirtazapine for insomnia, agitation, and
but also sedation, agitation, tremors, gastrointestinal side effects
headache, dizziness)

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(continued) PAROXETINE

• Benzodiazepines for jitteriness and anxiety, (12.5 mg/day CR) once a week; maximum
especially at initiation of treatment and 60 mg/day (75 mg/day CR); single dose
especially for anxious patients
• Many side effects are dose-dependent (i.e.,
they increase as dose increases, or they Dosing Tips
reemerge until tolerance re-develops) • 20 mg tablet is scored, so to save costs,
• Many side effects are time-dependent (i.e., give 10 mg as half of 20 mg tablet, since
they start immediately upon dosing and 10 mg and 20 mg tablets cost about the
upon each dose increase, but go away with same in many markets
time) • Given once daily, often at bedtime, but any
• Activation and agitation may represent the time of day tolerated
induction of a bipolar state, especially a • 20 mg/day (25 mg/day CR) is often
mixed dysphoric bipolar II condition sufficient for patients with social anxiety
sometimes associated with suicidal disorder and depression
ideation, and require the addition of • Other anxiety disorders, as well as difficult
lithium, a mood stabilizer or an atypical cases in general, may require higher
antipsychotic, and/or discontinuation of dosing
paroxetine • Occasional patients are dosed above 60
mg/day (75 mg/day CR), but this is for
experts and requires caution
DOSING AND USE • If intolerable anxiety, insomnia, agitation,
akathisia, or activation occur either upon
Usual Dosage Range dosing initiation or discontinuation,
• Depression: 20–50 mg (25–62.5 mg CR) consider the possibility of activated bipolar
disorder and switch to a mood stabilizer or
Dosage Forms an atypical antipsychotic
• Tablets 10 mg scored, 20 mg scored, • Liquid formulation easiest for doses below
30 mg, 40 mg 10 mg when used for cases that are very
• Controlled release tablets 12.5 mg, 25 mg intolerant to paroxetine or especially for
• Liquid 10 mg/5mL – 250 mL bottle very slow down-titration during
discontinuation for patients with
How to Dose withdrawal symptoms
• Depression: initial 20 mg (25 mg CR); • Paroxetine CR tablets not scored, so
usually wait a few weeks to assess drug chewing or cutting in half can destroy
effects before increasing dose, but can controlled release properties
increase by 10 mg/day (12.5 mg/day CR) • Unlike other SSRIs and antidepressants
once a week; maximum generally where dosage increments can be double
50 mg/day (62.5 mg/day CR); single dose and triple the starting dose, paroxetine’s
• Panic disorder: initial 10 mg/day dosing increments are in 50% increments
(12.5 mg/day CR); usually wait a few (i.e., 20, 30, 40; or 25, 37.5, 50 CR)
weeks to assess drug effects before • Paroxetine inhibits its own metabolism and
increasing dose, but can increase by thus plasma concentrations can double
10 mg/day (12.5 mg/day CR) once a week; when oral doses increase by 50%; plasma
maximum generally 60 mg/day (75 mg/day concentrations can increase 2–7 fold when
CR); single dose oral doses are doubled
• Social anxiety disorder: initial 20 mg/day
(25 mg/day CR); usually wait a few weeks
✽ Main advantage of CR is reduced side
effects, especially nausea and perhaps
to assess drug effects before increasing sedation, sexual dysfunction, and
dose, but can increase by 10 mg/day withdrawal
(12.5 mg/day CR) once a week; maximum
60 mg/day (75 mg/day CR); single dose
✽ For patients with severe problems
discontinuing paroxetine, dosing may need
• Other anxiety disorders: initial 20 mg/day to be tapered over many months (i.e.,
(25 mg/day CR); usually wait a few weeks reduce dose by 1% every 3 days by
to assess drug effects before increasing crushing tablet and suspending or
dose, but can increase by 10 mg/day

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PAROXETINE (continued)

dissolving in 100 mL of fruit juice and then Pharmacokinetics

disposing of 1 mL while drinking the rest; • Inactive metabolites
3–7 days later, dispose of 2 mL, and so • Half-life approximately 24 hours
on). This is both a form of very slow • Inhibits CYP450 2D6
biological tapering and a form of behavioral
desensitization
• For some patients with severe problems Drug Interactions
discontinuing paroxetine, it may be useful • Tramadol increases the risk of seizures in
to add an SSRI with a long half-life, patients taking an antidepressant
especially fluoxetine, prior to taper of • Can increase tricyclic antidepressant levels;
paroxetine; while maintaining fluoxetine use with caution with tricyclic
dosing, first slowly taper paroxetine and antidepressants or when switching from a
then taper fluoxetine TCA to paroxetine
• Be sure to differentiate between re- • Can cause a fatal “serotonin syndrome”
emergence of symptoms requiring re- when combined with MAO inhibitors, so do
institution of treatment and withdrawal not use with MAO inhibitors or for at least
symptoms 14 days after MAOIs are stopped
Overdose • Do not start an MAO inhibitor for at least
2 weeks after discontinuing paroxetine
• Rarely lethal in monotherapy overdose;
• May displace highly protein bound drugs
vomiting, sedation, heart rhythm
(e.g., warfarin)
disturbances, dilated pupils, dry mouth
• There are reports of elevated theophylline
Long-Term Use levels associated with paroxetine treatment,
• Safe so it is recommended that theophylline
levels be monitored when these drugs are
Habit Forming administered together
• No • May increase anticholinergic effects of
procyclidine and other drugs with
How to Stop anticholinergic properties
• Taper to avoid withdrawal effects • Can rarely cause weakness, hyperreflexia,
(dizziness, nausea, stomach cramps, and incoordination when combined with
sweating, tingling, dysesthesias) sumatriptan or possibly with other triptans,
• Many patients tolerate 50% dose reduction requiring careful monitoring of patient
for 3 days, then another 50% reduction for • Via CYP450 2D6 inhibition, paroxetine
3 days, then discontinuation could theoretically interfere with the
• If withdrawal symptoms emerge during analgesic actions of codeine, and increase
discontinuation, raise dose to stop the plasma levels of some beta blockers
symptoms and then restart withdrawal and of atomoxetine
much more slowly • Via CYP450 2D6 inhibition, paroxetine
✽ Withdrawal effects can be more common could theoretically increase concentrations
or more severe with paroxetine than with of thioridazine and cause dangerous
some other SSRIs cardiac arrhythmias
• Paroxetine’s withdrawal effects may be
related in part to the fact that it inhibits its Other Warnings/
own metabolism
Precautions
• Thus, when paroxetine is withdrawn, the
• Add or initiate other antidepressants with
rate of its decline can be faster as it stops
caution for up to 2 weeks after
inhibiting its metabolism
discontinuing paroxetine
• Controlled release paroxetine may slow the
• Use with caution in patients with history of
rate of decline and thus reduce withdrawal
seizures
reactions in some patients
• Use with caution in patients with bipolar
• Re-adaptation of cholinergic receptors after
disorder unless treated with concomitant
prolonged blockade may contribute to
mood stabilizing agent
withdrawal effects of paroxetine

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(continued) PAROXETINE

• Monitor patients for activation of suicidal • Not generally recommended for use during
ideation, especially children and pregnancy, especially during first trimester
adolescents • Nonetheless, continuous treatment during
pregnancy may be necessary and has not
Do Not Use been proven to be harmful to the fetus
• If patient is taking an MAO inhibitor • Preliminary research has not shown birth
• If patient is taking thioridazine defects in children whose mothers took
• If there is a proven allergy to paroxetine paroxetine during pregnancy
• Paroxetine use late in pregnancy may be
associated with higher risk of neonatal
SPECIAL POPULATIONS complications, including respiratory
distress
Renal Impairment • At delivery there may be more bleeding in
• Lower dose [initial 10 mg/day (12.5 mg the mother and transient irritability or
CR), maximum 40 mg/day (50 mg/day sedation in the newborn
CR)] • Must weigh the risk of treatment (first
trimester fetal development, third trimester
Hepatic Impairment newborn delivery) to the child against the
• Lower dose [initial 10 mg/day (12.5 mg risk of no treatment (recurrence of
CR), maximum 40 mg/day (50 mg/day depression, maternal health, infant
CR)] bonding) to the mother and child
• For many patients this may mean
Cardiac Impairment continuing treatment during pregnancy
• Preliminary research suggests that • Neonates exposed to SSRIs or SNRIs late
paroxetine is safe in these patients in the third trimester have developed
• Treating depression with SSRIs in patients complications requiring prolonged
with acute angina or following myocardial hospitalization, respiratory support, and
infarction may reduce cardiac events and tube feeding; reported symptoms are
improve survival as well as mood consistent with either a direct toxic effect
of SSRIs and SNRIs or, possibly, a drug
Elderly discontinuation syndrome, and include
• Lower dose [initial 10 mg/day (12.5 mg respiratory distress, cyanosis, apnea,
CR), maximum 40 mg/day (50 mg/day seizures, temperature instability, feeding
CR)] difficulty, vomiting, hypoglycemia,
hypotonia, hypertonia, hyperreflexia,
tremor, jitteriness, irritability, and constant
Children and Adolescents crying
• Use with caution, observing for activation
of known or unknown bipolar disorder Breast Feeding
and/or suicidal ideation, and strongly • Some drug is found in mother’s breast milk
consider informing parents or guardian of • Trace amounts may be present in nursing
this risk so they can help observe child or children whose mothers are on paroxetine
adolescent patients • If child becomes irritable or sedated, breast
• Not specifically approved, but preliminary feeding or drug may need to be
evidence suggests efficacy in children and discontinued
adolescents with OCD, social phobia, or • Immediate postpartum period is a high-risk
depression time for depression, especially in women
who have had prior depressive episodes,
so drug may need to be reinstituted late in
Pregnancy the third trimester or shortly after
childbirth to prevent a recurrence during
• Risk Category C [some animal studies
the postpartum period
show adverse effects, no controlled studies
• Must weigh benefits of breast feeding with
in humans]
risks and benefits of antidepressant

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PAROXETINE (continued)

treatment versus non-treatment to both the • Inhibits own metabolism, so dosing is not
infant and the mother linear
• For many patients, this may mean ✽ Paroxetine has mild anticholinergic
continuing treatment during breast feeding actions that can enhance the rapid onset of
anxiolytic and hypnotic efficacy but also
cause mild anticholinergic side effects
THE ART OF PSYCHOPHARMACOLOGY • Can cause cognitive and affective
“flattening”
Potential Advantages • May be less activating than other SSRIs
• Patients with anxiety disorders and • Paroxetine is a potent CYP450 2D6
insomnia inhibitor
• Patients with mixed anxiety/depression • SSRIs may be less effective in women over
50, especially if they are not taking
Potential Disadvantages estrogen
• Patients with hypersomnia • SSRIs may be useful for hot flushes in
• Alzheimer/cognitive disorders perimenopausal women
• Patients with psychomotor retardation, • Some anecdotal reports suggest greater
fatigue, and low energy weight gain and sexual dysfunction than
some other SSRIs, but the clinical
Primary Target Symptoms significance of this is unknown
• Depressed mood • For sexual dysfunction, can augment with
• Anxiety bupropion, sildenafil, tadalafil, or switch to
• Sleep disturbance, especially insomnia a non-SSRI such as bupropion or
• Panic attacks, avoidant behavior, re- mirtazapine
experiencing, hyperarousal • Some postmenopausal women’s
depression will respond better to
paroxetine plus estrogen augmentation
Pearls than to paroxetine alone
✽ Often a preferred treatment of anxious • Nonresponse to paroxetine in elderly may
depression as well as major depressive require consideration of mild cognitive
disorder comorbid with anxiety disorders impairment or Alzheimer disease
✽ Withdrawal effects may be more likely • CR formulation may enhance tolerability,
than for some other SSRIs when especially for nausea
discontinued (especially akathisia, • Can be better tolerated than some SSRIs
restlessness, gastrointestinal symptoms, for patients with anxiety and insomnia and
dizziness, tingling, dysesthesias, nausea, can reduce these symptoms early in dosing
stomach cramps, restlessness)

Suggested Reading
Bourin M, Chue P, Guillon Y. Paroxetine: a Wagstaff AJ, Cheer SM, Matheson AJ, Ormrod
review. CNS Drug Rev. 2001;7:25–47. D, Goa KL. Paroxetine: an update of its use in
psychiatric disorders in adults. Drugs.
Edwards JG, Anderson I. Systematic review 2002;62:655–703.
and guide to selection of selective serotonin
reuptake inhibitors. Drugs. 1999;57:507–533.
Green B. Focus on paroxetine. Curr Med Res
Opin. 2003;19:13–21.

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PEMOLINE
THERAPEUTICS Best Augmenting Combos
Brands • Cylert for Partial Response or
see index for additional brand names Treatment-Resistance
• Best to attempt another monotherapy prior
Generic? Yes to augmenting
✽ Drug combinations with pemoline have
Class not been systematically studied and this is
best left to the expert if used at all
• Stimulant

Commonly Prescribed For Tests

(bold for FDA approved) ✽ At present, there is no way to predict who
is likely to develop liver failure; however,
• Attention deficit hyperactivity disorder
only patients without liver disease and with
(ADHD) for patients who fail to respond to
normal baseline liver function tests should
other treatments
initiate pemoline therapy
✽ Liver function tests: Serum ALT (SGPT)
levels taken at baseline and every 2 weeks
How The Drug Works • If liver function tests increase to > twice
• Unknown baseline, discontinue treatment
• Theoretically enhances dopaminergic • In children, monitor height and weight
neurotransmission by an unknown
mechanism
• Structurally unrelated to amphetamine or SIDE EFFECTS
methylphenidate
How Drug Causes Side Effects
How Long Until It Works • Unknown
• First dose effects may not occur, as is • CNS side effects presumably due to
common with other stimulants excessive dopamine actions
• Substantial clinical benefits should occur • Mechanism of hepatic toxicity unknown
within 3 weeks of dosage titration or the
patient should be withdrawn from Notable Side Effects
treatment ✽ Insomnia
• Headache, exacerbation of tics, irritability,
If It Works drowsiness, dizziness
✽ Monitor need for continued treatment • Anorexia, weight loss
✽ Monitor liver function • Rash
• The goal of treatment of ADHD is reduction • Can temporarily slow normal growth in
of symptoms of inattentiveness, motor children (controversial)
hyperactivity, and/or impulsiveness that
disrupt social, school, and/or occupational
functioning Life Threatening or
• Continue treatment until all symptoms are Dangerous Side Effects
under control or improvement is stable and ✽ Liver failure, hepatitis, jaundice
then continue treatment indefinitely as long • Psychotic episodes
as improvement persists • Seizures
• Treatment begun in childhood may need to • Isolated reports of aplastic anemia
be continued into adolescence and • Theoretically, could activate mania or
adulthood if continued benefit is suicidal ideation
documented
Weight Gain
If It Doesn’t Work
✽ If no response is seen 3 weeks after dose
titration, discontinue use and try another
• Reported but not expected
agent

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PEMOLINE (continued)

• Some patients may experience weight loss, • Most side effects appear to be dose-
which is generally regained in 3–6 months dependent

Sedation Overdose
• Vomiting, agitation, tremor, hyperreflexia,
twitching, convulsion, coma, euphoria,
confusion, hallucination, sweating,
• Occurs in significant minority
headache, hyperpyrexia, tachycardia,
• Activation may also occur
hypertension, mydriasis
What To Do About Side Effects
Long-Term Use
• Wait
• Dependence and abuse less likely than with
• Adjust dose
amphetamine or methylphenidate
• If side effects persist, discontinue use
• Long-term stimulant use may be
• If signs of hepatic failure develop,
associated with growth suppression in
discontinue use
children (controversial)
Best Augmenting Agents for Side ✽ Must monitor serum ALT (SGPT) levels
Effects every 2 weeks for the duration of treatment
• Short-term use of hypnotics for insomnia ✽ Pemoline should be discontinued if
serum ALT (SGPT) is increased to a
• Dose reduction or switching to another
clinically significant level, if any increase
agent may be more effective since most
>2 times the upper limit of normal occurs,
side effects cannot be improved with an
or if clinical signs and symptoms suggest
augmenting agent
liver failure
✽ If pemoline therapy is discontinued and
then restarted, the liver testing should be
DOSING AND USE done prior to reinitiating treatment and
then every 2 weeks
Usual Dosage Range
• Periodic monitoring of weight and height
• 56.25–75 mg/day
may be prudent
Dosage Forms Habit Forming
• Tablet 18.75 mg scored, 37.5 mg scored,
• Low abuse potential, Schedule IV
37.5 mg scored chewable, 75 mg
• Some patients may develop tolerance, but
How to Dose abuse and psychological dependence are
rare
• Initial 37.5 mg/day in morning; increase by
18.75 mg each week; maximum How to Stop
112.5 mg/day
• Taper generally unnecessary and not
recommended when discontinuing for
hepatic toxicity
Dosing Tips • Discontinuation symptoms uncommon
✽ Has a relatively long half-life and
sustained duration of clinical activity, so it Pharmacokinetics
only needs to be administered once daily in • Serum half-life approximately 12 hours
the morning and there are no sustained • Metabolized by the liver
release formulations • Excreted primarily by the kidneys
• Chlorpromazine or atypical antipsychotics
may treat the stimulant effects of pemoline
overdose Drug Interactions
• May wish to stop treatment intermittently
to determine if behavioral symptoms return
✽ Drug interactions involving pemoline have
not been evaluated in humans
or if treatment is no longer necessary • Due to risk of hepatic toxicity, concomitant
• Administer in the morning to avoid therapy should generally be avoided
insomnia whenever possible

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(continued) PEMOLINE

• Not extensively studied in elderly patients

Other Warnings/
Precautions
✽ May cause liver failure; patients should Children and Adolescents
be advised to be alert for signs of liver
dysfunction (jaundice, anorexia, • Safety and efficacy not established under
gastrointestinal distress, malaise, etc.) and age 6
to report them immediately to their • Use in children should be reserved for the
physician expert
• Pemoline may worsen symptoms of
✽ Pemoline should be discontinued if behavioral disturbance and thought
serum ALT (SGPT) increases to twice the
normal upper limit disorder in psychotic children
• Children who are not growing or gaining • Pemoline may affect growth (predicted
weight should stop treatment, at least height, weight) in children with long-term
temporarily use (controversial); weight and height
• May worsen motor and phonic tics should be monitored during long-term
• May worsen symptoms of thought disorder treatment
and behavioral disturbance in psychotic
patients
• Use with caution in patients with history of Pregnancy
drug abuse • Risk Category B [animal studies do not
• Pemoline may be associated with growth show adverse effects, no controlled studies
suppression in humans]
• May lower seizure threshold • Use in women of childbearing potential
• Emergence or worsening of activation and requires weighing potential benefits to the
agitation could theoretically represent the mother against potential risks to the fetus
induction of a bipolar state, especially a ✽ For ADHD patients, pemoline should
mixed dysphoric bipolar II condition generally be discontinued before
sometimes associated with suicidal anticipated pregnancies
ideation, and require the addition of a
mood stabilizer and/or discontinuation of Breast Feeding
pemoline • Unknown if pemoline is secreted in human
breast milk, but all psychotropics assumed
Do Not Use to be secreted in breast milk
• If patient has hepatic impairment ✽ Recommended either to discontinue drug
• If patient has extreme anxiety or agitation or bottle feed
• If patient has Tourette’s syndrome
• If there is a proven allergy to pemoline
THE ART OF PSYCHOPHARMACOLOGY

SPECIAL POPULATIONS Potential Advantages

• Only for ADHD patients who respond to
Renal Impairment this agent and not to other treatments of
• Use with caution ADHD

Hepatic Impairment Potential Disadvantages

• Contraindicated • Hepatic toxicity may not justify its use

Cardiac Impairment Primary Target Symptoms

• Use with caution; less likely than other • Concentration, attention span
stimulants to raise blood pressure • Motor hyperactivity
• Impulsiveness
Elderly
• Use with caution; elderly patients are more
likely to have hepatic impairment

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PEMOLINE (continued)

• Has a more gradual onset of action than

some other stimulants
Pearls • Insomnia often occurs prior to the onset of
✽ Rarely if ever appropriate for off-label therapeutic actions
uses • It is not clear if baseline and periodic liver
✽ Not used first-line because of the risk of function testing is predictive of active liver
hepatotoxicity failure
✽ Written informed consent from the • However, it is generally believed that early
patient is required before initiating detection of drug-induced hepatic injury
treatment with pemoline along with immediate withdrawal of the
• Consent form available in manufacturer’s suspect drug enhances the likelihood for
package insert and published in the recovery
Physician’s Desk Reference, Thompson • Thus, liver function monitoring is a
PDR, Montvale, NJ. 58th edition, 2004 pp necessary component of pemoline therapy
419–420
• Although pharmacologic activity similar to
other CNS stimulants, pemoline has
minimal sympathomimetic effects

Suggested Reading
Cyr M, Brown CS. Current drug therapy Shevell M, Schreiber R. Pemoline-associated
recommendations for the treatment of hepatic failure: a critical analysis of the
attention deficit hyperactivity disorder. Drugs. literature. Pediatr Neurol. 1997; 16: 14–6.
1998; 56: 215–23.
Wender PH, Wolf LE, Wasserstein J. Adults
Greenhill LL, Pliszka S, Dulcan MK, Bernet W, with ADHD. An overview. Ann N Y Acad Sci.
Arnold V, Beitchman J, Benson RS, Bukstein 2001; 931: 1–16.
O, Kinlan J, McClellan J, Rue D, Shaw JA,
Stock S. Practice parameter for the use of
stimulant medications in the treatment of
children, adolescents, and adults. J Am Acad
Child Adolesc Psychiatry. 2002;41 (2 Suppl):
26S–49S.

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PEROSPIRONE
THERAPEUTICS • Such patients are considered super-
responders or “awakeners” since they may
Brands • Lullan be well enough to be employed, live
see index for additional brand names independently, and sustain long-term
relationships
Generic? No
• Continue treatment until reaching a plateau
of improvement
• After reaching a satisfactory plateau,
Class continue treatment for at least a year after
• Atypical antipsychotic (serotonin-dopamine first episode of psychosis
antagonist, second generation • For second and subsequent episodes of
antipsychotic) psychosis, treatment may need to be
indefinite
Commonly Prescribed For • Even for first episodes of psychosis, it may
(bold for FDA approved) be preferable to continue treatment
• Schizophrenia (Japan)
If It Doesn’t Work
• Consider trying one of the first-line atypical
How The Drug Works antipsychotics (e.g. risperidone,
• Blocks dopamine 2 receptors, reducing olanzapine, quetiapine, aripiprazole)
positive symptoms of psychosis • If 2 or more antipsychotic monotherapies
• Blocks serotonin 2A receptors, causing do not work, consider clozapine
enhancement of dopamine release in • If no first-line atypical antipsychotic is
certain brain regions and thus reducing effective, consider higher doses or
motor side effects and possibly improving augmentation with valproate or lamotrigine
cognitive and affective symptoms • Some patients may require treatment with
✽ Interactions at 5HT1A receptors may a conventional antipsychotic
contribute to efficacy for cognitive and • Consider noncompliance and switch to
affective symptoms in some patients another antipsychotic with fewer side
effects or to an antipsychotic that can be
How Long Until It Works given by depot injection
• Psychotic symptoms can improve within • Consider initiating rehabilitation and
1 week, but it may take several weeks for psychotherapy
full effect on behavior as well as on • Consider presence of concomitant drug
cognition and affective stabilization abuse
• Classically recommended to wait at least
4–6 weeks to determine efficacy of drug, Best Augmenting Combos
but in practice some patients require up to for Partial Response or
16–20 weeks to show a good response, Treatment-Resistance
especially on cognitive symptoms • Augmentation of perospirone has not been
systematically studied
If It Works • Addition of a benzodiazepine, especially
• Most often reduces positive symptoms in short-term for agitation
schizophrenia but does not eliminate them • Addition of a mood stabilizing
• Can improve negative symptoms, as well anticonvulsant such as valproate,
as aggressive, cognitive, and affective carbamazepine, or lamotrigine may
symptoms in schizophrenia theoretically be helpful in both
• Most schizophrenic patients do not have a schizophrenia and bipolar mania
total remission of symptoms but rather a • Augmentation with lithium in bipolar mania
reduction of symptoms by about a third may be helpful
• Perhaps 5–15% of schizophrenic patients
can experience an overall improvement of Tests
greater than 50–60%, especially when ✽ Potential of weight gain, diabetes, and
receiving stable treatment for more than a dyslipidemia associated with perospirone
year has not been systematically studied, but

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PEROSPIRONE (continued)

patients should be monitored the same as SIDE EFFECTS

for other atypical antipsychotics
How Drug Causes Side Effects
Before starting an atypical antipsychotic • By blocking dopamine 2 receptors in the
✽ Weigh all patients and track BMI during striatum, it can cause motor side effects
treatment • By blocking dopamine 2 receptors in the
• Get baseline personal and family history of pituitary, it can cause increased prolactin
obesity, dyslipidemia, hypertension, and (unusual)
cardiovascular disease • Mechanism of weight gain and increased
✽ Get waist circumference (at umbilicus), incidence of diabetes and dyslipidemia with
blood pressure, fasting plasma glucose, some atypical antipsychotics is unknown
and fasting lipid profile • Receptor binding portfolio of perospirone
• Determine if patient is is not well-characterized
• overweight (BMI 25.0–29.9)
• obese (BMI ≥30) Notable Side Effects
• has pre-diabetes (fasting plasma glucose ✽ Extrapyramidal symptoms, akathisia
100–125 mg/dl) ✽ Insomnia
• has diabetes (fasting plasma glucose • Sedation, anxiety, weakness, headache,
>126 mg/dl) anorexia, constipation
• has hypertension (BP >140/90 mm Hg) • Theoretically, tardive dyskinesia (should be
• has dyslipidemia (increased total reduced risk compared to conventional
cholesterol, LDL cholesterol, and antipsychotics)
triglycerides; decreased HDL cholesterol) • Elevated creatine phosphokinase levels
• Treat or refer such patients for treatment,
including nutrition and weight
management, physical activity counseling, Life Threatening or
smoking cessation, and medical Dangerous Side Effects
management • Rare neuroleptic malignant syndrome
• Theoretically, seizures are rarely associated
Monitoring after starting an atypical
with atypical antipsychotics
antipsychotic
✽ BMI monthly for 3 months, then quarterly Weight Gain
✽ Blood pressure, fasting plasma glucose, ✽ Not well characterized
fasting lipids within 3 months and then
annually, but earlier and more frequently Sedation
for patients with diabetes or who have
gained >5% of initial weight
• Treat or refer for treatment and consider
switching to another atypical antipsychotic • Occurs in significant minority
for patients who become overweight,
obese, pre-diabetic, diabetic, hypertensive,
What To Do About Side Effects
or dyslipidemic while receiving an atypical • Wait
antipsychotic • Wait
✽ Even in patients without known diabetes, • Wait
• For motor symptoms, add an
be vigilant for the rare but life threatening
onset of diabetic ketoacidosis, which anticholinergic agent
always requires immediate treatment, by • Reduce the dose
monitoring for the rapid onset of polyuria, • Switch to another atypical antipsychotic
polydipsia, weight loss, nausea, vomiting,
Best Augmenting Agents for Side
dehydration, rapid respiration, weakness
and clouding of sensorium, even coma
Effects
• Should check blood pressure in the elderly • Benztropine or trihexyphenidyl for motor
before starting and for the first few weeks side effects
of treatment • Sometimes amantadine can be helpful for
motor side effects

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(continued) PEROSPIRONE

• Benzodiazepines may be helpful for

akathisia
• Many side effects cannot be improved with Drug Interactions
an augmenting agent • Ketaconazole and possibly other CYP450
3A4 inhibitors such as nefazodone,
fluvoxamine, and fluoxetine may increase
plasma levels of perospirone
DOSING AND USE • Carbamazepine and possibly other inducers
Usual Dosage Range of CYP450 3A4 may decrease plasma
levels of perospirone
• 8–48 mg/day in 3 divided doses

Dosage Forms Other Warnings/

• Tablet 4 mg, 8 mg Precautions
• Not reported
How to Dose
• Begin at 4 mg 3 times a day, increasing as Do Not Use
tolerated up to 16 mg 3 times a day • If there is a proven allergy to perospirone

Dosing Tips SPECIAL POPULATIONS

• Some patients have been treated with up to
96 mg/day in 3 divided doses Renal Impairment
• Unknown whether dosing frequency can be • Use with caution
reduced to once or twice daily, but by
analogy with other agents in this class with Hepatic Impairment
half-lives shorter than 24 hours, this may • Use with caution
be possible
Cardiac Impairment
Overdose • Use with caution
• Not reported
Elderly
Long-Term Use • Some patients may tolerate lower doses
• Long-term studies not reported, but as for better
other atypical antipsychotics, long-term
use for treatment of schizophrenia is
common Children and Adolescents
• Use with caution
Habit Forming
• No

How to Stop Pregnancy

• Slow down-titration (over 6 to 8 weeks), • Psychotic symptoms may worsen during
especially when simultaneously beginning pregnancy and some form of treatment
a new antipsychotic while switching (i.e., may be necessary
cross-titration)
• Rapid discontinuation may lead to rebound Breast Feeding
psychosis and worsening of symptoms • Unknown if perospirone is secreted in
• If antiparkinson agents are being used, human breast milk, but all psychotropics
they should be continued for a few weeks assumed to be secreted in breast milk
after perospirone is discontinued ✽ Recommended either to discontinue drug
or bottle feed
Pharmacokinetics • Infants of women who choose to breast
• Metabolized primarily by CYP450 3A4 feed should be monitored for possible
• No active metabolites adverse effects

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PEROSPIRONE (continued)

THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages Pearls
• In Japan, studies suggest efficacy for • Extrapyramidal symptoms may be more
negative symptoms of schizophrenia frequent than with some other atypical
antipsychotics
Potential Disadvantages • Potent 5HT1A binding properties may be
• Patients who have difficulty complying with helpful for improving cognitive symptoms
three times daily administration of schizophrenia in long-term treatment
• Theoretically, should be effective in acute
Primary Target Symptoms bipolar mania
• Positive symptoms of psychosis
• Negative symptoms of psychosis
• Affective symptoms (depression, anxiety)
• Cognitive symptoms

Suggested Reading
Ohno Y. Pharmacological characteristics of
perospirone hydrochloride, a novel
antipsychotic agent. Nippon Yakurigaku Zasshi
2000; 116 (4): 225–31.

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PERPHENAZINE
THERAPEUTICS or as an effective maintenance treatment in
bipolar disorder
Brands • Trilafon • After reducing acute psychotic symptoms
see index for additional brand names in mania, switch to a mood stabilizer
and/or an atypical antipsychotic for mood
Generic? Yes
stabilization and maintenance

If It Doesn’t Work
Class • Consider trying one of the first-line atypical
• Conventional antipsychotic (neuroleptic, antipsychotics (risperidone, olanzapine,
phenothiazine, dopamine 2 antagonist, quetiapine, ziprasidone, aripiprazole,
antiemetic) amisulpride)
• Consider trying another conventional
Commonly Prescribed For antipsychotic
(bold for FDA approved) • If 2 or more antipsychotic monotherapies
• Schizophrenia do not work, consider clozapine
• Nausea, vomiting
• Other psychotic disorders Best Augmenting Combos
• Bipolar disorder for Partial Response or
Treatment-Resistance
• Augmentation of conventional
How The Drug Works antipsychotics has not been systematically
• Blocks dopamine 2 receptors, reducing studied
positive symptoms of psychosis • Addition of a mood stabilizing
• Combination of dopamine D2, histamine anticonvulsant such as valproate,
H1, and cholinergic M1 blockade in the carbamazepine, or lamotrigine may be
vomiting center may reduce nausea and helpful in both schizophrenia and bipolar
vomiting mania
• Augmentation with lithium in bipolar mania
How Long Until It Works may be helpful
• Psychotic symptoms can improve within • Addition of a benzodiazepine, especially
1 week, but may take several weeks for full short-term for agitation
effect on behavior
• Injection: initial effect after 10 minutes, Tests
peak after 1–2 hours ✽ Since conventional antipsychotics are
• Actions on nausea and vomiting are frequently associated with weight gain,
immediate before starting treatment, weigh all patients
and determine if the patient is already
If It Works overweight (BMI 25.0–29.9) or obese
• Most often reduces positive symptoms in (BMI ≥30)
schizophrenia but does not eliminate them • Before giving a drug that can cause weight
• Most schizophrenic patients do not have a gain to an overweight or obese patient,
total remission of symptoms but rather a consider determining whether the patient
reduction of symptoms by about a third already has pre-diabetes (fasting plasma
• Continue treatment in schizophrenia until glucose 100–125 mg/dl), diabetes (fasting
reaching a plateau of improvement plasma glucose >126 mg/dl), or
• After reaching a satisfactory plateau, dyslipidemia (increased total cholesterol,
continue treatment for at least a year after LDL cholesterol and triglycerides;
first episode of psychosis in schizophrenia decreased HDL cholesterol), and treat or
• For second and subsequent episodes of refer such patients for treatment, including
psychosis in schizophrenia, treatment may nutrition and weight management, physical
need to be indefinite activity counseling, smoking cessation, and
• Reduces symptoms of acute psychotic medical management
mania but not proven as a mood stabilizer ✽ Monitor weight and BMI during treatment

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PERPHENAZINE (continued)

✽ While giving a drug to a patient who has

gained >5% of initial weight, consider Life Threatening or
evaluating for the presence of pre-diabetes, Dangerous Side Effects
diabetes, or dyslipidemia, or consider • Rare neuroleptic malignant syndrome
switching to a different antipsychotic • Rare jaundice, agranulocytosis
• Should check blood pressure in the elderly • Rare seizures
before starting and for the first few weeks
of treatment Weight Gain
• Monitoring elevated prolactin levels of
dubious clinical benefit
• Phenothiazines may cause false-positive • Many experience and/or can be significant
phenylketonuria results in amount

Sedation
SIDE EFFECTS
How Drug Causes Side Effects
• Many experience and/or can be significant
• By blocking dopamine 2 receptors in the
in amount
striatum, it can cause motor side effects
• Sedation is usually transient
• By blocking dopamine 2 receptors in the
pituitary, it can cause elevations in What To Do About Side Effects
prolactin • Wait
• By blocking dopamine 2 receptors • Wait
excessively in the mesocortical and • Wait
mesolimbic dopamine pathways, especially • For motor symptoms, add an
at high doses, it can cause worsening of anticholinergic agent
negative and cognitive symptoms • Reduce the dose
(neuroleptic-induced deficit syndrome) • For sedation, give at night
• Anticholinergic actions may cause • Switch to an atypical antipsychotic
sedation, blurred vision, constipation, dry • Weight loss, exercise programs, and
mouth medical management for high BMIs,
• Antihistaminic actions may cause sedation, diabetes, dyslipidemia
weight gain
• By blocking alpha 1 adrenergic receptors, it Best Augmenting Agents for Side
can cause dizziness, sedation, and Effects
hypotension • Benztropine or trihexyphenidyl for motor
• Mechanism of weight gain and any side effects
possible increased incidence of diabetes or • Sometimes amantadine can be helpful for
dyslipidemia with conventional motor side effects
antipsychotics is unknown • Benzodiazepines may be helpful for
akathisia
Notable Side Effects
• Many side effects cannot be improved with
✽ Neuroleptic-induced deficit syndrome an augmenting agent
✽ Akathisia
✽ Extrapyramidal symptoms, Parkinsonism,
tardive dyskinesia
✽ Galactorrhea, amenorrhea DOSING AND USE
• Dizziness, sedation
• Dry mouth, constipation, urinary retention,
Usual Dosage Range
blurred vision • Psychosis: oral: 12–24 mg/day;
• Decreased sweating 16–64 mg/day in hospitalized patients
• Sexual dysfunction • Nausea/vomiting: 8–16 mg/day oral, 5 mg
• Hypotension, tachycardia, syncope intramuscularly
• Weight gain

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(continued) PERPHENAZINE

Dosage Forms
• Tablet 2 mg, 4 mg, 8 mg, 16 mg
• Injection 5 mg/mL
Drug Interactions
• May decrease the effects of levodopa,
How to Dose dopamine agonists
• Oral: Psychosis: 4–8 mg 3 times a day; • May increase the effects of
8–16 mg 2 times a day to 4 times a day in antihypertensive drugs except for
hospitalized patients; maximum 64 mg/day guanethidine, whose antihypertensive
• Oral: Nausea/vomiting: 8–16 mg/day in actions perphenazine may antagonize
divided doses; maximum 24 mg/day • Additive effects may occur if used with
• Intramuscular: Psychosis: initial 5 mg; can CNS depressants
repeat every 6 hours, maximum 15 mg/day • Anticholinergic effects may occur if used
(30 mg/day in hospitalized patients) with atropine or related compounds
• Some patients taking a neuroleptic and
lithium have developed an encephalopathic
syndrome similar to neuroleptic malignant
Dosing Tips syndrome
• Injection contains sulfites that may cause • Epinephrine may lower blood pressure;
allergic reactions, particularly in patients diuretics and alcohol may increase risk of
with asthma hypotension
• Oral perphenazine is less potent than the
injection, so patients should receive equal
or higher dosage when switched from Other Warnings/
injection to tablet Precautions
• If signs of neruoleptic malignant syndrome
Overdose develop, treatment should be immediately
• Extrapyramidal symptoms, coma, discontinued
hypotension, sedation, seizures, respiratory • Use cautiously in patients with respiratory
depression disorders
• Use cautiously in patients with alcohol
Long-Term Use withdrawal or convulsive disorders
• Some side effects may be irreversible (e.g., because of possible lowering of seizure
tardive dyskinesia) threshold
• Do not use epinephrine in event of
Habit Forming overdose as interaction with some pressor
• No agents may lower blood pressure
How to Stop • Avoid undue exposure to sunlight
• Avoid extreme heat exposure
• Slow down-titration of oral formulation
• Use with caution in patients with
(over 6 to 8 weeks), especially when
respiratory disorders, glaucoma or urinary
simultaneously beginning a new
retention
antipsychotic while switching (i.e., cross-
• Antiemetic effect of perphenazine may
titration)
mask signs of other disorders or overdose;
• Rapid oral discontinuation may lead to
suppression of cough reflex may cause
rebound psychosis and worsening of
asphyxia
symptoms
• Observe for signs of ocular toxicity
• If antiparkinson agents are being used,
(corneal and lenticular deposits)
they should be continued for a few weeks
• Use only with caution if at all in
after perphenazine is discontinued
Parkinson’s disease or Lewy Body
Pharmacokinetics dementia
• Half-life approximately 9.5 hours
Do Not Use
• If patient is in a comatose state or has CNS
depression

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PERPHENAZINE (continued)

• If there is the presence of blood Breast Feeding

dyscrasias, subcortical brain damage, bone • Unknown if perphenazine is secreted in
marrow depression, or liver disease human breast milk, but all psychotropics
• If there is a proven allergy to perphenazine assumed to be secreted in breast milk
• If there is a known sensitivity to any ✽ Recommended either to discontinue drug
phenothiazine or bottle feed

SPECIAL POPULATIONS THE ART OF PSYCHOPHARMACOLOGY

Renal Impairment Potential Advantages
• Use with caution • Intramuscular formulation for emergency
use
Hepatic Impairment
• Use with caution; may not be Potential Disadvantages
recommended as long-term treatment • Patients with tardive dyskinesia
because perphenazine may increase risk of • Children
further liver damage • Elderly

Cardiac Impairment Primary Target Symptoms

• Cardiovascular toxicity can occur, • Positive symptoms of psychosis
especially orthostatic hypotension • Motor and autonomic hyperactivity
• Violent or aggressive behavior
Elderly
• Lower doses should be used and patient
should be monitored closely Pearls
• Perphenazine is a higher potency
phenothiazine
Children and Adolescents • Less risk of sedation and orthostatic
• Not recommended for use under age 12 hypotension but greater risk of
• Over age 12: if given intramuscularly, extrapyramidal symptoms than with low
should receive lowest adult dose potency phenothiazines
• Generally consider second-line after • Conventional antipsychotics are much less
atypical antipsychotics expensive than atypical antipsychotics
• Patients have very similar antipsychotic
responses to any conventional
Pregnancy antipsychotic, which is different from
• Risk Category C [some animal studies atypical antipsychotics where antipsychotic
show adverse effects, no controlled studies responses of individual patients can
in humans] occasionally vary greatly from one atypical
• Reports of extrapyramidal symptoms, antipsychotic to another
jaundice, hyperreflexia, hyporeflexia in • Patients with inadequate responses to
infants whose mothers took a atypical antipsychotics may benefit from a
phenothiazine during pregnancy trial of augmentation with a conventional
• Perphenazine should only be used during antipsychotic such as perphenazine or
pregnancy if clearly needed from switching to a conventional
• Psychotic symptoms may worsen during antipsychotic such as perphenazine
pregnancy and some form of treatment • However, long-term polypharmacy with a
may be necessary combination of a conventional
• Atypical antipsychotics may be preferable antipsychotic such as perphenazine with an
to conventional antipsychotics or atypical antipsychotic may combine their
anticonvulsant mood stabilizers if side effects without clearly augmenting the
treatment is required during pregnancy efficacy of either

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(continued) PERPHENAZINE

• Although a frequent practice by some

prescribers, adding 2 conventional
antipsychotics together has little rationale
and may reduce tolerability without clearly
enhancing efficacy
• Availability of alternative treatments and
risk of tardive dyskinesia make utilization
of perphenazine for nausea and vomiting a
short-term and second-line treatment
option

Suggested Reading
Dencker SJ, Gios I, Martensson E, Norden T, Quraishi S, David A. Depot perphenazine
Nyberg G, Persson R, Roman G, Stockman O, decanoate and enanthate for schizophrenia.
Syard KO. A long-term cross-over Cochrane Database Syst Rev 2000; (2):
pharmacokinetic study comparing CD001717.
perphenazine decanoate and haloperidol
decanoate in schizophrenic patients.
Psychopharmacology (Berl) 1994; 114: 24–30.
Frankenburg FR. Choices in antipsychotic
therapy in schizophrenia. Harv Rev Psychiatry
1999; 6: 241–9.

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0521011698s07.qxd 9/2/04 2:44 PM Page 371

PHENELZINE
THERAPEUTICS • Use in anxiety disorders may also need to
be indefinite
Brands • Nardil
• Nardelzine If It Doesn’t Work
see index for additional brand names • Many patients only have a partial response
where some symptoms are improved but
Generic? Yes others persist (especially insomnia, fatigue,
and problems concentrating)
• Other patients may be nonresponders,
Class sometimes called treatment-resistant or
• Monoamine oxidase inhibitor (MAOI) treatment-refractory
• Some patients who have an initial response
Commonly Prescribed For may relapse even though they continue
(bold for FDA approved) treatment, sometimes called “poop-out”
• Depressed patients characterized as • Consider increasing dose, switching to
“atypical”, “nonendogenous”, or another agent, or adding an appropriate
“neurotic” augmenting agent
• Treatment-resistant depression • Consider psychotherapy
• Treatment-resistant panic disorder • Consider evaluation for another diagnosis
• Treatment-resistant social anxiety disorder or for a comorbid condition (e.g., medical
illness, substance abuse, etc.)
• Some patients may experience apparent
How The Drug Works lack of consistent efficacy due to activation
• Irreversibly blocks monoamine oxidase of latent or underlying bipolar disorder, and
(MAO) from breaking down require antidepressant discontinuation and
norepinephrine, serotonin, and dopamine a switch to a mood stabilizer
• This presumably boosts noradrenergic,
serotonergic, and dopaminergic Best Augmenting Combos
neurotransmission for Partial Response or
Treatment-Resistance
How Long Until It Works ✽ Augmentation of MAOIs has not been
• Onset of therapeutic actions usually not systematically studied, and this is
immediate, but often delayed 2 to 4 weeks something for the expert, to be done with
• If it is not working within 6 to 8 weeks, it caution and with careful monitoring
may require a dosage increase or it may ✽ A stimulant such as d-amphetamine or
not work at all methylphenidate (with caution; may
• May continue to work for many years to activate bipolar disorder and suicidal
prevent relapse of symptoms ideation; may elevate blood pressure)
• Lithium
If It Works • Mood stabilizing anticonvulsants
• The goal of treatment is complete • Atypical antipsychotics (with special
remission of current symptoms as well as caution for those agents with monoamine
prevention of future relapses reuptake blocking properties, such as
• Treatment most often reduces or even ziprasidone and zotepine)
eliminates symptoms, but not a cure since
symptoms can recur after medicine Tests
stopped • Patients should be monitored for changes
• Continue treatment until all symptoms are in blood pressure
gone (remission) • Patients receiving high doses or long-term
• Once symptoms gone, continue treating for treatment should have hepatic function
1 year for the first episode of depression evaluated periodically
• For second and subsequent episodes of ✽ Since MAO inhibitors are frequently
depression, treatment may need to be associated with weight gain, before starting
indefinite treatment, weigh all patients and determine

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PHENELZINE (continued)

if the patient is already overweight • Induction of mania and activation of

(BMI 25.0–29.9) or obese (BMI ≥30) suicidal ideation
• Before giving a drug that can cause weight • Seizures
gain to an overweight or obese patient, • Hepatotoxicity
consider determining whether the patient
already has pre-diabetes (fasting plasma Weight Gain
glucose 100–125 mg/dl), diabetes (fasting
plasma glucose >126 mg/dl), or
dyslipidemia (increased total cholesterol, • Many experience and/or can be significant
LDL cholesterol and triglycerides; in amount
decreased HDL cholesterol), and treat or
refer such patients for treatment, including Sedation
nutrition and weight management, physical
activity counseling, smoking cessation, and
medical management
✽ Monitor weight and BMI during treatment • Many experience and/or can be significant
✽ While giving a drug to a patient who has in amount
• Can also cause activation
gained >5% of initial weight, consider
evaluating for the presence of pre-diabetes,
What To Do About Side Effects
diabetes, or dyslipidemia, or consider
• Wait
switching to a different antidepressant
• Wait
• Wait
• Lower the dose
SIDE EFFECTS • Take at night if daytime sedation
• Switch after appropriate washout to an
How Drug Causes Side Effects SSRI or newer antidepressant
• Theoretically due to increases in
monoamines in parts of the brain and body Best Augmenting Agents for Side
and at receptors other than those that Effects
cause therapeutic actions (e.g., unwanted • Trazodone (with caution) for insomnia
actions of serotonin in sleep centers • Benzodiazepines for insomnia
causing insomnia, unwanted actions of
norepinephrine on vascular smooth muscle
✽ Single oral or sublingual dose of a
calcium channel blocker (e.g., nifedipine)
causing changes in blood pressure, etc.) for urgent treatment of hypertension due to
• Side effects are generally immediate, but drug interaction or dietary tyramine
immediate side effects often disappear in • Many side effects cannot be improved with
time an augmenting agent
Notable Side Effects
• Dizziness, sedation, headache, sleep
disturbances, fatigue, weakness, tremor, DOSING AND USE
movement problems, blurred vision,
increased sweating Usual Dosage Range
• Constipation, dry mouth, nausea, change in • 45–75 mg/day
appetite, weight gain
Dosage Forms
• Sexual dysfunction
• Tablet 15 mg
• Orthostatic hypotension (dose-related);
syncope may develop at high doses How to Dose
• Initial 45 mg/day in 3 divided doses;
Life Threatening or increase to 60–90 mg/day; after desired
Dangerous Side Effects therapeutic effect is achieved lower dose as
• Hypertensive crisis (especially when MAOIs far as possible
are used with certain tyramine-containing
foods or prohibited drugs)

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(continued) PHENELZINE

dopamine, epinephrine, norepinephrine,

and related compounds methyldopa,
Dosing Tips levodopa, L-tryptophan, L-tyrosine, and
• Once dosing is stabilized, some patients phenylalanine)
may tolerate once or twice daily dosing • Excitation, seizures, delirium, hyperpyrexia,
rather than 3-times-a-day dosing circulatory collapse, coma, and death may
• Orthostatic hypotension, especially at high result from combining MAO inhibitors with
doses, may require splitting into 4 daily mepiridine or dextromethorphan
doses • Do not combine with another MAO
• Patients receiving high doses may need to inhibitor, alcohol, buspirone, bupropion, or
be evaluated periodically for effects on the guanethidine
liver • Adverse drug reactions can result from
• Little evidence to support efficacy of combining MAO inhibitors with
phenelzine below doses of 45 mg/day tricyclic/tetracyclic antidepressants and
related compounds, including
Overdose
carbamazepine, cyclobenzaprine, and
• Death may occur; dizziness, ataxia,
mirtazapine, and should be avoided except
sedation, headache, insomnia,
by experts to treat difficult cases
restlessness, anxiety, irritability,
• MAO inhibitors in combination with spinal
cardiovascular effects, confusion,
anesthesia may cause combined
respiratory depression, coma
hypotensive effects
Long-Term Use • Combination of MAOIs and CNS
depressants may enhance sedation and
• May require periodic evaluation of hepatic
hypotension
function
• MAOIs may lose efficacy long-term
Other Warnings/
Habit Forming Precautions
• Some patients have developed dependence • Use requires low tyramine diet
to MAOIs • Patients taking MAO inhibitors should
avoid high protein food that has undergone
How to Stop
protein breakdown by aging, fermentation,
• Generally no need to taper, as the drug
pickling, smoking, or bacterial
wears off slowly over 2–3 weeks
contamination
Pharmacokinetics • Patients taking MAO inhibitors should
• Clinical duration of action may be up to 21 avoid cheeses (especially aged varieties),
days due to irreversible enzyme inhibition pickled herring, beer, wine, liver, yeast
extract, dry sausage, hard salami,
pepperoni, Lebanon bologna, pods of
broad beans (fava beans), yogurt, and
Drug Interactions excessive use of caffeine and chocolate
• Tramadol may increase the risk of seizures • Patient and prescriber must be vigilant to
in patients taking an MAO inhibitor potential interactions with any drug,
• Can cause a fatal “serotonin syndrome” including antihypertensives and over-the-
when combined with drugs that block counter cough/cold preparations
serotonin reuptake (e.g., SSRIs, SNRIs, • Over-the-counter medications to avoid
sibutramine, tramadol, etc.), so do not use include cough and cold preparations,
with a serotonin reuptake inhibitor or for including those containing
up to 5 weeks after stopping the serotonin dextromethorphan, nasal decongestants
reuptake inhibitor (tablets, drops, or spray), hay-fever
• Hypertensive crisis with headache, medications, sinus medications, asthma
intracranial bleeding, and death may result inhalant medications, anti-appetite
from combining MAO inhibitors with medications, weight reducing preparations,
sympathomimetic drugs (e.g., “pep” pills
amphetamines, methylphenidate, cocaine,

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PHENELZINE (continued)

• Hypoglycemia may occur in diabetic Elderly

patients receiving insulin or oral • Initial dose 7.5 mg/day; increase every few
antidiabetic agents days by 7.5–15 mg/day
• Use cautiously in patients receiving • Elderly patients may have greater
reserpine, anesthetics, disulfiram, sensitivity to adverse effects
metrizamide, anticholinergic agents
• Phenelzine is not recommended for use in
patients who cannot be monitored closely Children and Adolescents
• Monitor patients for activation of suicidal • Not recommended for use under age 16
ideation, especially children and • Use with caution, observing for activation
adolescents of known or unknown bipolar disorder
Do Not Use and/or suicidal ideation, and strongly
consider informing parents or guardian of
• If patient is taking meperidine (pethidine)
this risk so they can help observe child or
• If patient is taking a sympathomimetic
adolescent patients
agent or taking guanethidine
• If patient is taking another MAOI
• If patient is taking any agent that can
inhibit serotonin reuptake (e.g., SSRIs, Pregnancy
sibutramine, tramadol, milnacipran, • Risk Category C [some animal studies
duloxetine, venlafaxine, clomipramine, etc.) show adverse effects, no controlled studies
• If patient is taking diuretics, in humans]
dextromethorphan, buspirone, bupropion • Not generally recommended for use during
• If patient has pheochromocytoma pregnancy, especially during first trimester
• If patient has cardiovascular or • Possible increased incidence of fetal
cerebrovascular disease malformations if phenelzine is taken during
• If patient has frequent or severe headaches the first trimester
• If patient is undergoing elective surgery • Should evaluate patient for treatment with
and requires general anesthesia an antidepressant with a better risk/benefit
• If patient has a history of liver disease or ratio
abnormal liver function tests
• If patient is taking a prohibited drug Breast Feeding
• If patient is not compliant with a low- • Some drug is found in mother’s breast milk
tyramine diet • If child becomes irritable or sedated, breast
• If there is a proven allergy to phenelzine feeding or drug may need to be
discontinued
• Immediate postpartum period is a high-risk
time for depression, especially in women
SPECIAL POPULATIONS who have had prior depressive episodes,
Renal Impairment so drug may need to be reinstituted late in
• Use with caution – drug may accumulate in the third trimester or shortly after
plasma childbirth to prevent a recurrence during
• May require lower than usual adult dose the postpartum period
• Should evaluate patient for treatment with
Hepatic Impairment an antidepressant with a better risk/benefit
• Phenelzine should not be used ratio

Cardiac Impairment
• Contraindicated in patients with congestive THE ART OF PSYCHOPHARMACOLOGY
heart failure or hypertension
• Any other cardiac impairment may require Potential Advantages
lower than usual adult dose • Atypical depression
• Patients with angina pectoris or coronary • Severe depression
artery disease should limit their exertion • Treatment-resistant depression or anxiety
disorders

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(continued) PHENELZINE

Potential Disadvantages prohibitions against concomitant drugs

• Requires compliance to dietary restrictions, often not followed closely enough
concomitant drug restrictions • Orthostatic hypotension, insomnia, and
• Patients with cardiac problems or sexual dysfunction are often the most
hypertension troublesome common side effects
• Multiple daily doses ✽ MAOIs should be for the expert,
especially if combining with agents of
Primary Target Symptoms potential risk (e.g., stimulants, trazodone,
• Depressed mood TCAs)
• Somatic symptoms ✽ MAOIs should not be neglected as
• Sleep and eating disturbances therapeutic agents for the treatment-
• Psychomotor retardation resistant
• Morbid preoccupation • Although generally prohibited, a heroic but
potentially dangerous treatment for
severely treatment-resistant patients is for
Pearls an expert to give a tricyclic/tetracyclic
• MAOIs are generally reserved for second-line antidepressant other than clomipramine
use after SSRIs, SNRIs, and combinations simultaneously with an MAO inhibitor for
of newer antidepressants have failed patients who fail to respond to numerous
• Patient should be advised not to take any other antidepressants
prescription or over-the-counter drugs • Use of MAOIs with clomipramine is always
without consulting their doctor because of prohibited because of the risk of serotonin
possible drug interactions with the MAOI syndrome and death
• Headache is often the first symptom of • Amoxapine may be the preferred
hypertensive crisis trycyclic/tetracyclic antidepressant to
• Foods generally to avoid as they are combine with an MAOI in heroic cases due
usually high in tyramine content: dry to its theoretically protective 5HT2A
sausage, pickled herring, liver, broad bean antagonist properties
pods, sauerkraut, cheese, yogurt, alcoholic • If this option is elected, start the MAOI with
beverages, nonalcoholic beer and wine, the tricyclic/tetracyclic antidepressant
chocolate, caffeine, meat and fish simultaneously at low doses after
• The rigid dietary restrictions may reduce appropriate drug washout, then alternately
compliance increase doses of these agents every few
• Mood disorders can be associated with days to a week as tolerated
eating disorders (especially in adolescent • Although very strict dietary and
females), and phenelzine can be used to concomitant drug restrictions must be
treat both depression and bulimia observed to prevent hypertensive crises
• MAOIs are a viable second-line treatment and serotonin syndrome, the most
option in depression, but are not frequently common side effects of MAOI and
used tricyclic/tetracyclic combinations may be
✽ Myths about the danger of dietary weight gain and orthostatic hypotension
tyramine can be exaggerated, but

Suggested Reading
Kennedy SH. Continuation and maintenance Parsons B, Quitkin FM, McGrath PJ, Stewart
treatments in major depression: the neglected JW, Tricamo E, Ocepek-Welikson K, Harrison
role of monoamine oxidase inhibitors. J W, Rabkin JG, Wager SG, Nunes E.
Psychiatry Neurosci 1997;22:127–31. Phenelzine, imipramine, and placebo in
borderline patients meeting criteria for atypical
Lippman SB, Nash K. Monoamine oxidase depression. Psychopharmacol Bull 1989;
inhibitor update. Potential adverse food and 25:524–34.
drug interactions. Drug Saf 1990;5:195–204.

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PIMOZIDE
THERAPEUTICS • Consider trying another conventional
antipsychotic
Brands • Orap • If 2 or more antipsychotic monotherapies
see index for additional brand names do not work, consider clozapine
Generic? Not in U.S. Best Augmenting Combos
for Partial Response or
Treatment-Resistance
Class ✽ Augmentation of pimozide has not been
• Tourette’s syndrome/tic suppressant; systematically studied and can be
conventional antipsychotic (neuroleptic, dangerous, especially with drugs that can
dopamine 2 antagonist) either prolong QTc interval or raise
pimozide plasma levels
Commonly Prescribed For
(bold for FDA approved) Tests
• Suppression of motor and phonic tics in ✽ Baseline ECG and serum potassium levels
patients with Tourette Disorder who have should be determined
failed to respond satisfactorily to ✽ Periodic evaluation of ECG and serum
standard treatment potassium levels, especially during dose
• Psychotic disorders in patients who have titration
failed to respond satisfactorily to standard • Serum magnesium levels may also need to
treatment be monitored
✽ Since conventional antipsychotics are
frequently associated with weight gain,
How The Drug Works before starting treatment, weigh all patients
• Blocks dopamine 2 receptors in the and determine if the patient is already
nigrostriatal dopamine pathway, reducing overweight (BMI 25.0–29.9) or obese
tics in Tourette’s syndrome (BMI ≥30)
• When used for psychosis, can block • Before giving a drug that can cause weight
dopamine 2 receptors in the mesolimbic gain to an overweight or obese patient,
dopamine pathway, reducing positive consider determining whether the patient
symptoms of psychosis already has pre-diabetes (fasting plasma
glucose 100–125 mg/dl), diabetes (fasting
How Long Until It Works plasma glucose >126 mg/dl), or
• Relief from tics may occur more rapidly dyslipidemia (increased total cholesterol,
than antipsychotic actions LDL cholesterol and triglycerides;
• Psychotic symptoms can improve within decreased HDL cholesterol), and treat or
1 week, but it may take several weeks for refer such patients for treatment, including
full effect on behavior nutrition and weight management, physical
activity counseling, smoking cessation, and
If It Works medical management
✽ Is a second-line treatment option for ✽ Monitor weight and BMI during treatment
Tourette’s syndrome ✽ While giving a drug to a patient who has
✽ Is a secondary or tertiary treatment gained >5% of initial weight, consider
option for psychosis or other behavioral evaluating for the presence of pre-diabetes,
disorders diabetes, or dyslipidemia, or consider
• Should evaluate for switching to an switching to a different antipsychotic
antipsychotic with a better/risk benefit ratio • Should check blood pressure in the elderly
before starting and for the first few weeks
If It Doesn’t Work of treatment
• Consider trying one of the first-line atypical • Monitoring elevated prolactin levels of
antipsychotics (risperidone, olanzapine, dubious clinical benefit
quetiapine, ziprasidone, aripiprazole,
amisulpride)

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PIMOZIDE (continued)

SIDE EFFECTS Sedation

How Drug Causes Side Effects
• By blocking dopamine 2 receptors in the
striatum, it can cause motor side effects • Occurs in significant minority
• By blocking dopamine 2 receptors in the
pituitary, it can cause elevations in What To Do About Side Effects
prolactin • Wait
• By blocking dopamine 2 receptors • Wait
excessively in the mesocortical and • Wait
mesolimbic dopamine pathways, especially • For motor symptoms, add an
at high doses, it can cause worsening of anticholinergic agent
negative and cognitive symptoms • Reduce the dose
(neuroleptic-induced deficit syndrome) • For sedation, give at night
• Anticholinergic actions may cause • Switch to an atypical antipsychotic
sedation, blurred vision, constipation, dry • Weight loss, exercise programs, and
mouth medical management for high BMIs,
• Antihistaminic actions may cause sedation, diabetes, dyslipidemia
weight gain
• By blocking alpha 1 adrenergic receptors, it Best Augmenting Agents for Side
can cause dizziness, sedation, and Effects
hypotension ✽ Augmentation of pimozide has not been
• Mechanism of weight gain and any systematically studied and can be
possible increased incidence of diabetes or dangerous, especially with drugs that can
dyslipidemia with conventional either prolong QTc interval or raise
antipsychotics is unknown pimozide plasma levels
✽ Mechanism of potentially dangerous QTc
prolongation may be related to actions at
ion channels DOSING AND USE
Notable Side Effects Usual Dosage Range
✽ Neuroleptic-induced deficit syndrome • Less than 10 mg/day
✽ Akathisia
✽ Extrapyramidal symptoms, Parkinsonism, Dosage Forms
tardive dyskinesia • Tablet 1 mg scored, 2 mg scored
✽ Hypotension
• Sedation, akinesia How to Dose
• Galactorrhea, amenorrhea • Initial 1–2 mg/day in divided doses; can
• Dry mouth, constipation, blurred vision increase dose every other day; maximum
• Sexual dysfunction 10 mg/day or 0.2 mg/kg/day
✽ Weight gain • Children: initial 0.05 mg/kg/day at night;
can increase every 3 days; maximum
10 mg/day or 0.2 mg/kg/day
Life Threatening or
Dangerous Side Effects
• Rare neuroleptic malignant syndrome Dosing Tips
• Rare seizures
✽ Dose-dependent QTc prolongation ✽ The effects of pimozide on the QTc
interval are dose-dependent, so start low
• Ventricular arrhythmias and sudden death
and go slow while carefully monitoring QTc
Weight Gain interval

Overdose
• Deaths have occurred; extrapyramidal
• Occurs in significant minority symptoms, ECG changes, hypotension,
respiratory depression, coma

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(continued) PIMOZIDE

Long-Term Use • Use cautiously in patients with alcohol

• Some side effects may be irreversible (e.g., withdrawal or convulsive disorders
tardive dyskinesia) because of possible lowering of seizure
threshold
Habit Forming • Antiemetic effect can mask signs of other
• No disorders or overdose
• Do not use epinephrine in event of
How to Stop overdose as interaction with some pressor
• Slow down-titration (over 6 to 8 weeks), agents may lower blood pressure
especially when simultaneously beginning • Use only with caution if at all in
a new antipsychotic while switching (i.e., Parkinson’s disease or Lewy Body
cross-titration) dementia
• Rapid discontinuation may lead to rebound • Because pimozide may dose-dependently
psychosis and worsening of symptoms prolong QTc interval, use with caution in
• If antiparkinson agents are being used, patients who have bradycardia or who are
they should be continued for a few weeks taking drugs that can induce bradycardia
after pimozide is discontinued (e.g., beta blockers, calcium channel
blockers, clonidine, digitalis)
Pharmacokinetics • Because pimozide may dose-dependently
• Metabolized by CYP450 3A and to a lesser prolong QTc interval, use with caution in
extent by CYP450 1A2 patients who have hypokalemia and/or
• Mean elimination half-life approximately hypomagnesemia or who are taking drugs
55 hours that can induce hypokalemia and/or
magnesemia (e.g., diuretics, stimulant
laxatives, intravenous amphotericin B,
Drug Interactions glucocorticoids, tetracosactide)
• May decrease the effects of levodopa, • Pimozide can increase tumors in mice
dopamine agonists (dose-related effect)
• May enhance QTc prolongation of other ✽ Pimozide can increase the QTc interval
drugs capable of prolonging QTc interval and potentially cause arrhythmia or sudden
• May increase the effects of death, especially in combination with drugs
antihypertensive drugs that raise its levels
✽ Use with CYP450 3A4 inhibitors (e.g.,
drugs such as fluoxetine, sertraline, Do Not Use
fluvoxamine, and nefazodone; foods such • If patient is in a comatose state or has CNS
as grapefruit juice) can raise pimozide depression
levels and increase the risks of dangerous ✽ If patient is taking an agent capable of
arrhythmias significanty prolonging QTc interval (e.g.,
• Use of pimozide and fluoxetine may lead to thioridazine, selected antiarrhythmics,
bradycardia moxifoxacin, and sparfloxacin)
• Additive effects may occur if used with ✽ If there is a history of QTc prolongation
CNS depressants or cardiac arrhythmia, recent acute
• Some patients taking a neuroleptic and myocardial infarction, uncompensated
lithium have developed an encephalopathic heart failure
syndrome similar to neuroleptic malignant • If patient is taking drugs that can cause tics
syndrome ✽ If patient is taking drugs that inhibit
• Combined use with epinephrine may lower pimozide metabolism, such as macrolide
blood pressure antibiotics, azole antifungal agents
(ketoconazole, itraconazole), protease
inhibitors, nefazodone, fluvoxamine,
Other Warnings/ fluoxetine, sertaline, etc.
Precautions • If there is a proven allergy to pimozide
• If signs of neuroleptic malignant syndrome • If there is a known sensitivity to other
develop, treatment should be immediately antipsychotics
discontinued

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PIMOZIDE (continued)

SPECIAL POPULATIONS • Should evaluate for an antipsychotic with a

better risk/benefit ratio if treatment
Renal Impairment required during pregnancy
• Use with caution
Breast Feeding
Hepatic Impairment • Unknown if pimozide is secreted in human
• Use with caution breast milk, but all psychotropics assumed
to be secreted in breast milk
Cardiac Impairment
• Not recommended for use because of
• Pimozide produces a dose-dependent
potential for tumorigenicity or
prolongation of QTc interval, which may be
cardiovascular effects on infant
enhanced by the existence of bradycardia,
hypokalemia, congenital or acquired long ✽ Recommended either to discontinue drug
or bottle feed
QTc interval, which should be evaluated
prior to administering pimozide
• Use with caution if treating concomitantly
with a medication likely to produce THE ART OF PSYCHOPHARMACOLOGY
prolonged bradycardia, hypokalemia,
slowing of intracardiac conduction, or
Potential Advantages
prolongation of the QTc interval • Only for patients who respond to this agent
• Avoid pimozide in patients with a known and not to other antipsychotics
history of QTc prolongation, recent acute
Potential Disadvantages
myocardial infarction, and uncompensated
• Vulnerable populations such as children
heart failure
and elderly
Elderly • Patients on other drugs
• Some patients may tolerate lower doses
Primary Target Symptoms
better
• Vocal and motor tics in patients who fail to
respond to treatment with other
antipsychotics
Children and Adolescents • Psychotic symptoms in patients who fail to
• Safety and efficacy established for patients respond to treatment with other
over age 12 antipsychotics
• Preliminary data show similar safety for
patients age 2–12 as for patients over 12
• Generally use second-line after atypical
Pearls
antipsychotics and other conventional
antipsychotics ✽ In the past, was a first-line choice for
Tourette’s syndrome and for certain
behavioral disorders, including
monosymptomatic hypochondriasis;
Pregnancy however, it is now recognized that the
• Risk Category C [some animal studies benefits of pimozide generally do not
show adverse effects, no controlled studies outweigh its risks in most patients
in humans] ✽ Because of its effects on the QTc interval,
• Renal papillary abnormalities have been pimozide is not intended for use unless
seen in rats during pregnancy other options for tic disorders (or
• No studies in pregnant women psychotic disorders) have failed
• Psychotic symptoms may worsen during
pregnancy and some form of treatment
may be necessary
• Atypical antipsychotics may be preferable
to conventional antipsychotics or
anticonvulsant mood stabilizers if
treatment is required during pregnancy

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(continued) PIMOZIDE

Suggested Reading
Shapiro AK, Shapiro E, Fulop G. Pimozide Tueth MJ, Cheong JA. Clinical uses of
treatment of tic and Tourette disorders. pimozide. South Med J 1993; 86 (3): 344–9.
Pediatrics 1987; 79 (6): 1032–9.
Sultana A, McMonagle T. Pimozide for
schizophrenia or related psychoses. Cochrane
Database Syst Rev 2000; (3): CD001949.

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0521011698s07.qxd 9/2/04 2:44 PM Page 383

PIPOTHIAZINE
THERAPEUTICS quetiapine, ziprasidone, aripiprazole,
amisulpride)
Brands • Piportil • Consider trying another conventional
see index for additional brand names antipsychotic
• If 2 or more antipsychotic monotherapies
Generic? No
do not work, consider clozapine

Best Augmenting Combos

Class for Partial Response or
• Conventional antipsychotic (neuroleptic, Treatment-Resistance
phenothiazine, dopamine 2 antagonist) • Augmentation of conventional
antipsychotics has not been systematically
Commonly Prescribed For studied
(bold for FDA approved) • Addition of a mood stabilizing
• Maintenance treatment of schizophrenia anticonvulsant such as valproate,
• Other psychotic disorders carbamazepine, or lamotrigine may be
• Bipolar disorder helpful in both schizophrenia and bipolar
mania
• Augmentation with lithium in bipolar mania
How The Drug Works may be helpful
• Blocks dopamine 2 receptors, reducing • Addition of a benzodiazepine, especially
positive symptoms of psychosis short-term for agitation

How Long Until It Works Tests

• Psychotic symptoms can improve within ✽ Since conventional antipsychotics are
1 week, but it may take several weeks for frequently associated with weight gain,
full effect on behavior before starting treatment, weigh all patients
and determine if the patient is already
If It Works overweight (BMI 25.0–29.9) or obese
• Most often reduces positive symptoms in (BMI ≥30)
schizophrenia but does not eliminate them • Before giving a drug that can cause weight
• Most schizophrenic patients do not have a gain to an overweight or obese patient,
total remission of symptoms but rather a consider determining whether the patient
reduction of symptoms by about a third already has pre-diabetes (fasting plasma
• Continue treatment in schizophrenia until glucose 100–125 mg/dl), diabetes (fasting
reaching a plateau of improvement plasma glucose >126 mg/dl), or
• After reaching a satisfactory plateau, dyslipidemia (increased total cholesterol,
continue treatment for at least a year after LDL cholesterol and triglycerides;
first episode of psychosis in schizophrenia decreased HDL cholesterol), and treat or
• For second and subsequent episodes of refer such patients for treatment, including
psychosis in schizophrenia, treatment may nutrition and weight management, physical
need to be indefinite activity counseling, smoking cessation, and
• Reduces symptoms of acute psychotic medical management
mania but not proven as a mood stabilizer ✽ Monitor weight and BMI during treatment
or as an effective maintenance treatment in ✽ While giving a drug to a patient who has
bipolar disorder gained >5% of initial weight, consider
• After reducing acute psychotic symptoms evaluating for the presence of pre-diabetes,
in mania, switch to a mood stabilizer diabetes, or dyslipidemia, or consider
and/or an atypical antipsychotic for mood switching to a different antipsychotic
stabilization and maintenance • Should check blood pressure in the elderly
before starting and for the first few weeks
If It Doesn’t Work • Monitoring elevated prolactin levels of
• Consider trying one of the first-line atypical dubious clinical benefit
antipsychotics (risperidone, olanzapine, • Phenothiazines may cause false-positive
phenylketonuria results

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PIPOTHIAZINE (continued)

SIDE EFFECTS • Reported but not expected

How Drug Causes Side Effects What To Do About Side Effects
• By blocking dopamine 2 receptors in the • Wait
striatum, it can cause motor side effects • Wait
• By blocking dopamine 2 receptors in the • Wait
pituitary, it can cause elevations in • For motor symptoms, add an
prolactin anticholinergic agent
• By blocking dopamine 2 receptors • Reduce the dose
excessively in the mesocortical and • For sedation, take at night
mesolimbic dopamine pathways, especially • Switch to an atypical antipsychotic
at high doses, it can cause worsening of • Weight loss, exercise programs, and
negative and cognitive symptoms medical management for high BMIs,
(neuroleptic-induced deficit syndrome) diabetes, dyslipidemia
• Anticholinergic actions may cause
sedation, blurred vision, constipation, dry Best Augmenting Agents for Side
mouth Effects
• Antihistaminic actions may cause sedation, • Benztropine or trihexyphenidyl for motor
weight gain side effects
• By blocking alpha 1 adrenergic receptors, it • Sometimes amantadine can be helpful for
can cause dizziness, sedation, and motor side effects
hypotension • Benzodiazepines may be helpful for
• Mechanism of weight gain and any akathisia
possible increased incidence of diabetes or • Many side effects cannot be improved with
dyslipidemia with conventional an augmenting agent
antipsychotics is unknown

Notable Side Effects

✽ Excitement, insomnia, restlessness DOSING AND USE
✽ Rare tardive dyskinesia (risk increases Usual Dosage Range
with duration of treatment and with dose)
• 50–100 mg once a month
✽ Galactorrhea, amenorrhea
• Dry mouth, nausea, blurred vision, Dosage Forms
sweating, appetite change
• Injection 50 mg/mL
• Sexual dysfunction (impotence)
• Hypotension, arrhythmia, tachycardia How to Dose
• Weight gain • Initial 25 mg; can be increased by
• Rare rash 25–50 mg; maximum 200 mg once a
month
Life Threatening or • Drug should be administerd
Dangerous Side Effects intramuscularly in the gluteal region
• Rare neuroleptic malignant syndrome
• Jaundice, leucopenia
• Rare seizures Dosing Tips
✽ Only available as long acting intramuscular
Weight Gain formulation and not as oral formulation
• The peak of action generally occurs after
9–10 days
• Many experience and/or can be significant • May need to treat with an oral
in amount antipsychotic for 1–2 weeks when initiating
treatment
Sedation • One of the few conventional antipsychotics
available in a depot formulation lasting for
up to a month

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(continued) PIPOTHIAZINE

Overdose • Use with caution in patients with

• Sedation, tachycardia, extrapyramidal respiratory disease, Lewy Body dementia,
symptoms, arrhythmia, hypothermia, ECG narrow angle-closure glaucoma (including
changes, hypotension family history), alcohol withdrawal
syndrome, brain damage, epilepsy,
Long-Term Use hypothyroidism, myaesthenia gravis,
• Some side effects may be irreversible (e.g., prostatic hypertrophy, thyrotoxicosis
tardive dyskinesia) • Contact with skin can cause rash
• Antiemetic effect can mask signs of other
Habit Forming disorders or overdose
• No • Do not use epinephrine in event of
overdose as interaction with some pressor
How to Stop agents may lower blood pressure
• If antiparkinson agents are being used,
they should be continued for a few weeks Do Not Use
after pipothiazine is discontinued • If patient is comatose
• If there is cerebral atherosclerosis
Pharmacokinetics • If patient has phaeochromocytoma
• Onset of action of palmitic ester • If patient has renal or liver failure, blood
formulation within 2–3 days dyscrasias
• Duration of action of palmitic ester • If patient has severe cardiac impairment
formulation 3–6 weeks • If patient has subcortical brain damage
• If there is a proven allergy to pipothiazine
• If there is a known sensitivity to any
Drug Interactions phenothiazine
• Use with tricyclic antidepressants may
increase risk of cardiac symptoms
• CNS effects may be increased if used with SPECIAL POPULATIONS
other CNS depressants
• May increase the effects of Renal Impairment
antihypertensive agents • Use with caution
• May decrease the effects of amphetamines,
levodopa, dopamine agonists, clonidine, Hepatic Impairment
guanethidine, adrenaline • Use with caution
• Effects may be reduced by anticholinergic
agents Cardiac Impairment
• Antacids, antiparkinson drugs, and lithium • Use with caution
may reduce pipothiazine absorption
• Combined use with epinephrine may lower Elderly
blood pressure • Elderly patients do not metabolize the drug
• Some patients taking a neuroleptic and as quickly
lithium have developed an encephalopathic • Dose should be reduced
syndrome similar to neuroleptic malignant • Recommended starting dose 5–10 mg
syndrome

Children and Adolescents

Other Warnings/
• Not recommended for use in children
Precautions
• Patients may be more sensitive to extreme
temperatures
• Use with caution in patients with Pregnancy
Parkinson’s disease, Lewy Body dementia, • Risk Category C [some animal studies
or extrapyramidal symptoms with previous show adverse effects, no controlled studies
treatments in humans]
• Avoid undue exposure to sunlight

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PIPOTHIAZINE (continued)

• Reports of extrapyramidal symptoms,

jaundice, hyperreflexia, hyporeflexia in
infants whose mothers took a Pearls
phenothiazine during pregnancy • Pipothiazine is a higher potency
• Not recommended unless absolutely phenothiazine
necessary • Less risk of sedation and orthostatic
• Psychotic symptoms may worsen during hypotension but greater risk of
pregnancy and some form of treatment extrapyramidal symptoms than with low
may be necessary potency phenothiazines
• Atypical antipsychotics may be preferable ✽ Only available in long-acting parenteral
to conventional antipsychotics or formulation
anticonvulsant mood stabilizers if • Generally, patients must be stabilized on an
treatment is required during pregnancy oral antipsychotic prior to switching to
parenteral long-acting pipothiazine
Breast Feeding • Patients have very similar antipsychotic
• Unknown if pipothiazine is secreted in responses to any conventional
human breast milk, but all psychotropics antipsychotic, which is different from
assumed to be secreted in breast milk atypical antipsychotics where antipsychotic
✽ Recommended either to discontinue drug responses of individual patients can
or bottle feed occasionally vary greatly from one atypical
antipsychotic to another
• Patients with inadequate responses to
THE ART OF PSYCHOPHARMACOLOGY atypical antipsychotics may benefit from a
trial of augmentation with a conventional
Potential Advantages antipsychotic such as pipothiazine or from
• Non-compliant patients switching to a conventional antipsychotic
such as pipothiazine
Potential Disadvantages • However, long-term polypharmacy with a
• Patients who need immediate onset of combination of a conventional
antipsychotic actions antipsychotic with an atypical antipsychotic
such as pipothiazine may combine their
Primary Target Symptoms side effects without clearly augmenting the
• Positive symptoms of psychosis efficacy of either
• Negative symptoms of psychosis • Although a frequent practice by some
• Aggressive symptoms prescribers, adding 2 conventional
antipsychotics together has little rationale
and may reduce tolerability without clearly
enhancing efficacy

Suggested Reading
Leong OK, Wong KE, Tay WK, Gill RC. A Schmidt K. Pipothiazine palmitate: a versatile,
comparative study of pipothiazine palmitate sustained-action neuroleptic in psychiatric
and fluphenazine decanoate in the practice. Curr Med Res Opin 1986; 10 (5):
maintenance of remission of schizophrenia. 326–9.
Singapore Med J 1989; 30 (5): 436–40.
Quraishi S, David A. Depot pipothiazine
palmitate and undecylenate for schizophrenia.
Cochrane Database Syst Rev 2001; (3):
CD001720.

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PREGABALIN
THERAPEUTICS necessary in combination with other
treatments
Brands • Lyrica • Treatment of neuropathic pain most often
see index for additional brand names reduces but does not eliminate all
symptoms and is not a cure since
Generic? No
symptoms usually recur after medicine
stopped
• Continue treatment until all symptoms are
Class gone or until improvement is stable and
• Anticonvulsant, antineuralgic for chronic then continue treating indefinitely as long
pain, alpha 2 delta ligand at voltage- as improvement persists
sensitive calcium channels
If It Doesn’t Work (for neuropathic
Commonly Prescribed For pain)
(bold for FDA approved) • Many patients only have a partial response
• Peripheral neuropathic pain where some symptoms are improved but
• Partial seizures with or without secondary others persist
generalization (adjunctive) • Other patients may be nonresponders,
• Generalized anxiety disorder sometimes called treatment-resistant or
• Panic disorder treatment-refractory
• Social anxiety disorder • Consider increasing dose, switching to
• Fibromyalgia another agent or adding an appropriate
augmenting agent
• Consider biofeedback or hypnosis for pain
How The Drug Works • Consider psychotherapy for anxiety
• Is a leucine analogue and is transported • Consider the presence of noncompliance
both into the blood from the gut and also and counsel patient
across the blood-brain barrier into the • Consider evaluation for another diagnosis
brain from the blood by the system L or for a comorbid condition (e.g., medical
transport system (a sodium independent illness, substance abuse, etc.)
transporter) as well as by additional
sodium-dependent amino acid transporter Best Augmenting Combos
systems for Partial Response or
✽ Binds to the alpha 2 delta subunit of Treatment-Resistance
voltage-sensitive calcium channels ✽ In addition to being a first-line treatment
• This closes N and P/Q presynaptic calcium for neuropathic pain and anxiety disorders,
channels, diminishing excessive neuronal pregabalin is itself an augmenting agent to
activity and neurotransmitter release numerous other anticonvulsants in treating
• Although structurally related to gamma- epilepsy
aminobutyric acid (GABA), no known direct • For postherpetic neuralgia, pregabalin can
actions on GABA or its receptors decrease concomitant opiate use
✽ For neuropathic pain, tricyclic
How Long Until It Works antidepressants and SNRIs as well as
• Can reduce neuropathic pain and anxiety tiagabine, other anticonvulsants, and even
within a week opiates can augment pregabalin if done by
• Should reduce seizures by 2 weeks experts while carefully monitoring in
• If it is not producing clinical benefits within difficult cases
6–8 weeks, it may require a dosage • For anxiety, SSRIs, SNRIs, or
increase or it may not work at all benzodiazepines can augment pregabalin
If It Works Tests
• The goal of treatment of neuropathic pain, • None for healthy individuals
seizures, and anxiety disorders is to reduce
symptoms as much as possible, and if

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PREGABALIN (continued)

SIDE EFFECTS DOSING AND USE

How Drug Causes Side Effects Usual Dosage Range
• CNS side effects may be due to excessive • 150–600 mg/day in 2–3 doses
blockade of voltage-sensitive calcium
channels Dosage Forms
• Capsule 25 mg, 50 mg, 75 mg, 100 mg,
Notable Side Effects 150 mg, 200 mg, 300 mg
✽ Sedation, dizziness
• Ataxia, fatigue, tremor, dysarthria, How to Dose
paraesthesia, memory impairment, • Neuropathic pain: initial 150 mg/day in
coordination abnormal, impaired attention, 2–3 doses; can increase to 300 mg/day in
confusion, euphoric mood, irritability 2–3 doses after 3–7 days; can increase to
• Vomiting, dry mouth, constipation, weight 600 mg/day in 2–3 doses after 7 more
gain, increased appetite, flatulence days; maximum dose generally 600 mg/day
• Blurred vision, diplopia • Seizures: initial 150 mg/day in 2–3 doses;
• Peripheral edema can increase to 300 mg/day in 2–3 doses
• Libido decreased, erectile dysfunction after 7 days; can increase to 600 mg/day in
2–3 doses after 7 more days; maximum
dose generally 600 mg/day
Life Threatening or
Dangerous Side Effects
• None
Dosing Tips
Weight Gain ✽ Generally given in one-third to one-sixth
the dose of gabapentin
• If pregabalin is added to a second sedating
agent, such as another anticonvulsant, a
• Occurs in significant minority benzodiazepine, or an opiate, the titration
period should be at least a week to
Sedation improve tolerance to sedation
• Most patients only need to take pregabalin
twice daily
• Many experience and/or can be significant • At the high end of the dosing range,
in amount tolerability may be enhanced by splitting
• Dose-related dose into 3 or more divided doses
• Can wear off with time • For intolerable sedation, can give most of
the dose at night and less during the day
What To Do About Side Effects • To improve slow-wave sleep, may only
• Wait need to take pregabalin at bedtime
• Wait • May be taken with or without food
• Wait
• Take more of the dose at night to reduce Overdose
daytime sedation • No fatalities
• Lower the dose
• Switch to another agent Long-Term Use
• Safe
Best Augmenting Agents for Side
Effects Habit Forming
• Many side effects cannot be improved with • No
an augmenting agent
How to Stop
• Taper over a minimum of 1 week
• Epilepsy patients may seize upon
withdrawal, especially if withdrawal is
abrupt

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(continued) PREGABALIN

• Discontinuation symptoms uncommon • Starting dose should be at the bottom of

the range; titrate as usual up to maximum
Pharmacokinetics dose
• Pregabalin is not metabolized but excreted • Can be removed by hemodialysis; patients
intact renally receiving hemodialysis may require a
• Elimination half-life approximately supplemental dose of pregabalin following
5–7 hours hemodialysis (25–100 mg)

Hepatic Impairment
Drug Interactions • Dose adjustment not necessary
• Pregabalin has not been shown to have
Cardiac Impairment
significant pharmacokinetic drug
• No specific recommendations
interactions
• Because pregabalin is excreted unchanged, Elderly
it is unlikely to have significant
• Some patients may tolerate lower doses
pharmacokinetic drug interactions
better
• May add to or potentiate the sedative
• Elderly patients may be more susceptible
effects of oxycodone, lorazepam, and
to adverse effects
alcohol

Other Warnings/ Children and Adolescents

Precautions • Safety and efficacy have not been
• Dizziness and sedation could increase the established
chances of accidental injury (falls) in the • Use should be reserved for the expert
elderly
• Increased incidence of hemangiosarcoma
at high doses in mice involves platelet Pregnancy
changes and associated endothelial cell • Some animal studies have shown adverse
proliferation not present in rats or humans; effects, no controlled studies in humans
no evidence to suggest an associated risk • Use in women of childbearing potential
for humans requires weighing potential benefits to the
Do Not Use mother against the risks to the fetus
• Taper drug if discontinuing
• If there is a proven allergy to pregabalin or
• Seizures, even mild seizures, may cause
gabapentin
harm to the embryo/fetus
• If patient has a problem of galactose
intolerance, the Lapp lactase deficiency, or Breast Feeding
glucose-galactose malabsorption • Unknown if pregabalin is secreted in
human breast milk, but all psychotropics
assumed to be secreted in breast milk
SPECIAL POPULATIONS ✽ Recommended either to discontinue drug
or bottle feed
Renal Impairment • If drug is continued while breast feeding,
• Pregabalin is renally excreted, so the dose infant should be monitored for possible
may need to be lowered adverse effects
• Dosing can be adjusted according to • If infant becomes irritable or sedated,
creatinine clearance, such that patients breast feeding or drug may need to be
with clearance below 15 mL/min should discontinued
receive 25–75 mg/day in 1 dose, patients
with clearance between 15–29 mL/min
should receive 25–150 mg/day in
1–2 doses, and patients with clearance
between 30–59 mL/min should receive
75–300 mg/day in 2–3 doses

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PREGABALIN (continued)

THE ART OF PSYCHOPHARMACOLOGY • Well-studied in epilepsy, peripheral

neuropathic pain, and generalized anxiety
Potential Advantages disorder
• First-line for diabetic peripheral neuropathy
• Fibromyalgia
✽ Off-label use for generalized anxiety
disorder, panic disorder, and social anxiety
• Anxiety disorders disorder may be justified
• Sleep • May have uniquely robust therapeutic
• Has relatively mild side effect profile actions for both the somatic and the
• Has few pharmacokinetic drug interactions psychic symptoms of generalized anxiety
• More potent and probably better tolerated disorder
than gabapentin
✽ Off-label use as an adjunct for bipolar
disorder may not be justified
Potential Disadvantages
• Requires 2–3 times a day dosing ✽ One of the few agents that enhances
slow-wave delta sleep, which may be
• Not yet approved for anxiety disorders
helpful in chronic neuropathic pain
• Not yet available in the United States
syndromes
Primary Target Symptoms • Pregabalin is generally well-tolerated, with
• Seizures only mild adverse effects
• Pain ✽ Although no head-to-head studies,
• Anxiety appears to be better tolerated and more
consistently efficacious at high doses than
gabapentin
Pearls
✽ Drug absorption and clinical efficacy may
be more consistent at high doses for
✽ First and only treatment currently pregabalin compared to gabapentin
approved for neuropathic pain associated because of the higher potency of
with diabetic peripheral neuropathy pregabalin and the fact that, unlike
• Also effective in postherpetic neuralgia gabapentin, it is transported by more than
• Improves sleep interference as well as pain one transport system
in patients with painful diabetic peripheral
neuropathy or postherpetic neuralgia
• Improves pain and sleep interference
associated with fibromyalgia

Suggested Reading
Hovinga CA. Novel anticonvulsant medications Stahl SM. Anticonvulsants as anxiolytics, part
in development. Expert Opin Investig Drugs 2: Pregabalin and gabapentin as alpha(2)delta
2002;11:1387–406. ligands at voltage-gated calcium channels. J
Clin Psychiatry 2004;65:460–1.
Lauria-Horner BA, Pohl RB. Pregabalin: a new
anxiolytic. Expert Opin Investig Drugs 2003;
12:663–72.
Stahl SM. Anticonvulsants and the relief of
chronic pain: pregabalin and gabapentin as
alpha(2)delta ligands at voltage-gated calcium
channels. J Clin Psychiatry 2004;65:596–7.

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PROTRIPTYLINE
THERAPEUTICS If It Works
• The goal of treatment is complete
Brands • Triptil
remission of current symptoms as well as
• Vivactil
prevention of future relapses
see index for additional brand names
• Treatment most often reduces or even
Generic? Yes eliminates symptoms, but not a cure since
symptoms can recur after medicine
stopped
• Continue treatment until all symptoms are
Class gone (remission)
• Tricyclic antidepressant (TCA) • Once symptoms gone, continue treating for
• Predominantly a norepinephrine/ 1 year for the first episode of depression
noradrenaline reuptake inhibitor • For second and subsequent episodes of
depression, treatment may need to be
Commonly Prescribed For indefinite
(bold for FDA approved) • Use in anxiety disorders may also need to
• Mental depression be indefinite
• Treatment-resistant depression
If It Doesn’t Work
• Many patients only have a partial response
How The Drug Works where some symptoms are improved but
others persist (especially insomnia, fatigue,
• Boosts neurotransmitter
and problems concentrating)
norepinephrine/noradrenaline
• Other patients may be nonresponders,
• Blocks norepinephrine reuptake pump
sometimes called treatment-resistant or
(norepinephrine transporter), presumably
treatment-refractory
increasing noradrenergic
• Consider increasing dose, switching to
neurotransmission
another agent or adding an appropriate
• Since dopamine is inactivated by
augmenting agent
norepinephrine reuptake in frontal cortex,
• Consider psychotherapy
which largely lacks dopamine transporters,
• Consider evaluation for another diagnosis
protriptyline can increase dopamine
or for a comorbid condition (e.g., medical
neurotransmission in this part of the brain
illness, substance abuse, etc.)
• A more potent inhibitor of norepinephrine
• Some patients may experience apparent
reuptake pump than serotonin reuptake
lack of consistent efficacy due to activation
pump (serotonin transporter)
of latent or underlying bipolar disorder, and
• At high doses may also boost
require antidepressant discontinuation and
neurotransmitter serotonin and presumably
a switch to a mood stabilizer
increase serotonergic neurotransmission

How Long Until It Works Best Augmenting Combos

for Partial Response or
✽ Some evidence it may have an early onset Treatment-Resistance
of action with improvement in activity and
energy as early as 1 week • Lithium, buspirone, thyroid hormone
• Onset of therapeutic actions usually not
immediate, but often delayed 2 to 4 weeks
Tests
• If it is not working within 6 to 8 weeks for • None for healthy individuals
depression, it may require a dosage ✽ Since tricyclic and tetracyclic
increase or it may not work at all antidepressants are frequently associated
• May continue to work for many years to with weight gain, before starting treatment,
prevent relapse of symptoms weigh all patients and determine if the
patient is already overweight
(BMI 25.0–29.9) or obese (BMI ≥30)
• Before giving a drug that can cause weight
gain to an overweight or obese patient,
consider determining whether the patient

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PROTRIPTYLINE (continued)

already has pre-diabetes (fasting plasma • Fatigue, weakness, dizziness, sedation,

glucose 100–125 mg/dl), diabetes (fasting headache, anxiety, nervousness,
plasma glucose >126 mg/dl), or restlessness
dyslipidemia (increased total cholesterol, • Sexual dysfunction (impotence, change in
LDL cholesterol and triglycerides; libido)
decreased HDL cholesterol), and treat or • Sweating, rash, itching
refer such patients for treatment, including
nutrition and weight management, physical
activity counseling, smoking cessation, and
Life Threatening or
medical management Dangerous Side Effects
✽ Monitor weight and BMI during treatment • Paralytic ileus, hyperthermia (TCAs +
✽ While giving a drug to a patient who has anticholinergic agents)
gained >5% of initial weight, consider • Lowered seizure threshold and rare
evaluating for the presence of pre-diabetes, seizures
diabetes, or dyslipidemia, or consider • Orthostatic hypotension, sudden death,
switching to a different antidepressant arrhythmias, tachycardia
• EKGs may be useful for selected patients • QTc prolongation
(e.g., those with personal or family history • Hepatic failure, extrapyramidal symptoms
of QTc prolongation; cardiac arrhythmia; • Increased intraocular pressure
recent myocardial infarction; • Rare induction of mania and activation of
uncompensated heart failure; or taking suicidal ideation
agents that prolong QTc interval such as
pimozide, thioridazine, selected
Weight Gain
antiarrhythmics, moxifloxacin, sparfloxacin,
etc.)
• Patients at risk for electrolyte disturbances • Many experience and/or can be significant
(e.g., patients on diuretic therapy) should in amount
have baseline and periodic serum • Can increase appetite and carbohydrate
potassium and magnesium measurements craving

Sedation
SIDE EFFECTS
How Drug Causes Side Effects • Many experience and/or can be significant
✽ Anticholinergic activity for protriptyline in amount
may be more potent than for some other ✽ Not as sedating as other TCAs; more
TCAs and may explain sedative effects, dry likely to be activating than other TCAs
mouth, constipation, blurred vision,
tachycardia, and hypotension What To Do About Side Effects
• Sedative effects and weight gain may be • Wait
due to antihistamine properties • Wait
• Blockade of alpha adrenergic 1 receptors • Wait
may explain dizziness, sedation, and • Lower the dose
hypotension • Switch to an SSRI or newer antidepressant
• Cardiac arrhythmias, especially in
overdose, may be caused by blockade of Best Augmenting Agents for Side
ion channels Effects
• Trazodone or a hypnotic for insomnia
Notable Side Effects • Benzodiazepines for agitation and anxiety
• Blurred vision, constipation, urinary • Many side effects cannot be improved with
retention, increased appetite, dry mouth, an augmenting agent
nausea, diarrhea, heartburn, unusual taste
in mouth, weight gain

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(continued) PROTRIPTYLINE

DOSING AND USE symptoms and then restart withdrawal

much more slowly
Usual Dosage Range
• 15–40 mg/day in 3–4 divided doses Pharmacokinetics
• Substrate for CYP450 2D6
Dosage Forms • Half-life approximately 74 hours
• Tablets 5 mg, 10 mg

How to Dose
• Initial 15 mg/day in divided doses; increase Drug Interactions
morning dose as needed; maximum dose • Tramadol increases the risk of seizures in
60 mg/day patients taking TCAs
• Use of TCAs with anticholinergic drugs
may result in paralytic ileus or
hyperthermia
Dosing Tips
• Fluoxetine, paroxetine, bupropion,
✽ Be aware that among this class of agents duloxetine, and other 2D6 inhibitors may
(tricyclic/tetracyclic antidepressants),
increase TCA concentrations
protriptyline has uniquely low dosing
• Cimetidine may increase plasma
(15–40 mg/day for protriptyline compared
concentrations of TCAs and cause anti-
to 75–300 mg/day for most other
cholinergic symptoms
tricyclic/tetracyclic antidepressants)
• Phenothiazines or haloperidol may raise
✽ Be aware that among this class of agents TCA blood concentrations
(tricyclic/tetracyclic antidepressants),
• May alter effects of antihypertensive drugs;
protriptyline has uniquely frequent dosing
may inhibit hypotensive effects of clonidine
(3–4 times a day compared to once daily
• Use with sympathomimetic agents may
for most other tricyclic/tetracyclic
increase sympathetic activity
antidepressants)
• Methylphenidate may inhibit metabolism of
• If intolerable anxiety, insomnia, agitation,
TCAs
akathisia, or activation occur either upon
• Activation and agitation, especially
dosing initiation or discontinuation,
following switching or adding
consider the possibility of activated bipolar
antidepressants, may represent the
disorder, and switch to a mood stabilizer or
induction of a bipolar state, especially a
an atypical antipsychotic
mixed dysphoric bipolar II condition
Overdose sometimes associated with suicidal
• Death may occur; CNS depression, ideation, and require the addition of
convulsions, cardiac dysrhythmias, severe lithium, a mood stabilizer or an atypical
hypotension, ECG changes, coma antipsychotic, and/or discontinuation of
protriptyline
Long-Term Use
• Safe Other Warnings/
Habit Forming Precautions
• Add or initiate other antidepressants with
• No
caution for up to 2 weeks after
How to Stop discontinuing protriptyline
• Taper to avoid withdrawal effects • Generally, do not use with MAO inhibitors,
• Even with gradual dose reduction some including 14 days after MAOIs are stopped;
withdrawal symptoms may appear within do not start an MAOI until 2 weeks after
the first 2 weeks discontinuing protriptyline
• Many patients tolerate 50% dose reduction • Use with caution in patients with history of
for 3 days, then another 50% reduction for seizures, urinary retention, narrow angle-
3 days, then discontinuation closure glaucoma, hyperthyroidism
• If withdrawal symptoms emerge during • TCAs can increase QTc interval, especially
discontinuation, raise dose to stop at toxic doses, which can be attained not
only by overdose but also by combining

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PROTRIPTYLINE (continued)

with drugs that inhibit TCA metabolism via tachycardia, and heart failure, especially in
CYP450 2D6, potentially causing torsade the diseased heart
de pointes-type arrhythmia or sudden • Myocardial infarction and stroke have been
death reported with TCAs
• Because TCAs can prolong QTc interval, • TCAs produce QTc prolongation, which
use with caution in patients who have may be enhanced by the existence of
bradycardia or who are taking drugs that bradycardia, hypokalemia, congenital or
can induce bradycardia (e.g., beta blockers, acquired long QTc interval, which should
calcium channel blockers, clonidine, be evaluated prior to administering
digitalis) protriptyline
• Because TCAs can prolong QTc interval, • Use with caution if treating concomitantly
use with caution in patients who have with a medication likely to produce
hypokalemia and/or hypomagnesemia or prolonged bradycardia, hypokalemia,
who are taking drugs that can induce slowing of intracardiac conduction, or
hypokalemia and/or magnesemia (e.g., prolongation of the QTc interval
diuretics, stimulant laxatives, intravenous • Avoid TCAs in patients with a known
amphotericin B, glucocorticoids, history of QTc prolongation, recent acute
tetracosactide) myocardial infarction, and uncompensated
heart failure
Do Not Use • TCAs may cause a sustained increase in
• If patient is recovering from myocardial heart rate in patients with ischemic heart
infarction disease and may worsen (decrease) heart
• If patient is taking agents capable of rate variability, an independent risk of
significantly prolonging QTc interval (e.g., mortality in cardiac populations
pimozide, thioridazine, selected • Since SSRIs may improve (increase) heart
antiarrhythmics, moxifloxacin, rate variability in patients following a
sparfloxacin) myocardial infarct and may improve
• If there is a history of QTc prolongation or survival as well as mood in patients with
cardiac arrhythmia, recent acute acute angina or following a myocardial
myocardial infarction, uncompensated infarction, these are more appropriate
heart failure agents for cardiac population than
• If patient is taking drugs that inhibit TCA tricyclic/tetracyclic antidepressants
metabolism, including CYP450 2D6 ✽ Risk/benefit ratio may not justify use of
inhibitors, except by an expert TCAs in cardiac impairment
• If there is reduced CYP450 2D6 function,
such as patients who are poor 2D6 Elderly
metabolizers, except by an expert and at • May be more sensitive to anticholinergic,
low doses cardiovascular, hypotensive, and sedative
• If there is a proven allergy to protriptyline effects
• Recommended dose is between
15–20 mg/day; doses >20 mg/day require
SPECIAL POPULATIONS close monitoring of patient

Renal Impairment
• Use with caution; may need to lower dose Children and Adolescents
• Patient may need to be monitored closely • Use with caution, observing for activation
of known or unknown bipolar disorder
Hepatic Impairment and/or suicidal ideation, and strongly
• Use with caution; may need to lower dose consider informing parents or guardian of
• Patient may need to be monitored closely this risk so they can help observe child or
adolescent patients
Cardiac Impairment • Not recommended for use under age 12
• TCAs have been reported to cause • Not intended for use under age 6
arrhythmias, prolongation of conduction
time, orthostatic hypotension, sinus

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(continued) PROTRIPTYLINE

• Several studies show lack of efficacy of • Patients noncompliant with 3–4 times daily
TCAs for depression dosing
• Some cases of sudden death have
occurred in children taking TCAs Primary Target Symptoms
• Recommended dose: 15–20 mg/day • Depressed mood

Pregnancy Pearls
• Risk Category C [some animal studies • Tricyclic antidepressants are no longer
show adverse effects, no controlled studies generally considered a first-line treatment
in humans] option for depression because of their side
• Crosses the placenta effect profile
• Adverse effects have been reported in • Tricyclic antidepressants continue to be
infants whose mothers took a TCA useful for severe or treatment-resistant
(lethargy, withdrawal symptoms, fetal depression
malformations) ✽ Has some potential advantages for
• Must weigh the risk of treatment (first withdrawn, anergic patients
trimester fetal development, third trimester ✽ May have a more rapid onset of action
newborn delivery) to the child against the than some other TCAs
risk of no treatment (recurrence of ✽ May aggravate agitation and anxiety more
depression, maternal health, infant than some other TCAs
bonding) to the mother and child ✽ May have more anticholinergic side
• For many patients this may mean effects, hypotension, and tachycardia than
continuing treatment during pregnancy some other TCAs
• Noradrenergic reuptake inhibitors such as
Breast Feeding protriptyline can be used as a second-line
• Some drug is found in mother’s breast milk treatment for smoking cessation, cocaine
✽ Recommended either to discontinue drug dependence, and attention deficit disorder
or bottle feed • TCAs may aggravate psychotic symptoms
• Immediate postpartum period is a high-risk • Alcohol should be avoided because of
time for depression, especially in women additive CNS effects
who have had prior depressive episodes, • Underweight patients may be more
so drug may need to be reinstituted late in susceptible to adverse cardiovascular
the third trimester or shortly after effects
childbirth to prevent a recurrence during • Children, patients with inadequate
the postpartum period hydration, and patients with cardiac
• Must weigh benefits of breast feeding with disease may be more susceptible to TCA-
risks and benefits of antidepressant induced cardiotoxicity than healthy adults
treatment versus non-treatment to both the • For the expert only: a heroic treatment (but
infant and the mother potentially dangerous) for severely
• For many patients this may mean treatment-resistant patients is to give
continuing treatment during breast feeding simultaneously with monoamine oxidase
inhibitors for patients who fail to respond
to numerous other antidepressants, but
THE ART OF PSYCHOPHARMACOLOGY generally recommend a different TCA than
protriptyline for this use
Potential Advantages • If this option is elected, start the MAOI with
• Severe or treatment-resistant depression the tricyclic/tetracyclic antidepressant
• Withdrawn, anergic patients simultaneously at low doses after
appropriate drug washout, then alternately
Potential Disadvantages increase doses of these agents every few
• Pediatric, geriatric, and cardiac patients days to a week as tolerated
• Patients concerned with weight gain • Although very strict dietary and
concomitant drug restrictions must be

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PROTRIPTYLINE (continued)

observed to prevent hypertensive crises activity of 2D6, such patients may not
and serotonin syndrome, the most safely tolerate normal doses of
common side effects of MAOI and tricyclic/tetracyclic antidepressants and
tricyclic/tetracyclic antidepressant may require dose reduction
combinations may be weight gain and • Phenotypic testing may be necessary to
orthostatic hypotension detect this genetic variant prior to dosing
• Patients on TCAs should be aware that they with a tricyclic/tetracyclic antidepressant,
may experience symptoms such as especially in vulnerable populations such
photosensitivity or blue-green urine as children, elderly, cardiac populations,
• SSRIs may be more effective than TCAs in and those on concomitant medications
women, and TCAs may be more effective • Patients who seem to have extraordinarily
than SSRIs in men severe side effects at normal or low doses
• Since tricyclic/tetracyclic antidepressants may have this phenotypic CYP450 2D6
are substrates for CYP450 2D6, and 7% of variant and require low doses or switching
the population (especially Caucasians) may to another antidepressant not metabolized
have a genetic variant leading to reduced by 2D6

Suggested Reading
Anderson IM. Meta-analytical studies on new Rudorfer MV, Potter WZ. Metabolism of
antidepressants. Br Med Bull. 2001; 57: tricyclic antidepressants. Cell Mol Neurobiol.
161–178. 1999; 19 (3): 373–409.
Anderson IM. Selective serotonin reuptake
inhibitors versus tricyclic antidepressants: a
meta-analysis of efficacy and tolerability. J Aff
Disorders. 2000; 58: 19–36.

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QUAZEPAM
THERAPEUTICS Tests
• In patients with seizure disorders,
Brands • Doral
concomitant medical illness, and/or those
see index for additional brand names
with multiple concomitant long-term
Generic? No medications, periodic liver tests and blood
counts may be prudent

Class
SIDE EFFECTS
• Benzodiazepine (hypnotic)
How Drug Causes Side Effects
Commonly Prescribed For
• Same mechanism for side effects as for
(bold for FDA approved)
therapeutic effects – namely due to
• Short-term treatment of insomnia
excessive actions at benzodiazepine
receptors
• Actions at benzodiazepine receptors that
How The Drug Works carry over to the next day can cause
• Binds to benzodiazepine receptors at the daytime sedation, amnesia, and ataxia
GABA-A ligand-gated chloride channel • Long-term adaptations in benzodiazepine
complex receptors may explain the development of
• Enhances the inhibitory effects of GABA dependence, tolerance, and withdrawal
• Boosts chloride conductance through
GABA-regulated channels Notable Side Effects
• Inhibitory actions in sleep centers may ✽ Sedation, fatigue, depression
provide sedative hypnotic effects ✽ Dizziness, ataxia, slurred speech,
weakness
How Long Until It Works ✽ Forgetfulness, confusion
• Generally takes effect in less than an hour ✽ Hyper-excitability, nervousness
• Rare hallucinations, mania
If It Works • Rare hypotension
• Improves quality of sleep • Hypersalivation, dry mouth
• Effects on total wake-time and number of • Rebound insomnia when withdrawing from
nighttime awakenings may be decreased long-term treatment
over time

If It Doesn’t Work Life Threatening or

• If insomnia does not improve after Dangerous Side Effects
7–10 days, it may be a manifestation of a • Respiratory depression, especially when
primary psychiatric or physical illness such taken with CNS depressants in overdose
as obstructive sleep apnea or restless leg • Rare hepatic dysfunction, renal
syndrome, which requires independent dysfunction, blood dyscrasias
evaluation
• Increase the dose Weight Gain
• Improve sleep hygiene
• Switch to another agent
• Reported but not expected
Best Augmenting Combos
for Partial Response or Sedation
Treatment-Resistance
• Generally, best to switch to another agent
• Trazodone
• Agents with antihistamine actions (e.g., • Many experience and/or can be significant
diphenhydramine, tricyclic antidepressants) in amount

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QUAZEPAM (continued)

What To Do About Side Effects sedation and/or impaired motor/cognitive

• Wait function, and may do so progressively over
• To avoid problems with memory, only take time
quazepam if planning to have a full night’s
sleep Habit Forming
• Lower the dose • Quazepam is a Schedule IV drug
• Switch to a shorter-acting sedative • Some patients may develop dependence
hypnotic and/or tolerance; risk may be greater with
• Switch to a non-benzodiazepine hypnotic higher doses
• Administer flumazenil if side effects are • History of drug addiction may increase risk
severe or life-threatening of dependence

Best Augmenting Agents for Side How to Stop

Effects • If taken for more than a few weeks, taper
• Many side effects cannot be improved with to reduce chances of withdrawal effects
an augmenting agent • Patients with seizure history may seize
upon sudden withdrawal
• Rebound insomnia may occur the first
1–2 nights after stopping
DOSING AND USE • For patients with severe problems
Usual Dosage Range discontinuing a benzodiazepine, dosing
• 15 mg/day at bedtime may need to be tapered over many months
(i.e., reduce dose by 1% every 3 days by
Dosage Forms crushing tablet and suspending or
• Tablet 7.5 mg, 15 mg dissolving in 100 ml of fruit juice and then
disposing of 1 ml while drinking the rest;
How to Dose 3–7 days later, dispose of 2 ml, and so on).
• 15 mg/day at bedtime; increase to This is both a form of very slow biological
30 mg/day if ineffective; maximum dose tapering and a form of behavioral
30 mg/day desensitization

Pharmacokinetics
• Half life 25–41 hours
Dosing Tips • Active metabolite
• Use lowest possible effective dose and • Metabolized in part by CYP450 3A4
assess need for continued treatment
regularly
• Quazepam should generally not be
prescribed in quantities greater than a Drug Interactions
1-month supply • Increased depressive effects when taken
• Patients with lower body weights may with other CNS depressants
require lower doses • Effects of quazepam may be increased by
• Risk of dependence may increase with CYP450 3A4 inhibitors such as nefazodone
dose and duration of treatment or fluvoxamine

Overdose Other Warnings/

• No death reported in monotherapy;
Precautions
sedation, respiratory depression, poor
• Insomnia may be a symptom of a primary
coordination, confusion, coma
disorder, rather than a primary disorder
Long-Term Use itself
• Not generally intended for use beyond • Some patients may exhibit abnormal
4 weeks thinking or behavioral changes similar to
✽ Because of its relatively longer half-life, those caused by other CNS depressants
(i.e., either depressant actions or
quazepam may cause some daytime
disinhibiting actions)

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(continued) QUAZEPAM

• Some depressed patients may experience a • Neonatal flaccidity has been reported in
worsening of suicidal ideation infants whose mothers took a
• Use only with extreme caution in patients benzodiazepine during pregnancy
with impaired respiratory function or
obstructive sleep apnea Breast Feeding
• Quazepam should only be administered at • Some drug is found in mother’s breast milk
bedtime ✽ Recommended either to discontinue drug
or bottle feed
Do Not Use • Effects on infant have been observed and
• If patient is pregnant include feeding difficulties, sedation, and
• If patient has narrow angle-closure weight loss
glaucoma
• If there is a proven allergy to quazepam or
any benzodiazepine THE ART OF PSYCHOPHARMACOLOGY
Potential Advantages
SPECIAL POPULATIONS • Transient insomnia

Renal Impairment Potential Disadvantages

• Recommended dose: 7.5 mg/day • Chronic nightly insomnia

Hepatic Impairment Primary Target Symptoms

• Recommended dose: 7.5 mg/day • Time to sleep onset
• Total night sleep
Cardiac Impairment • Nighttime awakening
• Benzodiazepines have been used to treat
insomnia associated with acute myocardial
infarction Pearls
Elderly ✽ Because quazepam tends to accumulate
over time, perhaps not the best hypnotic
• Recommended dose: 7.5 mg/day
for chronic nightly use
• If 15 mg/day is given initially, try to reduce
• If tolerance develops, it may result in
the dose to 7.5 mg/day after the first
increased anxiety during the day and/or
1–2 nights
increased wakefulness during the latter
part of the night
• Quazepam has a longer half-life than some
Children and Adolescents other sedative hypnotics, so it may be less
• Safety and efficacy have not been likely to cause rebound insomnia on
established discontinuation
• Long-term effects of quazepam in ✽ Long-term accumulation of quazepam
children/adolescents are unknown and its active metabolites may cause
• Should generally receive lower doses and insidious onset of confusion or falls,
be more closely monitored especially in the elderly

Pregnancy
• Risk Category X [positive evidence of risk
to human fetus; contraindicated for use in
pregnancy]
• Infants whose mothers received a
benzodiazepine late in pregnancy may
experience withdrawal effects

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QUAZEPAM (continued)

Suggested Reading
Ankier SI, Goa KL. Quazepam. A preliminary Kales A. Quazepam: hypnotic efficacy and side
review of its pharmacodynamic and effects. Pharmacotherapy 1990;10:1–10.
pharmacokinetic properties, and therapeutic
efficacy in insomnia. Drugs 1988;35:42–62. Kirkwood CK. Management of insomnia. J Am
Pharm Assoc (Wash) 1999;39:688–96.
Hilbert JM, Battista D. Quazepam and
flurazepam: differential pharmacokinetic and Roth T, Roehrs TA. A review of the safety
pharmacodynamic characteristics. J Clin profiles of benzodiazepine hypnotics. J Clin
Psychiatry 1991;52(Suppl):21–6. Psychiatry 1991;52 (Suppl):38–41.

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QUETIAPINE
THERAPEUTICS • Classically recommended to wait at least
4–6 weeks to determine efficacy of drug,
Brands • Seroquel but in practice some patients require up to
see index for additional brand names 16–20 weeks to show a good response,
especially on cognitive symptoms
Generic? Not in U.S., Europe, or Japan
If It Works
• Most often reduces positive symptoms in
Class schizophrenia but does not eliminate them
• Atypical antipsychotic (serotonin-dopamine • Can improve negative symptoms, as well
antagonist; second generation as aggressive, cognitive, and affective
antipsychotic; also a mood stabilizer) symptoms in schizophrenia
• Most schizophrenic patients do not have a
Commonly Prescribed For total remission of symptoms but rather a
(bold for FDA approved) reduction of symptoms by about a third
• Schizophrenia • Perhaps 5–15% of schizophrenic patients
• Acute mania (monotherapy and adjunct to can experience an overall improvement of
lithium or valproate) greater than 50–60%, especially when
• Other psychotic disorders receiving stable treatment for more than a
• Bipolar maintenance year
• Bipolar depression • Such patients are considered super-
• Behavioral disturbances in dementias responders or “awakeners” since they may
• Behavioral disturbances in Parkinson’s be well enough to be employed, live
disease and Lewy Body dementia independently, and sustain long-term
• Psychosis associated with levodopa relationships
treatment in Parkinson’s disease • Many bipolar patients may experience a
• Behavioral disturbances in children and reduction of symptoms by half or more
adolescents • Continue treatment until reaching a plateau
• Disorders associated with problems with of improvement
impulse control • After reaching a satisfactory plateau,
continue treatment for at least a year after
first episode of psychosis
How The Drug Works • For second and subsequent episodes of
• Blocks dopamine 2 receptors, reducing psychosis, treatment may need to be
positive symptoms of psychosis and indefinite
stabilizing affective symptoms • Even for first episodes of psychosis, it may
• Blocks serotonin 2A receptors, causing be preferable to continue treatment
enhancement of dopamine release in indefinitely to avoid subsequent episodes
certain brain regions and thus reducing • Treatment may not only reduce mania but
motor side effects and possibly improving also prevent recurrences of mania in
cognitive and affective symptoms bipolar disorder
• Interactions at a myriad of other
neurotransmitter receptors may contribute If It Doesn’t Work
to quetiapine’s efficacy • Try one of the other atypical antipsychotics
✽ Specifically, actions at 5HT1A receptors (risperidone, olanzapine, ziprasidone,
may contribute to efficacy for cognitive and aripiprazole, amisulpride)
affective symptoms in some patients, • If 2 or more antipsychotic monotherapies
especially at moderate to high doses do not work, consider clozapine
• If no first-line atypical antipsychotic is
How Long Until It Works effective, consider higher doses or
• Psychotic symptoms can improve within augmentation with valproate or lamotrigine
1 week, but it may take several weeks for • Some patients may require treatment with
full effect on behavior as well as on a conventional antipsychotic
cognition and affective stabilization • Consider noncompliance and switch to
another antipsychotic with fewer side

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QUETIAPINE (continued)

effects or to an antipsychotic that can be for patients who become overweight,

given by depot injection obese, pre-diabetic, diabetic, hypertensive,
• Consider initiating rehabilitation and or dyslipidemic while receiving an atypical
psychotherapy antipsychotic
• Consider presence of concomitant drug ✽ Even in patients without known diabetes,
abuse be vigilant for the rare but life threatening
onset of diabetic ketoacidosis, which
Best Augmenting Combos always requires immediate treatment, by
for Partial Response or monitoring for the rapid onset of polyuria,
Treatment-Resistance polydipsia, weight loss, nausea, vomiting,
• Valproic acid (valproate, divalproex, dehydration, rapid respiration, weakness
divalproex ER) and clouding of sensorium, even coma
• Other mood stabilizing anticonvulsants • Although U.S. manufacturer recommends
(carbamazepine, oxcarbazepine, 6-month eye checks for cataracts, clinical
lamotrigine) experience suggests this may be
• Lithium unnecessary
• Benzodiazepines

Tests SIDE EFFECTS

Before starting an atypical antipsychotic
✽ Weigh all patients and track BMI during How Drug Causes Side Effects
treatment • By blocking histamine 1 receptors in the
• Get baseline personal and family history of brain, it can cause sedation and possibly
obesity, dyslipidemia, hypertension, and weight gain
cardiovascular disease • By blocking alpha 1 adrenergic receptors, it
✽ Get waist circumference (at umbilicus), can cause dizziness, sedation, and
blood pressure, fasting plasma glucose, hypotension
and fasting lipid profile • By blocking muscarinic 1 receptors, it can
• Determine if the patient is cause dry mouth, constipation, and
• overweight (BMI 25.0–29.9) sedation
• obese (BMI ≥30) • By blocking dopamine 2 receptors in the
• has pre-diabetes (fasting plasma glucose striatum, it can cause motor side effects
100–125 mg/dl) (rare)
• has diabetes (fasting plasma glucose • Mechanism of weight gain and increased
>126 mg/dl) incidence of diabetes and dyslipidemia with
• has hypertension (BP >140/90 mm Hg) atypical antipsychotics is unknown
• has dyslipidemia (increased total
cholesterol, LDL cholesterol, and Notable Side Effects
triglycerides; decreased HDL cholesterol) ✽ May increase risk for diabetes and
• Treat or refer such patients for treatment, dyslipidemia
including nutrition and weight ✽ Dizziness, sedation
management, physical activity counseling, • Dry mouth, constipation, dyspepsia,
smoking cessation, and medical abdominal pain, weight gain
management • Tachycardia
• Orthostatic hypotension, usually during
Monitoring after starting an atypical initial dose titration
antipsychotic • Theoretical risk of tardive dyskinesia
✽ BMI monthly for 3 months, then quarterly
✽ Blood pressure, fasting plasma glucose,
fasting lipids within 3 months and then Life Threatening or
annually, but earlier and more frequently Dangerous Side Effects
for patients with diabetes or who have • Hyperglycemia, in some cases extreme and
gained >5% of initial weight associated with ketoacidosis or
• Treat or refer for treatment and consider hyperosmolar coma or death, has been
switching to another atypical antipsychotic

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(continued) QUETIAPINE

reported in patients taking atypical DOSING AND USE

antipsychotics
• Rare neuroleptic malignant syndrome
Usual Dosage Range
(much reduced risk compared to • 150–750 mg/day (in divided doses) for
conventional antipsychotics) schizophrenia
• Rare seizures • 400–800 mg/day (in divided doses) for
acute bipolar mania
Weight Gain
Dosage Forms
• Tablets 25 mg, 100 mg, 200 mg, 300 mg

• Many patients experience and/or can be How to Dose

significant in amount at effective • (according to manufacturer for
antipsychotic doses schizophrenia): initial 25 mg/day twice a
• Can become a health problem in some day; increase by 25–50 mg twice a day
• May be less than for some antipsychotics, each day until desired efficacy is reached;
more than for others maximum approved dose 800 mg/day
• In practice, can start adults with
Sedation schizophrenia under age 65 with same
doses as recommended for acute bipolar
mania
• Frequent and can be significant in amount • (according to manufacturing for acute
• Some patients may not tolerate it bipolar mania): initiate in twice daily doses,
• More than for some other antipsychotics, totaling 100 mg/day on day 1, increasing to
but never say always as not a problem in 400 mg/day on day 4 in increments of up
everyone to 100 mg/day; further dosage adjustments
• Can wear off over time up to 800 mg/day by day 6 should be in
• Can reemerge as dose increases and then increments of no greater than 200 mg/day
wear off again over time

What To Do About Side Effects Dosing Tips

• Wait ✽ More may be much more: Clinical
• Wait practice suggests quetiapine often
• Wait underdosed, then switched prior to
• Usually dosed twice daily, so take more of adequate trials
the total daily dose at bedtime to help • Clinical practice suggests that at low doses
reduce daytime sedation it may be a sedative hypnotic, possibly due
• Start dosing low and increase slowly as to potent H1 antihistamine actions, but this
side effects wear off at each dosing is an expensive use for which there are
increment many other options
• Weight loss, exercise programs, and ✽ Initial target dose of 400–800 mg/day
medical management for high BMIs, should be reached in most cases to
diabetes, dyslipidemia optimize the chances of success in treating
• Switch to another atypical antipsychotic acute psychosis and acute mania, but only
a minority of patients are adequately dosed
Best Augmenting Agents for Side in clinical practice
Effects • May be lower cost than some other
• Many side effects cannot be improved with atypical antipsychotics at 200 mg twice
an augmenting agent daily, but higher doses can be among the
most costly for atypical antipsychotics
• Recommended titration to 400 mg/day by
the fourth day can often be achieved when
necessary to control acute symptoms
✽ Higher doses generally achieve greater
response

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QUETIAPINE (continued)

✽ Occasional patients may require more Other Warnings/

than 800–1000 mg/day
• Rather than raise the dose above these
Precautions
levels in acutely agitated patients requiring • In the U.S., manufacturer recommends
acute antipsychotic actions, consider examination for cataracts before and every
augmentation with a benzodiazepine or 6 months after initiating quetiapine, but
conventional antipsychotic, either orally or this does not seem to be necessary in
intramuscularly clinical practice
• Rather than raise the dose above these • Quetiapine should be used cautiously in
levels in partial responders, consider patients at risk for aspiration pneumonia,
augmentation with a mood stabilizing as dysphagia has been reported
anticonvulsant such as valproate or • Priapism has been reported
lamotrigine • Use with caution in patients with known
• Children and elderly should generally be cardiovascular disease, cerebrovascular
dosed at the lower end of the dosage disease
spectrum • Use with caution in patients with
conditions that predispose to hypotension
Overdose (dehydration, overheating)
• Rarely lethal in monotherapy overdose;
sedation, slurred speech, hypotension
Do Not Use
• If there is a proven allergy to quetiapine
Long-Term Use
• Often used for long-term maintenance in
schizophrenia, bipolar disorder, and various SPECIAL POPULATIONS
behavioral disorders
Renal Impairment
Habit Forming • No dose adjustment required
• No
Hepatic Impairment
How to Stop • Downward dose adjustment may be
• Slow down-titration (over 6 to 8 weeks), necessary
especially when simultaneously beginning
a new antipsychotic while switching (i.e., Cardiac Impairment
cross-titration) • Drug should be used with caution because
• Rapid discontinuation may lead to rebound of risk of orthostatic hypotension
psychosis and worsening of symptoms
Elderly
Pharmacokinetics • Lower dose is generally used (e.g.,
• Metabolites are inactive 25–100 mg twice a day), although higher
• Parent drug has 6–7 hour half-life doses may be used if tolerated

Drug Interactions Children and Adolescents

• CYP450 3A inhibitors and CYP450 2D6 • Not officially recommended for patients
inhibitors may reduce clearance of under age 18
quetiapine and thus raise quetiapine • Clinical experience and early data suggest
plasma levels, but dosage reduction of quetiapine may be safe and effective for
quetiapine usually not necessary behavioral disturbances in children and
• May increase effect of anti-hypertensive adolescents
agents • Children and adolescents using quetiapine
may need to be monitored more often than
adults
• May tolerate lower doses better

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(continued) QUETIAPINE

Primary Target Symptoms

• Positive symptoms of psychosis
Pregnancy • Negative symptoms of psychosis
• Risk Category C [some animal studies • Cognitive symptoms
show adverse effects, no controlled studies • Unstable mood (both depression and
in humans] mania)
• Psychotic symptoms may worsen during • Aggressive symptoms
pregnancy and some form of treatment
may be necessary
• Quetiapine may be preferable to
anticonvulsant mood stabilizers if
Pearls
treatment is required during pregnancy ✽ May be the preferred antipsychotic for
psychosis in Parkinson’s disease and Lewy
Breast Feeding Body dementia
• Unknown if quetiapine is secreted in • Anecdotal reports of efficacy in treatment-
human breast milk, but all psychotropics refractory cases and positive symptoms of
assumed to be secreted in breast milk psychoses other than schizophrenia
• Recommended either to discontinue drug ✽ Efficacy may be underestimated since
or bottle feed quetiapine is mostly under-dosed in clinical
• Infants of women who choose to breast practice
feed while on quetiapine should be • More sedation than some other
monitored for possible adverse effects antipsychotics
✽ Essentially no motor side effects or
prolactin elevation
• May have less weight gain than some
THE ART OF PSYCHOPHARMACOLOGY antipsychotics, more than others
Potential Advantages ✽ Controversial as to whether quetiapine
has more or less risk of diabetes and
• Some cases of psychosis and bipolar
dyslipidemia than some other
disorder refractory to treatment with other
antipsychotics
antipsychotics
• Can be a more expensive atypical
✽ Patients with Parkinson’s disease who antipsychotic than some others when
need an antipsychotic or mood stabilizer
dosed appropriately in schizophrenia or
✽ Patients with Lewy Body dementia who acute mania; some patients respond to
need an antipsychotic or mood stabilizer
moderate doses, which are less expensive
Potential Disadvantages • Commonly used at low doses to augment
• Patients requiring rapid onset of action other atypical antipsychotics, but such
• Patients noncompliant with twice daily antipsychotic polypharmacy has not been
dosing systematically studied and can be quite
expensive

Suggested Reading
Kapur S, Remington G. Atypical Tandon R, Jibson MD. Efficacy of newer
antipsychotics: new directions and new generation antipsychotics in the treatment of
challenges in the treatment of schizophrenia. schizophrenia. Psychoneuroendocrinology
Annu Rev Med 2001;52:503–17. 2003;28:9–26.
Srisurapanont M, Disayavanish C, Taimkaew K. Yatham LN. Efficacy of atypical antipsychotics
Quetiapine for schizophrenia. Cochrane in mood disorders. J Clin Psychopharmacol
Database Syst Rev 2000;3:CD000967. 2003;23(3 Suppl 1):S9–14.
Tandon R. Safety and tolerability: how do new
generation “atypical” antipsychotics compare?
Psychiatric Quarterly 2002;73:297–311.

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0521011698s08.qxd 9/2/04 2:46 PM Page 407

REBOXETINE
THERAPEUTICS • For second and subsequent episodes of
depression, treatment may need to be
Brands • Norebox indefinite
• Edronax
see index for additional brand names If It Doesn’t Work
• Many patients only have a partial response
Generic? No where some symptoms are improved but
others persist (especially insomnia, fatigue,
and problems concentrating)
Class • Other patients may be nonresponders,
• Selective norepinephrine reuptake inhibitor sometimes called treatment-resistant or
(NRI); antidepressant treatment-refractory
• Consider increasing dose, switching to
Commonly Prescribed For another agent or adding an appropriate
(bold for FDA approved) augmenting agent
• Major depressive disorder • Consider psychotherapy
• Dysthymia • Consider evaluation for another diagnosis
• Panic disorder or for a comorbid condition (e.g., medical
• Attention deficit hyperactivity disorder illness, substance abuse, etc.)
• Some patients may experience apparent
lack of consistent efficacy due to activation
How The Drug Works of latent or underlying bipolar disorder, and
• Boost neurotransmitters norepinephrine/ require antidepressant discontinuation and
noradrenaline and dopamine a switch to a mood stabilizer
• Blocks norepinephrine reuptake pump
(norepinephrine transporter) Best Augmenting Combos
• Presumably, this increases noradrenergic for Partial Response or
neurotransmission Treatment-Resistance
• Since dopamine is inactivated by • Trazodone, especially for insomnia
norepinephrine reuptake in frontal cortex • SSRIs, SNRIs, mirtazapine (use
which largely lacks dopamine transporters, combinations of antidepressants with
reboxetine can increase dopamine caution as this may activate bipolar
neurotransmission in this part of the brain disorder and suicidal ideation)
• Modafinil, especially for fatigue, sleepiness,
How Long Until It Works and lack of concentration
• Onset of therapeutic actions usually not • Mood stabilizers or atypical antipsychotics
immediate, but often delayed 2 to 4 weeks for bipolar depression, psychotic depression
• If it is not working within 6 to 8 weeks for or treatment-resistant depression
depression, it may require a dosage • Benzodiazepines for anxiety
increase or it may not work at all • Hypnotics for insomnia
• May continue to work for many years to • Classically, lithium, buspirone, or thyroid
prevent relapse of symptoms hormone

If It Works Tests
• The goal of treatment is complete • None for healthy individuals
remission of current symptoms as well as
prevention of future relapses
• Treatment most often reduces or even SIDE EFFECTS
eliminates symptoms, but not a cure since
symptoms can recur after medicine How Drug Causes Side Effects
stopped • Norepinephrine increases in parts of the
• Continue treatment until all symptoms are brain and body and at receptors other than
gone (remission) those that cause therapeutic actions (e.g.,
• Once symptoms gone, continue treating for unwanted actions of norepinephrine on
1 year for the first episode of depression

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REBOXETINE (continued)

acetylcholine release causing constipation upon each dose increase, but go away with
and dry mouth, etc.) time)
• Most side effects are immediate but often • Activation and agitation may represent the
go away with time induction of a bipolar state, especially a
mixed dysphoric bipolar II condition
Notable Side Effects sometimes associated with suicidal
• Insomnia, dizziness, anxiety, agitation ideation, and require the addition of
• Dry mouth, constipation lithium, a mood stabilizer or an atypical
• Urinary hesitancy, urinary retention antipsychotic, and/or discontinuation of
• Sexual dysfunction (impotence) reboxetine
• Dose-dependent hypotension

Life Threatening or DOSING AND USE

Dangerous Side Effects
Usual Dosage Range
• Rare seizures
• 8 mg/day in 2 doses (10 mg usual
• Rare induction of mania and activation of
maximum daily dose)
suicidal ideation

Weight Gain Dosage Forms

• Tablet 2 mg, 4 mg scored

How to Dose
• Reported but not expected • Initial 2 mg/day twice a day for 1 week,
4 mg/day twice a day for second week
Sedation

Dosing Tips
• Reported but not expected • When switching from another
antidepressant or adding to another
What To Do About Side Effects antidepressant, dosing may need to be
• Wait lower and titration slower to prevent
• Wait activating side effects (e.g., 2 mg in the
• Wait daytime for 2–3 days, then 2 mg bid for
• Lower the dose 1–2 weeks)
• In a few weeks, switch or add other drugs • Give second daily dose in late afternoon
rather than at bedtime to avoid undesired
Best Augmenting Agents for Side activation or insomnia in the evening
Effects • May not need full dose of 8 mg/day when
• For urinary hesitancy, give an alpha 1 given in conjunction with another
blocker such as tamsulosin antidepressant
• Often best to try another antidepressant • Some patients may need 10 mg/day or
monotherapy prior to resorting to more if well-tolerated without orthostatic
augmentation strategies to treat side hypotension and if additional efficacy is
effects seen at high doses in difficult cases
• Trazodone or a hypnotic for drug-induced • Early dosing in patients with panic and
insomnia anxiety may need to be lower and titration
• Benzodiazepines for drug-induced anxiety slower, perhaps with the use of
and activation concomitant short-term benzodiazepines to
• Mirtazapine for drug-induced insomnia or increase tolerability
anxiety
• Many side effects are dose-dependent (i.e., Overdose
they increase as dose increases, or they • Postural hypotension, anxiety, hypertension
reemerge until tolerance re-develops)
• Many side effects are time-dependent (i.e., Long-Term Use
they start immediately upon dosing and • Safe

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(continued) REBOXETINE

Habit Forming
• No
Other Warnings/
Precautions
How to Stop • Use with caution in patients with bipolar
• Taper not necessary disorder unless treated with concomitant
mood stabilizing agent
Pharmacokinetics • Use with caution in patients with urinary
• Metabolized by CYP450 3A4 retention, benign prostatic hyperplasia,
• Inhibits CYP450 2D6 and 3A4 at high glaucoma, epilepsy
doses • Use with caution with drugs that lower
• Elimination half-life approximately 13 hours blood pressure
• Monitor patients for activation of suicidal
ideation, especially children and
Drug Interactions adolescents
• Tramadol increases the risk of seizures in Do Not Use
patients taking an antidepressant
• If patient has narrow angle-closure
• May need to reduce reboxetine dose or
glaucoma
avoid concomitant use with inhibitors of
• If patient is taking an MAO inhibitor
CYP450 3A4, such as azole and
• If patient is taking pimozide or thioridazine
antifungals, macrolide antibiotics,
• If there is a proven allergy to reboxetine
fluvoxamine, nefazodone, fluoxetine,
sertraline, etc.
• Via CYP450 2D6 inhibition, reboxetine
could theoretically interfere with the SPECIAL POPULATIONS
analgesic actions of codeine, and increase
the plasma levels of some beta blockers
Renal Impairment
and of atomoxetine and TCAs • Plasma concentrations are increased
• Via CYP450 2D6 inhibition, reboxetine • May need to lower dose
could theoretically increase concentrations Hepatic Impairment
of thioridazine and cause dangerous
• Plasma concentrations are increased
cardiac arrhythmias
• May need to lower dose
• Via CYP450 3A4 inhibition, reboxetine may
increase the levels of alprazolam, Cardiac Impairment
buspirone, and triazolam • Use with caution
• Via CYP450 3A4 inhibition, reboxetine
could theoretically increase concentrations Elderly
of certain cholesterol lowering HMG CoA • Lower dose is recommended (4–6 mg/day)
reductase inhibitors, especially simvastatin,
atorvastatin, and lovastatin, but not
pravastatin or fluvastatin, which would
increase the risk of rhabdomyolysis; thus,
Children and Adolescents
coadministration of reboxetine with certain • Use with caution, observing for activation
HMG CoA reductase inhibitors should of known or unknown bipolar disorder
proceed with caution and/or suicidal ideation, and strongly
• Via CYP450 3A4 inhibition, reboxetine consider informing parents or guardian of
could theoretically increase the this risk so they can help observe child or
concentrations of pimozide, and cause QTc adolescent patients
prolongation and dangerous cardiac • No guidelines for children; safety and
arrhythmias efficacy have not been established
• Use with ergotamine may increase blood
pressure
• Hypokalemia may occur if reboxetine is Pregnancy
used with diuretics • No controlled studies in humans
• Do not use with MAO inhibitors, including • Not generally recommended for use during
14 days after MAOIs are stopped pregnancy, especially during first trimester

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REBOXETINE (continued)

• Must weigh the risk of treatment (first Primary Target Symptoms

trimester fetal development, third trimester • Depressed mood
newborn delivery) to the child against the • Energy, motivation, and interest
risk of no treatment (recurrence of • Suicidal ideation
depression, maternal health, infant • Cognitive disturbance
bonding) to the mother and child • Psychomotor retardation
• For many patients this may mean
continuing treatment during pregnancy

Breast Feeding Pearls

• May be effective if SSRIs have failed or for
• Some drug is found in mother’s breast milk
SSRI “poop-out”
• Immediate postpartum period is a high-risk
time for depression, especially in women ✽ May be more likely than SSRIs to
improve social and work functioning
who have had prior depressive episodes,
• Reboxetine is a mixture of an active and an
so drug may need to be reinstituted late in
inactive enantiomer, and the active
the third trimester or shortly after
enantiomer may be developed in future
childbirth to prevent a recurrence during
clinical testing
the postpartum period
• Must weigh benefits of breast feeding with ✽ Side effects may appear “anticholinergic”,
but reboxetine does not directly block
risks and benefits of antidepressant
muscarinic receptors
treatment versus non-treatment to both the
• Constipation, dry mouth, and urinary
infant and the mother
retention are noradrenergic, due in part to
• For many patients, this may mean
peripheral alpha 1 receptor stimulation
continuing treatment during breast feeding
causing decreased acetylcholine release
✽ Thus, antidotes for these side effects can
be alpha 1 antagonists such as tamsulosin,
THE ART OF PSYCHOPHARMACOLOGY especially for urinary retention in men over
50 with borderline urine flow
Potential Advantages • Novel use of reboxetine may be for
• Tired, unmotivated patients attention deficit disorder, analogous to the
• Patients with cognitive disturbances actions of another norepinephrine selective
• Patients with psychomotor retardation reuptake inhibitor, atomoxetine, but few
controlled studies
Potential Disadvantages
• Another novel use may be for neuropathic
• Patients unable to comply with twice-daily
pain, alone or in combination with other
dosing
antidepressants, but few controlled studies
• Patients unable to tolerate activation
• Some studies suggest efficacy in panic
disorder

Suggested Reading
Fleishaker JC. Clinical pharmacokinetics of Keller M. Role of serotonin and noradrenaline
reboxetine, a selective norepinephrine reuptake in social dysfunction: a review of data on
inhibitor for the treatment of patients with reboxetine and the Social Adaptation Self-
depression. Clin Pharmacokinet evaluation Scale (SASS). Gen Hosp Psychiatry
2000;39(6):413–27. 2001;23(1):15–9.
Kasper S, el Giamal N, Hilger E. Reboxetine: Tanum L. Reboxetine: tolerability and safety
the first selective noradrenaline re-uptake profile in patients with major depression. Acta
inhibitor. Expert Opin Pharmacother Psychiatr Scand Suppl 2000;402:37–40.
2000;1(4):771–82.

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RISPERIDONE
THERAPEUTICS If It Works
• Most often reduces positive symptoms in
Brands • Risperdal • CONSTA
schizophrenia but does not eliminate them
see index for additional brand names
• Can improve negative symptoms, as well
Generic? Not in U.S., Europe, or Japan as aggressive, cognitive, and affective
symptoms in schizophrenia
• Most schizophrenic patients do not have a
total remission of symptoms but rather a
Class reduction of symptoms by about a third
• Atypical antipsychotic (serotonin-dopamine • Perhaps 5–15% of schizophrenic patients
antagonist; second generation can experience an overall improvement of
antipsychotic; also a mood stabilizer) greater than 50–60%, especially when
receiving stable treatment for more than a
Commonly Prescribed For year
(bold for FDA approved) • Such patients are considered super-
• Schizophrenia (oral, long-acting responders or “awakeners” since they may
microspheres intramuscularly) be well enough to be employed, live
• Delaying relapse in schizophrenia (oral) independently, and sustain long-term
• Other psychotic disorders (oral) relationships
• Acute mania (oral, monotherapy and • Many bipolar patients may experience a
adjunct to lithium or valproate) reduction of symptoms by half or more
• Bipolar maintenance • Continue treatment until reaching a plateau
• Bipolar depression of improvement
• Behavioral disturbances in dementias • After reaching a satisfactory plateau,
• Behavioral disturbances in children and continue treatment for at least a year after
adolescents first episode of psychosis
• Disorders associated with problems with • For second and subsequent episodes of
impulse control psychosis, treatment may need to be
indefinite
• Even for first episodes of psychosis, it may
How The Drug Works be preferable to continue treatment
• Blocks dopamine 2 receptors, reducing indefinitely to avoid subsequent episodes
positive symptoms of psychosis and • Treatment may not only reduce mania but
stabilizing affective symptoms also prevent recurrences of mania in
• Blocks serotonin 2A receptors, causing bipolar disorder
enhancement of dopamine release in
certain brain regions and thus reducing If It Doesn’t Work
motor side effects and possibly improving • Try one of the other atypical antipsychotics
cognitive and affective symptoms (olanzapine, quetiapine, ziprasidone,
• Interactions at a myriad of other aripiprazole, amisulpride)
neurotransmitter receptors may contribute • If 2 or more antipsychotic monotherapies
to risperidone’s efficacy do not work, consider clozapine
✽ Specifically, alpha 2 antagonist properties • If no first-line atypical antipsychotic is
may contribute to antidepressant actions effective, consider higher doses or
augmentation with valproate or lamotrigine
How Long Until It Works • Some patients may require treatment with
• Psychotic symptoms can improve within a conventional antipsychotic
1 week, but it may take several weeks for • Consider noncompliance and switch to
full effect on behavior as well as on another antipsychotic with fewer side
cognition and affective stabilization effects or to an antipsychotic that can be
• Classically recommended to wait at least given by depot injection
4–6 weeks to determine efficacy of drug, • Consider initiating rehabilitation and
but in practice some patients require up to psychotherapy
16–20 weeks to show a good response, • Consider presence of concomitant drug
especially on cognitive symptoms abuse

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RISPERIDONE (continued)

Best Augmenting Combos polydipsia, weight loss, nausea, vomiting,

for Partial Response or dehydration, rapid respiration, weakness
Treatment-Resistance and clouding of sensorium, even coma
• Valproic acid (valproate, divalproex, • Should check blood pressure in the elderly
divalproex ER) before starting and for the first few weeks
• Other mood stabilizing anticonvulsants of treatment
(carbamazepine, oxcarbazepine, lamotrigine) • Monitoring elevated prolactin levels of
• Lithium dubious clinical benefit
• Benzodiazepines

Tests SIDE EFFECTS

Before starting an atypical antipsychotic
How Drug Causes Side Effects
✽ Weigh all patients and track BMI during • By blocking alpha 1 adrenergic receptors, it
treatment
• Get baseline personal and family history of can cause dizziness, sedation, and
obesity, dyslipidemia, hypertension, and hypotension
cardiovascular disease • By blocking dopamine 2 receptors in the
✽ Get waist circumference (at umbilicus), striatum, it can cause motor side effects,
especially at high doses
blood pressure, fasting plasma glucose,
and fasting lipid profile • By blocking dopamine 2 receptors in the
• Determine if the patient is pituitary, it can cause elevations in
• overweight (BMI 25.0–29.9) prolactin
• obese (BMI ≥30) • Mechanism of weight gain and increased
• has pre-diabetes (fasting plasma glucose incidence of diabetes and dyslipidemia with
100–125 mg/dl) atypical antipsychotics is unknown
• has diabetes (fasting plasma glucose
Notable Side Effects
>126 mg/dl)
• has hypertension (BP >140/90 mm Hg) ✽ May increase risk for diabetes and
dyslipidemia
• has dyslipidemia (increased total
cholesterol, LDL cholesterol, and ✽ Dose-dependent extrapyramidal symptoms
triglycerides; decreased HDL cholesterol) ✽ Dose-related hyperprolactinemia
• Rare tardive dyskinesia (much reduced risk
•Treat or refer such patients for treatment,
compared to conventional antipsychotics)
including nutrition and weight management,
• Dizziness, insomnia, headache, anxiety,
physical activity counseling, smoking
sedation
cessation, and medical management
• Nausea, constipation, abdominal pain,
Monitoring after starting an atypical weight gain
antipsychotic • Rare orthostatic hypotension, usually
✽ BMI monthly for 3 months, then quarterly during initial dose titration
✽ Blood pressure, fasting plasma glucose, • Tachycardia, sexual dysfunction
fasting lipids within 3 months and then
annually, but earlier and more frequently
for patients with diabetes or who have Life Threatening or
gained >5% of initial weight Dangerous Side Effects
• Treat or refer for treatment and consider • Hyperglycemia, in some cases extreme and
switching to another atypical antipsychotic associated with ketoacidosis or
for patients who become overweight, hyperosmolar coma or death, has been
obese, pre-diabetic, diabetic, hypertensive, reported in patients taking atypical
or dyslipidemic while receiving an atypical antipsychotics
antipsychotic • Increased incidence of cerebrovascular
✽ Even in patients without known diabetes, events, including stroke, transient ischemic
be vigilant for the rare but life threatening attacks, and fatalities in elderly patients
onset of diabetic ketoacidosis, which with dementia
always requires immediate treatment, by • Increased incidence of mortality in elderly
monitoring for the rapid onset of polyuria, patients with dementia-related psychosis

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(continued) RISPERIDONE

• Rare neuroleptic malignant syndrome Dosage Forms

(much reduced risk compared to • Tablets 0.25 mg, 0.5 mg, 1 mg, 2 mg,
conventional antipsychotics) 3 mg, 4 mg
• Rare seizures • Orally disintegrating tablets 0.5 mg, 1 mg,
2 mg
Weight Gain • Liquid 1 mg/mL — 30 mL bottle
• Risperidone long-acting depot
microspheres formulation for deep
• Many patients experience and/or can be intramuscular administration 25 mg vial/kit,
significant in amount 37.5 mg vial/kit, 50 mg vial/kit
• Can become a health problem in some
• May be less than for some antipsychotics,
How to Dose
more than for others • In adults with psychosis in non-emergent
settings, initial dosage recommendation is
Sedation 1 mg/day orally in 2 divided doses
• Increase each day by 1 mg/day orally until
desired efficacy is reached
• Maximum generally 16 mg/day orally
• Many patients experience and/or can be • Typically maximum effect is seen at
significant in amount 4–8 mg/day orally
• Usually transient • Can be administered on a once daily
• May be less than for some antipsychotics, schedule as well as twice daily orally
more than for others • Long-acting risperidone is not recommended
for patients who have not first
What To Do About Side Effects demonstrated tolerability to oral risperidone
• Wait • Long-acting risperidone should be
• Wait administered every 2 weeks by deep
• Wait intramuscular gluteal injection
• Take at bedtime to help reduce daytime • Oral antipsychotic medication should be
sedation given with the first injection of long-acting
• Anticholinergics may reduce motor side risperidone and continued for 3 weeks,
effects when present then discontinued
• Weight loss, exercise programs, and • Long-acting risperidone should only be
medical management for high BMIs, administered by a health care professional
diabetes, dyslipidemia • Typically maximum effect with long-acting
• Switch to another atypical antipsychotic risperidone is seen at 25–50 mg every
Best Augmenting Agents for Side 2 weeks; maximum recommended dose is
50 mg every 2 weeks
Effects • Titration of long-acting risperidone should
• Benztropine or trihexyphenidyl for motor occur at intervals of no less than 4 weeks
side effects • Two different dosage strengths of long-
• Many side effects cannot be improved with acting risperidone should not be combined
an augmenting agent in a single administration

DOSING AND USE Dosing Tips –

Oral Formulation
Usual Dosage Range ✽ Less may be more: lowering the dose in
• 2–8 mg/day orally for acute psychosis and some patients with stable efficacy but side
bipolar disorder effects may reduce side effects without
• 0.5–2.0 mg/day orally for children and loss of efficacy, especially for doses over
elderly 6 mg/day orally
• 25–50 mg depot intramuscularly every ✽ Target doses for best efficacy/best
2 weeks tolerability in many adults with psychosis

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RISPERIDONE (continued)

or bipolar disorder may be 2–6 mg/day • For missed long-acting risperidone

(average 4.5 mg/day) orally injections up to 2 weeks late (i.e., within
• Patients who respond to these doses may 28 days of last injection), may not need to
have one of the lowest drug costs among provide oral coverage
the atypical antipsychotics • Long-acting risperidone must be kept
• Low doses may not be adequate in difficult refrigerated
patients • Must deliver each syringe in full since drug
• Rather than raise the dose above these is not in a solution (i.e., half a syringe is
levels in acutely agitated patients requiring not necessarily half the drug dose)
acute antipsychotic actions, consider
augmentation with a benzodiazepine or Overdose
conventional antipsychotic, either orally or • Rarely lethal in monotherapy overdose;
intramuscularly sedation, rapid heartbeat, convulsions, low
• Rather than raise the dose above these levels blood pressure, difficulty breathing
in partial responders, consider augmentation
with a mood stabilizing anticonvulsant, Long-Term Use
such as valproate or lamotrigine • Approved to delay relapse in long-term
• Approved for use up to 16 mg/day orally, treatment of schizophrenia
but data suggest that risk of extrapyramidal • Often used for long-term maintenance in
symptoms is increased above 6 mg/day bipolar disorder and various behavioral
• Risperidone oral solution is not compatible disorders
with cola or tea
• Children and elderly may need to have oral Habit Forming
twice daily dosing during initiation and • No
titration of drug dosing and then can
How to Stop
switch to oral once daily when
• Slow down-titration of oral formulation
maintenance dose is reached
(over 6 to 8 weeks), especially when
• Children and elderly should generally be
simultaneously beginning a new antipsychotic
dosed at the lower end of the dosage
while switching (i.e., cross-titration)
spectrum
• Rapid oral discontinuation may lead to
Dosing Tips – rebound psychosis and worsening of
Long-Acting Microsphere symptoms
Depot Formulation Pharmacokinetics
✽ When initiating long-acting risperidone • Metabolites are active
formulation by intramuscular injection, • Metabolized by CYP450 2D6
onset of action can be delayed for 2 weeks • Parent drug of oral formulation has
while microspheres are being absorbed 20–24 hour half-life
✽ For antipsychotic coverage during • Long-acting risperidone has 3–6 day half-
initiation of long-acting risperidone, life
continue ongoing treatment with an oral • Long-acting risperidone has elimination
antipsychotic or initiate treatment with phase of approximately 7–8 weeks after
some oral antipsychotic for 3 weeks last injection
• Steady-state plasma concentrations are
reached after 4 injections of long-acting
risperidone and maintained for 4–6 weeks
after the last injection Drug Interactions
• For missed long-acting risperidone • May increase effect of anti-hypertensive
injections 2 or more weeks late (i.e., 28 or agents
more days following last injection), may • May antagonize levodopa, dopamine
need to provide antipsychotic coverage agonists
with oral administration for 3 weeks while • Clearance of risperidone may be reduced
reinitiating injections and thus plasma levels increased by
clozapine; dosing adjustment usually not
necessary

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(continued) RISPERIDONE

• Co-administration with carbamazepine may Cardiac Impairment

decrease plasma levels of risperidone • Drug should be used with caution because
• Co-administration with fluoxetine and of risk of orthostatic hypotension
paroxetine may increase plasma levels of ✽ When administered to elderly patients
risperidone with atrial fibrillation, may increase the
• Since risperidone is metabolized by CYP450 chances of stroke
2D6, any agent that inhibits this enzyme
could theoretically raise risperidone plasma Elderly
levels; however, dose reduction of • Initial 0.5 mg orally twice a day; increase
risperidone is usually not necessary when by 0.5 mg twice a day; titrate once a week
such combinations are used for doses above 1.5 mg twice a day
• Recommended dose of long-acting
risperidone is 25 mg every 2 weeks; oral
Other Warnings/ administration should be continued for
Precautions 3 weeks after the first injection
• Use with caution in patients with
conditions that predispose to hypotension
(dehydration, overheating)
• Risperidone should be used cautiously in
Children and Adolescents
patients at risk for aspiration pneumonia, • Safety and effectiveness have not been
as dysphagia has been reported established
• Priapism has been reported ✽ However, risperidone is the most
frequently used atypical antipsychotic in
Do Not Use children and adolescents
• If there is a proven allergy to risperidone • Clinical experience and early data suggest
risperidone is safe and effective for
behavioral disturbances in children and
adolescents
SPECIAL POPULATIONS • Children and adolescents using risperidone
Renal Impairment may need to be monitored more often than
adults
• Initial 0.5 mg orally twice a day for first
week; increase to 1 mg twice a day during
second week
• Long-acting risperidone should not be Pregnancy
administered unless patient has • Risk Category C [some animal studies
demonstrated tolerability of at least show adverse effects, no controlled studies
2 mg/day orally in humans]
• Long-acting risperidone should be dosed at • Psychotic symptoms may worsen during
25 mg every 2 weeks; oral administration pregnancy and some form of treatment
should be continued for 3 weeks after the may be necessary
first injection • Early findings of infants exposed to
risperidone in utero do not show adverse
Hepatic Impairment consequences
• Initial 0.5 mg orally twice a day for first • Risperidone may be preferable to
week; increase to 1 mg twice a day during anticonvulsant mood stabilizers if
second week treatment is required during pregnancy
• Long-acting risperidone should not be • Effects of hyperprolactinemia on the fetus
administered unless patient has are unknown
demonstrated tolerability of at least
2 mg/day orally Breast Feeding
• Long-acting risperidone should be dosed at • Unknown if risperidone is secreted in
25 mg every two weeks; oral human breast milk, but all psychotropics
administration should be continued for assumed to be secreted in breast milk
3 weeks after the first injection ✽ Recommended either to discontinue drug
or bottle feed

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RISPERIDONE (continued)

• Infants of women who choose to breast

feed while on risperidone should be
monitored for possible adverse effects Pearls
✽ Well accepted for treatment of agitation
and aggression in elderly demented patients
THE ART OF PSYCHOPHARMACOLOGY ✽ Well accepted for treatment of behavioral
symptoms in children and adolescents, but
Potential Advantages may have more sedation and weight gain in
• Some cases of psychosis and bipolar pediatric populations than in adult
disorder refractory to treatment with other populations
antipsychotics • Many anecdotal reports of utility in
✽ Often a preferred treatment for dementia treatment-refractory cases and for positive
symptoms of psychosis in disorders other
with aggressive features
✽ Often a preferred atypical antipsychotic than schizophrenia
• Only atypical antipsychotic to consistently
for children with behavioral disturbances of
multiple causations raise prolactin, but this is of unproven and
✽ Non-compliant patients (long-acting uncertain clinical significance
• Hyperprolactinemia in women with low
risperidone)
✽ Long-term outcomes may be enhanced estrogen may accelerate osteoporosis
• Less weight gain than some antipsychotics,
when compliance is enhanced (long-acting
risperidone) more than others
• Less sedation than some antipsychotics,
Potential Disadvantages more than others
• Patients for whom elevated prolactin may • Risperidone is one of the least expensive
not be desired (e.g., possibly pregnant atypical antipsychotics within the usual
patients; pubescent girls with amenorrhea; therapeutic dosing range
postmenopausal women with low estrogen • Increased risk of stroke may be most
who do not take estrogen replacement relevant in the elderly with atrial fibrillation
therapy) ✽ Controversial as to whether risperidone
has more or less risk of diabetes and
Primary Target Symptoms dyslipidemia than some other
• Positive symptoms of psychosis antipsychotics
• Negative symptoms of psychosis • May cause more motor side effects than
• Cognitive functioning some other atypical antipsychotics, especially
• Unstable mood (both depression and when administered to patients with
mania) Parkinson’s disease or Lewy Body dementia
• Aggressive symptoms ✽ Only atypical antipsychotic with a long-
acting depot formulation

Suggested Reading
Kapur S, Remington G. Atypical Tandon R. Safety and tolerability: how do new
antipsychotics: new directions and new generation “atypical” antipsychotics compare?
challenges in the treatment of schizophrenia. Psychiatric Quarterly 2002;73:297–311.
Annu Rev Med 2001;52:503–17.
Tandon R, Jibson MD. Efficacy of newer
Schweitzer I. Does risperidone have a place in generation antipsychotics in the treatment of
the treatment of nonschizophrenic patients? schizophrenia. Psychoneuroendocrinology
International Clinical Psychopharmacology 2003;28:9–26.
2001;16:1–19.
Yatham LN. Efficacy of atypical antipsychotics
in mood disorders. J Clin Psychopharmacol
2003;23(3 Suppl 1):S9–14.

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RIVASTIGMINE
THERAPEUTICS Best Augmenting Combos
Brands • Exelon for Partial Response or
see index for additional brand names Treatment-Resistance
✽ Atypical antipsychotics to reduce
Generic? No behavioral disturbances
✽ Antidepressants if concomitant
depression, apathy, or lack of interest
Class ✽ Memantine for moderate to severe
Alzheimer disease
• Cholinesterase inhibitor
• Divalproex, carbamazepine, or
(acetylcholinesterase inhibitor and
oxcarbazepine for behavioral disturbances
butyrylcholinesterase inhibitor); cognitive
enhancer Tests
• None for healthy individuals
Commonly Prescribed For
(bold for FDA approved)
• Alzheimer disease
• Memory disorders in other conditions SIDE EFFECTS
• Mild cognitive impairment
How Drug Causes Side Effects
• Peripheral inhibition of acetylcholinesterase
can cause gastrointestinal side effects
How The Drug Works • Peripheral inhibition of
✽ Pseudoirreversibly inhibits centrally- butyrylcholinesterase can cause
active acetylcholinesterase (AChE), making gastrointestinal side effects
more acetylcholine available • Central inhibition of acetylcholinesterase
• Increased availability of acetylcholine may contribute to nausea, vomiting, weight
compensates in part for degenerating loss, and sleep disturbances
cholinergic neurons in neocortex that
regulate memory Notable Side Effects
✽ Inhibits butyrylcholinesterase (BuChE) ✽ Nausea, diarrhea, vomiting, appetite loss,
• May release growth factors or interfere weight loss, dyspepsia, increased gastric
with amyloid deposition acid secretion
• Headache, dizziness
How Long Until It Works • Fatigue, asthenia, sweating
• May take up to 6 weeks before any
improvement in baseline memory or
behavior is evident Life Threatening or
• May take months before any stabilization in Dangerous Side Effects
degenerative course is evident • Rare seizures
• Rare syncope
If It Works
• May improve symptoms and slow Weight Gain
progression of disease, but does not
reverse the degenerative process
• Reported but not expected
If It Doesn’t Work
• Some patients may experience weight loss
• Consider adjusting dose, switching to a
different cholinesterase inhibitor or adding Sedation
an appropriate augmenting agent
• Reconsider diagnosis and rule out other
conditions such as depression or a
dementia other than Alzheimer disease • Reported but not expected

What To Do About Side Effects

• Wait

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RIVASTIGMINE (continued)

• Wait bradycardia, collapse, convulsions, muscle

• Wait weakness (weakness of respiratory
• Use slower dose titration muscles can lead to death)
• Consider lowering dose, switching to a
different agent or adding an appropriate Long-Term Use
augmenting agent • Drug may lose effectiveness in slowing
degenerative course of Alzheimer disease
Best Augmenting Agents for Side after 6 months
Effects • Can be effective in many patients for
• Many side effects cannot be improved with several years
an augmenting agent
Habit Forming
• No
DOSING AND USE How to Stop
Usual Dosage Range • Taper not necessary
• Discontinuation may lead to notable
• 6–12 mg/day
deterioration in memory and behavior
Dosage Forms which may not be restored when drug is
• Capsule 1.5 mg, 3 mg, 4.5 mg, 6 mg restarted or another cholinesterase
• Liquid 2 mg/mL – 120 mL bottle inhibitor is initiated

How to Dose Pharmacokinetics

• Initial 1.5 mg twice daily; increase by 3 mg • Elimination half-life 1–2 hours
every 2 weeks; titrate to tolerability; • Not hepatically metabolized; no CYP450-
maximum dose generally 6 mg twice daily mediated pharmacokinetic drug
interactions

Dosing Tips
• Incidence of nausea is generally higher
Drug Interactions
during the titration phase than during • Rivastigmine may increase the effects of
maintenance treatment anesthetics and should be discontinued
✽ If restarting treatment after a lapse of prior to surgery
• Rivastigmine may interact with
several days or more, dose titration should
occur as when starting drug for the first anticholinergic agents and the combination
time may decrease the efficacy of both
• Doses between 6–12 mg/day have been • Clearance of rivastigmine may be increased
shown to be more effective than doses by nicotine
between 1–4 mg/day • May have synergistic effect if administered
• Recommended to take rivastigmine with with cholinomimetics (e.g., bethanechol)
food • Bradycardia may occur if combined with
• Rapid dose titration increases the incidence beta blockers
of gastrointestinal side effects • Theoretically, could reduce the efficacy of
• Probably best to utilize highest tolerated levodopa in Parkinson’s disease
dose within the usual dosage range • Not rational to combine with another
✽ When switching to another cholinesterase cholinesterase inhibitor
inhibitor, probably best to cross-titrate
from one to the other to prevent Other Warnings/
precipitous decline in function if the patient Precautions
washes out of one drug entirely • May exacerbate asthma or other pulmonary
disease
Overdose
• Increased gastric acid secretion may
• Can be lethal; nausea, vomiting, excess
increase the risk of ulcers
salivation, sweating, hypotension,

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(continued) RIVASTIGMINE

• Bradycardia or heart block may occur in THE ART OF PSYCHOPHARMACOLOGY

patients with or without cardiac impairment
Potential Advantages
✽ Severe vomiting with esophageal rupture • Theoretically, butyrylcholinesterase
may occur if rivastigmine therapy is
resumed without re-titrating the drug to full inhibition centrally could enhance
dosing therapeutic efficacy
• May be useful in some patients who do not
Do Not Use respond to or do not tolerate other
• If there is a proven allergy to rivastigmine cholinesterase inhibitors
or other carbamates • Later stages or rapidly progressive
Alzheimer disease

Potential Disadvantages
SPECIAL POPULATIONS • Theoretically, butyrylcholinesterase
inhibition peripherally could enhance side
Renal Impairment
effects
• Dose adjustment not necessary; titrate to
point of tolerability Primary Target Symptoms
• Memory loss in Alzheimer disease
Hepatic Impairment
• Behavioral symptoms in Alzheimer disease
• Dose adjustment not necessary; titrate to
• Memory loss in other dementias
point of tolerability

Cardiac Impairment
• Should be used with caution Pearls
• Syncopal episodes have been reported with • Dramatic reversal of symptoms of
the use of rivastigmine Alzheimer disease is not generally seen
with cholinesterase inhibitors
Elderly • Can lead to therapeutic nihilism among
• Some patients may tolerate lower doses prescribers and lack of an appropriate trial
better of a cholinesterase inhibitor
✽ Perhaps only 50% of Alzheimer patients
are diagnosed, and only 50% of those
Children and Adolescents diagnosed are treated, and only 50% of
• Safety and efficacy have not been those treated are given a cholinesterase
established inhibitor, and then only for 200 days in a
disease that lasts 7–10 years
• Must evaluate lack of efficacy and loss of
efficacy over months, not weeks
Pregnancy
• Risk Category B [animal studies do not
✽ Treats behavioral and psychological
symptoms of Alzheimer dementia as well
show adverse effects, no controlled studies as cognitive symptoms (i.e., especially
in humans] apathy, disinhibition, delusions, anxiety,
✽ Not recommended for use in pregnant cooperation, pacing)
women or women of childbearing potential • Patients who complain themselves of
memory problems may have depression,
Breast Feeding
whereas patients whose spouses or
• Unknown if rivastigmine is secreted in
children complain of the patient’s memory
human breast milk, but all psychotropics
problems may have Alzheimer disease
assumed to be secreted in breast milk
• Treat the patient but ask the caregiver
✽ Recommended either to discontinue drug about efficacy
or bottle feed
• What you see may depend upon how early
• Rivastigmine is not recommended for use
you treat
in nursing women
• The first symptoms of Alzheimer disease
are generally mood changes; thus,

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RIVASTIGMINE (continued)

Alzheimer disease may initially be resolution of side effects prior to switching

diagnosed as depression to another cholinesterase inhibitor
• Women may experience cognitive • Cognitive improvement may be linked to
symptoms in perimenopause as a result of substantial (>65%) inhibition of
hormonal changes that are not a sign of acetylcholinesterase
dementia or Alzheimer disease • Rivastigmine may be more selective for the
• Aggressively treat concomitant symptoms form of acetylcholinesterase in
with augmentation (e.g., atypical hippocampus (G1)
antipsychotics for agitation, ✽ More potent inhibitor of the G1 form of
antidepressants for depression) acetylcholinesterase enzyme, found in high
• If treatment with antidepressants fails to concentrations in Alzheimer patient’s
improve apathy and depressed mood in the brains, than the G4 form of the enzyme
elderly, it is possible that this represents • Butyrylcholinesterase action in the brain
early Alzheimer disease and a may not be relevant in individuals without
cholinesterase inhibitor like rivastigmine Alzheimer disease or in early Alzheimer
may be helpful disease; in the later stages of the disease,
• What to expect from a cholinesterase enzyme actively increases as gliosis occurs
inhibitor: • Rivastigmine’s effects on
• Patients do not generally improve butyrylcholinesterase may be more relevant
dramatically although this can be in later stages of Alzheimer disease, when
observed in a significant minority of gliosis is occurring
patients ✽ May be more useful for later stages or for
• Onset of behavioral problems and more rapidly progressive forms of
nursing home placement can be delayed Alzheimer disease, when gliosis increases
• Functional outcomes, including activities butyrlylcholinesterase
of daily living, can be preserved ✽ Butyrylcholinesterase actively could
• Caregiver burden and stress can be interfere with amyloid plaque formation,
reduced which contains this enzyme
• Delay in progression in Alzheimer disease • Some Alzheimer patients who fail to
is not evidence of disease-modifying respond to another cholinesterase inhibitor
actions of cholinesterase inhibition may respond when switched to
• Cholinesterase inhibitors like rivastigmine rivastigmine
depend upon the presence of intact targets • Some Alzheimer patients who fail to
for acetylcholine for maximum respond to rivastigmine may respond to
effectiveness and thus may be most another cholinesterase inhibitor
effective in the early stages of Alzheimer • To prevent potential clinical deterioration,
disease generally switch from long-term treatment
• The most prominent side effects of with one cholinesterase inhibitor to another
rivastigmine are gastrointestinal effects, without a washout period
which are usually mild and transient ✽ May slow the progression of mild
✽ May cause more gastrointestinal side cognitive impairment to Alzheimer disease
effects than some other cholinesterase ✽ May be useful for dementia with Lewy
inhibitors, especially if not slowly titrated bodies (DLB, constituted by early loss of
• Use with caution in underweight or frail attentiveness and visual perception with
patients possible hallucinations, Parkinson-like
• Weight loss can be a problem in Alzheimer movement problems, fluctuating cognition
patients with debilitation and muscle such as daytime drowsiness and lethargy,
wasting staring into space for long periods,
• Women over 85, particularly with low body episodes of disorganized speech)
weights, may experience more adverse • May decrease delusion, apathy, agitation,
effects and hallucinations in dementia with Lewy
• For patients with intolerable side effects, bodies
generally allow a washout period with ✽ May be useful for vascular dementia
(e.g., acute onset with slow stepwise

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(continued) RIVASTIGMINE

progression that has plateaus, often with • Theoretically, may be useful for ADHD, but
gait abnormalities, focal signs, imbalance, not yet proven
and urinary incontinence) • Theoretically, could be useful in any
• May be helpful for dementia in Down’s memory condition characterized by
Syndrome cholinergic deficiency (e.g., some cases of
• Suggestions of utility in some cases of brain injury, cancer chemotherapy-induced
treatment-resistant bipolar disorder cognitive changes, etc.)

Suggested Reading
Bentue-Ferrer D, Tribut O, Polard E, Allain H. Stahl SM. The new cholinesterase inhibitors
Clinically significant drug interactions with for Alzheimer’s disease, part 1. J Clin
cholinesterase inhibitors: a guide for Psychiatry 2000;61:710–11.
neurologists. CNS Drugs 2003;17:947–63.
Stahl SM. The new cholinesterase inhibitors
Bonner LT, Peskind ER. Pharmacologic for Alzheimer’s disease, part 2. J Clin
treatments of dementia. Med Clin North Am Psychiatry 2000;61:813–14.
2002;86:657–74.
Williams BR, Nazarians A, Gill MA. A review of
Jones RW. Have cholinergic therapies reached rivastigmine: a reversible cholinesterase
their clinical boundary in Alzheimer’s disease? inhibitor. Clin Ther 2003;25:1634–53.
Int J Geriatr Psychiatry 2003;18(Suppl 1):
S7–S13.
Stahl SM. Cholinesterase inhibitors for
Alzheimer’s disease. Hosp Pract (Off Ed)
1998;33:131–6.

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SELEGILINE
THERAPEUTICS If It Works
• Continue use in Parkinson’s disease as
Brands • Eldepryl
long as there is evidence that selegiline is
• Deprenyl
favorably enhancing the actions of
see index for additional brand names
levodopa
Generic? Yes • Use of selegiline to slow functional loss in
Parkinson’s disease or Alzheimer disease
would be long-term if proven effective for
this use
Class • The goal of treatment in depression is
• Selective monoamine oxidase B (MAO-B) complete remission of current symptoms
inhibitor as well as prevention of future relapses
• Treatment of depression most often
Commonly Prescribed For reduces or even eliminates symptoms, but
(bold for FDA approved) not a cure since symptoms can recur after
• Parkinson’s disease or symptomatic medicine stopped
Parkinsonism (adjunctive) • Continue treatment of depression until all
• Alzheimer disease and other dementias symptoms of depression are gone
• Treatment-resistant depression (remission)
• Once symptoms of depression are gone,
continue treating for 1 year for the first
How The Drug Works episode of depression
• At recommended doses, selectively and • For second and subsequent episodes of
irreversibly blocks monoamine oxidase depression, treatment may need to be
type B (MAO-B) from breaking down indefinite
dopamine
• This presumably boosts dopaminergic If It Doesn’t Work
neurotransmission • Use alternate treatments for Parkinson’s
• Above recommended doses, irreversibly disease or Alzheimer disease
blocks both monoamine oxidase A and • Oral administration is not approved for
monoamine oxidase B from breaking down treatment in depression, so lack of
norepinephrine, serotonin, and tyramine as antidepressant response should lead to
well as dopamine and phenethylamine treatment with well-established
• This presumably boosts noradrenergic, antidepressants
serotonergic, and dopaminergic
neurotransmission as well as causes Best Augmenting Combos
interaction with tyramine-containing foods for Partial Response or
Treatment-Resistance
How Long Until It Works • Carbidopa-levodopa (for Parkinson’s
• Can enhance the actions of levodopa in disease)
Parkinson’s disease within a few weeks of ✽ Augmentation of selegiline has not been
initiating dosing systematically studied in depression, and
• Theoretical slowing of functional loss in this is something for the expert, to be done
both Parkinson’s disease and Alzheimer with caution and with careful monitoring
disease is a provocative possibility under
investigation and would take many months Tests
or more than a year to observe • Patients should be monitored for changes
• Onset of therapeutic actions in depression in blood pressure
at high doses usually not immediate, but • Since nonselective MAO inhibitors are
often delayed 2 to 4 weeks or longer in frequently associated with weight gain,
patients with treatment-resistant before starting treatment for depression
depression with high doses of selegiline, weigh all
patients and determine if the patient is
already overweight (BMI 25.0–29.9) or
obese (BMI ≥30)

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SELEGILINE (continued)

• Before giving a drug that can cause weight Weight Gain

gain to an overweight or obese patient,
consider determining whether the patient
already has pre-diabetes (fasting plasma
• Occurs in significant minority
glucose 100–125 mg/dl), diabetes (fasting
plasma glucose >126 mg/dl), or Sedation
dyslipidemia (increased total cholesterol,
LDL cholesterol and triglycerides;
decreased HDL cholesterol), and treat or
refer such patients for treatment, including • Reported but not expected
nutrition and weight management, physical
activity counseling, smoking cessation, and What To Do About Side Effects
medical management • Wait
✽ Monitor weight and BMI during treatment • Wait
✽ While giving a drug to a patient who has • Wait
gained >5% of initial weight, consider • Lower the dose
evaluating for the presence of pre-diabetes, • Switch to other anti-parkinsonian therapies
diabetes, or dyslipidemia, or consider (Parkinson’s Disease)
switching to a different antidepressant • Switch after appropriate washout to an
SSRI or newer antidepressant (depression)

Best Augmenting Agents for Side

SIDE EFFECTS Effects
How Drug Causes Side Effects • Many side effects cannot be improved with
• At recommended doses, dopamine an augmenting agent, especially at lower
increases in parts of the brain and body doses
and at receptors other than those that
cause therapeutic actions
• Serotonin and norepinephrine increase at DOSING AND USE
high doses
• Side effects are generally immediate, but Usual Dosage Range
immediate side effects often disappear in • Parkinson’s disease/Alzheimer disease:
time 5–10 mg/day
• Depression: 30–60 mg/day
Notable Side Effects
• Exacerbation of levodopa side effects, Dosage Forms
especially nausea, dizziness, abdominal • Capsule 5 mg
pain, dry mouth, headache, dyskinesia, • Tablet 5 mg scored
confusion, hallucinations, vivid dreams
How to Dose
• Parkinson’s disease: Initial 2.5 mg/day
Life Threatening or twice daily; increase to 5 mg twice daily;
Dangerous Side Effects reduce dose of levodopa after 2–3 days
• Hypertensive crisis (especially when MAOIs
are used with certain tyramine-containing
foods or prohibited drugs) – reduced risk Dosing Tips
at low doses compared to nonselective ✽ Dosage above 10 mg/day generally not
MAOIs recommended for Parkinson’s disease
• Theoretically, when used at high doses may • Dosage of carbidopa-levodopa can at times
induce seizures, mania, and suicidal be reduced by 10–30% after 2–3 days of
ideation, as do nonselective MAOIs administering selegiline 5–10 mg/day in
Parkinson’s disease
✽ At doses above 10 mg/day, selegiline may
become nonselective and inhibit both
MAO-A and MAO-B

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(continued) SELEGILINE

✽ At doses above 30 mg/day, selegiline may syndrome” when combined with drugs that
have antidepressant properties block serotonin reuptake (e.g., SSRIs,
• Patients receiving high doses may need to SNRIs, sibutramine, tramadol, etc.), so do
be evaluated periodically for effects on the not use with a serotonin reuptake inhibitor
liver or for up to 5 weeks after stopping the
✽ Doses above 10 mg/day may increase the serotonin reuptake inhibitor
risk of hypertensive crisis, tyramine • Hypertensive crisis with headache,
interactions, and drug interactions similar intracranial bleeding, and death may result
to those of phenelzine and tranylcypromine from combining nonselective MAO
✽ A transdermal patch for delivery of 20–40 inhibitors with sympathomimetic drugs
mg/day selegiline (e.g., 20mg/20cm2) is in (e.g., amphetamines, methylphenidate,
late testing for depression and may prove cocaine, dopamine, epinephrine,
to be a more viable treatment option for norepinephrine, and related compounds
selegiline in depression than oral methyldopa, levodopa, L-tryptophan, L-
administration tyrosine, and phenylalanine
• Excitation, seizures, delirium, hyperpyrexia,
Overdose circulatory collapse, coma, and death may
• Dizziness, anxiety, ataxia, insomnia, result from combining nonselective MAO
sedation, irritability, headache, inhibitors with mepiridine or
cardiovascular effects, confusion, dextromethorphan
respiratory depression, coma • Do not combine with another MAO
inhibitor, alcohol, buspirone, bupropion, or
Long-Term Use guanethidine
• MAOIs may lose efficacy long-term • Adverse drug reactions can result from
combining MAO inhibitors with
Habit Forming tricyclic/tetracyclic antidepressants and
• Some patients have developed dependence related compounds, including
to MAOIs carbamazepine, cyclobenzaprine, and
• Lack of evidence for abuse potential with mirtazapine, and should be avoided except
selegiline by experts to treat difficult cases
• MAO inhibitors in combination with spinal
How to Stop
anesthesia may cause combined
• Generally no need to taper, as the drug
hypotensive effects
wears off slowly over 2–3 weeks
• Combination of MAOIs and CNS
Pharmacokinetics depressants may enhance sedation and
hypotension
• Steady-state mean elimination half-life
approximately 10 hours
• Clinical duration of action may be up to 21 Other Warnings/
days due to irreversible enzyme inhibition Precautions
• Major metabolite of orally administered • Although risk may be reduced with
selegiline is desmethylselegiline selective MAOIs, patient and prescriber
• Other metabolites are L-methamphetamine must be vigilant to potential interactions
and L-amphetamine with any drug, including antihypertensives
• Metabolite profile different for transdermal and over-the-counter cough/cold
administration preparations
• Over-the-counter medications to avoid
include cough and cold preparations,
Drug Interactions including those containing
• Tramadol may increase the risk of seizures dextromethorphan, nasal decongestants
in patients taking an MAO inhibitor (tablets, drops, or spray), hay-fever
• Selegiline may interact with opiate agonists medications, sinus medications, asthma
to cause agitation, hallucination, or death inhalant medications, anti-appetite
• Theoretically and especially at high doses, medications, weight reducing preparations,
selegiline could cause a fatal “serotonin “pep” pills

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SELEGILINE (continued)

• Hypoglycemia may occur in diabetic • Not generally recommended for use during
patients receiving insulin or oral pregnancy, especially during first trimester
antidiabetic agents • Should evaluate patient for treatment with
• Use cautiously in patients receiving an antidepressant with a better risk/benefit
reserpine, anesthetics, disulfiram, ratio
metrizamide, anticholinergic agents
• Selegiline is not recommended for use in Breast Feeding
patients who cannot be monitored closely • Some drug is found in mother’s breast milk
• Monitor patients for activation of suicidal • Immediate postpartum period is a high-risk
ideation, especially children and time for depression, especially in women
adolescents who have had prior depressive episodes,
• Although risk is reduced with selective so drug may need to be reinstituted late in
MAOIs, foods that contain large amounts the third trimester or shortly after
of tyramine or tryptophan, alcohol, and childbirth to prevent a recurrence during
caffeine should be avoided the postpartum period
• Only use sympathomimetic agents or • Should evaluate patient for treatment with
guanethidine with doses of selegiline below an antidepressant with a better risk/benefit
10 mg/day ratio

Do Not Use
• If patient is taking meperidine (pethidine) THE ART OF PSYCHOPHARMACOLOGY
• If patient is taking a sympathomimetic
agent or taking guanethidine Potential Advantages
• If patient is taking another MAOI • Parkinson’s patients inadequately
• If there is a proven allergy to selegiline responsive to levodopa
• Treatment-resistant depression

SPECIAL POPULATIONS Potential Disadvantages

• Patients with motor complications and
Renal Impairment fluctuations on levodopa treatment
• Use with caution – drug may accumulate in • Patients with cardiac problems or
plasma hypertension
• May require lower than usual adult dose • Non-compliant patients

Hepatic Impairment Primary Target Symptoms

• May require lower than usual adult dose • Motor symptoms (Parkinson’s disease)
• Psychomotor disturbances (depression)
Cardiac Impairment • Depressed mood (depression)
• May require lower than usual adult dose • Sleep and eating disturbances (depression)
• Somatic symptoms (depression)
Elderly
• Initial dose should be lower than usual
adult dose Pearls
✽ Low doses may have minimal tyramine
and drug interactions
Children and Adolescents • Generally used as an adjunctive treatment
• Not recommended for use under age 16 for Parkinson’s disease after other drugs
have lost efficacy
• At doses used for Parkinson’s disease,
Pregnancy virtually no risk of interactions with food
• Risk Category C [some animal studies • Neuroprotective effects are possible but
show adverse effects, no controlled studies unproved
in humans] ✽ Enhancement of levodopa action can
occur for Parkinson’s patients at low

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(continued) SELEGILINE

doses, but antidepressant actions probably ✽ Myths about the danger of dietary
require high doses tyramine can be exaggerated, but
✽ High doses may lose safety features prohibitions against concomitant drugs
• High doses can be very expensive often not followed closely enough
• Because of its effects on dopamine, ✽ MAOIs should be for the expert,
selegiline may be effective treatment for especially if combining with agents of
sexual dysfunction potential risk (e.g., stimulants, trazodone,
✽ A transdermal patch for delivery of TCAs)
selegiline (Emsam) is in late testing for ✽ MAOIs should not be neglected as
depression and may prove to be a more therapeutic agents for the treatment-
viable treatment option for selegiline in resistant
depression than oral administration • Although generally prohibited, a heroic but
✽ Transdermal administration of high doses potentially dangerous treatment for
of selegiline may reduce the potential for severely treatment-resistant patients is for
tyramine-associated blood pressure an expert to give a tricyclic/tetracyclic
reactions due to reduced inhibition of antidepressant other than clomipramine
gastrointestinal MAO simultaneously with an MAO inhibitor for
✽ Transdermal administration of high doses patients who fail to respond to numerous
of selegiline may improve the other antidepressants
pharmacokinetic and active metabolite • Use of MAOIs with clomipramine is always
profile of this drug’s use as an prohibited because of the risk of serotonin
antidepressant syndrome and death
• MAOIs are generally reserved for second- • Amoxapine may be the preferred
line use after SSRIs, SNRIs, and trycyclic/tetracyclic antidepressant to
combinations of newer antidepressants combine with an MAOI in heroic cases due
have failed to its theoretically protective 5HT2A
• Patient should be advised not to take any antagonist properties
prescription or over-the-counter drugs • If this option is elected, start the MAOI with
without consulting their doctor because of the tricyclic/tetracyclic antidepressant
possible drug interactions with the MAOI simultaneously at low doses after
• Headache is often the first symptom of appropriate drug washout, then alternately
hypertensive crisis increase doses of these agents every few
• Foods generally to avoid at high doses of days to a week as tolerated
selegiline, as they are usually high in • Although very strict dietary and
tyramine content: dry sausage, pickled concomitant drug restrictions must be
herring, liver, broad bean pods, sauerkraut, observed to prevent hypertensive crises
cheese, yogurt, alcoholic beverages, and serotonin syndrome, the most
nonalcoholic beer and wine, chocolate, common side effects of MAOI and
caffeine, meat and fish tricyclic/tetracyclic combinations may be
• The rigid dietary restrictions may reduce weight gain and orthostatic hypotension
compliance

Suggested Reading
Selegiline-transdermal—Somerset: Emsam. Knoll J. (-)Deprenyl (Selegiline): past, present
Drugs R D. 2003;4(1):59–60. and future. Neurobiology (Bp) 2000;8:179–99.
Kennedy SH. Continuation and maintenance Kuhn W, Muller T. The clinical potential of
treatments in major depression: the neglected Deprenyl in neurologic and psychiatric
role of monoamine oxidase inhibitors. J disorders. J Neural Transm Suppl
Psychiatry Neurosci. 1997;22:127–31. 1996;48:85–93.

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SERTRALINE
THERAPEUTICS If It Works
• The goal of treatment is complete
Brands • Zoloft
remission of current symptoms as well as
see index for additional brand names
prevention of future relapses
Generic? Not in U.S. • Treatment most often reduces or even
eliminates symptoms, but not a cure since
symptoms can recur after medicine
stopped
Class • Continue treatment until all symptoms are
• SSRI (selective serotonin reuptake gone (remission) or significantly reduced
inhibitor); often classified as an (e.g., OCD, PTSD)
antidepressant, but it is not just an • Once symptoms gone, continue treating for
antidepressant 1 year for the first episode of depression
• For second and subsequent episodes of
Commonly Prescribed For depression, treatment may need to be
(bold for FDA approved) indefinite
• Major depressive disorder • Use in anxiety disorders may also need to
• Premenstrual dysphoric disorder (PMDD) be indefinite
• Panic disorder
• Posttraumatic stress disorder (PTSD) If It Doesn’t Work
• Social anxiety disorder (social phobia) • Many patients only have a partial response
• Obsessive-compulsive disorder (OCD) where some symptoms are improved but
• Generalized anxiety disorder (GAD) others persist (especially insomnia, fatigue,
and problems concentrating in depression)
• Other patients may be nonresponders,
How The Drug Works sometimes called treatment-resistant or
• Boosts neurotransmitter serotonin treatment-refractory
• Blocks serotonin reuptake pump (serotonin • Some patients who have an initial response
transporter) may relapse even though they continue
• Desensitizes serotonin receptors, especially treatment, sometimes called “poop-out”
serotonin 1A receptors • Consider increasing dose, switching to
• Presumably increases serotonergic another agent or adding an appropriate
neurotransmission augmenting agent
✽ Sertraline also has some ability to block • Consider psychotherapy
dopamine reuptake pump (dopamine • Consider evaluation for another diagnosis
transporter), which could increase or for a comorbid condition (e.g., medical
dopamine neurotransmission and illness, substance abuse, etc.)
contribute to its therapeutic actions • Some patients may experience apparent
• Sertraline also has mild antagonist actions lack of consistent efficacy due to activation
at sigma receptors of latent or underlying bipolar disorder, and
require antidepressant discontinuation and
How Long Until It Works a switch to a mood stabilizer
✽ Some patients may experience increased
energy or activation early after initiation of Best Augmenting Combos
treatment for Partial Response or
• Onset of therapeutic actions usually not Treatment-Resistance
immediate, but often delayed 2 to 4 weeks • Trazodone, especially for insomnia
• If it is not working within 6 to 8 weeks, it • In the U.S., sertraline (Zoloft) is commonly
may require a dosage increase or it may augmented with bupropion (Wellbutrin)
not work at all with good results in a combination
• May continue to work for many years to anecdotally called “Well-loft” (use
prevent relapse of symptoms combinations of antidepressants with
caution as this may activate bipolar
disorder and suicidal ideation)

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SERTRALINE (continued)

• Mirtazapine, reboxetine, or atomoxetine women: decreased sexual desire,

(add with caution and at lower doses since anorgasmia)
sertraline could theoretically raise • Gastrointestinal (decreased appetite,
atomoxetine levels); use combinations of nausea, diarrhea, constipation, dry mouth)
antidepressants with caution as this may • Mostly central nervous system (insomnia
activate bipolar disorder and suicidal but also sedation, agitation, tremors,
ideation headache, dizziness)
• Modafinil, especially for fatigue, sleepiness, • Note: patients with diagnosed or
and lack of concentration undiagnosed bipolar or psychotic disorders
• Mood stabilizers or atypical antipsychotics may be more vulnerable to CNS-activating
for bipolar depression, psychotic actions of SSRIs
depression, treatment-resistant depression, • Autonomic (sweating)
or treatment-resistant anxiety disorders • Bruising and rare bleeding
• Benzodiazepines • Rare hyponatremia (mostly in elderly
• If all else fails for anxiety disorders, patients and generally reversible on
consider gabapentin or tiagabine discontinuation of sertraline)
• Hypnotics for insomnia • Rare hypotension
• Classically, lithium, buspirone, or thyroid
hormone
Life Threatening or
Tests Dangerous Side Effects
• None for healthy individuals • Rare seizures
• Rare induction of mania and activation of
suicidal ideation
SIDE EFFECTS Weight Gain
How Drug Causes Side Effects
• Theoretically due to increases in serotonin
concentrations at serotonin receptors in • Reported but not expected
parts of the brain and body other than • Some patients may actually experience
those that cause therapeutic actions (e.g., weight loss
unwanted actions of serotonin in sleep
centers causing insomnia, unwanted Sedation
actions of serotonin in the gut causing
diarrhea, etc.)
✽ Increasing serotonin can cause • Reported but not expected
diminished dopamine release and might • Possibly activating in some patients
contribute to emotional flattening, cognitive
slowing, and apathy in some patients, What To Do About Side Effects
although this could theoretically be • Wait
diminished in some patients by sertraline’s • Wait
dopamine reuptake blocking properties • Wait
• Most side effects are immediate but often • If sertraline is activating, take in the
go away with time, in contrast to most morning to help reduce insomnia
therapeutic effects which are delayed and • Reduce dose to 25 mg or even 12.5 mg
are enhanced over time until side effects abate, then increase dose
• Sertraline’s possible dopamine reuptake as tolerated, usually to at least 50 mg/day
blocking properties could contribute to • In a few weeks, switch or add other drugs
agitation, anxiety, and undesirable
activation, especially early in dosing Best Augmenting Agents for Side
Effects
Notable Side Effects • Often best to try another SSRI or another
• Sexual dysfunction (men: delayed antidepressant monotherapy prior to
ejaculation, erectile dysfunction; men and

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(continued) SERTRALINE

resorting to augmentation strategies to 100 mg and 50 mg tablets cost about the

treat side effects same in many markets
• Trazodone or a hypnotic for insomnia • Give once daily, often in the mornings to
• Bupropion, sildenafil, vardenafil or tadalafil reduce chances of insomnia
for sexual dysfunction • Many patients ultimately require more than
• Bupropion for emotional flattening, 50 mg dose per day
cognitive slowing, or apathy • Some patients are dosed above 200 mg
• Mirtazapine for insomnia, agitation, and • Evidence that some treatment-resistant
gastrointestinal side effects OCD patients may respond safely to doses
• Benzodiazepines for jitteriness and anxiety, up to 400 mg/day, but this is for experts
especially at initiation of treatment and and use with caution
especially for anxious patients • The more anxious and agitated the patient,
• Many side effects are dose-dependent (i.e., the lower the starting dose, the slower the
they increase as dose increases, or they titration, and the more likely the need for a
reemerge until tolerance re-develops) concomitant agent such as trazodone or a
• Many side effects are time-dependent (i.e., benzodiazepine
they start immediately upon dosing and • If intolerable anxiety, insomnia, agitation,
upon each dose increase, but go away with akathisia, or activation occur either upon
time) dosing initiation or discontinuation,
• Activation and agitation may represent the consider the possibility of activated bipolar
induction of a bipolar state, especially a disorder and switch to a mood stabilizer or
mixed dysphoric bipolar II condition atypical antipsychotic
sometimes associated with suicidal • Utilize half a 25 mg tablet (12.5 mg) when
ideation, and require the addition of initiating treatment in patients with a
lithium, a mood stabilizer or an atypical history of intolerance to previous
antipsychotic, and/or discontinuation of antidepressants
sertraline
Overdose
• Rarely lethal in monotherapy overdose;
DOSING AND USE vomiting, sedation, heart rhythm
disturbances, dilated pupils, agitation;
Usual Dosage Range fatalities have been reported in sertraline
• 50–200 mg/day overdose combined with other drugs or
alcohol
Dosage Forms
• Tablets 25 mg scored, 50 mg scored, Long-Term Use
100 mg • Safe

How to Dose Habit Forming

• Depression and OCD: initial 50 mg/day; • No
usually wait a few weeks to assess drug
effects before increasing dose, but can
How to Stop
increase once a week; maximum generally • Taper to avoid withdrawal effects
200 mg/day; single dose (dizziness, nausea, stomach cramps,
• Panic and PTSD: initial 25 mg/day; increase sweating, tingling, dysesthesias)
to 50 mg/day after 1 week thereafter, • Many patients tolerate 50% dose reduction
usually wait a few weeks to assess drug for 3 days, then another 50% reduction for
effects before increasing dose; maximum 3 days, then discontinuation
generally 200 mg/day; single dose • If withdrawal symptoms emerge during
discontinuation, raise dose to stop
symptoms and then restart withdrawal
much more slowly
Dosing Tips
• All tablets are scored, so to save costs, Pharmacokinetics
give 50 mg as half of 100 mg tablet, since • Parent drug has 22–36 hour half-life

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SERTRALINE (continued)

• Metabolite half-life 62–104 hours

Other Warnings/
• Inhibits CYP450 2D6 (weakly at low doses)
• Inhibits CYP450 3A4 (weakly at low doses)
Precautions
• Add or initiate other antidepressants with
caution for up to 2 weeks after
discontinuing sertraline
Drug Interactions • Use with caution in patients with history of
• Tramadol increases the risk of seizures in seizures
patients taking an antidepressant • Use with caution in patients with bipolar
• Can increase tricyclic antidepressant levels; disorder unless treated with concomitant
use with caution with tricyclic mood stabilizing agent
antidepressants or when switching from a • Monitor patients for activation of suicidal
TCA to sertraline ideation, especially children and
• Can cause a fatal “serotonin syndrome” adolescents
when combined with MAO inhibitors, so do
not use with MAO inhibitors or for at least Do Not Use
14 days after MAOIs are stopped • If patient is taking an MAO inhibitor
• Do not start an MAO inhibitor for at least • If patient is taking pimozide
2 weeks after discontinuing sertraline • If patient is taking thioridazine
• May displace highly protein bound drugs • Use of sertraline oral concentrate is
(e.g., warfarin) contraindicated with disulfiram due to the
• Can rarely cause weakness, hyperreflexia, alcohol content of the concentrate
and incoordination when combined with • If there is a proven allergy to sertraline
sumatriptan or possibly with other triptans,
requiring careful monitoring of patient
• Via CYP450 2D6 inhibition, sertraline could SPECIAL POPULATIONS
theoretically interfere with the analgesic
actions of codeine, and increase the Renal Impairment
plasma levels of some beta blockers and of • No dose adjustment
atomoxetine • Not removed by hemodialysis
• Via CYP450 2D6 inhibition sertraline could
theoretically increase concentrations of Hepatic Impairment
thioridazine and cause dangerous cardiac • Lower dose or give less frequently, perhaps
arrhythmias by half
• Via CYP450 3A4 inhibition, sertraline may
increase the levels of alprazolam, Cardiac Impairment
buspirone, and triazolam • Preliminary research suggests that
• Via CYP450 3A4 inhibition, sertraline could sertraline is safe in these patients
theoretically increase concentrations of • Treating depression with SSRIs in patients
certain cholesterol lowering HMG CoA with acute angina or following myocardial
reductase inhibitors, especially simvastatin, infarction may reduce cardiac events and
atorvastatin, and lovastatin, but not improve survival as well as mood
pravastatin or fluvastatin, which would
increase the risk of rhabdomyolysis; thus, Elderly
coadministration of sertraline with certain • Some patients may tolerate lower doses
HMG CoA reductase inhibitors should and/or slower titration better
proceed with caution
• Via CYP450 3A4 inhibition, sertraline could
theoretically increase the concentrations of Children and Adolescents
pimozide, and cause QTc prolongation and • Use with caution, observing for activation
dangerous cardiac arrhythmias of known or unknown bipolar disorder
and/or suicidal ideation, and strongly
consider informing parents or guardian of
this risk so they can help observe child or
adolescent patients

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(continued) SERTRALINE

• Approved for use in OCD so drug may need to be reinstituted late in

• Ages 6–12: initial dose 25 mg/day the third trimester or shortly after
• Ages 13 and up: adult dosing childbirth to prevent a recurrence during
• Long-term effects, particularly on growth, the postpartum period
have not been studied • Must weigh benefits of breast feeding with
risks and benefits of antidepressant
treatment versus nontreatment to both the
Pregnancy infant and the mother
• Risk Category C [some animal studies • For many patients, this may mean
show adverse effects, no controlled studies continuing treatment during breast feeding
in humans]
• Not generally recommended for use during
pregnancy, especially during first trimester THE ART OF PSYCHOPHARMACOLOGY
• Nonetheless, continuous treatment during
pregnancy may be necessary and has not Potential Advantages
been proven to be harmful to the fetus • Patients with atypical depression
• At delivery there may be more bleeding in (hypersomnia, increased appetite)
the mother and transient irritability or • Patients with fatigue and low energy
sedation in the newborn • Patients who wish to avoid
• Must weigh the risk of treatment (first hyperprolactinemia (e.g., pubescent
trimester fetal development, third trimester children, girls and women with
newborn delivery) to the child against the galactorrhea, girls and women with
risk of no treatment (recurrence of unexplained amenorrhea, postmenopausal
depression, maternal health, infant women who are not taking estrogen
bonding) to the mother and child replacement therapy)
• For many patients this may mean • Patients who are sensitive to the prolactin-
continuing treatment during pregnancy elevating properties of other SSRIs
• Neonates exposed to SSRIs or SNRIs late (sertraline is the one SSRI that generally
in the third trimester have developed does not elevate prolactin)
complications requiring prolonged
hospitalization, respiratory support, and Potential Disadvantages
tube feeding; reported symptoms are • Initiating treatment in anxious patients with
consistent with either a direct toxic effect some insomnia
of SSRIs and SNRIs or, possibly, a drug • Patients with comorbid irritable bowel
discontinuation syndrome, and include syndrome
respiratory distress, cyanosis, apnea, • Can require dosage titration
seizures, temperature instability, feeding
difficulty, vomiting, hypoglycemia,
Primary Target Symptoms
hypotonia, hypertonia, hyperreflexia, • Depressed mood
tremor, jitteriness, irritability, and constant • Anxiety
crying • Sleep disturbance, both insomnia and
hypersomnia (eventually, but may actually
Breast Feeding cause insomnia, especially short-term)
• Some drug is found in mother’s breast milk • Panic attacks, avoidant behavior, re-
• Trace amounts may be present in nursing experiencing, hyperarousal
children whose mothers are on sertraline
• Sertraline has shown efficacy in treating
postpartum depression Pearls
• If child becomes irritable or sedated, breast ✽ May be a first-line choice for atypical
feeding or drug may need to be depression (e.g., hypersomnia,
discontinued hyperphagia, low energy, mood reactivity)
• Immediate postpartum period is a high-risk ✽ May block dopamine reuptake pump and
time for depression, especially in women enhance dopaminergic neurotransmission
who have had prior depressive episodes,

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SERTRALINE (continued)

• May block sigma 1 receptors, enhancing or switch to a non-SSRI such as bupropion

sertraline’s anxiolytic actions or mirtazapine
• Has more gastrointestinal effects, • Some postmenopausal women’s
particularly diarrhea, than some other depression will respond better to sertraline
antidepressants plus estrogen augmentation than to
• Can cause cognitive and affective sertraline alone
“flattening”, although this could • Nonresponse to sertraline in elderly may
theoretically be diminished in some require consideration of mild cognitive
patients by sertraline’s dopamine reuptake impairment or Alzheimer disease
blocking properties • Not as well tolerated as some SSRIs for
• May be more effective treatment for panic, especially when dosing is initiated,
women with PTSD or depression than for unless given with co-therapies such as
men with PTSD or depression, but the benzodiazepines or trazodone
clinical significance of this is unknown • Relative lack of effect on prolactin may
• SSRIs may be less effective in women over make it a preferred agent for some
50, especially if they are not taking children, adolescents, and women
estrogen • Some evidence suggests that sertraline
• SSRIs may be useful for hot flushes in treatment during only the luteal phase may
perimenopausal women be more effective than continuous
• For sexual dysfunction, can augment with treatment for patients with PMDD
bupropion, sildenafil, vardenafil, tadalafil,

Suggested Reading
DeVane CL, Liston HL, Markowitz JS. Clinical Khouzam HR, Emes R, Gill T, Raroque R. The
pharmacokinetics of sertraline. Clin antidepressant sertraline: a review of its uses
Pharmacokinet. 2002;41:1247–66. in a range of psychiatric and medical
conditions. Compr Ther. 2003;29:47–53.
Flament MF, Lane RM, Zhu R, Ying Z.
Predictors of an acute antidepressant McRae AL, Brady KT. Review of sertraline and
response to fluoxetine and sertraline. its clinical applications in psychiatric
International Clinical Psychopharmacology. disorders. Expert Opin Pharmacother.
1999;14:259–275. 2001;2:883–92.

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SULPIRIDE
THERAPEUTICS • Consider trying another conventional
antipsychotic
Brands • Dolmatil • If 2 or more antipsychotic monotherapies
see index for additional brand names do not work, consider clozapine
Generic? Yes Best Augmenting Combos
for Partial Response or
Treatment-Resistance
Class • Augmentation of conventional
• Conventional antipsychotic (neuroleptic, antipsychotics has not been systematically
benzamide, dopamine 2 antagonist) studied
• Addition of a mood stabilizing
Commonly Prescribed For anticonvulsant such as valproate,
(bold for FDA approved) carbamazepine, or lamotrigine may be
• Schizophrenia helpful in both schizophrenia and bipolar
• Depression mania
• Augmentation with lithium in bipolar mania
may be helpful
How The Drug Works • Addition of a benzodiazepine, especially
• Blocks dopamine 2 receptors, reducing short-term for agitation
positive symptoms of psychosis
• Blocks dopamine 3 and 4 receptors, which Tests
may contribute to sulpiride’s actions ✽ Since conventional antipsychotics are
✽ Possibly blocks presynaptic dopamine 2 frequently associated with weight gain,
autoreceptors more potently at low doses, before starting treatment, weigh all patients
which could theoretically contribute to and determine if the patient is already
improving negative symptoms of overweight (BMI 25.0–29.9) or obese
schizophrenia as well as depression (BMI ≥30)
• Before giving a drug that can cause weight
How Long Until It Works gain to an overweight or obese patient,
• Psychotic symptoms can improve within 1 consider determining whether the patient
week, but it may take several weeks for full already has pre-diabetes (fasting plasma
effect on behavior glucose 100–125 mg/dl), diabetes (fasting
plasma glucose >126 mg/dl), or
If It Works dyslipidemia (increased total cholesterol,
• Most often reduces positive symptoms in LDL cholesterol and triglycerides;
schizophrenia but does not eliminate them decreased HDL cholesterol), and treat or
• Most schizophrenic patients do not have a refer such patients for treatment, including
total remission of symptoms but rather a nutrition and weight management, physical
reduction of symptoms by about a third activity counseling, smoking cessation, and
• Continue treatment in schizophrenia until medical management
reaching a plateau of improvement ✽ Monitor weight and BMI during treatment
• After reaching a satisfactory plateau, ✽ While giving a drug to a patient who has
continue treatment for at least a year after gained >5% of initial weight, consider
first episode of psychosis in schizophrenia evaluating for the presence of pre-diabetes,
• For second and subsequent episodes of diabetes, or dyslipidemia, or consider
psychosis in schizophrenia, treatment may switching to a different antipsychotic
need to be indefinite • Monitoring elevated prolactin levels of
dubious clinical benefit
If It Doesn’t Work
• Consider trying one of the first-line atypical
antipsychotics (risperidone, olanzapine,
quetiapine, ziprasidone, aripiprazole,
amisulpride)

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SULPIRIDE (continued)

SIDE EFFECTS Sedation

How Drug Causes Side Effects
• By blocking dopamine 2 receptors in the
striatum, it can cause motor side effects • Many experience and/or can be significant
• By blocking dopamine 2 receptors in the in amount, especially at high doses
pituitary, it can cause elevations in
prolactin What To Do About Side Effects
• By blocking dopamine 2 receptors • Wait
excessively in the mesocortical and • Wait
mesolimbic dopamine pathways, especially • Wait
at high doses, it can cause worsening of • For motor symptoms, add an
negative and cognitive symptoms anticholinergic agent
(neuroleptic-induced deficit syndrome) • Reduce the dose
• Anticholinergic actions may cause • For sedation, give at night
sedation, blurred vision, constipation, dry • Switch to an atypical antipsychotic
mouth • Weight loss, exercise programs, and
• Antihistaminic actions may cause sedation, medical management for high BMIs,
weight gain diabetes, dyslipidemia
• By blocking alpha 1 adrenergic receptors, it
can cause dizziness, sedation, and Best Augmenting Agents for Side
hypotension Effects
• Mechanism of weight gain and any • Benztropine or trihexyphenidyl for motor
possible increased incidence of diabetes or side effects
dyslipidemia with conventional • Sometimes amantadine can be helpful for
antipsychotics is unknown motor side effects
• Benzodiazepines may be helpful for
Notable Side Effects akathisia
✽ Extrapyramidal symptoms, akathisia • Many side effects cannot be improved with
✽ Prolactin elevation, galactorrhea, an augmenting agent
amenorrhea
• Sedation, dizziness, sleep disturbance,
headache, impaired concentration DOSING AND USE
• Dry mouth, nausea, vomiting, constipation,
anorexia Usual Dosage Range
• Impotence • Schizophrenia: 400–800 mg/day in 2 doses
• Rare tardive dyskinesia (oral)
• Rare hypomania • Predominantly negative symptoms:
• Palpitations, hypertension 50–300 mg/day (oral)
• Weight gain • Intramuscular injection: 600–800 mg/day
• Depression: 150–300 mg/day (oral)
Life Threatening or Dosage Forms
Dangerous Side Effects • Different formulations may be available in
• Rare neuroleptic malignant syndrome different markets
• Rare seizures • Tablet 200 mg, 400 mg, 500 mg
• Intramuscular injection 50 mg/mL,
Weight Gain 100 mg/mL

How to Dose
• Many experience and/or can be significant • Initial 400–800 mg/day in 1–2 doses; may
in amount need to increase dose to control positive
symptoms; maximum generally
2,400 mg/day

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(continued) SULPIRIDE

Other Warnings/
Dosing Tips Precautions
✽ Low doses of sulpiride may be more • If signs of neuroleptic malignant syndrome
effective at reducing negative symptoms develop, treatment should be immediately
than positive symptoms in schizophrenia; discontinued
high doses may be equally effective at • Use cautiously in patients with alcohol
reducing both symptom dimensions withdrawal or convulsive disorders because
✽ Lower doses are more likely to be of possible lowering of seizure threshold
activating; higher doses are more likely to • Antiemetic effect of sulpiride may mask
be sedating signs of other disorders or overdose;
• Some patients receive more than suppression of cough reflex may cause
2,400 mg/day asphyxia
• Use with caution in patients with
Overdose hypertension, cardiovascular disease,
• Can be fatal; vomiting, agitation, pulmonary disease, hyperthyroidism,
hypotension, hallucinations, CNS urinary retention, glaucoma
depression, sinus tachycardia, arrhythmia, • May exacerbate symptoms of mania or
dystonia, dysarthria, hyperreflexia hypomania
• Use only with caution if at all in
Long-Term Use Parkinson’s disease or Lewy Body
• Apparently safe, but not well-studied dementia
Habit Forming Do Not Use
• No • If patient has pheochromocytoma
• If patient has prolactin-dependent tumor
How to Stop • If patient is pregnant or nursing
• Recommended to reduce dose over a week • In children under age 15
• Slow down-titration (over 6 to 8 weeks), • If there is a proven allergy to sulpiride
especially when simultaneously beginning
a new antipsychotic while switching (i.e.,
cross-titration)
• Rapid discontinuation may lead to rebound
SPECIAL POPULATIONS
psychosis and worsening of symptoms Renal Impairment
• If antiparkinson agents are being used,
• Use with caution; drug may accumulate
they should be continued for a few weeks
• Sulpiride is eliminated by the renal route; in
after sulpiride is discontinued
cases of severe renal insufficiency, the
Pharmacokinetics dose should be decreased and intermittent
treatment or switching to another
• Elimination half-life approximately 6–8
antipsychotic should be considered
hours
• Excreted largely unchanged Heptic Impairment
• Use with caution

Drug Interactions Cardiac Impairment

• Sulpiride may increase the effects of • Use with caution
antihypertensive drugs
• CNS effects may be increased if sulpiride is Elderly
used with other CNS depressants • Some patients may tolerate lower doses
• May decrease the effects of levodopa, better
dopamine agonists
• Antacids or sucralfate may reduce the
absorption of sulpiride Children and Adolescents
• Not recommended for use under age 15
• 14 and older: recommended 3–5 mg/kg/day

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SULPIRIDE (continued)

Pregnancy Pearls
• Potential risks should be weighed against ✽ There is some controversy over whether
the potential benefits, and sulpiride should sulpiride is more effective than older
be used only if deemed necessary conventionals at treating negative symptoms
• Psychotic symptoms may worsen during • Sulpiride has been used to treat migraine
pregnancy and some form of treatment associated with hormonal changes
may be necessary ✽ Some patients with inadequate response
• Atypical antipsychotics may be preferable to clozapine may benefit from
to conventional antipsychotics or augmentation with sulpiride
anticonvulsant mood stabilizers if • Sulpiride is poorly absorbed from the
treatment is required during pregnancy gastrointestinal tract and penetrates the
blood brain barrier poorly, which can lead
Breast Feeding to highly variable clinical responses,
• Some drug is found in mother’s breast milk especially at lower doses
✽ Recommended either to discontinue drug • Small studies and clinical anecdotes
or bottle feed suggest efficacy in depression and anxiety
• Immediate postpartum period is a high-risk disorders (“neuroses”) at low doses
time for relapse of psychosis • Patients have very similar antipsychotic
responses to any conventional
antipsychotic, which is different from
THE ART OF PSYCHOPHARMACOLOGY atypical antipsychotics where antipsychotic
responses of individual patients can
Potential Advantages occasionally vary greatly from one atypical
• For negative symptoms in some patients antipsychotic to another
• Patients with inadequate responses to
Potential Disadvantages atypical antipsychotics may benefit from a
• Patients who cannot tolerate sedation at trial of augmentation with a conventional
high doses antipsychotic such as sulpiride or from
• Patients with severe renal impairment switching to a conventional antipsychotic
such as sulpiride
Primary Target Symptoms • However, long-term polypharmacy with a
• Positive symptoms of psychosis combination of a conventional
• Negative symptoms of psychosis antipsychotic with an atypical antipsychotic
• Cognitive functioning may combine their side effects without
• Depressive symptoms clearly augmenting the efficacy of either
• Aggressive symptoms • Although a frequent practice by some
prescribers, adding 2 conventional
antipsychotics together has little rationale
and may reduce tolerability without clearly
enhancing efficacy

Suggested Reading
Caley CF, Weber SS. Sulpiride: an O’Connor SE, Brown RA. The pharmacology of
antipsychotic with selective dopaminergic sulpiride—a dopamine receptor antagonist.
antagonist properties. Ann Pharmacother Gen Pharmacol 1982; 13 (3): 185–93.
1995; 29 (2): 152–60.
Soares BG, Fenton M, Chue P. Sulpiride for
Mauri MC, Bravin S, Bitetto A, Rudelli R, schizophrenia. Cochrane Database Syst Rev
Invernizzi G. A risk-benefit assessment of 2000; (2): CD001162.
sulpiride in the treatment of schizophrenia.
Drug Saf 1996; 14 (5): 288–98.

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TACRINE
THERAPEUTICS Best Augmenting Combos
Brands • Cognex for Partial Response or
see index for additional brand names Treatment-Resistance
• Atypical antipsychotics to reduce
Generic? Yes behavioral disturbances
• Antidepressants if concomitant depression,
apathy, or lack of interest
• Memantine for moderate to severe
Class
Alzheimer disease
• Cholinesterase inhibitor (inhibits both
• Divalproex, carbamazepine, or
acetylcholinesterase and
oxcarbazepine for behavioral disturbances
butyrylcholinesterase); cognitive enhancer
Tests
Commonly Prescribed For
(bold for FDA approved)
✽ Serum hepatic transaminase levels
should be monitored
• Alzheimer disease
• Memory disorders in other conditions
• Dementia
SIDE EFFECTS
How Drug Causes Side Effects
How The Drug Works • Peripheral inhibition of acetylcholinesterase
✽ Reversibly inhibits centrally-active can cause gastrointestinal side effects
acetylcholinesterase (AChE), making more • Peripheral inhibition of
acetylcholine available butyrylcholinesterase can cause
• Increased availability of acetylcholine gastrointestinal side effects
compensates in part for degenerating • Central inhibition of acetylcholinesterase
cholinergic neurons in neocortex that may contribute to nausea, vomiting, weight
regulate memory loss, and sleep disturbances
✽ Inhibits butyrylcholinesterase (BuChE)
• May release growth factors or interfere Notable Side Effects
with amyloid deposition ✽ Nausea, diarrhea, vomiting, appetite loss,
increased gastric acid secretion, dyspepsia,
How Long Until It Works weight loss
• May take up to 6 weeks before any • Myalgia, rhinitis, rash
improvement in baseline memory or
behavior is evident
• May take months before any stabilization in Life Threatening or
degenerative course is evident Dangerous Side Effects
✽ Elevated hepatic transaminase
If It Works • Liver toxicity
• May improve symptoms and slow • Rare seizures
progression of disease, but does not
reverse the degenerative process Weight Gain
If It Doesn’t Work
• Consider adjusting dose, switching to a
• Reported but not expected
different cholinesterase inhibitor or adding
• Some patients may experience weight loss
an appropriate augmenting agent
• Reconsider diagnosis and rule out other Sedation
conditions such as depression or a
dementia other than Alzheimer disease

• Reported but not expected

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TACRINE (continued)

What To Do About Side Effects weakness (weakness of respiratory

• Wait muscles can lead to death)
• Wait
• Wait Long-Term Use
• Use slower dose titration • Drug may lose effectiveness in slowing
• Consider lowering dose, switching to a degenerative course of Alzheimer disease
different agent or adding an appropriate after 6 months
augmenting agent • Can be effective in some patients for
several years
Best Augmenting Agents for Side
Effects Habit Forming
• Many side effects cannot be improved with • No
an augmenting agent
How to Stop
• May need to taper large doses
• Discontinuation may lead to notable
DOSING AND USE deterioration in memory and behavior
which may not be restored when drug is
Usual Dosage Range
restarted or another cholinesterase
• 40–160 mg/day
inhibitor is initiated
Dosage Forms Pharmacokinetics
• Capsule 10 mg, 20 mg, 30 mg, 40 mg
• Metabolized principally by CYP450 1A2
How to Dose • CYP450 1A2 inhibitor
• Initial 40 mg/day in 4 divided doses; dose • Short half-life, only a few hours
should be maintained for 4 weeks; if
tolerable after 4 weeks, dose should be
increased to 80 mg/day in 4 divided doses; Drug Interactions
additional titration should occur at 4 week • Tacrine may increase the effects of
intervals if tolerable; maximum dose anesthetics and should be discontinued
160 mg/day prior to surgery
• If ALT is between 3 and 5 times the upper • Tacrine may increase plasma levels of
limit of normal, dose should be decreased drugs metabolized by CYP450 1A2 (e.g.,
by 40 mg/day and increased after ALT theophylline) and require dose adjustment
returns to normal • Fluvoxamine and other CYP450 1A2
• If ALT is greater than 5 times the upper inhibitors may increase plasma levels of
limit of normal, tacrine should be tacrine
discontinued; rechallenge may occur after • Tacrine may interact with anticholinergic
ALT returns to normal agents and the combination may decrease
the efficacy of both agents
• May have synergistic effect if administered
Dosing Tips with cholinomimetics (e.g., bethanechol)
• Dose titration may need to be slowed to • Cimetidine may increase tacrine plasma
reduce adverse effects levels
• Dose titration should not be accelerated • Tacrine plasma concentrations may be
beyond the recommended regimen lower in smokers than in nonsmokers due
• Taking tacrine with meals may reduce to induction of CYP450 1A2
gastrointestinal effects; however, food • Bradycardia may occur when tacrine is
decreases plasma concentrations of tacrine combined with beta blockers
• Tacrine may reduce the efficacy of
Overdose levodopa in Parkinson’s disease
• Can be lethal; nausea, vomiting, excess • Not rational to combine with another
salivation, sweating, hypotension, cholinesterase inhibitor
bradycardia, collapse, convulsions, muscle

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(continued) TACRINE

Other Warnings/ ✽ Recommended either to discontinue drug

or bottle feed
Precautions • Tacrine is not recommended for use in
• May exacerbate asthma or other pulmonary nursing women
disease
• Increased gastric acid secretion may
increase the risk of ulcers
• Bradycardia or heart block may occur in
THE ART OF PSYCHOPHARMACOLOGY
patients with or without cardiac impairment Potential Advantages
✽ Tacrine may cause liver toxicity • For some patients who fail to respond to
Do Not Use several other cholinesterase inhibitors
• If previous treatment with tacrine was Potential Disadvantages
discontinued because of treatment- • Hepatotoxicity
associated jaundice, serum bilirubin • Patients with gastrointestinal problems
>3 mg/dL, or hypersensitivity associated • Patients who have difficulty taking
with ALT/SGPT elevation medication several times a day
• If there is a proven allergy to tacrine
Primary Target Symptoms
• Memory loss in Alzheimer disease
SPECIAL POPULATIONS • Behavioral symptoms in Alzheimer disease
• Memory loss in other dementias
Renal Impairment
• No dose adjustment

Hepatic Impairment Pearls

• Use with caution ✽ Hepatotoxicity in up to a third of patients
and 4 times daily dosing make tacrine a
• Potential for liver toxicity
second-line treatment for Alzheimer
Cardiac Impairment disease
• Should be used with caution ✽ Patients who discontinue treatment with
tacrine because of ALT/SGPT elevation may
Elderly be rechallenged with an initial dose of 40
• Some patients may tolerate lower doses mg 4 times per day maintained for 6 weeks
better before titration
• Treats behavioral and psychological
symptoms of dementia as well as cognitive
symptoms (i.e., especially apathy,
Children and Adolescents
disinhibition, delusions, anxiety,
• Safety and efficacy have not been
cooperation, pacing)
established
• Plasma concentrations of tacrine are higher
in women than in men
• Women may experience cognitive
Pregnancy symptoms in perimenopause as a result of
• Risk Category C [no controlled studies in hormonal changes that are not a sign of
animals, no controlled studies in humans] dementia or Alzheimer disease
✽ Not recommended for use in pregnant • Some data that hormone replacement
women or in women of childbearing therapy in women with Alzheimer disease
potential can enhance the effects of tacrine
• The first symptoms of Alzheimer disease
Breast Feeding are generally mood changes; thus,
• Unknown if tacrine is secreted in human Alzheimer disease may initially be
breast milk, but all psychotropics assumed diagnosed as depression
to be secreted in breast milk • If treatment with antidepressants fails to
improve apathy and depressed mood in the

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TACRINE (continued)

elderly, it is possible that this represents for acetylcholine for maximum

early Alzheimer disease and a effectiveness and thus may be most
cholinesterase inhibitor may be helpful effective in the early stages of Alzheimer
• Cholinesterase inhibitors like tacrine disease
depend upon the presence of intact targets

Suggested Reading
Bentue-Ferrer D, Tribut O, Polard E, Allain H. Oizilbash N, Birks J, Lopez-Arrieta J,
Clinically significant drug interactions with Lewington S, Szeto S. Tacrine for Alzheimer’s
cholinesterase inhibitors: a guide for disease. Cochrane Database Syst Rev
neurologists. CNS Drugs 2003;17:947–63. 2000;(3):CD000202.
Bonner LT, Peskind ER. Pharmacologic Stahl SM. The new cholinesterase inhibitors
treatments of dementia. Med Clin North Am for Alzheimer’s disease, part 1. J Clin
2002;86:657–74. Psychiatry 2000;61:710–11.
Jones RW. Have cholinergic therapies reached Stahl SM. The new cholinesterase inhibitors
their clinical boundary in Alzheimer’s disease? for Alzheimer’s disease, part 2. J Clin
Int J Geriatr Psychiatry 2003;18(Suppl 1): Psychiatry 2000;61:813–14.
S7–S13.

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TEMAZEPAM
THERAPEUTICS Tests
• In patients with seizure disorders,
Brands • Restoril
concomitant medical illness, and/or those
see index for additional brand names
with multiple concomitant long-term
Generic? Yes medications, periodic liver tests and blood
counts may be prudent

Class
SIDE EFFECTS
• Benzodiazepine (hypnotic)
How Drug Causes Side Effects
Commonly Prescribed For
• Same mechanism for side effects as for
(bold for FDA approved)
therapeutic effects – namely due to
• Short-term treatment of insomnia
excessive actions at benzodiazepine
receptors
• Actions at benzodiazepine receptors that
How The Drug Works carry over to the next day can cause
• Binds to benzodiazepine receptors at the daytime sedation, amnesia, and ataxia
GABA-A ligand-gated chloride channel • Long-term adaptations in benzodiazepine
complex receptors may explain the development of
• Enhances the inhibitory effects of GABA dependence, tolerance, and withdrawal
• Boosts chloride conductance through
GABA-regulated channels Notable Side Effects
• Inhibitory actions in sleep centers may ✽ Sedation, fatigue, depression
provide sedative hypnotic effects ✽ Dizziness, ataxia, slurred speech,
weakness
How Long Until It Works ✽ Forgetfulness, confusion
• Generally takes effect in less than an hour, ✽ Hyper-excitability, nervousness
but can take longer in some patients • Rare hallucinations, mania
• Rare hypotension
If It Works • Hypersalivation, dry mouth
• Improves quality of sleep • Rebound insomnia when withdrawing from
• Effects on total wake-time and number of long-term treatment
nighttime awakenings may be decreased
over time
Life Threatening or
If It Doesn’t Work Dangerous Side Effects
• If insomnia does not improve after • Respiratory depression, especially when
7–10 days, it may be a manifestation of a taken with CNS depressants in overdose
primary psychiatric or physical illness such • Rare hepatic dysfunction, renal
as obstructive sleep apnea or restless leg dysfunction, blood dyscrasias
syndrome, which requires independent
evaluation Weight Gain
• Increase the dose
• Improve sleep hygiene
• Switch to another agent • Reported but not expected
Best Augmenting Combos Sedation
for Partial Response or
Treatment-Resistance
• Generally, best to switch to another agent
• Trazodone • Many experience and/or can be significant
• Agents with antihistamine actions (e.g., in amount
diphenhydramine, tricyclic antidepressants)

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TEMAZEPAM (continued)

What To Do About Side Effects Habit Forming

• Wait • Temazepam is a Schedule IV drug
• To avoid problems with memory, only take • Some patients may develop dependence
temazepam if planning to have a full night’s and/or tolerance; risk may be greater with
sleep higher doses
• Lower the dose • History of drug addiction may increase risk
• Switch to a shorter-acting sedative of dependence
hypnotic
• Switch to a non-benzodiazepine hypnotic How to Stop
• Administer flumazenil if side effects are • If taken for more than a few weeks, taper
severe or life-threatening to reduce chances of withdrawal effects
• Patients with history of seizure may seize
Best Augmenting Agents for Side upon sudden withdrawal
Effects • Rebound insomnia may occur the first
• Many side effects cannot be improved with 1–2 nights after stopping
an augmenting agent • For patients with severe problems
discontinuing a benzodiazepine, dosing
may need to be tapered over many months
DOSING AND USE (i.e., reduce dose by 1% every 3 days by
crushing tablet and suspending or
Usual Dosage Range dissolving in 100 ml of fruit juice and then
• 15 mg/day at bedtime disposing of 1 ml while drinking the rest;
3–7 days later, dispose of 2 ml, and so on).
Dosage Forms This is both a form of very slow biological
• Capsule 7.5 mg, 15 mg, 30 mg tapering and a form of behavioral
desensitization
How to Dose
• 15 mg/day at bedtime; may increase to Pharmacokinetics
30 mg/day at bedtime if ineffective • No active metabolites
• Half-life approximately 8–15 hours

Dosing Tips
• Use lowest possible effective dose and Drug Interactions
assess need for continued treatment • Increased depressive effects when taken
regularly with other CNS depressants
• Temazepam should generally not be • If temazepam is used with kava, clearance
prescribed in quantities greater than a of either drug may be affected
1-month supply
• Patients with lower body weights may Other Warnings/
require lower doses
Precautions
✽ Because temazepam is slowly absorbed, • Insomnia may be a symptom of a primary
administering the dose 1–2 hours before
bedtime may improve onset of action and disorder, rather than a primary disorder
shorter sleep latency itself
• Risk of dependence may increase with • Some patients may exhibit abnormal
dose and duration of treatment thinking or behavioral changes similar to
those caused by other CNS depressants
Overdose (i.e., either depressant actions or
• Can be fatal in monotherapy; slurred disinhibiting actions)
speech, poor coordination, respiratory • Some depressed patients may experience a
depression, sedation, confusion, coma worsening of suicidal ideation
• Use only with extreme caution in patients
Long-Term Use with impaired respiratory function or
• Not generally intended for long-term use obstructive sleep apnea

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(continued) TEMAZEPAM

• Temazepam should only be administered at ✽ Recommended either to discontinue drug

bedtime or bottle feed
• Effects on infant have been observed and
Do Not Use include feeding difficulties, sedation, and
• If patient is pregnant weight loss
• If patient has narrow angle-closure
glaucoma
• If there is a proven allergy to temazepam or THE ART OF PSYCHOPHARMACOLOGY
any benzodiazepine
Potential Advantages
• Patients with middle insomnia (nocturnal
SPECIAL POPULATIONS awakening)

Renal Impairment Potential Disadvantages

• Recommended dose: 7.5 mg/day • Patients with early insomnia (problems
falling asleep)
Hepatic Impairment
• Recommended dose: 7.5 mg/day Primary Target Symptoms
• Time to sleep onset
Cardiac Impairment • Total sleep time
• Dosage adjustment may not be necessary • Nighttime awakenings
• Benzodiazepines have been used to treat
insomnia associated with acute myocardial
infarction Pearls
Elderly • If tolerance develops, it may result in
increased anxiety during the day and/or
• Recommended dose: 7.5 mg/day
increased wakefulness during the latter
part of the night
✽ Slow gastrointestinal absorption
Children and Adolescents compared to other sedative
• Safety and efficacy have not been benzodiazepines, so may be more effective
established for nocturnal awakening than for initial
• Long-term effects of temazepam in insomnia unless dosed 1–2 hours prior to
children/adolescents are unknown bedtime
• Should generally receive lower doses and ✽ Notable for delayed onset of action
be more closely monitored compared to some other sedative
hypnotics

Pregnancy
• Risk Category X [positive evidence of risk
to human fetus; contraindicated for use in
pregnancy]
• Infants whose mothers received a
benzodiazepine late in pregnancy may
experience withdrawal effects
• Neonatal flaccidity has been reported in
infants whose mothers took a
benzodiazepine during pregnancy

Breast Feeding
• Unknown if temazepam is secreted in
human breast milk, but all psychotropics
assumed to be secreted in breast milk

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TEMAZEPAM (continued)

Suggested Reading
Ashton H. Guidelines for the rational use of Heel RC, Brogden RN, Speight TM, Avery GS.
benzodiazepines. When and what to use. Temazepam: a review of its pharmacological
Drugs 1994;48:25–40. properties and therapeutic efficacy as an
hypnotic. Drugs 1981;21:321–40.
Fraschini F, Stankov B. Temazepam:
pharmacological profile of a benzodiazepine McElnay JC, Jones ME, Alexander B.
and new trends in its clinical application. Temazepam (Restoril, Sandoz
Pharmacol Res 1993;27:97–113. Pharmaceuticals). Drug Intell Clin Pharm
1982;16:650–6.

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THIORIDAZINE
THERAPEUTICS Tests
Brands • Mellaril ✽ Baseline ECG and serum potassium levels
should be determined
see index for additional brand names
✽ Periodic evaluation of ECG and serum
Generic? Yes potassium levels
• Serum magnesium levels may also need to
be monitored
Class
✽ Since conventional antipsychotics are
frequently associated with weight gain,
• Conventional antipsychotic (neuroleptic, before starting treatment, weigh all patients
phenothiazine, dopamine 2 antagonist) and determine if the patient is already
overweight (BMI 25.0–29.9) or obese
Commonly Prescribed For (BMI ≥30)
(bold for FDA approved) • Before giving a drug that can cause weight
• Schizophrenic patients who fail to gain to an overweight or obese patient,
respond to treatment with other consider determining whether the patient
antipsychotic drugs already has pre-diabetes (fasting plasma
glucose 100–125 mg/dl), diabetes (fasting
plasma glucose >126 mg/dl), or
How The Drug Works dyslipidemia (increased total cholesterol,
• Blocks dopamine 2 receptors, reducing LDL cholesterol and triglycerides;
positive symptoms of psychosis decreased HDL cholesterol), and treat or
refer such patients for treatment, including
How Long Until It Works nutrition and weight management, physical
• Psychotic symptoms can improve within activity counseling, smoking cessation, and
1 week, but it may take several weeks for medical management
full effect on behavior ✽ Monitor weight and BMI during treatment
✽ While giving a drug to a patient who has
If It Works gained >5% of initial weight, consider
• Is a second-line treatment option evaluating for the presence of pre-diabetes,
✽ Should evaluate for switching to an diabetes, or dyslipidemia, or consider
antipsychotic with a better risk/benefit ratio switching to a different antipsychotic
• Should check blood pressure in the elderly
If It Doesn’t Work before starting and for the first few weeks
• Consider trying one of the first-line atypical of treatment
antipsychotics (risperidone, olanzapine, • Monitoring elevated prolactin levels of
quetiapine, ziprasidone, aripiprazole, dubious clinical benefit
amisulpride) • Phenothiazines may cause false-positive
• Consider trying another conventional phenylketonuria results
antipsychotic
• If 2 or more antipsychotic monotherapies
do not work, consider clozapine
SIDE EFFECTS
Best Augmenting Combos
How Drug Causes Side Effects
for Partial Response or
• By blocking dopamine 2 receptors in the
Treatment-Resistance striatum, it can cause motor side effects
✽ Augmentation of thioridazine has not • By blocking dopamine 2 receptors in the
been systematically studied and can be pituitary, it can cause elevations in
dangerous, especially with drugs that can prolactin
either prolong QTc interval or raise • By blocking dopamine 2 receptors
thioridazine plasma levels excessively in the mesocortical and
mesolimbic dopamine pathways, especially
at high doses, it can cause worsening of

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THIORIDAZINE (continued)

negative and cognitive symptoms What To Do About Side Effects

(neuroleptic-induced deficit syndrome) • Wait
• Anticholinergic actions may cause • Wait
sedation, blurred vision, constipation, dry • Wait
mouth • For motor symptoms, add an
• Antihistaminic actions may cause sedation, anticholinergic agent
weight gain • Reduce the dose
• By blocking alpha 1 adrenergic receptors, it • For sedation, give at night
can cause dizziness, sedation, and • Switch to an atypical antipsychotic
hypotension • Weight loss, exercise programs, and
• Mechanism of weight gain and any medical management for high BMIs,
possible increased incidence of diabetes or diabetes, dyslipidemia
dyslipidemia with conventional
antipsychotics is unknown Best Augmenting Agents for Side
✽ Mechanism of potentially dangerous QTc Effects
prolongation may be related to actions at ✽ Augmentation of thioridazine has not
ion channels been systematically studied and can be
dangerous
Notable Side Effects
✽ Neuroleptic-induced deficit syndrome
✽ Akathisia DOSING AND USE
✽ Priapism
✽ Extrapyramidal symptoms, Parkinsonism, Usual Dosage Range
tardive dyskinesia • 200–800 mg/day in divided doses
✽ Galactorrhea, amenorrhea
✽ Pigmentary retinopathy at high doses Dosage Forms
• Dizziness, sedation • Tablet 10 mg, 15 mg, 25 mg, 50 mg,
• Dry mouth, constipation, blurred vision 100 mg, 150 mg, 200 mg
• Decreased sweating • Liquid 30 mg/mL, 100 mg/mL
• Sexual dysfunction • Suspension 5 mg/mL, 20 mg/mL
• Hypotension
• Weight gain How to Dose
• 50–100 mg 3 times a day; increase
gradually; maximum 800 mg/day in divided
Life Threatening or
doses
Dangerous Side Effects
• Rare neuroleptic malignant syndrome
• Rare jaundice, agranulocytosis
• Rare seizures Dosing Tips
✽ Dose-dependent QTc prolongation ✽ Prolongation of the QTc interval is dose-
• Ventricular arrhythmias and sudden death dependent, so start low and go slow while
carefully monitoring QTc interval
Weight Gain • Pigmentary retinopathy has been reported
in patients taking doses exceeding the
recommended range
• Many experience and/or can be significant Overdose
in amount • Sedation, confusion, respiratory
depression, cardiac disturbance,
Sedation hypotension, seizure, coma

Long-Term Use
• Many experience and/or can be significant • Some side effects may be irreversible (e.g.,
in amount tardive dyskinesia)
• Sedation is usually transient

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(continued) THIORIDAZINE

Habit Forming • Use cautiously in patients with respiratory

• No disorders, glaucoma, or urinary retention
• Avoid extreme heat exposure
How to Stop • Antiemetic effect can mask signs of other
• Slow down-titration (over 6 to 8 weeks), disorders or overdose
especially when simultaneously beginning • Use cautiously in patients with alcohol
a new antipsychotic while switching (i.e., withdrawal or convulsive disorders
cross-titration) because of possible lowering of seizure
• Rapid discontinuation may lead to rebound threshold
psychosis and worsening of symptoms • Do not use epinephrine in event of
• If antiparkinson agents are being used, overdose, as interaction with some pressor
they should be continued for a few weeks agents may lower blood pressure
after thioridazine is discontinued • Use only with caution if at all in
Parkinson’s disease or Lewy Body
Pharmacokinetics dementia
• Metabolized by CYP450 2D6 • Observe for signs of pigmentary
retinopathy, especially at higher doses
• Because thioridazine may dose-
Drug Interactions dependently prolong QTc interval, use with
• May decrease the effects of levodopa, caution in patients who have bradycardia
dopamine agonists or who are taking drugs that can induce
• May increase the effects of bradycardia (e.g., beta blockers, calcium
antihypertensive drugs channel blockers, clonidine, digitalis)
• May enhance QTc prolongation of other • Because thioridazine may dose-
drugs capable of prolonging QTc interval dependently prolong QTc interval, use with
✽ CYP450 2D6 inhibitors including caution in patients who have hypokalemia
paroxetine, fluoxetine, duloxetine, and/or hypomagnesemia or who are taking
bupropion, sertraline, citalopram, and others drugs that can induce hypokalemia and/or
can raise thioridazine to dangerous levels magnesemia (e.g., diuretics, stimulant
✽ Fluvoxamine, propranolol, and pindolol laxatives, intravenous amphotericin B,
also inhibit thioridazine metabolism and glucocorticoids, tetracosactide)
can raise thioridazine to dangerous levels
• Respiratory depression / arrest may occur Do Not Use
if used with a barbiturate • If patient is in a comatose state or has CNS
• Additive effects may occur if used with depression
CNS depressants • If patient suffers from extreme
• Alcohol and diuretics may increase the risk hypertension/hypotension
of hypotension; epinephrine may lower ✽ If QTc interval greater than 450 msec or if
blood pressure taking an agent capable of significantly
• Some patients taking a neuroleptic and prolonging QTc interval (e.g., pimozide,
lithium have developed an encephalopathic selected antiarrhythmics, moxifoxacin, and
syndrome similar to neuroleptic malignant sparfloxacin)
syndrome ✽ If there is a history of QTc prolongation
or cardiac arrhythmia, recent acute
myocardial infarction, uncompensated
Other Warnings/ heart failure
Precautions ✽ If patient is taking drugs that inhibit
• If signs of neuroleptic malignant syndrome thioridazine metabolism, including CYP450
develop, treatment should be immediately inhibitors
discontinued ✽ If there is reduced CYP450 2D6 function,
✽ Thioridazine can increase the QTc interval such as in patients who are 2D6 poor
and potentially cause torsades de pointes- metabolizers
type arrhythmia or sudden death, especially • If there is a proven allergy to thioridazine
in combination with drugs that raise its • If there is a known sensitivity to any
levels phenothiazine

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THIORIDAZINE (continued)

SPECIAL POPULATIONS • Atypical antipsychotic may be preferable to

conventional antipsychotics or
Renal Impairment anticonvulsant mood stabilizers if
• Use with caution treatment is required during pregnancy
• Should evaluate for an antipsychotic with a
Hepatic Impairment
better risk/benefit ratio if treatment is
• Use with caution
required during pregnancy
Cardiac Impairment Breast Feeding
• Thioridazine produces a dose-dependent
• Unknown if thioridazine is secreted in
prolongation of QTc interval, which may be
human breast milk, but all psychotropics
enhanced by the existence of bradycardia,
assumed to be secreted in breast milk
hypokalemia, congenital or acquired long
QTc interval, which should be evaluated ✽ Recommended either to discontinue drug
or bottle feed
prior to administering thioridazine
• Use with caution if treating concomitantly
with a medication likely to produce
prolonged bradycardia, hypokalemia THE ART OF PSYCHOPHARMACOLOGY
slowing of intracardiac conduction, or
prolongation of the QTc interval
Potential Advantages
• Avoid thioridazine in patients with a known • Only for patients who respond to this agent
history of QTc prolongation, recent acute and not other antipsychotics
myocardial infarction, and uncompensated
Potential Disadvantages
heart failure
• Children
✽ Risk/benefit ratio may not justify use in • Elderly
cardiac impairment
• Patients on other drugs
Elderly • Those with low CYP450 2D6 metabolism
• Some patients may tolerate lower doses
Primary Target Symptoms
better
• Positive symptoms of psychosis in patients
• Elderly patients may be more sensitive to
who fail to respond to treatment with other
adverse effects, including agranulocytosis
antipsychotics
and leukopenia
• Motor and autonomic hyperactivity in
patients who fail to respond to treatment
with other antipsychotics
Children and Adolescents • Violent or aggressive behavior in patients
• Safety and efficacy not established under who fail to respond to treatment with other
age 2 antipsychotics
• Dose: initial 0.5 mg/kg/day in divided doses;
increase gradually; maximum 3 mg/kg/day
• Risk/benefit ratio may not justify use in
Pearls
children or adolescents
✽ Generally, the benefits of thioridazine do
not outweigh its risks for most patients
✽ Because of its effects on the QTc interval,
Pregnancy thioridazine is not intended for use unless
• Risk Category C [some animal studies other options (at least 2 antipsychotics)
show adverse effects, no controlled studies have failed
in humans] • Thioridazine has not been systematically
• Reports of extrapyramidal symptoms, studied in treatment-refractory
jaundice, hyperreflexia, hyporeflexia in schizophrenia
infants whose mothers took a ✽ Phenotypic testing may be necessary in
phenothiazine during pregnancy order to detect the 7% of the normal
• Psychotic symptoms may worsen during population for whom thioridazine is
pregnancy and some form of treatment
may be necessary

450
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(continued) THIORIDAZINE

contraindicated due to a genetic variant sedating low potency phenothiazine with a

leading to reduced activity of CYP450 2D6 lower incidence of extrapyramidal
• Conventional antipsychotics are much less symptoms
expensive than atypical antipsychotics ✽ However, now it is recognized that the
• Thioridazine causes less extrapyramidal dangers of cardiac arrhythmias and drug
symptoms than some other conventional interactions outweigh the benefits of
antipsychotics thioridazine, and it is now considered a
✽ Was once a preferred antipsychotic for second-line treatment if it is considered at
children and the elderly, and for those all
whose symptoms benefited from a

Suggested Reading
Frankenburg FR. Choices in antipsychotic Sultana A, Reilly J, Fenton M. Thioridazine for
therapy in schizophrenia. Harv Rev Psychiatry schizophrenia. Cochrane Database Syst Rev
1999;6:241–9. 2000;(3):CD001944.
Gardos G, Tecce JJ, Hartmann E, Bowers P, Leucht S, Wahlbeck K, Hamann J, Kissling W.
Cole JO. Treatment with mesoridazine and New generation antipsychotics versus low-
thioridazine in chronic schizophrenia: II. potency conventional antipsychotics: a
Potential predictors of drug response. Compr systematic review and meta-analysis. The
Psychiatry 1978;19:527–32. Lancet 2003;361:1581–9.

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0521011698s09.qxd 9/2/04 2:48 PM Page 453

THIOTHIXENE
THERAPEUTICS quetiapine, ziprasidone, aripiprazole,
amisulpride)
Brands • Navane • Consider trying another conventional
see index for additional brand names antipsychotic
• If 2 or more antipsychotic monotherapies
Generic? Yes
do not work, consider clozapine

Best Augmenting Combos

Class for Partial Response or
• Conventional antipsychotic (neuroleptic, Treatment-Resistance
thioxanthene, dopamine 2 antagonist) • Augmentation of conventional
antipsychotics has not been systematically
Commonly Prescribed For studied
(bold for FDA approved) • Addition of a mood stabilizing
• Schizophrenia anticonvulsant such as valproate,
• Other psychotic disorders carbamazepine, or lamotrigine may be
• Bipolar disorder helpful in both schizophrenia and bipolar
mania
• Augmentation with lithium in bipolar mania
How The Drug Works may be helpful
• Blocks dopamine 2 receptors, reducing • Addition of a benzodiazepine, especially
positive symptoms of psychosis short-term for agitation

How Long Until It Works Tests

• Psychotic symptoms can improve within ✽ Since conventional antipsychotics are
1 week, but it may take several weeks for frequently associated with weight gain,
full effect on behavior before starting treatment, weigh all patients
and determine if the patient is already
If It Works overweight (BMI 25.0–29.9) or obese
• Most often reduces positive symptoms in (BMI ≥30)
schizophrenia but does not eliminate them • Before giving a drug that can cause weight
• Most schizophrenic patients do not have a gain to an overweight or obese patient,
total remission of symptoms but rather a consider determining whether the patient
reduction of symptoms by about a third already has pre-diabetes (fasting plasma
• Continue treatment in schizophrenia until glucose 100–125 mg/dl), diabetes (fasting
reaching a plateau of improvement plasma glucose >126 mg/dl), or
• After reaching a satisfactory plateau, dyslipidemia (increased total cholesterol,
continue treatment for at least a year after LDL cholesterol and triglycerides;
first episode of psychosis in schizophrenia decreased HDL cholesterol), and treat or
• For second and subsequent episodes of refer such patients for treatment, including
psychosis in schizophrenia, treatment may nutrition and weight management, physical
need to be indefinite activity counseling, smoking cessation, and
• Reduces symptoms of acute psychotic medical management
mania but not proven as a mood stabilizer ✽ Monitor weight and BMI during treatment
or as an effective maintenance treatment in ✽ While giving a drug to a patient who has
bipolar disorder gained >5% of initial weight, consider
• After reducing acute psychotic symptoms evaluating for the presence of pre-diabetes,
in mania, switch to a mood stabilizer diabetes, or dyslipidemia, or consider
and/or an atypical antipsychotic for mood switching to a different antipsychotic
stabilization and maintenance • Monitoring elevated prolactin levels of
dubious clinical benefit
If It Doesn’t Work
• Consider trying one of the first-line atypical
antipsychotics (risperidone, olanzapine,

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THIOTHIXENE (continued)

SIDE EFFECTS Sedation

How Drug Causes Side Effects
• By blocking dopamine 2 receptors in the
striatum, it can cause motor side effects • Occurs in significant minority
• By blocking dopamine 2 receptors in the
pituitary, it can cause elevations in What To Do About Side Effects
prolactin • Wait
• By blocking dopamine 2 receptors • Wait
excessively in the mesocortical and • Wait
mesolimbic dopamine pathways, especially • For motor symptoms, add an
at high doses, it can cause worsening of anticholinergic agent
negative and cognitive symptoms • For sedation, take at night
(neuroleptic-induced deficit syndrome) • Reduce the dose
• Anticholinergic actions may cause • Switch to an atypical antipsychotic
sedation, blurred vision, constipation, dry • Weight loss, exercise programs, and
mouth medical management for high BMIs,
• Antihistaminic actions may cause sedation, diabetes, dyslipidemia
weight gain
• By blocking alpha 1 adrenergic receptors, it Best Augmenting Agents for Side
can cause dizziness, sedation, and Effects
hypotension • Benztropine or trihexyphenidyl for motor
• Mechanism of weight gain and any side effects
possible increased incidence of diabetes or • Sometimes amantadine can be helpful for
dyslipidemia with conventional motor side effects
antipsychotics is unknown • Benzodiazepines may be helpful for
akathisia
Notable Side Effects • Many side effects cannot be improved with
✽ Neuroleptic-induced deficit syndrome an augmenting agent
✽ Akathisia
✽ Extrapyramidal symptoms, Parkinsonism,
tardive dyskinesia DOSING AND USE
✽ Galactorrhea, amenorrhea
• Sedation Usual Dosage Range
• Dry mouth, constipation, vision • 15–30 mg/day
disturbance, urninary retention
• Hypotension, tachycardia Dosage Forms
• Rare fine lenticular pigmentation • Capsule 2 mg, 5 mg, 10 mg

How to Dose
Life Threatening or • Initial 5–10 mg/day; maximum dose
Dangerous Side Effects generally 60 mg/day; higher doses may be
• Rare neuroleptic malignant syndrome given in divided doses
• Rare seizures
• Rare blood dyscrasias
• Rare hepatic toxicity Dosing Tips
Weight Gain • When thiothixene is dosed too high, it can
induce or worsen negative symptoms of
schizophrenia
• Lower doses may provide the best benefit
✽ Reported but not expected with fewest side effects in patients who
respond to low doses

454
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(continued) THIOTHIXENE

Overdose • Use cautiously in patients with alcohol

• Muscle twitching, sedation, dizziness, CNS withdrawal or convulsive disorders
depression, rigidity, weakness, torticollis, because of possible lowering of seizure
dysphagia, hypotension, coma threshold
• Antiemetic effect can mask signs of other
Long-Term Use disorders or overdose
• Some side effects may be irreversible (e.g., • Do not use epinephrine in event of
tardive dyskinesia) overdose, as interaction with some pressor
agents may lower blood pressure
Habit Forming • Use cautiously in patients with glaucoma,
• No urinary retention
• Observe for signs of ocular toxicity
How to Stop (pigmentary retinopathy, lenticular
• Slow down-titration (over 6 to 8 weeks), pigmentation)
especially when simultaneously beginning • Avoid extreme heat exposure
a new antipsychotic while switching (i.e., • Use only with caution if at all in
cross-titration) Parkinson’s disease or Lewy Body
• Rapid discontinuation may lead to rebound dementia
psychosis and worsening of symptoms
• If antiparkinson agents are being used, Do Not Use
they should be continued for a few weeks • If patient has CNS depression, is in a
after thiothixene is discontinued comatose state, has circulatory collapse, or
there is presence of blood dyscrasias
Pharmacokinetics • If there is a proven allergy to thiothixene
• Initial elimination half-life approximately
3.4 hours
• Terminal elimination half-life approximately
SPECIAL POPULATIONS
34 hours
Renal Impairment
• Use with caution
Drug Interactions
• Respiratory depression may occur when Hepatic Impairment
thiothixene is combined with lorazepam • Use with caution
• Additive effects may occur if used with
CNS depressants Cardiac Impairment
• May decrease the effects of levodopa, • Thiothixene may cause or aggravate ECG
dopamine agonists changes
• Some patients taking a neuroleptic and
lithium have developed an encephalopathic Elderly
syndrome similar to neuroleptic malignant • Some patients may tolerate lower doses
syndrome better
• Combined use with epinephrine may lower
blood pressure
• May increase the effects of Children and Adolescents
antihypertensive drugs except for • Safety and efficacy have not been
guanethidine, whose antihypertensive established in children under age 12
actions thiothixene may antagonize • Generally consider second-line after
atypical antipsychotics
Other Warnings/
Precautions
• If signs of neuroleptic malignant syndrome Pregnancy
develop, treatment should be immediately • Use of thiothixene has not been studied in
discontinued pregnant women

455
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THIOTHIXENE (continued)

• Reports of extrapyramidal symptoms,

jaundice, hyperreflexia, hyporeflexia in
infants whose mothers took a Pearls
phenothiazine during pregnancy ✽ Although not systematically studied, may
• Psychotic symptoms may worsen during cause less weight gain than other
pregnancy and some form of treatment antipsychotics
may be necessary • Conventional antipsychotics are less
• Atypical antipsychotics may be preferable expensive than atypical antipsychotics
to conventional antipsychotics or • Patients have very similar antipsychotic
anticonvulsant mood stabilizers if responses to any conventional
treatment is required during pregnancy antipsychotic, which is different from
• Thiothixene should generally not be used atypical antipsychotics where antipsychotic
during the first trimester responses of individual patients can
• Thiothixene should only be used during occasionally vary greatly from one atypical
pregnancy if clearly needed antipsychotic to another
• Patients with inadequate responses to
Breast Feeding atypical antipsychotics may benefit from a
• Unknown if thiothixene is secreted in trial of augmentation with a conventional
human breast milk, but all psychotropics antipsychotic such as thiothixene or from
assumed to be secreted in breast milk switching to a conventional antipsychotic
✽ Recommended either to discontinue drug such as thiothixene
or bottle feed • However, long-term polypharmacy with a
combination of a conventional
antipsychotic such as thiothixene with an
THE ART OF PSYCHOPHARMACOLOGY atypical antipsychotic may combine their
side effects without clearly augmenting the
Potential Advantages efficacy of either
• For patients who do not respond to other • Although a frequent practice by some
antipsychotics prescribers, adding 2 conventional
antipsychotics together has little rationale
Potential Disadvantages and may reduce tolerability without clearly
• Patients with tardive dyskinesia enhancing efficacy
• Children
• Elderly

Primary Target Symptoms

• Positive symptoms of psychosis
• Negative symptoms of psychosis

Suggested Reading
Huang CC, Gerhardstein RP, Kim DY, Hollister Sterlin C, Ban TA, Jarrold L. The place of
L. Treatment-resistant schizophrenia: thiothixene among the thioxanthenes. Curr
controlled study of moderate- and high-dose Ther Res Clin Exp 1972;14:205–14.
thiothixene. Int Clin Psychopharmacol
1987;2:69–75.

456
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TIAGABINE
THERAPEUTICS • Other patients may be nonresponders,
sometimes called treatment-resistant or
Brands • Gabitril treatment-refractory
see index for additional brand names • May only be effective in a subset of
patients with neuropathic pain or anxiety
Generic? No
disorders, in some patients who fail to
respond to other treatments, or it may not
work at all
Class • Consider increasing dose, switching to
• Anticonvulsant; selective GABA reuptake another agent or adding an appropriate
inhibitor (SGRI) augmenting agent
• Consider biofeedback or hypnosis for pain
Commonly Prescribed For • Consider evaluation for another diagnosis
(bold for FDA approved) or for a comorbid condition (e.g., medical
• Partial seizures (adjunctive; adults and illness, substance abuse, etc.)
children 12 years and older) • Switch to another agent with fewer side
• Anxiety disorders effects
• Neuropathic pain/chronic pain • Consider evaluation for another diagnosis
or for a comorbid condition (e.g., medical
illness, substance abuse, etc.)
How The Drug Works
• Selectively blocks reuptake of gamma- Best Augmenting Combos
aminobutyric acid (GABA) by presynaptic for Partial Response or
and glial GABA transporters Treatment-Resistance
• Tiagabine is itself an augmenting agent for
How Long Until It Works numerous other anticonvulsants in treating
• Should reduce seizures by 2 weeks epilepsy
• Not clear that it works in anxiety disorders ✽ For neuropathic pain, tiagabine can
or chronic pain but some patients may augment tricyclic antidepressants and
respond, and if they do, therapeutic actions SNRIs as well as gabapentin, other
can be seen by 2 weeks anticonvulsants, and even opiates if done
by experts while carefully monitoring in
If It Works difficult cases
• The goal of treatment is complete • For anxiety, tiagabine is a second-line
remission of symptoms (e.g., seizures, treatment to augment SSRIs, SNRIs, or
anxiety) benzodiazepines
• The goal of treatment of chronic
neuropathic pain is to reduce symptoms as Tests
much as possible, especially in • None for healthy individuals
combination with other treatments • Tiagabine may bind to tissue that contains
• Treatment of chronic neuropathic pain melanin, so for long-term treatment
most often reduces but does not eliminate opthalmological checks may be considered
symptoms and is not a cure since
symptoms usually recur after medicine
stopped SIDE EFFECTS
• Continue treatment until all symptoms are
gone or until improvement is stable and How Drug Causes Side Effects
then continue treating indefinitely as long • CNS side effects may be due to excessive
as improvement persists actions of GABA
If It Doesn’t Work (for neuropathic Notable Side Effects
pain or anxiety disorders) ✽ Sedation, dizziness, asthenia,
• Many patients only have a partial response nervousness, difficulty concentrating,
where some symptoms are improved but
others persist

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TIAGABINE (continued)

speech/language problems, confusion, How to Dose

tremor • Adjunct to enzyme-inducing antiepileptic
• Diarrhea, vomiting, nausea drugs: initial 4 mg once daily; after 1 week
• Ecchymosis, depression can increase dose by 4–8 mg/day each
week; maximum dose generally 56 mg/day
in 2–4 divided doses
Life Threatening or
• Dosing for chronic pain or anxiety
Dangerous Side Effects disorders not well established, but start as
• Exacerbation of EEG abnormalities in low as 2 mg at night, increasing by 2 mg
epilepsy increments every few days as tolerated to
• Status epilepticus in epilepsy (unknown if 8–12 mg/day
associated with tiagabine use)
• Sudden unexplained deaths have occurred
in epilepsy (unknown if related to tiagabine
use) Dosing Tips
• Usually administered as adjunctive
Weight Gain medication to other anticonvulsants in the
treatment of epilepsy
✽ Usually administered as adjunctive
medication to benzodiazepines, SSRIs,
• Reported but not expected and/or SNRIs in the treatment of anxiety
• Some patients experience increased disorders; and to SNRIs, gabapentin, other
appetite anticonvulsants, and even opiates in the
treatment of chronic pain
Sedation
✽ Dosing varies considerably among
individual patients but is definitely at the
lower end of the dosing spectrum for
• Many experience and/or can be significant patients with chronic neuropathic pain or
in amount anxiety disorders (i.e., 2–12 mg either as a
split dose or all at night)
What To Do About Side Effects ✽ Patients with chronic neuropathic pain
• Wait and anxiety disorders are far less tolerant
• Wait of CNS side effects, so they require a much
• Wait slower dosage titration as well as a lower
• Take more of the dose at night or all of the maintenance dose
dose at night to reduce daytime sedation • Gastrointestinal absorption is markedly
• Lower the dose slowed by the concomitant intake of food,
• Switch to another agent which also lessens the peak plasma
concentrations
Best Augmenting Agents for Side ✽ Thus, for improved tolerability and
Effects consistent clinical actions, instruct patients
• Many side effects cannot be improved with to always take with food
an augmenting agent • Side effects may increase with dose

Overdose
DOSING AND USE • No fatalities have been reported; sedation,
agitation, confusion, speech difficulty,
Usual Dosage Range hostility, depression, weakness, myoclonus
• 32–56 mg/day in 2–4 divided doses for
adjunctive treatment of epilepsy Long-Term Use
• 2–12 mg/day for adjunctive treatment of • Safe
chronic pain and anxiety disorders
Habit Forming
Dosage Forms • No
• Tablet 2 mg, 4 mg, 12 mg, 16 mg, 20 mg

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(continued) TIAGABINE

How to Stop • Tiagabine may bind to melanin, raising the

• Taper possibility of long-term opthalmologic
• Epilepsy patients may seize upon effects
withdrawal, especially if withdrawal is
abrupt Do Not Use
• Discontinuation symptoms uncommon • If there is a proven allergy to tiagabine

Pharmacokinetics
• Primarily metabolized by CYP450 3A4 SPECIAL POPULATIONS
• Steady state concentrations tend to be
lower in the evening than in the morning Renal Impairment
• Half-life approximately 7–9 hours • Although tiagabine is renally excreted, the
• Renally excreted pharmacokinetics of tiagabine in healthy
patients and in those with impaired renal
function are similar and no dose
Drug Interactions adjustment is recommended
• Clearance of tiagabine may be reduced and
thus plasma levels increased if taken with a
Hepatic Impairment
non-enzyme inducing antiepileptic drug • Clearance is decreased
(e.g., valproate, gabapentin, lamotrigine), • May require lower dose
so tiagabine dose may need to be reduced
Cardiac Impairment
• CYP450 3A4 inducers such as
• No dose adjustment recommended
carbamazepine can lower the plasma levels
of tiagabine Elderly
• CYP450 3A4 inhibitors such as • Some patients may tolerate lower doses
nefazodone, fluvoxamine, and fluoxetine better
could theoretically increase the plasma
levels of tiagabine
• Clearance of tiagabine is increased if taken
with an enzyme-inducing antiepileptic drug Children and Adolescents
(e.g., carbamazepine, phenobarbital, • Safety and efficacy not established under
phenytoin, primidone) and thus plasma age 12
levels are reduced; however, no dose • Maximum recommended dose generally
adjustments are necessary for treatment of 32 mg/day in 2–4 divided doses
epilepsy as the dosing recommendations
for epilepsy are based on adjunctive
treatment with an enzyme-inducing Pregnancy
antiepileptic drug • Risk category C [some animal studies
• Despite common actions upon GABA, no show adverse effects, no controlled studies
pharmacodynamic or pharmacokinetic in humans]
interations have been shown when • Use in women of childbearing potential
tiagabine is combined with the requires weighing potential benefits to the
benzodiazepine triazolam or with alcohol mother against the risks to the fetus
• However, sedating actions of any two • Taper drug if discontinuing
sedative drugs given in combination can be • Seizures, even mild seizures, may cause
additive harm to the embryo/fetus
✽ Lack of definitive evidence of efficacy for
chronic neuropathic pain or anxiety
Other Warnings/
disorders suggests risk/benefit ratio is in
Precautions favor of discontinuing tiagabine during
• Depressive effects may be increased by pregnancy for those indications
other CNS depressants (alcohol, MAOIs,
other anticonvulsants, etc.) Breast Feeding
• Some drug is found in mother’s breast milk

459
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TIAGABINE (continued)

✽ Recommended either to discontinue drug Primary Target Symptoms

or bottle feed • Incidence of seizures
• If drug is continued while breast feeding, • Pain
infant should be monitored for possible • Anxiety
adverse effects
• If infant shows signs of irritability or
sedation, drug may need to be Pearls
discontinued • Well studied in epilepsy
• Much use is off-label
✽ Off-label use second-line and as an
THE ART OF PSYCHOPHARMACOLOGY augmenting agent may be justified for
treatment resistant anxiety disorders and
Potential Advantages neuropathic pain and also for fibromyalgia
• Treatment-resistant chronic neuropathic ✽ Off-label use for bipolar disorder may not
pain be justified
• Treatment-resistant anxiety disorders ✽ One of the few agents that enhances
slow-wave delta sleep, which may be
Potential Disadvantages helpful in chronic neuropathic pain
• May require 2–4 times a day dosing syndromes
• Needs to be taken with food

Suggested Reading
Backonja NM. Use of anticonvulsants for Schmidt D, Gram L, Brodie M, Kramer G,
treatment of neuropathic pain. Neurology 2002 Perucca E, Kalviainen R, Elger CE. Tiagabine in
10;59(Suppl 2):S14–7. the treatment of epilepsy—a clinical review
with a guide for the prescribing physician.
Carta MG, Hardoy MC, Grunze H, Carpiniello Epilepsy Res. 2000; 41: 245–51.
B. The use of tiagabine in affective disorders.
Pharmacopsychiatry 2002;35:33–4. Stahl SM. Psychopharmacology of
anticonvulsants: do all anticonvulsants have
Evans EA. Efficacy of newer anticonvulsant the same mechanism of action? J Clin
medications in bipolar spectrum mood Psychiatry. 2004;65:149–50.
disorders. J Clin Psychiatry 2003;64(Suppl
8):9–14. Stahl SM. Anticonvulsants as anxiolytics, part
1: tiagabine and other anticonvulsants with
Lydiard RB. The role of GABA in anxiety actions on GABA. J Clin Psychiatry.
disorders. J Clin Psychiatry 2003;64(Suppl 2004;65:291–2.
3):21–7.

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TIANEPTINE
THERAPEUTICS others persist (especially insomnia, fatigue,
and problems concentrating)
Brands • Coaxil • Other patients may be nonresponders,
• Stablon sometimes called treatment-resistant or
see index for additional brand names treatment-refractory
• Consider increasing dose, switching to
Generic? No
another agent or adding an appropriate
augmenting agent
• Consider psychotherapy
Class • Consider evaluation for another diagnosis
• Tricyclic antidepressant or for a comorbid condition (e.g., medical
• Serotonin reuptake enhancer illness, substance abuse, etc.)

Commonly Prescribed For Best Augmenting Combos

(bold for FDA approved) for Partial Response or
• Major depressive disorder Treatment-Resistance
• Dysthymia • Augmentation has not been systematically
• Anxiety associated with depression, alcohol studied with tianeptine
dependence
Tests
• None for healthy individuals
How The Drug Works ✽ Since other tricyclic and tetracyclic
antidepressants are frequently associated
✽ Possibly increases serotonin uptake, but with weight gain, it is possible that this
could also act similarly to agents that block
may also be the case for tianeptine; thus,
serotonin reuptake
before starting treatment, weigh all patients
How Long Until It Works and determine if the patient is already
• Onset of therapeutic actions usually not overweight (BMI 25.0–29.9) or obese
immediate, but often delayed 2 to 4 weeks (BMI ≥30)
• If it is not working within 6 to 8 weeks for • Before giving a drug that can cause weight
depression, it may require a dosage gain to an overweight or obese patient,
increase or it may not work at all consider determining whether the patient
• May continue to work for many years to already has pre-diabetes (fasting plasma
prevent relapse of symptoms glucose 100–125 mg/dl), diabetes (fasting
plasma glucose >126 mg/dl), or
If It Works dyslipidemia (increased total cholesterol,
• The goal of treatment is complete LDL cholesterol and triglycerides;
remission of current symptoms as well as decreased HDL cholesterol), and treat or
prevention of future relapses refer such patients for treatment, including
• Treatment most often reduces or even nutrition and weight management, physical
eliminates symptoms, but not a cure since activity counseling, smoking cessation, and
symptoms can recur after medicine medical management
stopped ✽ Monitor weight and BMI during treatment
• Continue treatment until all symptoms are ✽ While giving a drug to a patient who has
gone (remission) gained >5% of initial weight, consider
• Once symptoms gone, continue treating for evaluating for the presence of pre-diabetes,
1 year for the first episode of depression diabetes, or dyslipidemia, or consider
• For second and subsequent episodes of switching to a different antidepressant
depression, treatment may need to be • Theoretically, by analogy with other TCAs,
indefinite EKGs may be useful for selected patients
(e.g., those with personal or family history
If It Doesn’t Work of QTc prolongation; cardiac arrhythmia;
• Many patients only have a partial response recent myocardial infarction;
where some symptoms are improved but uncompensated heart failure; or taking
agents that prolong QTc interval such as

461
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TIANEPTINE (continued)

pimozide, thioridazine, selected What To Do About Side Effects

antiarrhythmics, moxifloxacin, sparfloxacin, • Wait
etc.) • Wait
• On a theoretical basis and by analogy with • Wait
other TCAs, patients at risk for electrolyte • Lower the dose
disturbances (e.g., patients on diuretic • In a few weeks, switch or add other drugs
therapy) should have baseline and periodic
serum potassium and magnesium Best Augmenting Agents for Side
measurements Effects
• Augmentation for side effects of tianeptine
has not been systematically studied
SIDE EFFECTS
How Drug Causes Side Effects DOSING AND USE
✽ Mild anticholinergic activity (less than
some other tricyclic antidepressants) could Usual Dosage Range
possibly lead to sedative effects, dry • 25–50 mg/day
mouth, constipation, and blurred vision
• Most side effects are immediate but often Dosage Forms
go away with time • Tablet 12.5 mg
✽ Pharmacologic studies indicate tianeptine
may not be a potent alpha 1antagonist or How to Dose
H1 antihistamine • 12.5 mg 3 times/day
• Theoretically, cardiac arrhythmias and
seizures, especially in overdose, may be
caused by blockade of ion channels Dosing Tips
• Tianeptine’s rapid elimination necessitates
Notable Side Effects strict adherence to the dosing schedule
• Headache, dizziness, insomnia, sedation ✽ Short half-life means multiple daily doses
• Nausea, constipation, abdominal pain, dry ✽ Although tianeptine has a tricyclic
mouth structure, it is dosed lower than usual TCA
• Abnormal dreams dosing
• Rare hepatotoxicity
• Tachycardia Overdose
• Effects are generally mild and nonfatal;
Life Threatening or unlikely to cause cardiovascular effects
Dangerous Side Effects Long-Term Use
• Theoretically, lowered seizure threshold • Safe
and rare seizures
• Theoretically, rare induction of mania and Habit Forming
activation of suicidal ideation • No
• Theoretically, could prolong QTc interval,
but not well-studied How to Stop
• Taper to avoid withdrawal symptoms
Weight Gain • Many patients tolerate 50% dose reduction
for 3 days, then another 50% reduction for
3 days, then discontinuation
• Not well studied • If withdrawal symptoms emerge during
discontinuation, raise dose to stop
Sedation symptoms and then restart withdrawal
much more slowly

• Occurs in significant minority

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(continued) TIANEPTINE

Pharmacokinetics Do Not Use

• Not primarily metabolized by CYP 450 • If patient is taking an MAO inhibitor
enzyme system • If patient is pregnant or nursing
• Tianeptine is rapidly eliminated • On a theoretical basis, if patient is taking
• Half-life approximately 3 hours agents capable of significantly prolonging
QTc interval (e.g., pimozide, thioridazine,
selected antiarrhythmics, moxifloxacin,
Drug Interactions sparfloxacin)
• Tramadol increases the risk of seizures in • On a theoretical basis, if there is a history
patients taking TCAs of QTc prolongation or cardiac arrhythmia,
• Activation and agitation, especially following recent acute myocardial infarction,
switching or adding antidepressants, may uncompensated heart failure
represent the induction of a bipolar state, • If there is a proven allergy to tianeptine
especially a mixed dysphoric bipolar II
condition sometimes associated with
suicidal ideation, and require the addition SPECIAL POPULATIONS
of lithium, a mood stabilizer or an atypical
antipsychotic, and/or discontinuation of Renal Impairment
tianeptine • Dose should be reduced for severe
• Other drug interactions not well-studied impairment to 25 mg/day
• Dose reduction not necessary for patients
on hemodialysis
Other Warnings/
Precautions Hepatic Impairment
• Add or initiate other antidepressants with • No dose adjustment necessary
caution for up to 2 weeks after
discontinuing tianeptine Cardiac Impairment
• For elective surgery, tianeptine should be • No dose adjustment necessary
stopped 24–48 hours before general • Safety of tianeptine in patients with cardiac
anesthesia is administered impairment has not been specifically
• Generally, do not use with MAO inhibitors, demonstrated
including 14 days after MAOIs are stopped; • TCAs have been reported to cause
do not start an MAOI until 2 weeks after arrhythmias, prolongation of conduction
discontinuing tianeptine time, orthostatic hypotension, sinus
• Although not well studied for tianeptine, tachycardia, and heart failure, especially in
other TCAs can prolong QTc interval, the diseased heart
especially at toxic doses, potentially • Myocardial infarction and stroke have been
causing torsade de pointes-type arrhythmia reported with TCAs
or sudden death; this has not been • TCAs produce QTc prolongation, which
reported specifically for tianeptine may be enhanced by the existence of
• Because other TCAs can prolong QTc bradycardia, hypokalemia, congenital or
interval, use with caution in patients who acquired long QTc interval, which should
have bradycardia or who are taking drugs be evaluated prior to administering
that can induce bradycardia (e.g., beta tianeptine
blockers, calcium channel blockers, • Avoid TCAs in patients with a known
clonidine, digitalis) history of QTc prolongation, recent acute
• Because other TCAs can prolong QTc myocardial infarction, and uncompensated
interval, use with caution in patients who heart failure
have hypokalemia and/or hypomagnesemia • TCAs may cause a sustained increase in
or who are taking drugs that can induce heart rate in patients with ischemic heart
hypokalemia and/or magnesemia (e.g., disease and may worsen (decrease) heart
diuretics, stimulant laxatives, intravenous rate variability, an independent risk of
amphotericin B, glucocorticoids, mortality in cardiac populations
tetracosactide) ✽ Risk/benefit ratio may not justify use of
TCAs in cardiac impairment

463
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TIANEPTINE (continued)

Elderly • Must weigh benefits of breast feeding with

• Dose should be reduced to 25 mg/day risks and benefits of antidepressant
treatment versus non-treatment to both the
infant and the mother
Children and Adolescents • For many patients, this may mean
• Use with caution, observing for activation continuing treatment during breast feeding
of known or unknown bipolar disorder
and/or suicidal ideation, and strongly
consider informing parents or guardian of THE ART OF PSYCHOPHARMACOLOGY
this risk so they can help observe child or
adolescent patients Potential Advantages
• Has been used successfully to treat • Elderly patients
asthmatic symptoms in children • Alcohol withdrawal
• Not recommended for use under age 15
Potential Disadvantages
• Patients who have difficulty being
compliant with multiple daily dosing
Pregnancy
• Risk Category not formally assessed by the Primary Target Symptoms
US FDA • Depressed mood
• Not recommended for use during • Symptoms of anxiety
pregnancy

Breast Feeding
• Some drug is found in mother’s breast milk
Pearls
✽ Not recommended for use during ✽ Possibly a unique mechanism of action
pregnancy • However, mechanism of action not well
• Immediate postpartum period is a high-risk understood
time for depression, especially in women • Not marketed widely throughout the world,
who have had prior depressive episodes, but mostly in France
so drug may need to be reinstituted late in ✽ Effects on QTc prolongation not
the third trimester or shortly after systematically studied
childbirth to prevent a recurrence during
the postpartum period

Suggested Reading
Ginestet D. Efficacy of tianeptine in major Wilde MI, Benfield P. Tianeptine. A review of
depressive disorders with or without its pharmacodynamic and pharmacokinetic
melancholia. Eur Neuropsychopharmacol properties, and therapeutic efficacy in
1997;7 Suppl 3:S341–5. depression and coexisting anxiety and
depression. Drugs 1995;49(3):411–39.
Wagstaff AJ, Ormrod D, Spencer CM.
Tianeptine: a review of its use in depressive
disorders. CNS Drugs 2001;15(3):231–59.

464
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TOPIRAMATE
THERAPEUTICS • Continue treatment indefinitely to avoid
recurrence of mania, seizures, and
Brands • Topamax headaches
• Epitomax
• Topamac If It Doesn’t Work (for bipolar
• Topimax disorder)
see index for additional brand names
✽ May only be effective in a subset of
bipolar patients, in some patients who fail
Generic? No
to respond to other mood stabilizers, or it
may not work at all
✽ Consider increasing dose or switching to
Class another agent with better demonstrated
• Anticonvulsant, voltage-sensitive sodium efficacy in bipolar disorder
channel modulator
Best Augmenting Combos
Commonly Prescribed For for Partial Response or
(bold for FDA approved) Treatment-Resistance
• Partial onset seizures (adjunctive; adults • Topiramate is itself a second-line
and pediatric patients 2–16 years of age) augmenting agent for numerous other
• Primary generalized tonic-clonic seizures anticonvulsants, lithium, and
(adjunctive; adults and pediatric patients antipsychotics in treating bipolar disorder
2–16 years of age)
• Seizures associated with Lennox-Gastaut Tests
Syndrome (2 years of age or older) ✽ Baseline and periodic serum bicarbonate
• Migraine prophylaxis levels to monitor for hyperchloremic, non-
• Bipolar disorder (adjunctive; no longer in anion gap metabolic acidosis (i.e.,
development) decreased serum bicarbonate below the
• Psychotropic drug-induced weight gain normal reference range in the absence of
• Binge-eating disorder chronic respiratory alkalosis)

How The Drug Works SIDE EFFECTS

✽ Blocks voltage-sensitive sodium channels
by an unknown mechanism How Drug Causes Side Effects
• Inhibits release of glutamate • CNS side effects theoretically due to
• Potentiates activity of gamma-aminobutyric excessive actions at voltage-sensitive
acid (GABA) sodium channels
• Carbonic anhydrase inhibitor • Weak inhibition of carbonic anhydrase may
lead to kidney stones and paresthesias
How Long Until It Works • Inhibition of carbonic anhydrase may also
• Should reduce seizures by 2 weeks lead to metabolic acidosis
• Not clear that it has mood stabilizing
properties, but some bipolar patients may Notable Side Effects
respond and if so, it may take several ✽ Sedation, asthenia, dizziness, ataxia,
weeks to months to optimize an effect on parasthesia, nervousness, nystagmus,
mood stabilization tremor
✽ Nausea, appetite loss, weight loss
If It Works • Blurred or double vision, mood problems,
• The goal of treatment is complete problems concentrating, confusion,
remission of symptoms (e.g., mania, memory problems, psychomotor
seizures, migraine) retardation, language problems, speech
• Continue treatment until all symptoms are problems, fatigue, taste perversion
gone or until improvement is stable and
then continue treating indefinitely as long
as improvement persists

465
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TOPIRAMATE (continued)

doses; maximum dose generally

Life Threatening or 1600 mg/day
Dangerous Side Effects • Seizures (ages 2–16): see Children and
✽ Metabolic acidosis Adolescents
✽ Kidney stones
• Secondary narrow angle-closure glaucoma
• Oligohidrosis and hyperthermia (more Dosing Tips
common in children)
• Adverse effects may increase as dose
• Sudden unexplained deaths have occurred
increases
in epilepsy (unknown if related to
• Topiramate is available in a sprinkle
topiramate use)
capsule formulation, which can be
Weight Gain swallowed whole or sprinkled over
approximately a teaspoon of soft food
(e.g., applesauce); the mixture should be
consumed immediately
• Reported but not expected • Bipolar patients are generally administered
✽ Patients may experience weight loss doses at the lower end of the dosing range
• Slow upward titration from doses as low as
Sedation 25 mg/day can reduce the incidence of
unacceptable sedation
• Many bipolar patients do not tolerate more
• Many experience and/or can be significant than 200 mg/day
in amount ✽ Weight loss is dose-related but most
patients treated for weight gain receive
What To Do About Side Effects doses at the lower end of the dosing range
• Wait
• Wait Overdose
• Wait • No fatalities have been reported in
• Take at night to reduce daytime sedation monotherapy; convulsions, sedation,
• Increase fluid intake to reduce the risk of speech disturbance, blurred or double
kidney stones vision, metabolic acidosis, impaired
• Switch to another agent coordination, hypotension, abdominal pain,
agitation, dizziness
Best Augmenting Agents for Side
Effects Long-Term Use
• Many side effects cannot be improved with • Probably safe
an augmenting agent • Periodic monitoring of serum bicarbonate
levels may be required

Habit Forming
DOSING AND USE • No
Usual Dosage Range How to Stop
• Adults: 200–400 mg/day in 2 divided doses • Taper
for epilepsy; 50–300 mg/day for adjunctive • Epilepsy patients may seize upon
treatment of bipolar disorder withdrawal, especially if withdrawal is
abrupt
Dosage Forms
• Tablet 25 mg, 100 mg, 200 mg
✽ Rapid discontinuation may increase the
risk of relapse in bipolar patients
• Sprinkle capsule 15 mg, 25 mg
✽ Discontinuation symptoms uncommon
How to Dose Pharmacokinetics
• Adults: initial 25–50 mg/day; increase each • Elimination half-life approximately 21 hours
week by 50 mg/day; administer in 2 divided • Renally excreted

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(continued) TOPIRAMATE

Hepatic Impairment
• Drug should be used with caution
Drug Interactions
• Carbamazepine, phenytoin, and valproate Cardiac Impairment
may increase the clearance of topiramate, • Drug should be used with caution
and thus decrease topiramate levels,
possibly requiring a higher dose of Elderly
topiramate • Elderly patients may be more susceptible
• Topiramate may increase the clearance of to adverse effects
phenytoin and thus decrease phenytoin
levels, possibly requiring a higher dose of
phenytoin Children and Adolescents
• Topiramate may increase the clearance of
• Approved for use in children age 2 and
valproate and thus decrease valproate
older for treatment of seizures
levels, possibly requiring a higher dose of
• Clearance is increased in pediatric patients
valproate
• Seizures (ages 2–16): initial 1–3 mg/kg/day
• Topiramate may increase plasma levels of
at night; after 1 week increase by
metformin; also, metformin may reduce
1–3 mg/kg/day every 1–2 weeks with total
clearance of topiramate and increase
daily dose administered in 2 divided doses;
topiramate levels
recommended dose generally
• Topiramate may interact with carbonic
5–9 mg/kg/day in 2 divided doses
anhydrase inhibitors to increase the risk of
kidney stones
• Topiramate may reduce the effectiveness of
oral contraceptives Pregnancy
• Risk category C [some animal studies
show adverse effects, no controlled studies
Other Warnings/ in humans]
Precautions • Use in women of childbearing potential
✽ If symptoms of metabolic acidosis requires weighing potential benefits to the
develop (hyperventilation, fatigue, anorexia, mother against the risks to the fetus
cardiac arrhythmias, stupor), then dose • Hypospadia has occurred in some male
may need to be reduced or treatment may infants whose mothers took topiramate
need to be discontinued during pregnancy
• Depressive effects may be increased by ✽ Lack of convincing efficacy for treatment
other CNS depressants (alcohol, MAOIs, of bipolar disorder suggests risk/benefit
other anticonvulsants, etc.) ratio is in favor of discontinuing topiramate
• Use with caution when combining with in bipolar patients during pregnancy
other drugs that predispose patients to ✽ For bipolar patients, topiramate should
heat-related disorders, including carbonic generally be discontinued before
anhydrase inhibitors and anticholinergics anticipated pregnancies
• Taper drug if discontinuing
Do Not Use ✽ For bipolar patients, given the risk of
• If there is a proven allergy to topiramate relapse in the postpartum period, mood
stabilizer treatment, especially with agents
with better evidence of efficacy than
SPECIAL POPULATIONS topiramate, should generally be restarted
immediately after delivery if patient is
Renal Impairment unmedicated during pregnancy
• Topiramate is renally excreted, so the dose ✽ Atypical antipsychotics may be preferable
should be lowered by half to topiramate if treatment of bipolar
• Can be removed by hemodialysis; patients disorder is required during pregnancy
receiving hemodialysis may require • Bipolar symptoms may recur or worsen
supplemental doses of topiramate during pregnancy and some form of
treatment may be necessary

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TOPIRAMATE (continued)

• Seizures, even mild seizures, may cause • Some anecdotes, case series, and open-
harm to the embryo/fetus label studies have been published and are
widely known suggesting efficacy in bipolar
Breast Feeding disorder
• Some drug is found in mother’s breast milk ✽ However, randomized clinical trials do not
✽ Recommended either to discontinue drug suggest efficacy in bipolar disorder;
or bottle feed unfortunately these important studies have
• If drug is continued while breast feeding, not been published by the manufacturer,
infant should be monitored for possible who has dropped topiramate from further
adverse effects development as a mood stabilizer, though
• If infant shows signs of irritability or this is not widely known
sedation, drug may need to be ✽ Misperceptions about topiramate’s
discontinued efficacy in bipolar disorder have led to its
✽ Bipolar disorder may recur during the use in more patients than other agents with
postpartum period, particularly if there is a proven efficacy, such as lamotrigine
history of prior postpartum episodes of ✽ Due to reported weight loss in some
either depression or psychosis patients in trials with epilepsy, topiramate
✽ Relapse rates may be lower in women is commonly used to treat weight gain,
who receive prophylactic treatment for especially in patients with psychotropic
postpartum episodes of bipolar disorder drug-induced weight gain
• Atypical antipsychotics and anticonvulsants ✽ Weight loss in epilepsy patients is dose
such as valproate may be safer and more related with more weight loss at high
effective than topiramate during the doses (mean 6.5 kg or 7.3% decline) and
postpartum period when treating nursing less weight loss at lower doses (mean
mother with bipolar disorder 1.6 kg or 2.2% decline)
✽ Changes in weight were greatest in
epilepsy patients who weighed the most at
THE ART OF PSYCHOPHARMACOLOGY baseline (>100 kg), with mean loss of
9.6 kg or 8.4% decline, while those
Potential Advantages weighing <60 kg had only a mean loss of
• Treatment-resistant bipolar disorder 1.3 kg or 2.5% decline
• Patients who wish to avoid weight gain ✽ Long-term studies demonstrate that
weight losses in epilepsy patients were
Potential Disadvantages seen within the first 3 months of treatment
• Efficacy in bipolar disorder uncertain and peaked at a mean of 6 kg after 12 to
• Patients with a history of kidney stones or 18 months of treatment; however, weight
risks for metabolic acidosis tended to return to pretreatment levels
after 18 months
Primary Target Symptoms ✽ Some patients with psychotropic drug-
• Incidence of seizures induced weight gain may experience
• Unstable mood significant weight loss (>7% of body
weight) with topiramate up to 200 mg/day
for 3 months, but this is not typical, is not
Pearls often sustained, and has not been
• Side effects may actually occur less often systemically studied
in pediatric patients • Early studies suggest potential efficacy in
• Has been studied in a wide range of binge-eating disorder
psychiatric disorders, including bipolar
disorder, posttraumatic stress disorder,
binge-eating disorder, obesity and others

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(continued) TOPIRAMATE

Suggested Reading
Chengappa KR, Gershon S, Levine J. The Shank RP, Gardocki JF, Streeter AJ, Maryanoff
evolving role of topiramate among other mood BE. An overview of the preclinical aspects of
stabilizers in the management of bipolar topiramate: pharmacology, pharmacokinetics,
disorder. Bipolar Disord. 2001; 3: 215–232. and mechanism of action. Epilepsia. 2000; 41
(Suppl 1): S3–9.
Ormrod D, McClellan K. Topiramate: a review
of its use in childhood epilepsy. Paediatr Suppes T. Review of the use of topiramate for
Drugs. 2001; 3: 293–319. treatment of bipolar disorders. J Clin
Psychopharmacol 2002;22:599–609.
MacDonald KJ, Young LT. Newer antiepileptic
drugs in bipolar disorder. CNS Drugs
2002;16:549–62.

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TRANYLCYPROMINE
THERAPEUTICS • For second and subsequent episodes of
depression, treatment may need to be
Brands • Parnate indefinite
see index for additional brand names • Use in anxiety disorders may also need to
be indefinite
Generic? Not in U.S.
If It Doesn’t Work
• Many patients only have a partial response
Class where some symptoms are improved but
• Monoamine oxidase inhibitor (MAOI) others persist (especially insomnia, fatigue,
and problems concentrating)
Commonly Prescribed For • Other patients may be nonresponders,
(bold for FDA approved) sometimes called treatment-resistant or
• Major depressive episode without treatment-refractory
melancholia • Some patients who have an initial response
• Treatment-resistant depression may relapse even though they continue
• Treatment-resistant panic disorder treatment, sometimes called “poop-out”
• Treatment-resistant social anxiety disorder • Consider increasing dose, switching to
another agent or adding an appropriate
augmenting agent
How The Drug Works • Consider psychotherapy
• Irreversibly blocks monoamine oxidase • Consider evaluation for another diagnosis
(MAO) from breaking down or for a comorbid condition (e.g., medical
norepinephrine, serotonin, and dopamine illness, substance abuse, etc.)
• This presumably boosts noradrenergic, • Some patients may experience apparent
serotonergic, and dopaminergic lack of consistent efficacy due to activation
neurotransmission of latent or underlying bipolar disorder, and
✽ As the drug is structurally related to require antidepressant discontinuation and
amphetamine, it may have some stimulant- a switch to a mood stabilizer
like actions due to monoamine release and
reuptake inhibition Best Augmenting Combos
for Partial Response or
How Long Until It Works Treatment-Resistance
• Some patients may experience stimulant- ✽ Augmentation of MAOIs has not been
like actions early in dosing systematically studied, and this is
• Onset of therapeutic actions usually not something for the expert, to be done with
immediate, but often delayed 2 to 4 weeks caution and with careful monitoring
• If it is not working within 6 to 8 weeks, it ✽ A stimulant such as d-amphetamine or
may require a dosage increase or it may methylphenidate (with caution; may
not work at all activate bipolar disorder and suicidal
• May continue to work for many years to ideation; may elevate blood pressure)
prevent relapse of symptoms • Lithium
• Mood stabilizing anticonvulsants
If It Works • Atypical antipsychotics (with special
• The goal of treatment is complete caution for those agents with monoamine
remission of current symptoms as well as reuptake blocking properties, such as
prevention of future relapses ziprasidone and zotepine)
• Treatment most often reduces or even
eliminates symptoms, but not a cure since Tests
symptoms can recur after medicine • Patients should be monitored for changes
stopped in blood pressure
• Continue treatment until all symptoms are • Patients receiving high doses or long-term
gone (remission) treatment should have hepatic function
• Once symptoms gone, continue treating for evaluated periodically
1 year for the first episode of depression

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TRANYLCYPROMINE (continued)

SIDE EFFECTS • Switch after appropriate washout to an

SSRI or newer antidepressant
How Drug Causes Side Effects
• Theoretically due to increases in Best Augmenting Agents for Side
monoamines in parts of the brain and body Effects
and at receptors other than those that • Trazodone (with caution) for insomnia
cause therapeutic actions (e.g., unwanted • Benzodiazepines for insomnia
actions of serotonin in sleep centers
causing insomnia, unwanted actions of
✽ Single oral or sublingual dose of a
calcium channel blocker (e.g., nifedipine)
norepinephrine on vascular smooth muscle for urgent treatment of hypertension due to
causing hypertension, etc.) drug interaction or dietary tyramine
• Side effects are generally immediate, but • Many side effects cannot be improved with
immediate side effects often disappear in an augmenting agent
time

Notable Side Effects

• Agitation, anxiety, insomnia, weakness, DOSING AND USE
sedation, dizziness
• Constipation, dry mouth, nausea, diarrhea,
Usual Dosage Range
change in appetite, weight gain • 30 mg/day in divided doses
• Sexual dysfunction
Dosage Forms
• Orthostatic hypotension (dose-related);
• Tablet 10 mg
syncope may develop at high doses
How to Dose
Life Threatening or • Initial 30 mg/day in divided doses; after
Dangerous Side Effects 2 weeks increase by 10 mg/day each
• Hypertensive crisis (especially when MAOIs 1–3 weeks; maximum 60 mg/day
are used with certain tyramine-containing
foods or prohibited drugs)
• Induction of mania and activation of Dosing Tips
suicidal ideation • Orthostatic hypotension, especially at high
• Seizures doses, may require splitting into 3–4 daily
• Hepatotoxicity doses
• Patients receiving high doses may need to
Weight Gain be evaluated periodically for effects on the
liver

• Occurs in significant minority

Overdose
• Dizziness, sedation, ataxia, headache,
Sedation insomnia, restlessness, anxiety, irritability;
cardiovascular effects, confusion,
respiratory depression, or coma may also
occur
• Many experience and/or can be significant
in amount Long-Term Use
• Can also cause activation • May require periodic evaluation of hepatic
function
What To Do About Side Effects • MAOIs may lose efficacy long-term
• Wait
• Wait Habit Forming
• Wait • Some patients have developed dependence
• Lower the dose to MAOIs
• Take at night if daytime sedation; take in
daytime if overstimulated at night

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(continued) TRANYLCYPROMINE

How to Stop protein breakdown by aging, fermentation,

• Generally no need to taper, as the drug pickling, smoking, or bacterial
wears off slowly over 2–3 weeks contamination
• Patients taking MAO inhibitors should
Pharmacokinetics avoid cheeses (especially aged varieties),
• Clinical duration of action may be up to 21 pickled herring, beer, wine, liver, yeast
days due to irreversible enzyme inhibition extract, dry sausage, hard salami,
pepperoni, Lebanon bologna, pods of
broad beans (fava beans), yogurt, and
Drug Interactions excessive use of caffeine and chocolate
• Tramadol may increase the risk of seizures • Patient and prescriber must be vigilant to
in patients taking an MAO inhibitor potential interactions with any drug,
• Can cause a fatal “serotonin syndrome” including antihypertensives and over-the-
when combined with drugs that block counter cough/cold preparations
serotonin reuptake (e.g., SSRIs, SNRIs, • Over-the-counter medications to avoid
sibutramine, tramadol, etc.), so do not use include cough and cold preparations,
with a serotonin reuptake inhibitor or for including those containing
up to 5 weeks after stopping the serotonin dextromethorphan, nasal decongestants
reuptake inhibitor (tablets, drops, or spray), hay-fever
• Hypertensive crisis with headache, medications, sinus medications, asthma
intracranial bleeding, and death may result inhalant medications, anti-appetite
from combining MAO inhibitors with medications, weight reducing preparations,
sympathomimetic drugs (e.g., “pep” pills
amphetamines, methylphenidate, cocaine, • Hypoglycemia may occur in diabetic
dopamine, epinephrine, norepinephrine, and patients receiving insulin or oral
related compounds methyldopa, levodopa, antidiabetic agents
L-tryptophan, L-tyrosine, and phenylalanine • Use cautiously in patients receiving
• Excitation, seizures, delirium, hyperpyrexia, reserpine, anesthetics, disulfiram,
circulatory collapse, coma, and death may metrizamide, anticholinergic agents
result from combining MAO inhibitors with • Tranylcypromine is not recommended for
mepiridine or dextromethorphan use in patients who cannot be monitored
• Do not combine with another MAO closely
inhibitor, alcohol, buspirone, bupropion, or • Monitor patients for activation of suicidal
guanethidine ideation, especially children and
• Adverse drug reactions can result from adolescents
combining MAO inhibitors with
tricyclic/tetracyclic antidepressants and
Do Not Use
related compounds, including • If patient is taking meperidine (pethidine)
carbamazepine, cyclobenzaprine, and • If patient is taking a sympathomimetic
mirtazapine, and should be avoided except agent or taking guanethidine
by experts to treat difficult cases • If patient is taking another MAOI
• MAO inhibitors in combination with spinal • If patient is taking any agent that can
anesthesia may cause combined inhibit serotonin reuptake (e.g., SSRIs,
hypotensive effects sibutramine, tramadol, milnacipran,
• Combination of MAOIs and CNS duloxetine, venlafaxine, clomipramine, etc.)
depressants may enhance sedation and • If patient is taking diuretics,
hypotension dextromethorphan, buspirone, bupropion
• If patient has pheochromocytoma
• If patient has cardiovascular or
Other Warnings/ cerebrovascular disease
Precautions • If patient has frequent or severe headaches
• Use requires low tyramine diet • If patient is undergoing elective surgery
• Patients taking MAO inhibitors should and requires general anesthesia
avoid high protein food that has undergone • If patient has a history of liver disease or
abnormal liver function tests

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TRANYLCYPROMINE (continued)

• If patient is taking a prohibited drug • Immediate postpartum period is a high-risk

• If patient is not compliant with a low- time for depression, especially in women
tyramine diet who have had prior depressive episodes,
• If there is a proven allergy to so drug may need to be reinstituted late in
tranylcypromine the third trimester or shortly after
childbirth to prevent a recurrence during
the postpartum period
SPECIAL POPULATIONS • Should evaluate patient for treatment with
an antidepressant with a better risk/benefit
Renal Impairment ratio
• Use with caution – drug may accumulate in
plasma
• May require lower than usual adult dose THE ART OF PSYCHOPHARMACOLOGY
Hepatic Impairment Potential Advantages
• Tranylcypromine should not be used in • Atypical depression
patients with history of hepatic impairment • Severe depression
or in patients with abnormal liver function • Treatment-resistant depression or anxiety
tests disorders
Cardiac Impairment Potential Disadvantages
• Contraindicated in patients with any cardiac • Requires compliance to dietary restrictions,
impairment concomitant drug restrictions
• Patients with cardiac problems or
Elderly hypertension
• Initial dose lower than usual adult dose • Multiple daily doses
• Elderly patients may have greater
sensitivity to adverse effects Primary Target Symptoms
• Depressed mood
• Somatic symptoms
Children and Adolescents • Sleep and eating disturbances
• Not generally recommended for use under • Psychomotor retardation
age 18 • Morbid preoccupation
• Use with caution, observing for activation
of known or unknown bipolar disorder
and/or suicidal ideation, and strongly Pearls
consider informing parents or guardian of • MAOIs are generally reserved for second-
this risk so they can help observe child or line use after SSRIs, SNRIs, and
adolescent patients combinations of newer antidepressants
have failed
• Patient should be advised not to take any
Pregnancy prescription or over-the-counter drugs
• Risk Category C [some animal studies without consulting their doctor because of
show adverse effects, no controlled studies possible drug interactions with the MAOI
in humans] • Headache is often the first symptom of
• Not generally recommended for use during hypertensive crisis
pregnancy, especially during first trimester • Foods generally to avoid as they are
• Should evaluate patient for treatment with usually high in tyramine content: dry
an antidepressant with a better risk/benefit sausage, pickled herring, liver, broad bean
ratio pods, sauerkraut, cheese, yogurt, alcoholic
beverages, nonalcoholic beer and wine,
Breast Feeding chocolate, caffeine, meat and fish
• Some drug is found in mother’s breast milk • The rigid dietary restrictions may reduce
• Effects on infant unknown compliance

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(continued) TRANYLCYPROMINE

• Mood disorders can be associated with antidepressant other than clomipramine

eating disorders (especially in adolescent simultaneously with an MAO inhibitor for
females), and tranylcypromine can be used patients who fail to respond to numerous
to treat both depression and bulimia other antidepressants
• MAOIs are a viable second-line treatment • Use of MAOIs with clomipramine is always
option in depression, but are not frequently prohibited because of the risk of serotonin
used syndrome and death
✽ Myths about the danger of dietary • Amoxapine may be the preferred
tyramine can be exaggerated, but trycyclic/tetracyclic antidepressant to
prohibitions against concomitant drugs combine with an MAOI in heroic cases due
often not followed closely enough to its theoretically protective 5HT2A
• Orthostatic hypotension, insomnia, and antagonist properties
sexual dysfunction are often the most • If this option is elected, start the MAOI with
troublesome common side effects the tricyclic/tetracyclic antidepressant
✽ MAOIs should be for the expert, simultaneously at low doses after
especially if combining with agents of appropriate drug washout, then alternately
potential risk (e.g., stimulants, trazodone, increase doses of these agents every few
TCAs) days to a week as tolerated
✽ MAOIs should not be neglected as • Although very strict dietary and
therapeutic agents for the treatment- concomitant drug restrictions must be
resistant observed to prevent hypertensive crises
• Although generally prohibited, a heroic but and serotonin syndrome, the most
potentially dangerous treatment for common side effects of MAOI and
severely treatment-resistant patients is for tricyclic/tetracyclic combinations may be
an expert to give a tricyclic/tetracyclic weight gain and orthostatic hypotension

Suggested Reading
Baker GB, Coutts RT, McKenna KF, Sherry- Lippman SB, Nash K. Monoamine oxidase
McKenna RL. Insights into the mechanisms of inhibitor update. Potential adverse food and
action of the MAO inhibitors phenelzine and drug interactions. Drug Saf 1990;5:195–204.
tranylcypromine: a review. J Psychiatry
Neurosci 1992;17:206–14. Thase ME, Triyedi MH, Rush AJ. MAOIs in the
contemporary treatment of depression.
Kennedy SH. Continuation and maintenance Neuropsychopharmacology 1995;12:185–219.
treatments in major depression: the neglected
role of monoamine oxidase inhibitors. J
Psychiatry Neurosci 1997;22:127–31.

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TRAZODONE
THERAPEUTICS • Treatment most often reduces or even
eliminates symptoms of depression, but is
Brands • Desyrel not a cure since symptoms can recur after
see index for additional brand names medicine stopped
• Continue treatment until all symptoms of
Generic? Yes
depression are gone (remission)
• Once symptoms of depression are gone,
continue treating for 1 year for the first
Class episode of depression
• SARI (serotonin 2 antagonist/reuptake • For second and subsequent episodes of
inhibitor); antidepressant; hypnotic depression, treatment may need to be
indefinite
Commonly Prescribed For
(bold for FDA approved) If It Doesn’t Work
• Depression • For insomnia, try escalating doses or
• Insomnia (primary and secondary) switch to another agent
• Anxiety • Many patients only have a partial
antidepressant response where some
symptoms are improved but others persist
How The Drug Works (especially insomnia, fatigue, and problems
concentrating)
• Blocks serotonin 2A receptors potently
• Other patients may be nonresponders,
• Blocks serotonin reuptake pump (serotonin
sometimes called treatment-resistant or
transporter) less potently
treatment-refractory
How Long Until It Works • Consider increasing dose, switching to
✽ Onset of therapeutic actions in insomnia another agent or adding an appropriate
augmenting agent for treatment of
are immediate if dosing is correct
• Onset of therapeutic actions in depression depression
usually not immediate, but often delayed • Consider psychotherapy
2 to 4 weeks whether given as an adjunct • Consider evaluation for another diagnosis
to another antidepressant or as a or for a comorbid condition (e.g., medical
monotherapy illness, substance abuse, etc.)
• If it is not working within 6 to 8 weeks for • Some patients may experience apparent
depression, it may require a dosage lack of consistent efficacy due to activation
increase or it may not work at all of latent or underlying bipolar disorder, and
• May continue to work for many years to require antidepressant discontinuation and
prevent relapse of symptoms in depression a switch to a mood stabilizer
and to reduce symptoms of chronic
Best Augmenting Combos
insomnia
for Partial Response or
If It Works Treatment-Resistance
✽ For insomnia, use possibly can be • Trazodone is not frequently used as a
indefinite as there is no reliable evidence of monotherapy for insomnia, but can be
tolerance, dependence, or withdrawal, but combined with sedative hypnotic
few long-term studies benzodiazepines in difficult cases
• For secondary insomnia, if underlying • Trazodone is most frequently used in
condition (e.g., depression, anxiety depression as an augmenting agent to
disorder) is in remission, trazodone numerous psychotropic drugs
treatment may be discontinued if insomnia • Trazodone can not only improve insomnia
does not reemerge in depressed patients treated with
• The goal of treatment for depression is antidepressants, but can also be an
complete remission of current symptoms effective booster of antidepressant actions
of depression as well as prevention of of other antidepressants (use combinations
future relapses of antidepressants with caution as this may

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TRAZODONE (continued)

activate bipolar disorder and suicidal • Wait

ideation) • Wait
• Trazodone can also improve insomnia in • Take larger dose at night to prevent
numerous other psychiatric conditions daytime sedation
(e.g., bipolar disorder, schizophrenia, • Switch to another agent
alcohol withdrawal) and be added to
numerous other psychotropic drugs (e.g., Best Augmenting Agents for Side
lithium, mood stabilizers, antipsychotics) Effects
• Most side effects cannot be improved with
Tests an augmenting agent
• None for healthy individuals • Activation and agitation may represent the
induction of a bipolar state, especially a
mixed dysphoric bipolar II condition
SIDE EFFECTS sometimes associated with suicidal
ideation, and require the addition of
How Drug Causes Side Effects lithium, a mood stabilizer or an atypical
• Sedative effects may be due to antipsychotic, and/or discontinuation of
antihistamine properties trazodone
• Blockade of alpha adrenergic 1 receptors
may explain dizziness, sedation, and
hypotension DOSING AND USE
• Most side effects are immediate but often
go away with time Usual Dosage Range
• 150–600 mg/day
Notable Side Effects
• Nausea, vomiting, edema, blurred vision, Dosage Forms
constipation, dry mouth • Tablet 50 mg scored, 100 mg scored,
• Dizziness, sedation, fatigue, headache, 150 mg, 150 mg with pividone scored,
incoordination, tremor 300 mg with pividone scored
• Hypotension, syncope
• Occasional sinus bradycardia (long-term) How to Dose
• Rare rash • For depression as a monotherapy, initial
150 mg/day in divided doses; can increase
every 3–4 days by 50 mg/day as needed;
Life Threatening or maximum 400 mg/day (outpatient) or
Dangerous Side Effects 600 mg/day (inpatient), split into 2 daily
• Rare priapism doses
• Rare seizures • For insomnia, initial 25–50 mg at bedtime;
• Rare induction of mania and acivation of increase as tolerated, usually to
suicidal ideation 50–100 mg/day, but some patients may
require up to full antidepressant dose
Weight Gain range
• For augmentation of other antidepressants
in the treatment of depression, dose as
• Reported but not expected recommended for insomnia

Sedation
Dosing Tips
• Start low and go slow
• Many experience and/or can be significant ✽ Patients can have carryover sedation,
in amount ataxia, and intoxicated-like feeling if dosed
too aggressively, particularly when
What To Do About Side Effects initiating dosing
• Wait

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(continued) TRAZODONE

✽ Do not discontinue trials if ineffective at Other Warnings/

low doses (<50 mg) as many patients with
difficult cases may respond to higher
Precautions
doses (150–300 mg, even up to 600 mg in • Possibility of additive effects if trazodone is
some cases) used with other CNS depressants
• For relief of daytime anxiety, can give part • Treatment should be discontinued if
of the dose in the daytime if not too prolonged penile erection occurs because
sedating of the risk of permanent erectile
• Although use as a monotherapy for dysfunction
depression is usually in divided doses due • Advise patients to seek medical attention
to its short half-life, use as an adjunct is immediately if painful erections occur
often effective and best tolerated once daily lasting more than one hour
at bedtime • Generally, priapism reverses
spontaneously, while penile blood flow and
Overdose other signs being monitored, but in urgent
• Rarely lethal; sedation, vomiting, priapism, cases, local phenylephrine injections or
respiratory arrest, seizure, EKG changes even surgery may be indicated
• Use with caution in patients with history of
Long-Term Use seizures
• Safe • Use with caution in patients with bipolar
disorder unless treated with concomitant
Habit Forming mood stabilizing agent
• No • Monitor patients for activation of suicidal
ideation, especially children and
How to Stop adolescents
• Taper is prudent to avoid withdrawal
effects, but tolerance, dependence, and Do Not Use
withdrawal effects have not been reliably • If patient is taking an MAO inhibitor, but
demonstrated see Pearls
• If there is a proven allergy to trazodone
Pharmacokinetics
• Metabolized by CYP450 3A4
• Half-life is biphasic; first phase is SPECIAL POPULATIONS
approximately 3–6 hours; second phase is
approximately 5–9 hours Renal Impairment
• No dose adjustment necessary

Drug Interactions Hepatic Impairment

• Tramadol increases the risk of seizures in • Drug should be used with caution
patients taking an antidepressant
• Fluoxetine and other SSRIs may raise
Cardiac Impairment
trazodone plasma levels • Trazodone may be arrhythmogenic
• Trazodone may block the hypotensive • Monitor patients closely
effects of some anti-hypertensive drugs • Not recommended for use during recovery
• Trazodone may increase digoxin or from myocardial infarction
phenytoin concentrations
Elderly
• Trazodone may interfere with the
• Elderly patients may be more sensitive to
antihypertensive effects of clonidine
adverse effects and may require lower
• Generally, do not use with MAO inhibitors,
doses
including 14 days after MAOIs are stopped
• Reports of increased and decreased
prothrombin time in patients taking
warfarin and trazodone Children and Adolescents
• Use with caution, observing for activation
of known or unknown bipolar disorder

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TRAZODONE (continued)

and/or suicidal ideation, and strongly • As an adjunct to the treatment of residual

consider informing parents or guardian of anxiety and insomnia with other
this risk so they can help observe child or antidepressants
adolescent patients • Depressed patients with anxiety
• Safety and efficacy have not been • Patients concerned about sexual side
established, but trazodone has been used effects or weight gain
for behavioral disturbances, depression,
and night terrors Potential Disadvantages
• Children require lower initial dose and slow • For patients with fatigue, hypersomnia
titration • For patients intolerant to sedating effects
• Boys may be even more sensitive to having
prolonged erections than adult men Primary Target Symptoms
• Depression
• Anxiety
• Sleep disturbances
Pregnancy
• Risk Category C [some animal studies
show adverse effects; no controlled studies
in humans] Pearls
• Avoid use during first trimester • May be less likely than some
• Must weigh the risk of treatment (first antidepressants to precipitate hypomania
trimester fetal development, third trimester or mania
newborn delivery) to the child against the • Preliminary data suggest that trazodone
risk of no treatment (recurrence of may be effective treatment for drug-
depression, maternal health, infant induced dyskinesias, perhaps in part
bonding) to the mother and child because it reduces accompanying anxiety
• For many patients this may mean • Trazodone may have some efficacy in
continuing treatment during pregnancy treating agitation and aggression
associated with dementia
Breast Feeding ✽ May cause sexual dysfunction only
• Some drug is found in mother’s breast milk infrequently
• If child becomes irritable or sedated, breast • Can cause carryover sedation, sometimes
feeding or drug may need to be severe, if dosed too high
discontinued • Often not tolerated as a monotherapy for
• Immediate postpartum period is a high-risk moderate to severe cases of depression, as
time for depression, especially in women many patients cannot tolerate high doses
who have had prior depressive episodes, (>150 mg)
so drug may need to be reinstituted late in • Do not forget to try at high doses, up to
the third trimester or shortly after 600 mg/day, if lower doses well tolerated
childbirth to prevent a recurrence during but ineffective
the postpartum period ✽ For the expert psychopharmacologist,
• Must weigh benefits of breast feeding with trazodone can be used cautiously for
risks and benefits of antidepressant insomnia associated with MAO inhibitors,
treatment versus non-treatment to both the despite the warning – must be attempted
infant and the mother only if patients closely monitored and by
• For many patients, this may mean experts experienced in the use of MAOIs
continuing treatment during breast feeding • Priapism may occur in one in 8,000 men
• Early indications of impending priapism
may be slow penile detumescence when
THE ART OF PSYCHOPHARMACOLOGY awakening from REM sleep
• When using to treat insomnia, remember
Potential Advantages that insomnia may be a symptom of some
• For insomnia when it is preferred to avoid other primary disorder, and not a primary
the use of dependence-forming agents disorder itself, and thus warrant evaluation

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(continued) TRAZODONE

for comorbid psychiatric and/or medical

conditions
• Rarely, patients may complain of visual
“trails” or after-images on trazodone

Suggested Reading
DeVane CL. Differential pharmacology of Rotzinger S, Bourin M, Akimoto Y, Coutts RT,
newer antidepressants. J Clin Psychiatry Baker GB. Metabolism of some “second”- and
1998;59 Suppl 20:85–93. “fourth”-generation antidepressants: iprindole,
viloxazine, bupropion, mianserin, maprotiline,
Haria M, Fitton A, McTavish D. Trazodone. A trazodone, nefazodone, and venlafaxine. Cell
review of its pharmacology, therapeutic use in Mol Neurobiol 1999;19:427–42.
depression and therapeutic potential in other
disorders. Drugs Aging 1994;4:331–55.

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TRIAZOLAM
THERAPEUTICS Tests
• In patients with seizure disorders,
Brands • Halcion
concomitant medical illness, and/or those
see index for additional brand names
with multiple concomitant long-term
Generic? Yes medications, periodic liver tests and blood
counts may be prudent

Class
SIDE EFFECTS
• Benzodiazepine (hypnotic)
How Drug Causes Side Effects
Commonly Prescribed For
• Same mechanism for side effects as for
(bold for FDA approved)
therapeutic effects – namely due to
• Short-term treatment of insomnia
excessive actions at benzodiazepine
receptors
• Actions at benzodiazepine receptors that
How The Drug Works carry over to the next day can cause
• Binds to benzodiazepine receptors at the daytime sedation, amnesia, and ataxia
GABA-A ligand-gated chloride channel • Long-term adaptations in benzodiazepine
complex receptors may explain the development of
• Enhances the inhibitory effects of GABA dependence, tolerance, and withdrawal
• Boosts chloride conductance through
GABA-regulated channels Notable Side Effects
• Inhibitory actions in sleep centers may ✽ Sedation, fatigue, depression
provide sedative hypnotic effects ✽ Dizziness, ataxia, slurred speech,
weakness
How Long Until It Works ✽ Forgetfulness, confusion
• Generally takes effect in less than an hour ✽ Hyper-excitability, nervousness
If It Works
✽ Anterograde amnesia
• Rare hallucinations, mania
• Improves quality of sleep • Rare hypotension
• Effects on total wake-time and number of • Hypersalivation, dry mouth
nighttime awakenings may be decreased • Rebound insomnia when withdrawing from
over time long-term treatment
If It Doesn’t Work
• If insomnia does not improve after Life Threatening or
7–10 days, it may be a manifestation of a Dangerous Side Effects
primary psychiatric or physical illness such • Respiratory depression, especially when
as obstructive sleep apnea or restless leg taken with CNS depressants in overdose
syndrome, which requires independent • Rare hepatic dysfunction, renal
evaluation dysfunction, blood dyscrasias
• Increase the dose
• Improve sleep hygiene Weight Gain
• Switch to another agent

Best Augmenting Combos

• Reported but not expected
for Partial Response or
Treatment-Resistance Sedation
• Generally, best to switch to another agent
• Trazodone
• Agents with antihistamine actions (e.g.,
diphenhydramine, tricyclic antidepressants) • Many experience and/or can be significant
in amount

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TRIAZOLAM (continued)

What To Do About Side Effects Overdose

• Wait • Can be fatal in monotherapy; poor
• To avoid problems with memory, only take coordination, confusion, seizure, slurred
triazolam if planning to have a full night’s speech, sedation, coma, respiratory
sleep depression
• Lower the dose
• Switch to a shorter-acting sedative Long-Term Use
hypnotic • Not generally intended for long-term use
• Switch to a non-benzodiazepine hypnotic • Increased wakefulness during the latter
• Administer flumazenil if side effects are part of night (wearing off) or an increase in
severe or life-threatening daytime anxiety (rebound) may occur
because of short half-life
Best Augmenting Agents for Side
Effects Habit Forming
• Many side effects cannot be improved with • Triazolam is a Schedule IV drug
an augmenting agent • Some patients may develop dependence
and/or tolerance; risk may be greater with
higher doses
• History of drug addiction may increase risk
DOSING AND USE
of dependence
Usual Dosage Range
How to Stop
• 0.125–0.25 mg/day at bedtime for
• If taken for more than a few weeks, taper
7–10 days
to reduce chances of withdrawal effects
Dosage Forms • Patients with seizure history may seize
• Tablet 0.125 mg, 0.25 mg upon sudden withdrawal
• Rebound insomnia may occur the first
How to Dose 1–2 nights after stopping
• Initial 0.125 or 0.25 mg/day at bedtime; • For patients with severe problems
may increase cautiously to 0.5 mg/day if discontinuing a benzodiazepine, dosing
ineffective; maximum dose generally may need to be tapered over many months
0.5 mg/day (i.e., reduce dose by 1% every 3 days by
crushing tablet and suspending or
dissolving in 100 ml of fruit juice and then
disposing of 1 ml while drinking the rest;
Dosing Tips
3–7 days later, dispose of 2 ml, and so on).
• Use lowest possible effective dose and
This is both a form of very slow biological
assess need for continued treatment
tapering and a form of behavioral
regularly
desensitization
✽ Many patients cannot tolerate 0.5 mg
dose (e.g., developing anterograde Pharmacokinetics
amnesia) • Half-life 1.5–5.5 hours
• Triazolam should generally not be • Inactive metabolites
prescribed in quantities greater than a
1-month supply
• Some side effects (sedation, dizziness,
lightheadedness, amnesia) seem to Drug Interactions
increase with dose • CYP450 3A inhibitors such as nefazodone,
• Patients with lower weights may require fluoxetine, and fluvoxamine may decrease
only a 0.125 mg dose clearance of triazolam and raise triazolam
• Risk of dependence may increase with levels significantly
dose and duration of treatment • Ranitidine may increase plasma
✽ Higher doses associated with more concentrations of triazolam
• Increased depressive effects when taken
behavioral problems and anterograde
amnesia with other CNS depressants

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(continued) TRIAZOLAM

• Should generally receive lower doses and

Other Warnings/ be more closely monitored
Precautions
• Insomnia may be a symptom of a primary
disorder, rather than a primary disorder
itself Pregnancy
• Some patients may exhibit abnormal • Risk Category X [positive evidence of risk
thinking or behavioral changes similar to to human fetus; contraindicated for use in
those caused by other CNS depressants pregnancy]
(i.e., either depressant actions or • Infants whose mothers received a
disinhibiting actions) benzodiazepine late in pregnancy may
• Some depressed patients may experience a experience withdrawal effects
worsening of suicidal ideation • Neonatal flaccidity has been reported in
• Use only with extreme caution in patients infants whose mothers took a
with impaired respiratory function or benzodiazepine during pregnancy
obstructive sleep apnea
Breast Feeding
• Triazolam should only be administered at
• Unknown if triazolam is secreted in human
bedtime
breast milk, but all psychotropics assumed
• Grapefruit juice could increase triazolam
to be secreted in breast milk
levels
✽ Recommended either to discontinue drug
Do Not Use or bottle feed
• If patient is pregnant • Effects on infant have been observed and
• If patient has narrow angle-closure include feeding difficulties, sedation, and
glaucoma weight loss
• If patient is taking ketoconazole,
itraconazole, nefazodone, or other potent
CYP450 3A4 inhibitors THE ART OF PSYCHOPHARMACOLOGY
• If there is a proven allergy to triazolam or
any benzodiazepine Potential Advantages
• Short-acting

Potential Disadvantages
SPECIAL POPULATIONS • Patients on concomitant CYP450 3A4
Renal Impairment inhibitors
• Patients with terminal insomnia (early
• Drug should be used with caution
morning awakenings)
Hepatic Impairment
Primary Target Symptoms
• Drug should be used with caution
• Time to sleep onset
Cardiac Impairment • Total sleep time
• Benzodiazepines have been used to treat • Nighttime awakenings
insomnia associated with acute myocardial
infarction
Pearls
Elderly ✽ The shorter half-life should prevent
• Recommended initial dose: 0.125 mg impairments in cognitive and motor
• May be more sensitive to adverse effects performance during the day as well as
daytime sedation
✽ If tolerance develops, the short half-life of
Children and Adolescents elimination may result in increased anxiety
• Safety and efficacy have not been during the day and/or increased
established wakefulness during the latter part of the
• Long-term effects of triazolam in night
children/adolescents are unknown

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TRIAZOLAM (continued)

• The short half-life may minimize the risk of over some benzodiazepines for patients
drug interactions with agents taken during with liver disease
the day (e.g., alcohol) ✽ The risk of unusual behaviors or
✽ However, the risk of drug interactions hallucinations may be greater with
with alcohol taken at night may be greater triazolam than with other sedative
than for some other sedative hypnotics, benzodiazepines
especially for anterograde amnesia • Clearance of triazolam may be slightly
✽ Anterograde amnesia may be more likely faster in women than in men
with triazolam than with other sedative • Women taking oral progesterone may be
benzodiazepines more sensitive to the effects of triazolam
• Because of its short half-life and inactive
metabolites, triazolam may be preferred

Suggested Reading
Jonas JM, Coleman BS, Sheridan AQ, Kalinske Yuan R, Flockhart DA, Balian JD.
RW. Comparative clinical profiles of triazolam Pharmacokinetic and pharmacodynamic
versus other shorter-acting hypnotics. J Clin consequences of metabolism-based drug
Psychiatry 1992;53(Suppl):19–31. interactions with alprazolam, midazolam, and
triazolam. J Clin Pharmacol 1999;39:1109–25.
Lobo BL, Greene WL. Zolpidem: distinct from
triazolam? Ann Pharmacother 1997;
31:625–32.
Rothschild AJ. Disinhibition, amnestic
reactions, and other adverse reactions
secondary to triazolam: a review of the
literature. J Clin Psychiatry 1992;
53(Suppl):69–79.

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TRIFLUOPERAZINE
THERAPEUTICS If It Doesn’t Work
• Consider trying one of the first-line atypical
Brands • Stelazine
antipsychotics (risperidone, olanzapine,
see index for additional brand names
quetiapine, ziprasidone, aripiprazole,
Generic? Yes amisulpride)
• Consider trying another conventional
antipsychotic
• If 2 or more antipsychotic monotherapies
Class do not work, consider clozapine
• Conventional antipsychotic (neuroleptic,
phenothiazine, dopamine 2 antagonist) Best Augmenting Combos
for Partial Response or
Commonly Prescribed For Treatment-Resistance
(bold for FDA approved)
• Augmentation of conventional
• Schizophrenia (oral, intramuscular)
antipsychotics has not been systematically
• Non-psychotic anxiety (short-term,
studied
second-line)
• Addition of a mood stabilizing
• Other psychotic disorders
anticonvulsant such as valproate,
• Bipolar disorder
carbamazepine, or lamotrigine may be
helpful in both schizophrenia and bipolar
mania
How The Drug Works • Augmentation with lithium in bipolar mania
• Blocks dopamine 2 receptors, reducing may be helpful
positive symptoms of psychosis • Addition of a benzodiazepine, especially
short-term for agitation
How Long Until It Works
• Psychotic symptoms can improve within 1 Tests
week, but it may take several weeks for full ✽ Since conventional antipsychotics are
effect on behavior frequently associated with weight gain,
before starting treatment, weigh all patients
If It Works and determine if the patient is already
• Most often reduces positive symptoms in overweight (BMI 25.0–29.9) or obese
schizophrenia but does not eliminate them (BMI ≥30)
• Most schizophrenic patients do not have a • Before giving a drug that can cause weight
total remission of symptoms but rather a gain to an overweight or obese patient,
reduction of symptoms by about a third consider determining whether the patient
• Continue treatment in schizophrenia until already has pre-diabetes (fasting plasma
reaching a plateau of improvement glucose 100–125 mg/dl), diabetes (fasting
• After reaching a satisfactory plateau, plasma glucose >126 mg/dl), or
continue treatment for at least a year after dyslipidemia (increased total cholesterol,
first episode of psychosis in schizophrenia LDL cholesterol and triglycerides;
• For second and subsequent episodes of decreased HDL cholesterol), and treat or
psychosis in schizophrenia, treatment may refer such patients for treatment, including
need to be indefinite nutrition and weight management, physical
• Reduces symptoms of acute psychotic activity counseling, smoking cessation, and
mania but not proven as a mood stabilizer medical management
or as an effective maintenance treatment in ✽ Monitor weight and BMI during treatment
bipolar disorder ✽ While giving a drug to a patient who has
• After reducing acute psychotic symptoms gained >5% of initial weight, consider
in mania, switch to a mood stabilizer evaluating for the presence of pre-diabetes,
and/or an atypical antipsychotic for mood diabetes, or dyslipidemia, or consider
stabilization and maintenance switching to a different antipsychotic

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TRIFLUOPERAZINE (continued)

• Should check blood pressure in the elderly • Rare jaundice, agranulocytosis

before starting and for the first few weeks • Rare seizures
of treatment
• Monitoring elevated prolactin levels of Weight Gain
dubious clinical benefit
• Phenothiazines may cause false-positive
phenylketonuria results
✽ Reported but not expected
Sedation
SIDE EFFECTS
How Drug Causes Side Effects
• Many experience and/or can be significant
• By blocking dopamine 2 receptors in the
in amount
striatum, it can cause motor side effects
• Sedation is usually transient
• By blocking dopamine 2 receptors in the
pituitary, it can cause elevations in What To Do About Side Effects
prolactin • Wait
• By blocking dopamine 2 receptors • Wait
excessively in the mesocortical and • Wait
mesolimbic dopamine pathways, especially • For motor symptoms, add an
at high doses, it can cause worsening of anticholinergic agent
negative and cognitive symptoms • Reduce the dose
(neuroleptic-induced deficit syndrome) • For sedation, give at night
• Anticholinergic actions may cause • Switch to an atypical antipsychotic
sedation, blurred vision, constipation, dry • Weight loss, exercise programs, and
mouth medical management for high BMIs,
• Antihistaminic actions may cause sedation, diabetes, dyslipidemia
weight gain
• By blocking alpha 1 adrenergic receptors, it Best Augmenting Agents for Side
can cause dizziness, sedation, and Effects
hypotension • Benztropine or trihexyphenidyl for motor
• Mechanism of weight gain and any side effects
possible increased incidence of diabetes or • Sometimes amantadine can be helpful for
dyslipidemia with conventional motor side effects
antipsychotics is unknown • Benzodiazepines may be helpful for
Notable Side Effects akathisia
• Many side effects cannot be improved with
✽ Neuroleptic-induced deficit syndrome an augmenting agent
✽ Akathisia
✽ Rash
✽ Priapism
✽ Extrapyramidal symptoms, Parkinsonism, DOSING AND USE
tardive dyskinesia, tardive dystonia
Usual Dosage Range
✽ Galactorrhea, amenorrhea • Oral: Psychosis: 15–20 mg/day
• Dizziness, sedation
• Dry mouth, constipation, blurred vision,
Dosage Forms
urinary retention
• Tablet 1 mg, 2 mg, 5 mg, 10 mg
• Decreased sweating
• Vial 2 mg/mL
• Sexual dysfunction
• Concentrate 10 mg/mL
• Hypotension
How to Dose
Life Threatening or • Psychosis: oral: initial 2–5 mg twice a day;
Dangerous Side Effects increase gradually over 2–3 weeks
• Rare neuroleptic malignant syndrome

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(continued) TRIFLUOPERAZINE

• Psychosis: intramuscular: 1–2 mg every guanethidine, whose antihypertensive

4–6 hours; generally do not exceed actions trifluoperazine may antagonize
6 mg/day • Additive effects may occur if used with
• Anxiety: initial 1–2 mg/day; maximum CNS depressants
6 mg/day • Alcohol and diuretics may increase the risk
of hypotension; epinephrine may lower
blood pressure
Dosing Tips • Phenothiazines may reduce effects of
✽ Use only low doses and short-term for anticoagulants
• Some patients taking a neuroleptic and
anxiety because trifluoperazine is now a
second-line treatment and has the risk of lithium have developed an encephalopathic
tardive dyskinesia syndrome similar to neuroleptic malignant
• Concentrate contains sulfites that may syndrome
cause allergic reactions, particularly in • If used with propranolol, plasma levels of
patients with asthma both drugs may rise
• Many patients can be dosed once a day
Other Warnings/
Overdose Precautions
• Extrapyramidal symptoms, sedation,
• If signs of neuroleptic malignant syndrome
seizures, coma, hypotension, respiratory
develop, treatment should be immediately
depression
discontinued
Long-Term Use • Use cautiously in patients with alcohol
• Some side effects may be irreversible (e.g., withdrawal or convulsive disorders
tardive dyskinesia) because of possible lowering of seizure
• Not intended to treat anxiety long-term threshold
(i.e., longer than 12 weeks) • Use with caution in patients with
respiratory disorders, glaucoma, or urinary
Habit Forming retention
• No • Avoid undue exposure to sunlight
• Avoid extreme heat exposure
How to Stop • Antiemetic effect may mask signs of other
• Slow down-titration of oral formulation disorders or overdose; suppression of
(over 6 to 8 weeks), especially when cough reflex may cause asphyxia
simultaneously beginning a new • Do not use epinephrine in event of
antipsychotic while switching (i.e., cross- overdose as interaction with some pressor
titration) agents may lower blood pressure
• Rapid oral discontinuation may lead to • Use only with caution if at all in
rebound psychosis and worsening of Parkinson’s disease or Lewy Body
symptoms dementia
• If antiparkinson agents are being used,
they should be continued for a few weeks Do Not Use
after trifluoperazine is discontinued • If patient is in a comatose state or has CNS
depression
Pharmacokinetics • If there is the presence of blood
• Mean elimination half-life approximately dyscrasias, bone marrow depression, or
12.5 hours liver disease
• If there is a proven allergy to
trifluoperazine
• If there is a known sensitivity to any
Drug Interactions
phenothiazine
• May decrease the effects of levodopa,
dopamine agonists
• May increase the effects of
antihypertensive drugs except for

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TRIFLUOPERAZINE (continued)

SPECIAL POPULATIONS THE ART OF PSYCHOPHARMACOLOGY

Renal Impairment Potential Advantages
• Use with caution • Intramuscular formulation for emergency
use
Hepatic Impairment
• Not recommended for use Potential Disadvantages
• Patients with tardive dyskinesia
Cardiac Impairment • Children
• Dose should be lowered • Elderly
• Do not use parenteral administration
unless necessary Primary Target Symptoms
• Positive symptoms of psychosis
Elderly • Motor and autonomic hyperactivity
• Lower doses should be used and patient • Violent or aggressive behavior
should be monitored closely

Pearls
Children and Adolescents • Trifluoperazine is a higher potency
• Not recommended for use under age 6 phenothiazine
• Children should be closely monitored when ✽ Although not systematically studied, may
taking trifluoperazine cause less weight gain than other
• Oral: initial 1 mg; increase gradually; antipsychotics
maximum 15 mg/day except in older • Less risk of sedation and orthostatic
children with severe symptoms hypotension but greater extrapyramidal
• Intramuscular: 1 mg once or twice a day symptoms than with low potency
• Generally consider second-line after phenothiazines
atypical antipsychotics • Conventional antipsychotics are much less
expensive than atypical antipsychotics
• Patients have very similar antipsychotic
Pregnancy responses to any conventional
• Risk Category C [some animal studies antipsychotic, which is different from
show adverse effects, no controlled studies atypical antipsychotics where antipsychotic
in humans] responses of individual patients can
• Reports of extrapyramidal symptoms, occasionally vary greatly from one atypical
jaundice, hyperreflexia, hyporeflexia in antipsychotic to another
infants whose mothers took a • Patients with inadequate responses to
phenothiazine during pregnancy atypical antipsychotics may benefit from a
• Trifluoperazine should only be used during trial of augmentation with a conventional
pregnancy if clearly needed antipsychotic such as trifluoperazine or
• Psychotic symptoms may worsen during from switching to a conventional
pregnancy and some form of treatment antipsychotic such as trifluoperazine
may be necessary • However, long-term polypharmacy with a
• Atypical antipsychotics may be preferable combination of a conventional
to conventional antipsychotics or antipsychotic such as trifluoperazine with
anticonvulsant mood stabilizers if an atypical antipsychotic may combine
treatment is required during pregnancy their side effects without clearly
augmenting the efficacy of either
Breast Feeding • Although a frequent practice by some
• Some drug is found in mother’s breast prescribers, adding 2 conventional
milk. antipsychotics together has little rationale
✽ Recommended either to discontinue drug and may reduce tolerability without clearly
or bottle feed enhancing efficacy

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(continued) TRIFLUOPERAZINE

Suggested Reading
Doongaji DR, Satoskar RS, Sheth AS, Apte JS, Kiloh LG, Williams SE, Grant DA, Whetton PS.
Desai AB, Shah BR. Centbutindole vs A double-blind comparative trial of loxapine
trifluoperazine: a double-blind controlled and trifluoperazine in acute and chronic
clinical study in acute schizophrenia. J schizophrenic patients. J Int Med Res 1976; 4:
Postgrad Med 1989; 35: 3–8. 441–8.
Frankenburg FR. Choices in antipsychotic
therapy in schizophrenia. Harv Rev Psychiatry
1999; 6: 241–9.

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0521011698s10.qxd 9/2/04 2:49 PM Page 493

TRIMIPRAMINE
THERAPEUTICS If It Works
• The goal of treatment of depression is
Brands • Surmontil
complete remission of current symptoms
see index for additional brand names
as well as prevention of future relapses
Generic? Yes • The goal of treatment of chronic
neuropathic pain is to reduce symptoms as
much as possible, especially in
combination with other treatments
Class • Treatment of depression most often
• Tricyclic antidepressant (TCA) reduces or even eliminates symptoms, but
• Serotonin and norepinephrine/ not a cure since symptoms can recur after
noradrenaline reuptake inhibitor medicine stopped
• Treatment of chronic neuropathic pain may
Commonly Prescribed For reduce symptoms, but rarely eliminates
(bold for FDA approved) them completely, and is not a cure since
• Depression symptoms can recur after medicine is
• Endogenous depression stopped
• Anxiety • Continue treatment of depression until all
• Insomnia symptoms are gone (remission)
• Neuropathic pain/chronic pain • Once symptoms of depression are gone,
• Treatment-resistant depression continue treating for 1 year for the first
episode of depression
• For second and subsequent episodes of
How The Drug Works depression, treatment may need to be
• Boosts neurotransmitters serotonin and indefinite
norepinephrine/noradrenaline • Use in anxiety disorders and chronic pain
• Blocks serotonin reuptake pump (serotonin may also need to be indefinite, but long-
transporter), presumably increasing term treatment is not well studied in these
serotonergic neurotransmission conditions
• Blocks norepinephrine reuptake pump
If It Doesn’t Work
(norepinephrine transporter), presumably
• Many depressed patients only have a
increasing noradrenergic
partial response where some symptoms
neurotransmission
are improved but others persist (especially
• Presumably desensitizes both serotonin 1A
insomnia, fatigue, and problems
receptors and beta adrenergic receptors
concentrating)
• Since dopamine is inactivated by
• Other depressed patients may be
norepinephrine reuptake in frontal cortex,
nonresponders, sometimes called
which largely lacks dopamine transporters,
treatment-resistant or treatment-refractory
trimipramine can increase dopamine
• Consider increasing dose, switching to
neurotransmission in this part of the brain
another agent or adding an appropriate
How Long Until It Works augmenting agent
• May have immediate effects in treating • Consider psychotherapy
insomnia, agitation, or anxiety • Consider evaluation for another diagnosis
• Onset of therapeutic actions usually not or for a comorbid condition (e.g., medical
immediate, but often delayed 2 to 4 weeks illness, substance abuse, etc.)
• If it is not working within 6 to 8 weeks for • Some patients may experience apparent
depression, it may require a dosage lack of consistent efficacy due to activation
increase or it may not work at all of latent or underlying bipolar disorder, and
• May continue to work for many years to require antidepressant discontinuation and
prevent relapse of symptoms a switch to a mood stabilizer

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TRIMIPRAMINE (continued)

Best Augmenting Combos SIDE EFFECTS

for Partial Response or How Drug Causes Side Effects
Treatment-Resistance • Anticholinergic activity may explain
• Lithium, buspirone, thyroid hormone (for sedative effects, dry mouth, constipation,
depression) and blurred vision
• Gabapentin, tiagabine, other • Sedative effects and weight gain may be
anticonvulsants, even opiates if done by due to antihistamine properties
experts while monitoring carefully in • Blockade of alpha adrenergic 1 receptors
difficult cases (for chronic pain) may explain dizziness, sedation, and
hypotension
Tests
• Cardiac arrhythmias and seizures,
• None for healthy individuals
especially in overdose, may be caused by
✽ Since tricyclic and tetracyclic blockade of ion channels
antidepressants are frequently associated
with weight gain, before starting treatment, Notable Side Effects
weigh all patients and determine if the • Blurred vision, constipation, urinary
patient is already overweight retention, increased appetite, dry mouth,
(BMI 25.0–29.9) or obese (BMI ≥30) nausea, diarrhea, heartburn, unusual taste
• Before giving a drug that can cause weight in mouth, weight gain
gain to an overweight or obese patient, • Fatigue, weakness, dizziness, sedation,
consider determining whether the patient headache, anxiety, nervousness,
already has pre-diabetes (fasting plasma restlessness
glucose 100–125 mg/dl), diabetes (fasting • Sexual dysfunction (impotence, change in
plasma glucose >126 mg/dl), or libido)
dyslipidemia (increased total cholesterol, • Sweating, rash, itching
LDL cholesterol and triglycerides;
decreased HDL cholesterol), and treat or
refer such patients for treatment, including Life Threatening or
nutrition and weight management, physical Dangerous Side Effects
activity counseling, smoking cessation, and • Paralytic ileus, hyperthermia (TCAs +
medical management anticholinergic agents)
✽ Monitor weight and BMI during treatment • Lowered seizure threshold and rare
✽ While giving a drug to a patient who has seizures
gained >5% of initial weight, consider • Orthostatic hypotension, sudden death,
evaluating for the presence of pre-diabetes, arrhythmias, tachycardia
diabetes, or dyslipidemia, or consider • QTc prolongation
switching to a different antipsychotic • Hepatic failure, extrapyramidal symptoms
• EKGs may be useful for selected patients • Increased intraocular pressure
(e.g., those with personal or family history • Rare induction of mania and activation of
of QTc prolongation; cardiac arrhythmia; suicidal ideation
recent myocardial infarction;
uncompensated heart failure; or taking Weight Gain
agents that prolong QTc interval such as
pimozide, thioridazine, selected
antiarrhythmics, moxifloxacin, sparfloxacin, • Many experience and/or can be significant
etc.) in amount
• Patients at risk for electrolyte disturbances • Can increase appetite and carbohydrate
(e.g., patients on diuretic therapy) should craving
have baseline and periodic serum
potassium and magnesium measurements Sedation

• Many experience and/or can be significant

in amount

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(continued) TRIMIPRAMINE

• Tolerance to sedative effects may develop Overdose

with long-term use • Death may occur; CNS depression,
convulsions, cardiac dysrhythmias, severe
What To Do About Side Effects hypotension, ECG changes, coma
• Wait
• Wait Long-Term Use
• Wait • Safe
• Lower the dose
• Switch to an SSRI or newer antidepressant Habit Forming
• No
Best Augmenting Agents for Side
Effects How to Stop
• Many side effects cannot be improved with • Taper to avoid withdrawal effects
an augmenting agent • Even with gradual dose reduction some
withdrawal symptoms may appear within
the first 2 weeks
DOSING AND USE • Many patients tolerate 50% dose reduction
for 3 days, then another 50% reduction for
Usual Dosage Range 3 days, then discontinuation
• 50–150 mg/day • If withdrawal symptoms emerge during
discontinuation, raise dose to stop
Dosage Forms symptoms and then restart withdrawal
• Capsule 25 mg, 50 mg, 100 mg much more slowly

How to Dose Pharmacokinetics

• Initial 25 mg/day at bedtime; increase by • Substrate for CYP450 2D6, 2C19, and 2C9
75 mg every 3–7 days • Half-life approximately 7–23 hours
• 75 mg/day in divided doses; increase to
150 mg/day; maximum 200 mg/day;
hospitalized patients may receive doses up Drug Interactions
to 300 mg/day • Tramadol increases the risk of seizures in
patients taking TCAs
• Use of TCAs with anticholinergic drugs
Dosing Tips may result in paralytic ileus or
• If given in a single dose, should generally hyperthermia
be administered at bedtime because of its • Fluoxetine, paroxetine, bupropion,
sedative properties duloxetine, and other CYP450 2D6
• If given in split doses, largest dose should inhibitors may increase TCA concentrations
generally be given at bedtime because of • Cimetidine may increase plasma
its sedative properties concentrations of TCAs and cause
• If patients experience nightmares, split anticholinergic symptoms
dose and do not give large dose at bedtime • Phenothiazines or haloperidol may raise
• Patients treated for chronic pain may only TCA blood concentrations
require lower doses • May alter effects of antihypertensive drugs;
• If intolerable anxiety, insomnia, agitation, may inhibit hypotensive effects of clonidine
akathisia, or activation occur either upon • Use with sympathomimetic agents may
dosing initiation or discontinuation, increase sympathetic activity
consider the possibility of activated bipolar • Methylphenidate may inhibit metabolism of
disorder, and switch to a mood stabilizer or TCAs
an atypical antipsychotic • Activation and agitation, especially
following switching or adding
antidepressants, may represent the
induction of a bipolar state, especially a
mixed dysphoric bipolar II condition
sometimes associated with suicidal

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TRIMIPRAMINE (continued)

ideation, and require the addition of • If there is reduced CYP450 2D6 function,
lithium, a mood stabilizer or an atypical such as patients who are poor 2D6
antipsychotic, and/or discontinuation of metabolizers, except by an expert and at
trimipramine low doses
• If there is a proven allergy to trimipramine
Other Warnings/
Precautions
• Add or initiate other antidepressants with
SPECIAL POPULATIONS
caution for up to 2 weeks after Renal Impairment
discontinuing trimipramine • Use with caution; may need to lower dose
• Generally, do not use with MAO inhibitors,
including 14 days after MAOIs are stopped; Hepatic Impairment
do not start an MAOI until 2 weeks after • Use with caution; may need to lower dose
discontinuing trimipramine, but see Pearls
• Use with caution in patients with history of Cardiac Impairment
seizures, urinary retention, narrow angle- • TCAs have been reported to cause
closure glaucoma, hyperthyroidism arrhythmias, prolongation of conduction
• TCAs can increase QTc interval, especially time, orthostatic hypotension, sinus
at toxic doses which can be attained not tachycardia, and heart failure, especially in
only by overdose but also by combining the diseased heart
with drugs that inhibit TCA metabolism via • Myocardial infarction and stroke have been
CYP450 2D6, potentially causing torsade reported with TCAs
de pointes-type arrhythmia or sudden • TCAs produce QTc prolongation, which
death may be enhanced by the existence of
• Because TCAs can prolong QTc interval, bradycardia, hypokalemia, congenital or
use with caution in patients who have acquired long QTc interval, which should
bradycardia or who are taking drugs that be evaluated prior to administering
can induce bradycardia (e.g., beta blockers, trimipramine
calcium channel blockers, clonidine, • Use with caution if treating concomitantly
digitalis) with a medication likely to produce
• Because TCAs can prolong QTc interval, prolonged bradycardia, hypokalemia,
use with caution in patients who have slowing of intracardiac conduction, or
hypokalemia and/or hypomagnesemia or prolongation of the QTc interval
who are taking drugs that can induce • Avoid TCAs in patients with a known
hypokalemia and/or magnesemia (e.g., history of QTc prolongation, recent acute
diuretics, stimulant laxatives, intravenous myocardial infarction, and uncompensated
amphotericin B, glucocorticoids, heart failure
tetracosactide) • TCAs may cause a sustained increase in
heart rate in patients with ischemic heart
Do Not Use disease and may worsen (decrease) heart
• If patient is recovering from myocardial rate variability, an independent risk of
infarction mortality in cardiac populations
• If patient is taking agents capable of • Since SSRIs may improve (increase) heart
significantly prolonging QTc interval (e.g., rate variability in patients following a
pimozide, thioridazine, selected myocardial infarct and may improve
antiarrhythmics, moxifloxacin, survival as well as mood in patients with
sparfloxacin) acute angina or following a myocardial
• If there is a history of QTc prolongation or infarction, these are more appropriate
cardiac arrhythmia, recent acute agents for cardiac population than
myocardial infarction, uncompensated tricyclic/tetracyclic antidepressants
heart failure
• If patient is taking drugs that inhibit TCA
✽ Risk/benefit ratio may not justify use of
TCAs in cardiac impairment
metabolism, including CYP450 2D6
inhibitors, except by an expert

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(continued) TRIMIPRAMINE

Elderly childbirth to prevent a recurrence during

• May be more sensitive to anticholinergic, the postpartum period
cardiovascular, hypotensive, and sedative • Must weigh the risk of treatment (first
effects trimester fetal development, third trimester
• Initial dose 50 mg/day; increase gradually newborn delivery) to the child against the
up to 100 mg/day risk of no treatment (recurrence of
depression, maternal health, infant
bonding) to the mother and child
Children and Adolescents • For many patients this may mean
• Use with caution, observing for activation continuing treatment during breast feeding
of known or unknown bipolar disorder
and/or suicidal ideation, and strongly
consider informing parents or guardian of THE ART OF PSYCHOPHARMACOLOGY
this risk so they can help observe child or
adolescent patients Potential Advantages
• Not recommended for use under age 12 • Patients with insomnia, anxiety
• Several studies show lack of efficacy of • Severe or treatment-resistant depression
TCAs for depression
• May be used to treat enuresis or
Potential Disadvantages
hyperactive/impulsive behaviors • Pediatric and geriatric patients
• Some cases of sudden death have • Patients concerned with weight gain and
occurred in children taking TCAs sedation
• Adolescents: initial dose 50 mg/day;
Primary Target Symptoms
increase gradually up to 100 mg/day
• Depressed mood
• Symptoms of anxiety
• Somatic symptoms
Pregnancy
• Risk Category C [some animal studies
show adverse effects, no controlled studies
Pearls
in humans]
• Crosses the placenta ✽ May be more useful than some other
TCAs for patients with anxiety, sleep
• Adverse effects have been reported in
disturbance, and depression with physical
infants whose mothers took a TCA
illness
(lethargy, withdrawal symptoms, fetal
malformations) ✽ May be more sedating than some other
TCAs
• Must weigh the risk of treatment (first
• Tricyclic antidepressants are often a first-
trimester fetal development, third trimester
line treatment option for chronic pain
newborn delivery) to the child against the
• Tricyclic antidepressants are no longer
risk of no treatment (recurrence of
generally considered a first-line option for
depression, maternal health, infant
depression because of their side effect
bonding) to the mother and child
profile
• For many patients this may mean
• Tricyclic antidepressants continue to be
continuing treatment during pregnancy
useful for severe or treatment-resistant
Breast Feeding depression
• Some drug is found in mother’s breast milk • TCAs may aggravate psychotic symptoms
✽ Recommended either to discontinue drug • Alcohol should be avoided because of
additive CNS effects
or bottle feed
• Immediate postpartum period is a high-risk • Underweight patients may be more
time for depression, especially in women susceptible to adverse cardiovascular
who have had prior depressive episodes, effects
so drug may need to be reinstituted late in • Children, patients with inadequate
the third trimester or shortly after hydration, and patients with cardiac

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TRIMIPRAMINE (continued)

disease may be more susceptible to TCA- • SSRIs may be more effective than TCAs in
induced cardiotoxicity than healthy adults women, and TCAs may be more effective
• For the expert only: although generally than SSRIs in men
prohibited, a heroic but potentially • Since tricyclic/tetracyclic antidepressants
dangerous treatment for severely are substrates for CYP450 2D6, and 7% of
treatment-resistant patients is for an expert the population (especially Caucasians) may
to give a tricyclic/tetracyclic antidepressant have a genetic variant leading to reduced
other than clomipramine simultaneously activity of 2D6, such patients may not
with an MAO inhibitor for patients who fail safely tolerate normal doses of
to respond to numerous other tricyclic/tetracyclic antidepressants and
antidepressants may require dose reduction
• If this option is elected, start the MAOI with • Phenotypic testing may be necessary to
the tricyclic/tetracyclic antidepressant detect this genetic variant prior to dosing
simultaneously at low doses after with a tricyclic/tetracyclic antidepressant,
appropriate drug washout, then alternately especially in vulnerable populations such
increase doses of these agents every few as children, elderly, cardiac populations,
days to a week as tolerated and those on concomitant medications
• Although very strict dietary and • Patients who seem to have extraordinarily
concomitant drug restrictions must be severe side effects at normal or low doses
observed to prevent hypertensive crises may have this phenotypic CYP450 2D6
and serotonin syndrome, the most variant and require low doses or switching
common side effects of MAOI and to another antidepressant not metabolized
tricyclic/tetracyclic antidepressant by 2D6
combinations may be weight gain and
orthostatic hypotension
• Patients on tricyclics should be aware that
they may experience symptoms such as
photosensitivity or blue-green urine

Suggested Reading
Anderson IM. Meta-analytical studies on new Berger M, Gastpar M. Trimipramine: a
antidepressants. Br Med Bull. 2001; challenge to current concepts on
57:161–178. antidepressives. Eur Arch Psychiatry Clin
Neurosci. 1996;246:235–9.
Anderson IM. Selective serotonin reuptake
inhibitors versus tricyclic antidepressants: a Lapierre YD. A review of trimipramine. 30
meta-analysis of efficacy and tolerability. J Aff years of clinical use. Drugs. 1989;38 (Suppl
Disorders. 2000;58:19–36. 1):17–24;discussion 49–50.

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VALPROATE
THERAPEUTICS then continue treating indefinitely as long
as improvement persists
Brands • Depakene • Continue treatment indefinitely to avoid
• Depacon recurrence of mania, depression, seizures,
• Depakote, Depakote ER and headaches
see index for additional brand names
If It Doesn’t Work (for bipolar
Generic? Yes (not for Depakote ER) disorder)
✽ Many patients only have a partial
response where some symptoms are
Class improved but others persist or continue to
• Anticonvulsant, mood stabilizer, migraine wax and wane without stabilization of
prophylaxis, voltage-sensitive sodium mood
channel modulator • Other patients may be nonresponders,
sometimes called treatment-resistant or
Commonly Prescribed For treatment-refractory
(bold for FDA approved) • Consider checking plasma drug level,
• Mania (divalproex only) increasing dose, switching to another agent
• Complex partial seizures that occur either or adding an appropriate augmenting agent
in isolation or in association with other • Consider adding psychotherapy
types of seizures (monotherapy and • Consider the presence of noncompliance
adjunctive) and counsel patient
• Simple and complex absence seizures • Switch to another mood stabilizer with
(monotherapy and adjunctive) fewer side effects
• Multiple seizure types which include • Consider evaluation for another diagnosis
absence seizures (adjunctive) or for a comorbid condition (e.g., medical
• Migraine prophylaxis (divalproex, illness, substance abuse, etc.)
divalproex ER)
• Maintenance treatment of bipolar disorder Best Augmenting Combos
• Bipolar depression for Partial Response or
• Psychosis, schizophrenia (adjunctive) Treatment-Resistance
(for bipolar disorder)
• Lithium
How The Drug Works • Atypical antipsychotics (especially
✽ Blocks voltage-sensitive sodium channels risperidone, olanzapine, quetiapine,
by an unknown mechanism ziprasidone, and aripiprazole)
• Increases brain concentrations of gamma- ✽ Lamotrigine (with caution and at half the
aminobutyric acid (GABA) by an unknown dose in the presence of valproate because
mechanism valproate can double lamotrigine levels)
How Long Until It Works
✽ Antidepressants (with caution because
antidepressants can destabilize mood in
• For acute mania, effects should occur some patients, including induction of rapid
within a few days cycling or suicidal ideation; in particular
• May take several weeks to months to consider bupropion; also SSRIs, SNRIs,
optimize an effect on mood stabilization others; generally avoid TCAs, MAOIs)
• Should also reduce seizures and improve
migraine within a few weeks Tests
If It Works
✽ Before starting treatment, platelet counts
and liver function tests
• The goal of treatment is complete • Consider coagulation tests prior to planned
remission of symptoms (e.g., mania, surgery or if there is a history of bleeding
seizures, migraine) • During the first few months of treatment,
• Continue treatment until all symptoms are regular liver function tests and platelet
gone or until improvement is stable and

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VALPROATE (continued)

counts; this can be shifted to once or twice

a year for the remainder of treatment Life Threatening or
• Plasma drug levels can assist monitoring Dangerous Side Effects
of efficacy, side effects, and compliance • Rare hepatotoxicity with liver failure
✽ Since valproate is frequently associated sometimes severe and fatal, particularly in
with weight gain, before starting treatment, children under 2
weigh all patients and determine if the • Rare pancreatitis, sometimes fatal
patient is already overweight
(BMI 25.0–29.9) or obese (BMI ≥30) Weight Gain
• Before giving a drug that can cause weight
gain to an overweight or obese patient,
consider determining whether the patient • Many experience and/or can be significant
already has pre-diabetes (fasting plasma in amount
glucose 100–125 mg/dl), diabetes (fasting • Can become a health problem in some
plasma glucose >126 mg/dl), or
dyslipidemia (increased total cholesterol, Sedation
LDL cholesterol and triglycerides;
decreased HDL cholesterol), and treat or
refer such patients for treatment, including
• Frequent and can be significant in amount
nutrition and weight management, physical
• Some patients may not tolerate it
activity counseling, smoking cessation, and
• Can wear off over time
medical management
• Can reemerge as dose increases and then
✽ Monitor weight and BMI during treatment wear off again over time
✽ While giving a drug to a patient who has
gained >5% of initial weight, consider What To Do About Side Effects
evaluating for the presence of pre-diabetes,
• Wait
diabetes, or dyslipidemia, or consider
• Wait
switching to a different agent
• Wait
• Take at night to reduce daytime sedation,
especially with divalproex ER
SIDE EFFECTS • Lower the dose
• Switch to another agent
How Drug Causes Side Effects
• CNS side effects theoretically due to Best Augmenting Agents for Side
excessive actions at voltage-sensitive Effects
sodium channels ✽ Propranolol 20–30 mg 2–3 times/day
may reduce tremor
Notable Side Effects
✽ Multivitamins fortified with zinc and
✽ Sedation, tremor, dizziness, ataxia, selenium may help reduce alopecia
asthenia, headache • Many side effects cannot be improved with
✽ Abdominal pain, nausea, vomiting, an augmenting agent
diarrhea, reduced appetite, constipation,
dyspepsia, weight gain
✽ Alopecia (unusual) DOSING AND USE
• Polycystic ovaries (controversial)
• Hyperandrogenism, hyperinsulinemia, lipid
Usual Dosage Range
dysregulation (controversial)
• Mania: 1200–1500 mg/day
• Decreased bone mineral density
• Migraine: 500–1000 mg/day
(controversial)
• Epilepsy: 10–60 mg/kg/day

Dosage Forms
• Tablet [delayed release, as divalproex
sodium (Depakote)] 125 mg, 250 mg,
500 mg

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(continued) VALPROATE

• Tablet [extended release, as divalproex ✽ Divalproex ER improves gastrointestinal

sodium (Depakote ER)] 250 mg, 500 mg side effects and alopecia compared to
• Capsule [sprinkle, as divalproex sodium immediate release divalproex or generic
(Depakote Sprinkle)] 125 mg valproate
• Capsule [as valproic acid (Depakene)] • The amide of valproic acid is available in
250 mg Europe [valpromide (Depamide)]
• Injection [as sodium valproate (Depacon)] • Trough plasma drug levels >45 µg/ml may
100 mg/mL (5 mL) be required for either antimanic effects or
• Syrup [as sodium valproate (Depakene)] anticonvulsant actions
250 mg/5mL (5 mL, 50 mL, 480 mL) • Trough plasma drug levels up to 100 µg/ml
are generally well tolerated
How to Dose • Trough plasma drug levels up to 125 µg/ml
• Usual starting dose for mania or epilepsy is may be required in some acutely manic
15 mg/kg in 2 divided doses (once daily for patients
extended release valproate) • Dosages to achieve therapeutic plasma
• Acute mania (adults): initial 1000 mg/day; levels vary widely, often between
increase dose rapidly; maximum dose 750–3000 mg/day
generally 60 mg/kg/day
• For less acute mania, may begin at Overdose
250–500 mg the first day, and then titrate • Fatalities have been reported; coma,
upward as tolerated restlessness, hallucinations, sedation, heart
• Migraine (adults): initial 500 mg/day, block
maximum recommended dose
1000 mg/day Long-Term Use
• Epilepsy (adults): initial 10–15 mg/kg/day; • Requires regular liver function tests and
increase by 5–10 mg/kg/week; maximum platelet counts
dose generally 60 mg/kg/day
Habit Forming
• No
Dosing Tips How to Stop
✽ Oral loading with 20–30 mg/kg/day may • Taper; may need to adjust dosage of
reduce onset of action to 5 days or less concurrent medications as valproate is
and may be especially useful for treatment being discontinued
of acute mania in inpatient settings • Patients may seize upon withdrawal,
• Given the half-life of immediate release especially if withdrawal is abrupt
valproate (e.g., Depakene, Depakote), twice
daily dosing is probably ideal
✽ Rapid discontinuation increases the risk
of relapse in bipolar disorder
• Extended release valproate (e.g., Depakote • Discontinuation symptoms uncommon
ER) can be given once daily
• However, extended release valproate is only Pharmacokinetics
about 80% as bioavailable as immediate • Mean terminal half-life 9–16 hours
release valproate, producing plasma drug • Metabolized primarily by the liver,
levels 10–20% lower than with immediate approximately 25% dependent upon
release valproate CYP450 system
✽ Thus, the dose of extended release
valproate may need to be higher (by about
one-third) when converting patients to the
Drug Interactions
ER formulation
• Depakote (divalproex sodium) is an ✽ Lamotrigine dose should be reduced by
perhaps 50% if used with valproate, as
enteric-coated stable compound containing
valproate inhibits metabolism of
both valproic acid and sodium valproate
lamotrigine and raises lamotrigine plasma
✽ Divalproex immediate release formulation levels, theoretically increasing the risk of
reduces gastrointestinal side effects
rash
compared to generic valproate

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VALPROATE (continued)

• Plasma levels of valproate may be lowered Do Not Use

by carbamazepine, phenytoin, • If patient has pancreatitis
ethosuximide, phenobarbital, rifampin • If patient has serious liver disease
• Aspirin may inhibit metabolism of valproate • If patient has urea cycle disorder
and increase valproate plasma levels • If there is a proven allergy to valproic acid,
• Plasma levels of valproate may also be valproate, or divalproex
increased by felbamate, chlorpromazine,
fluoxetine, fluvoxamine, topiramate,
cimetidine, erythromycin, and ibuprofen SPECIAL POPULATIONS
• Valproate inhibits metabolism of
ethosuximide, phenobarbital, and Renal Impairment
phenytoin, and can thus increase their • No dose adjustment necessary
plasma levels
• No likely pharmacokinetic interactions of Hepatic Impairment
valproate with lithium or atypical • Contraindicated
antipsychotics
• Use of valproate with clonazepam may Cardiac Impairment
cause absence status • No dose adjustment necessary

Elderly
Other Warnings/ • Reduce starting dose and titrate slowly;
Precautions dosing is generally lower than in healthy
✽ Be alert to the following symptoms of adults
hepatotoxicity that require immediate ✽ Sedation in the elderly may be more
attention: malaise, weakness, lethargy, common and associated with dehydration,
facial edema, anorexia, vomiting, yellowing reduced nutritional intake, and weight loss
of the skin and eyes • Monitor fluid and nutritional intake
✽ Be alert to the following symptoms of
pancreatitis that require immediate
attention: abdominal pain, nausea, Children and Adolescents
vomiting, anorexia
✽ Teratogenic effects in developing fetuses ✽ Not generally recommended for use
under age 10 for bipolar disorder except by
such as neural tube defects may occur with
experts and when other options have been
valproate use
considered
✽ Somnolence may be more common in the • Children under age 2 have significantly
elderly and may be associated with
increased risk of hepatotoxicity, as they
dehydration, reduced nutritional intake, and
have a markedly decreased ability to
weight loss, requiring slower dosage
eliminate valproate compared to older
increases, lower doses, and monitoring of
children and adults
fluid and nutritional intake
• Use requires close medical supervision
• Use in patients with thrombocytopenia is
not recommended; patients should report
easy bruising or bleeding
• Evaluate for urea cycle disorders, as Pregnancy
hyperammonemic encephalopathy, • Risk category D [positive evidence of risk
sometimes fatal, has been associated with to human fetus; potential benefits may still
valproate administration in these justify its use during pregnancy]
uncommon disorders; urea cycle disorders, ✽ Use during first trimester may raise risk
such as ormithine transcarbamylase of neural tube defects (e.g., spina bifida) or
deficiency, are associated with unexplained other congenital anomalies
encephalopathy, mental retardation, • Use in women of childbearing potential
elevated plasma ammonia, cyclical requires weighing potential benefits to the
vomiting, and lethargy mother against the risks to the fetus

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(continued) VALPROATE

✽ If drug is continued, monitor clotting THE ART OF PSYCHOPHARMACOLOGY

parameters and perform tests to detect
birth defects
Potential Advantages
✽ If drug is continued, start on folate • Manic phase of bipolar disorder
• Works well in combination with lithium
1 mg/day early in pregnancy to reduce risk
of neural tube defects and/or atypical antipsychotics
✽ If drug is continued, consider vitamin K • Patients for whom therapeutic drug
monitoring is desirable
during the last 6 weeks of pregnancy to
reduce risks of bleeding
Potential Disadvantages
• Taper drug if discontinuing
• Depressed phase of bipolar disorder
• Seizures, even mild seizures, may cause
• Patients unable to tolerate sedation or
harm to the embryo/fetus
weight gain
✽ For bipolar patients, valproate should • Multiple drug interactions
generally be discontinued before
• Multiple side effect risks
anticipated pregnancies
• Pregnant patients
• Recurrent bipolar illness during pregnancy
can be quite disruptive Primary Target Symptoms
✽ For bipolar patients, given the risk of • Unstable mood
relapse in the postpartum period, mood • Incidence of migraine
stabilizer treatment such as valproate • Incidence of partial complex seizures
should generally be restarted immediately
after delivery if patient is unmedicated
during pregnancy
✽ Atypical antipsychotics may be preferable Pearls (for bipolar disorder)
to lithium or anticonvulsants such as ✽ Valproate is a first-line treatment option
valproate if treatment of bipolar disorder is that may be best for patients with mixed
required during pregnancy states of bipolar disorder or for patients
• Bipolar symptoms may recur or worsen with rapid-cycling bipolar disorder
during pregnancy and some form of ✽ Seems to be more effective in treating
treatment may be necessary manic episodes than depressive episodes
in bipolar disorder (treats from above
Breast Feeding better than it treats from below)
• Some drug is found in mother’s breast milk ✽ May also be more effective in preventing
✽ Generally considered safe to breast feed manic relapses than in preventing
while taking valproate depressive episodes (stabilizes from above
• If drug is continued while breast feeding, better than it stabilizes from below)
infant should be monitored for possible • Only a third of bipolar patients experience
adverse effects adequate relief with a monotherapy, so
• If infant shows signs of irritability or most patients need multiple medications
sedation, drug may need to be for best control
discontinued • Useful in combination with atypical
✽ Bipolar disorder may recur during the antipsychotics and/or lithium for acute
postpartum period, particularly if there is a mania
history of prior postpartum episodes of ✽ May also be useful for bipolar disorder in
either depression or psychosis combination with lamotrigine, but must
✽ Relapse rates may be lower in women reduce lamotrigine dose by half when
who receive prophylactic treatment for combined with valproate
postpartum episodes of bipolar disorder • Usefulness for bipolar disorder in
• Atypical antipsychotics and anticonvulsants combination with anticonvulsants other
such as valproate may be safer than than lamotrigine is not well demonstrated;
lithium during the postpartum period when such combinations can be expensive and
breast feeding are possibly ineffective or even irrational
✽ May be useful as an adjunct to atypical
antipsychotics for rapid onset of action in
schizophrenia

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VALPROATE (continued)

✽ Used to treat aggression, agitation, and bearing potential, especially adolescent

impulsivity not only in bipolar disorder and female bipolar patients, and carefully
schizophrenia but also in many other monitor weight, endocrine status, and
disorders, including dementia, personality ovarian size and function
disorders, and brain injury ✽ In women of child bearing potential who
• Patients with acute mania tend to tolerate are or are likely to become sexually active,
side effects better than patients with should inform about risk of harm to the
hypomania or depression fetus and monitor contraceptive status
• Multivitamins fortified with zinc and • Association of valproate with decreased
selenium may help reduce alopecia bone mass is controversial and may be
• Association of valproate with polycystic related to activity levels, exposure to
ovaries is controversial and may be related sunlight, and epilepsy, and might be
to weight gain, obesity, or epilepsy prevented by supplemental vitamin D
• Nevertheless, may wish to be cautious in 2000 Iu/day and calcium 600–1000 mg/day
administering valproate to women of child

Suggested Reading
Bowden CL. Valproate. Bipolar Disorders Macritchie KA, Geddes JR, Scott J, Haslam
2003;5:189–202. DR, Goodwin GM. Valproic acid, valproate and
divalproex in the maintenance treatment of
Emilien G, Maloteaux JM, Seghers A, Charles bipolar disorder. Cochrane Database Syst Rev.
G. Lithium compared to valproic acid and 2001;(3):CD003196.
carbamazepine in the treatment of mania: a
statistical meta-analysis. Eur Strakowski SM, DelBello MP, Adler CM.
Neuropsychopharmacol. 1996;6:245–52. Comparative efficacy and tolerability of drug
treatments for bipolar disorder. CNS Drugs.
Landy SH, McGinnis J. Divalproex sodium— 2001;15:701–18.
review of prophylactic migraine efficacy, safety
and dosage, with recommendations. Tenn
Med. 1999;92:135–6.

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VENLAFAXINE
THERAPEUTICS rates may still occur after 8 weeks, and for
up to 6 months after initiating dosing
Brands • Effexor • May continue to work for many years to
• Effexor XR prevent relapse of symptoms
see index for additional brand names
If It Works
Generic? No • The goal of treatment is complete
remission of current symptoms as well as
prevention of future relapses
Class • Treatment most often reduces or even
• SNRI (dual serotonin and norepinephrine eliminates symptoms, but not a cure since
reuptake inhibitor); often classified as an symptoms can recur after medicine
antidepressant, but it is not just an stopped
antidepressant • Continue treatment until all symptoms are
gone (remission), especially in depression
Commonly Prescribed For and whenever possible in anxiety disorders
(bold for FDA approved) • Once symptoms gone, continue treating for
• Depression 1 year for the first episode of depression
• Generalized anxiety disorder (GAD) • For second and subsequent episodes of
• Social anxiety disorder (social phobia) depression, treatment may need to be
• Panic disorder indefinite
• Posttraumatic stress disorder (PTSD) • Use in anxiety disorders may also need to
• Premenstrual dysphoric disorder (PMDD) be indefinite

If It Doesn’t Work
How The Drug Works • Many patients only have a partial response
• Boosts neurotransmitters serotonin, where some symptoms are improved but
norepinephrine/noradrenaline, and others persist (especially insomnia, fatigue,
dopamine and problems concentrating)
• Blocks serotonin reuptake pump (serotonin • Other patients may be nonresponders,
transporter), presumably increasing sometimes called treatment-resistant or
serotonergic neurotransmission treatment-refractory
• Blocks norepinephrine reuptake pump • Some patients who have an initial response
(norepinephrine transporter), presumably may relapse even though they continue
increasing noradrenergic treatment, sometimes called “poop-out”
neurotransmission • Consider increasing dose, switching to
• Presumably desensitizes both serotonin 1A another agent or adding an appropriate
receptors and beta adrenergic receptors augmenting agent
• Since dopamine is inactivated by • Consider psychotherapy
norepinephrine reuptake in frontal cortex, • Consider evaluation for another diagnosis
which largely lacks dopamine transporters, or for a comorbid condition (e.g., medical
venlafaxine can increase dopamine illness, substance abuse, etc.)
neurotransmission in this part of the brain • Some patients may experience apparent
• Weakly blocks dopamine reuptake pump lack of consistent efficacy due to activation
(dopamine transporter), and may increase of latent or underlying bipolar disorder, and
dopamine neurotransmission require antidepressant discontinuation and
a switch to a mood stabilizer
How Long Until It Works
• Onset of therapeutic actions usually not Best Augmenting Combos
immediate, but often delayed 2 to 4 weeks for Partial Response or
• If it is not working within 6 to 8 weeks for Treatment-Resistance
depression, it may require a dosage ✽ Mirtazapine (“California rocket fuel”; a
increase or it may not work at all potentially powerful dual serotonin and
• By contrast, for generalized anxiety, onset norepinephrine combination, but observe
of response and increases in remission

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VENLAFAXINE (continued)

for activation of bipolar disorder and

suicidal ideation) Life Threatening or
• Bupropion, reboxetine, nortriptyline, Dangerous Side Effects
desipramine, maprotiline, atomoxetine (all • Rare seizures
potentially powerful enhancers of • Rare induction of hypomania and activation
noradrenergic action, but observe for of suicidal ideation
activation of bipolar disorder and suicidal
ideation) Weight Gain
• Modafinil, especially for fatigue, sleepiness,
and lack of concentration
• Mood stabilizers or atypical antipsychotics • Reported but not expected
for bipolar depression, psychotic • Possible weight loss, especially short-term
depression or treatment-resistant
depression Sedation
• Benzodiazepines
• If all else fails for anxiety disorders,
consider gabapentin or tiagabine
• Occurs in significant minority
• Hypnotics or trazodone for insomnia
• May also be activating in some patients
• Classically, lithium, buspirone, or thyroid
hormone What To Do About Side Effects
Tests • Wait
• Wait
• Check blood pressure before initiating
• Wait
treatment and regularly during treatment
• Lower the dose
• In a few weeks, switch or add other drugs
SIDE EFFECTS Best Augmenting Agents for Side
Effects
How Drug Causes Side Effects • Often best to try another antidepressant
• Theoretically due to increases in serotonin monotherapy prior to resorting to
and norepinephrine concentrations at augmentation strategies to treat side
receptors in parts of the brain and body effects
other than those that cause therapeutic • Trazodone or a hypnotic for insomnia
actions (e.g., unwanted actions of • Bupropion, sildenafil, vardenafil, or tadalafil
serotonin in sleep centers causing for sexual dysfunction
insomnia, unwanted actions of • Benzodiazepines for jitteriness and anxiety,
norepinephrine on acetylcholine release especially at initiation of treatment and
causing constipation and dry mouth, etc.) especially for anxious patients
• Most side effects are immediate but often • Mirtazapine for insomnia, agitation, and
go away with time gastrointestinal side effects
Notable Side Effects • Many side effects are dose-dependent (i.e.,
they increase as dose increases, or they
• Most side effects increase with higher
reemerge until tolerance re-develops)
doses, at least transiently
• Many side effects are time-dependent (i.e.,
• Headache, nervousness, insomnia,
they start immediately upon dosing and
sedation
upon each dose increase, but go away with
• Nausea, diarrhea, decreased appetite
time)
• Sexual dysfunction (abnormal
• Activation and agitation may represent the
ejaculation/orgasm, impotence)
induction of a bipolar state, especially a
• Asthenia, sweating
mixed dysphoric bipolar II condition
• SIADH (syndrome of inappropriate
sometimes associated with suicidal ideation,
antidiuretic hormone secretion)
and require the addition of lithium, a mood
• Hyponatremia
stabilizer or an atypical antipsychotic,
• Dose-dependent increase in blood pressure
and/or discontinuation of venlafaxine

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(continued) VENLAFAXINE

DOSING AND USE doses above 375 mg/day while monitoring

closely
Usual Dosage Range • Do not break or chew venlafaxine XR
• Depression: 75–225 mg/day, once daily capsules, as this will alter controlled
(extended release) or divided into release properties
2–3 doses (immediate release)
• GAD: 150–225 mg/day
✽ For patients with severe problems
discontinuing venlafaxine, dosing may need
to be tapered over many months (i.e.,
Dosage Forms
reduce dose by 1% every 3 days by
• Capsule (extended release) 37.5 mg,
crushing tablet and suspending or
75 mg, 150 mg
dissolving in 100 mL of fruit juice, and
• Tablet 25 mg scored, 37.5 mg scored,
then disposing of 1 mL while drinking the
50 mg scored, 75 mg scored, 100 mg
rest; 3–7 days later, dispose of 2 mL, and
scored
so on). This is both a form of very slow
How to Dose biological tapering and a form of behavioral
• Initial dose 37.5 mg once daily (extended desensitization
release) or 25–50 mg divided into • For some patients with severe problems
2–3 doses (immediate release) for a week, discontinuing venlafaxine, it may be useful
if tolerated; increase daily dose generally to add an SSRI with a long half-life,
no faster than 75 mg every 4 days until especially fluoxetine, prior to taper of
desired efficacy is reached; maximum dose venlafaxine; while maintaining fluoxetine
generally 375 mg/day dosing, first slowly taper venlafaxine and
• Usually try doses at 75 mg increments for then taper fluoxetine
a few weeks prior to incrementing by an • Be sure to differentiate between
additional 75 mg re-emergence of symptoms requiring
re-institution of treatment and withdrawal
symptoms
Dosing Tips Overdose
• At all doses, potent serotonin reuptake • Rarely lethal; may cause no symptoms;
blockade possible symptoms include sedation,
• 75–225 mg/day may be predominantly convulsions, rapid heartbeat
serotonergic in some patients, and dual
serotonin and norepinephrine acting in Long-Term Use
other patients • See doctor regularly to monitor blood
• 225–375 mg/day is dual serotonin and pressure, especially at doses >225 mg/day
norepinephrine acting in most patients
✽ Thus, nonresponders at lower doses Habit Forming
should try higher doses to be assured of • No
the benefits of dual SNRI action
• At very high doses (e.g., >375 mg/day), How to Stop
dopamine reuptake blocked as well in • Taper to avoid withdrawal effects
some patients (dizziness, nausea, stomach cramps,
• Up to 600 mg/day has been given for sweating, tingling, dysesthesias)
heroic cases • Many patients tolerate 50% dose reduction
• Venlafaxine has an active metabolite O- for 3 days, then another 50% reduction for
desmethylvenlafaxine (ODV), which is 3 days, then discontinuation
formed as the result of CYP450 2D6 • If withdrawal symptoms emerge during
• Thus, CYP450 2D6 inhibition reduces the discontinuation, raise dose to stop
formation of ODV, but this is of uncertain symptoms and then restart withdrawal
clinical significance much more slowly
✽ Consider checking plasma levels of ODV ✽ Withdrawal effects can be more common
and venlafaxine in nonresponders who or more severe with venlafaxine than with
tolerate high doses, and if plasma levels some other antidepressants
are low, experts can prudently prescribe

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VENLAFAXINE (continued)

Pharmacokinetics Elderly
• Parent drug has 3–7 hour half-life • Some patients may tolerate lower doses
• Active metabolite has 9–13 hour half-life better

Drug Interactions Children and Adolescents

• Tramadol increases the risk of seizures in • Use with caution, observing for activation
patients taking an antidepressant of known or unknown bipolar disorder
• Can cause a fatal “serotonin syndrome” and/or suicidal ideation, and strongly
when combined with MAO inhibitors, so do consider informing parents or guardian of
not use with MAO inhibitors or for at least this risk so they can help observe child or
14 days after MAOIs are stopped adolescent patients
• Do not start an MAO inhibitor for at least • Not specifically approved, but preliminary
2 weeks after discontinuing venlafaxine data suggest that venlafaxine is effective in
• Concomitant use with cimetidine may children and adolescents with depression,
reduce clearance of venlafaxine and raise anxiety disorders, and ADHD
venlafaxine levels
• Could theoretically interfere with the
analgesic actions of codeine or possibly Pregnancy
with other triptans • Risk Category C [some animal studies
• Few known adverse drug interactions show adverse effects, no controlled studies
in humans]
Other Warnings/ • Not generally recommended for use during
Precautions pregnancy, especially during first trimester
• Use with caution in patients with history of • Nonetheless, continuous treatment during
seizures pregnancy may be necessary and has not
• Use with caution in patients with bipolar been proven to be harmful to the fetus
disorder unless treated with concomitant • Must weigh the risk of treatment (first
mood stabilizing agent trimester fetal development, third trimester
• Monitor patients for activation of suicidal newborn delivery) to the child against the
ideation, especially children and risk of no treatment (recurrence of
adolescents depression, maternal health, infant
bonding) to the mother and child
Do Not Use • For many patients this may mean
• If patient has uncontrolled narrow angle- continuing treatment during pregnancy
closure glaucoma • Neonates exposed to SSRIs or SNRIs late
• If patient is taking an MAO inhibitor in the third trimester have developed
• If there is a proven allergy to venlafaxine complications requiring prolonged
hospitalization, respiratory support, and
tube feeding; reported symptoms are
consistent with either a direct toxic effect
SPECIAL POPULATIONS of SSRIs and SNRIs or, possibly, a drug
Renal Impairment discontinuation syndrome, and include
• Lower dose by 25–50% respiratory distress, cyanosis, apnea,
• Patients on dialysis should not receive seizures, temperature instability, feeding
subsequent dose until dialysis is completed difficulty, vomiting, hypoglycemia,
hypotonia, hypertonia, hyperreflexia,
Hepatic Impairment tremor, jitteriness, irritability, and constant
• Lower dose by 50% crying

Cardiac Impairment Breast Feeding

• Drug should be used with caution • Some drug is found in mother’s breast milk
• Venlafaxine has a dose-dependent effect on • Trace amounts may be present in nursing
blood pressure children whose mothers are on venlafaxine

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(continued) VENLAFAXINE

• If child becomes irritable or sedated, breast preferred treatments for treatment-resistant

feeding or drug may need to be depression
discontinued ✽ May be used in combination with other
• Immediate postpartum period is a high-risk antidepressants for treatment-refractory
time for depression, especially in women cases
who have had prior depressive episodes, • XR formulation improves tolerability,
so drug may need to be reinstituted late in reduces nausea, and requires only once-
the third trimester or shortly after daily dosing
childbirth to prevent a recurrence during • May be effective in a broad array of anxiety
the postpartum period disorders
• Must weigh benefits of breast feeding with • May be effective in adult ADHD
risks and benefits of antidepressant • Not studied in stress urinary incontinence
treatment versus non-treatment to both the ✽ Has greater potency for serotonin
infant and the mother reuptake blockade than for norepinephrine
• For many patients, this may mean reuptake blockade, but this is of unclear
continuing treatment during breast feeding clinical significance as a differentiating
feature from other SNRIs
✽ In vitro binding studies tend to
THE ART OF PSYCHOPHARMACOLOGY underestimate in vivo potency for reuptake
blockade, as they do not factor in the
Potential Advantages presence of high concentrations of an
• Patients with retarded depression active metabolite, higher oral mg dosing,
• Patients with atypical depression or the lower protein binding which can
• Patients with comorbid anxiety increase functional drug levels at receptor
• Patients with depression may have higher sites
remission rates on SNRIs than on SSRIs • Effective dose range is broad (i.e., 75 mg
• Depressed patients with somatic to 375 mg in many difficult cases, and up
symptoms, fatigue, and pain to 600 mg or more in heroic cases)
• Patients who do not respond or remit on ✽ Preliminary studies in neuropathic pain
treatment with SSRIs and fibromyalgia suggest potential efficacy
• Efficacy as well as side effects (especially
Potential Disadvantages nausea and increased blood pressure) are
• Patients sensitive to nausea dose-dependent
• Patients with borderline or uncontrolled • Blood pressure increases rare for XR
hypertension formulation in doses up to 225 mg
• More withdrawal reactions reported upon
Primary Target Symptoms discontinuation than for some other
• Depressed mood antidepressants
• Energy, motivation, and interest • May be helpful for hot flushes in
• Sleep disturbance perimenopausal women
• Anxiety • May be associated with higher depression
remission rates than SSRIs

Pearls
✽ May be effective in patients who fail to
respond to SSRIs, and may be one of the

509
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VENLAFAXINE (continued)

Suggested Reading
Hackett D. Venlafaxine XR in the treatment of venlafaxine compared with selective serotonin
anxiety. Acta Psychiatrica Scandinavica 2000; reuptake inhibitors and other antidepressants:
406[suppl]:30–35. a meta-analysis. Br J Psychiatry 2002;
180:396–404.
Sheehan DV. Attaining remission in
generalized anxiety disorder: venlafaxine Wellington K, Perry CM. Venlafaxine extended-
extended release comparative data. J Clin release: a review of its use in the management
Psychiatry 2001;62 Suppl 19:26–31. of major depression. CNS Drugs 2001;
15:643–69.
Smith D, Dempster C, Glanville J, Freemantle
N, Anderson I. Efficacy and tolerability of

510
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ZALEPLON
THERAPEUTICS • Agents with antihistamine actions (e.g.,
diphenhydramine, tricyclic antidepressants)
Brands • Sonata
see index for additional brand names Tests
• None for healthy individuals
Generic? No

Class SIDE EFFECTS

• Non-benzodiazepine hypnotic; alpha 1
How Drug Causes Side Effects
isoform antagonist of GABA-A/
• Actions at benzodiazepine receptors that
benzodiazepine receptors
carry over to the next day can cause
Commonly Prescribed For daytime sedation, amnesia, and ataxia
(bold for FDA approved) • Long-term adaptations of zaleplon not well
• Short-term treatment of insomnia studied, but chronic studies of other alpha
1 selective non-benzodiazepine hypnotics
suggest lack of notable tolerance or
dependence developing over time
How The Drug Works
• Binds selectively to a subtype of the Notable Side Effects
benzodiazepine receptor, the alpha 1 ✽ Sedation
isoform ✽ Dizziness, ataxia
• May enhance GABA inhibitory actions that ✽ Dose-dependent amnesia
provide sedative hypnotic effects more ✽ Hyper-excitability, nervousness
selectively than other actions of GABA • Rare hallucinations
• Boosts chloride conductance through • Headache
GABA-regulated channels • Decreased appetite
• Inhibitory actions in sleep centers may
provide sedative hypnotic effects
Life Threatening or
How Long Until It Works Dangerous Side Effects
• Generally takes effect in less than an hour • Respiratory depression, especially when
taken with other CNS depressants in
If It Works overdose
• Improves quality of sleep
• Effects on total wake-time and number of Weight Gain
nighttime awakenings may be decreased
over time

If It Doesn’t Work • Reported but not expected

• If insomnia does not improve after Sedation
7–10 days, it may be a manifestation of a
primary psychiatric or physical illness such
as obstructive sleep apnea or restless leg
syndrome, which requires independent • Many experience and/or can be significant
evaluation in amount
• Increase the dose
• Improve sleep hygiene What To Do About Side Effects
• Switch to another agent • Wait
• To avoid problems with memory, do not
Best Augmenting Combos take zaleplon if planning to sleep for less
for Partial Response or than 4 hours
Treatment-Resistance • Lower the dose
• Generally, best to switch to another agent • Administer flumazenil if side effects are
• Trazodone severe or life-threatening

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ZALEPLON (continued)

Best Augmenting Agents for Side How to Stop

Effects • Rebound insomnia may occur the first
• Many side effects cannot be improved with night after stopping
an augmenting agent • If taken for more than a few weeks, taper
to reduce chances of withdrawal effects

Pharmacokinetics
DOSING AND USE
• Terminal phase elimination half-life
Usual Dosage Range approximately 1 hour (ultra-short half-life)
• 10 mg/day at bedtime for 7–10 days

Dosage Forms Drug Interactions

• Capsule 5 mg, 10 mg • Increased depressive effects when taken
with other CNS depressants
How to Dose • Cimetidine may increase plasma
• Initial 10 mg/day at bedtime; may increase concentrations of zaleplon, requiring a
to 20 mg/day at bedtime if ineffective; lower initial dose of zaleplon (5 mg/day)
maximum dose generally 20 mg/day • CYP450 3A4 inducers such as
carbamazepine may reduce the
effectiveness of zaleplon
Dosing Tips
• Patients with lower body weights may Other Warnings/
require only a 5 mg dose
• Zaleplon should generally not be
Precautions
prescribed in quantities greater than a • Insomnia may be a symptom of a primary
1-month supply disorder, rather than a primary disorder
• Risk of dependence may increase with itself
dose and duration of treatment • Some patients may exhibit abnormal
thinking or behavioral changes similar to
✽ However, treatment with alpha 1 selective those caused by other CNS depressants
non-benzodiazepine hypnotics may cause
less tolerance or dependence than (i.e., either depressant actions or
benzodiazepine hypnotics disinhibiting actions)
• Some depressed patients may experience a
Overdose worsening of suicidal ideation
• No fatalities reported with zaleplon; • Use only with extreme caution in patients
fatalities have occurred with other sedative with impaired respiratory function or
hypnotics; sedation, confusion, ataxia, obstructive sleep apnea
hypotension, respiratory depression, coma • Zaleplon should only be administered at
bedtime
Long-Term Use
• Not generally intended for long-term use Do Not Use
• Increased wakefulness during the latter • If there is a proven allergy to zaleplon
part of night (wearing off) or an increase in
daytime anxiety (rebound) may occur
because of short half-life SPECIAL POPULATIONS
Habit Forming Renal Impairment
• Zaleplon is a Schedule IV drug • No dose adjustment necessary
• Some patients may develop dependence • Use with caution in patients with severe
and/or tolerance; risk may be greater with impairment
higher doses
• History of drug addiction may increase risk Hepatic Impairment
of dependence • Mild to moderate impairment:
recommended dose 5 mg

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(continued) ZALEPLON

• Not recommended for use in patients with THE ART OF PSYCHOPHARMACOLOGY

severe impairment
Potential Advantages
Cardiac Impairment • Those needing short duration of action
• Zaleplon has not been studied in patients
with cardiac impairment, but dose
Potential Disadvantages
adjustment may not be necessary • Those needing longer duration of action
• More expensive than some other sedative
Elderly hypnotics
• Recommended dose: 5 mg
Primary Target Symptoms
• Time to sleep onset
• Total sleep time
Children and Adolescents • Nighttime awakenings
• Safety and efficacy have not been
established
• Long-term effects of zaleplon in
children/adolescents are unknown
Pearls
• Should generally receive lower doses and • Zaleplon has not been shown to increase
be more closely monitored the total time asleep or to decrease the
number of awakenings
✽ May be preferred over benzodiazepines
because of its rapid onset of action, short
Pregnancy duration of effect, and safety profile
• Risk category C [some animal studies ✽ Popular for uses requiring short half-life
show adverse effects, no controlled studies (e.g., dosing in the middle of the night,
in humans] sleeping on airplanes, jet lag)
• Infants whose mothers took sedative ✽ May not be ideal for patients who desire
hypnotics during pregnancy may immediate hypnotic onset and eat just prior
experience some withdrawal symptoms to bedtime
• Neonatal flaccidity has been reported in • Not a benzodiazepine itself, but binds to
infants whose mothers took sedative benzodiazepine receptors
hypnotics during pregnancy • May have fewer carryover side effects than
some other sedative hypnotics
Breast Feeding • May not have sufficient efficacy in patients
• Some drug is found in mother’s breast milk with severe chronic insomnia resistant to
✽ Recommended either to discontinue drug some other sedative hypnotics
or bottle feed • May cause less dependence than some
other sedative hypnotics, especially in
those without a history of substance abuse
✽ Zaleplon is not absorbed as quickly if
taken with high fat foods, which may
reduce onset of action

Suggested Reading
Dooley M, Plosker GL. Zaleplon: a review of its Mangano RM. Efficacy and safety of zaleplon
use in the treatment of insomnia. Drugs 2000; at peak plasma levels. Int J Clin Pract Suppl
60:413–45. 2001;116:9–13.
Heydorn WE. Zaleplon – a review of a novel Weitzel KW, Wickman JM, Augustin SG, Strom
sedative hypnotic used in the treatment of JG. Zaleplon: a pyrazolopyrimidine sedative-
insomnia. Expert Opin Invest Drugs 2000; hypnotic agent for the treatment of insomnia.
9:841–58. Clin Ther 2000;22:1254–67.

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ZIPRASIDONE
THERAPEUTICS full effect on behavior as well as on
cognition and affective stabilization
Brands • Geodon • Classically recommended to wait at least
see index for additional brand names 4–6 weeks to determine efficacy of drug,
but in practice some patients require up to
Generic? Not in U.S. or Europe
16–20 weeks to show a good response,
especially on cognitive symptoms

Class If It Works
• Atypical antipsychotic (serotonin-dopamine • Most often reduces positive symptoms in
antagonist; second generation schizophrenia but does not eliminate them
antipsychotic; also a mood stabilizer) • Can improve negative symptoms, as well
as aggressive, cognitive, and affective
Commonly Prescribed For symptoms in schizophrenia
(bold for FDA approved) • Most schizophrenic patients do not have a
• Schizophrenia total remission of symptoms but rather a
• Delaying relapse in schizophrenia reduction of symptoms by about a third
• Acute agitation in schizophrenia • Perhaps 5–15% of schizophrenic patients
(intramuscular) can experience an overall improvement of
• Acute mania greater than 50–60%, especially when
• Other psychotic disorders receiving stable treatment for more than a
• Bipolar maintenance year
• Bipolar depression • Such patients are considered super-
• Behavioral disturbances in dementias responders or “awakeners” since they may
• Behavioral disturbances in children and be well enough to be employed, live
adolescents independently, and sustain long-term
• Disorders associated with problems with relationships
impulse control • Many bipolar patients may experience a
reduction of symptoms by half or more
• Continue treatment until reaching a plateau
How The Drug Works of improvement
• Blocks dopamine 2 receptors, reducing • After reaching a satisfactory plateau,
positive symptoms of psychosis and continue treatment for at least a year after
stabilizing affective symptoms first episode of psychosis
• Blocks serotonin 2A receptors, causing • For second and subsequent episodes of
enhancement of dopamine release in psychosis, treatment may need to be
certain brain regions and thus reducing indefinite
motor side effects and possibly improving • Even for first episodes of psychosis, it may
cognitive and affective symptoms be preferable to continue treatment
• Interactions at a myriad of other indefinitely to avoid subsequent episodes
neurotransmitter receptors may contribute • Treatment may not only reduce mania but
to ziprasidone’s efficacy also prevent recurrences of mania in
✽ Specifically, interactions at 5HT2C and bipolar disorder
5HT1A receptors may contribute to efficacy
for cognitive and affective symptoms in If It Doesn’t Work
some patients • Try one of the other atypical antipsychotics
✽ Specifically, interactions at 5HT1D (risperidone, olanzapine, quetiapine,
receptors and at serotonin, norepinephrine, aripiprazole, amisulpride)
and dopamine transporters (especially at • If 2 or more antipsychotic monotherapies
high doses) may contribute to efficacy for do not work, consider clozapine
affective symptoms in some patients • If no first-line atypical antipsychotic is
effective, consider higher doses or
How Long Until It Works augmentation with valproate or lamotrigine
• Psychotic symptoms can improve within • Some patients may require treatment with
1 week, but it may take several weeks for a conventional antipsychotic

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ZIPRASIDONE (continued)

• Consider noncompliance and switch to • Treat or refer for treatment and consider
another antipsychotic with fewer side switching to another atypical antipsychotic
effects or to an antipsychotic that can be for patients who become overweight,
given by depot injection obese, pre-diabetic, diabetic, hypertensive,
• Consider initiating rehabilitation and or dyslipidemic while receiving an atypical
psychotherapy antipsychotic
• Consider presence of concomitant drug ✽ Even in patients without known diabetes,
abuse be vigilant for the rare but life threatening
onset of diabetic ketoacidosis, which
Best Augmenting Combos always requires immediate treatment, by
for Partial Response or monitoring for the rapid onset of polyuria,
Treatment-Resistance polydipsia, weight loss, nausea, vomiting,
• Valproic acid (valproate, divalproex, dehydration, rapid respiration, weakness
divalproex ER) and clouding of sensorium, even coma
• Other mood stabilizing anticonvulsants • Routine EKGs for screening or monitoring
(carbamazepine, oxcarbazepine, of dubious clinical value
lamotrigine) • EKGs may be useful for selected patients
• Lithium (e.g., those with personal or family history
• Benzodiazepines of QTc prolongation; cardiac arrhythmia;
recent myocardial infarction;
Tests uncompensated heart failure; or those
Before starting an atypical antipsychotic taking agents that prolong QTc interval
✽ Weigh all patients and track BMI during such as pimozide, thioridazine, selected
antiarrhythmics, moxifloxacin, sparfloxacin,
treatment
• Get baseline personal and family history of etc.)
obesity, dyslipidemia, hypertension, and • Patients at risk for electrolyte disturbances
cardiovascular disease (e.g., patients on diuretic therapy) should
✽ Get waist circumference (at umbilicus), have baseline and periodic serum
potassium and magnesium measurements
blood pressure, fasting plasma glucose,
and fasting lipid profile
• Determine if the patient is
• overweight (BMI 25.0–29.9) SIDE EFFECTS
• obese (BMI ≥30)
• has pre-diabetes (fasting plasma glucose How Drug Causes Side Effects
100–125 mg/dl) • By blocking alpha 1 adrenergic receptors, it
• has diabetes (fasting plasma glucose can cause dizziness, sedation, and
>126 mg/dl) hypotension, especially at high doses
• has hypertension (BP >140/90 mm Hg) • By blocking dopamine 2 receptors in the
• has dyslipidemia (increased total striatum, it can cause motor side effects
cholesterol, LDL cholesterol, and (unusual)
triglycerides; decreased HDL cholesterol) ✽ Mechanism of any possible weight gain is
• Treat or refer such patients for treatment, unknown; weight gain is not common with
including nutrition and weight ziprasidone and may thus have a different
management, physical activity counseling, mechanism from atypical antipsychotics
smoking cessation, and medical for which weight gain is common or
management problematic
Monitoring after starting an atypical
✽ Mechanism of any possible increased
incidence of diabetes or dyslipidemia is
antipsychotic
unknown; early experience suggests these
✽ BMI monthly for 3 months, then quarterly complications are not clearly associated
✽ Blood pressure, fasting plasma glucose, with ziprasidone and if present may
fasting lipids within 3 months and then
therefore have a different mechanism from
annually, but earlier and more frequently
that of atypical antipsychotics associated
for patients with diabetes or who have
gained >5% of initial weight

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(continued) ZIPRASIDONE

with an increased incidence of diabetes and ✽ For sedating side effects at high doses,
dyslipidemia lower the dose
• Switch to another atypical antipsychotic
Notable Side Effects
✽ Some patients may experience activating Best Augmenting Agents for Side
side effects at very low to low doses Effects
• Dizziness, extrapyramidal symptoms, • Benztropine or trihexyphenidyl for motor
sedation, dystonia side effects
• Nausea, dry mouth • Many side effects cannot be improved with
• Asthenia, skin rash an augmenting agent
• Rare tardive dyskinesia (much reduced risk
compared to conventional antipsychotics)
• Orthostatic hypotension DOSING AND USE

Life Threatening or Usual Dosage Range

Dangerous Side Effects • Schizophrenia: 40–200 mg/day (in divided
doses) orally
• Rare neuroleptic malignant syndrome
• Bipolar disorder: 80–160 mg/day (in
(much reduced risk compared to
divided doses) orally
conventional antipsychotics)
• 10–20 mg intramuscularly
• Rare seizures

Weight Gain Dosage Forms

• Capsules 20 mg, 40 mg, 60 mg, 80 mg
• Injection 20 mg/mL

• Reported in a few patients, especially those How to Dose

with low BMIs, but not expected • Schizophrenia (according to manufacturer):
• Less frequent and less severe than for initial oral dose 20 mg twice a day;
most other antipsychotics however, 40 mg twice a day or 60 mg
twice a day may be better tolerated in many
Sedation patients (less activation); maximum
approved dose 100 mg twice a day
• Biplar disorder (according to
• Some patients experience manufacturer): initial oral dose 40 mg
• May be less than for some antipsychotics, twice a day; on day 2 increase to 60 or
more than for others 80 mg twice a day
• Usually transient and at higher doses • For intramuscular formulation,
• Can be activating at low doses recommended dose is 10–20 mg given as
required; doses of 10 mg may be
What To Do About Side Effects administered every 2 hours; doses of
• Wait 20 mg may be administered every 4 hours;
• Wait maximum daily dose 40 mg
• Wait intramuscularly; should not be
• Usually dosed twice daily, so take more of administered for more than 3 consecutive
the total daily dose at bedtime to help days
reduce daytime sedation
• Anticholinergics may reduce motor side
effects when present Dosing Tips
• Weight loss, exercise programs, and ✽ More may be much more: clinical
medical management for high BMIs, practice suggests ziprasidone often under-
diabetes, dyslipidemia dosed, then switched prior to adequate
✽ For activating side effects at low doses, trials, perhaps due to unjustified fears of
raise the dose QTc prolongation

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ZIPRASIDONE (continued)

✽ Dosing many patients at 20–40 mg twice • QTc prolongation of intramuscular

a day is too low and in fact activating, ziprasidone is the same or less than with
perhaps due to potent 5HT2C antagonist intramuscular haloperidol
properties
✽ Paradoxically, such activation is often Overdose
reduced by increasing the dose to • Rarely lethal in monotherapy overdose;
60–80 mg twice a day, perhaps due to sedation, slurred speech, transitory
increasing amounts of dopamine 2 hypertension
receptor antagonism
✽ Best efficacy in schizophrenia and bipolar Long-Term Use
disorder is at doses >120 mg/day, but only • Approved to delay relapse in long-term
a minority of patients are adequately dosed treatment of schizophrenia
in clinical practice • Often used for long-term maintenance in
• Doses up to 80 mg twice a day may have a bipolar disorder and various behavioral
lower cost than some other atypical disorders
antipsychotics
✽ Recommended to be taken with food Habit Forming
because food can double bioavailability by • No
increasing absorption and thus increasing
How to Stop
plasma drug levels
• Slow down-titration of oral formulation
• Some patients respond better to doses
(over 6 to 8 weeks), especially when
>160 mg/day and up to 320 mg/day in
simultaneously beginning a new
2 divided doses (i.e., 80–160 mg twice a
antipsychotic while switching (i.e. cross-
day)
titration)
• Although studies suggest patients
• Rapid oral discontinuation may lead to
switching to ziprasidone from another
rebound psychosis and worsening of
antipsychotic can do well with rapid cross-
symptoms
titration, clinical experience suggests many
patients do best by building up a full dose Pharmacokinetics
of ziprasidone (>120 mg/day) added to the
• Mean half-life 6.6 hours
maintenance dose of the first antipsychotic
• Protein binding >99%
for up to 3 weeks prior to slow down-
• Metabolized by CYP450 3A4
titration of the first antipsychotic
• QTc prolongation at 320 mg/day not
significantly greater than at 160 mg/day
• Rather than raise the dose above these Drug Interactions
levels in acutely agitated patients requiring • Neither CYP450 3A4 nor CYP450 2D6
acute antipsychotic actions, consider inhibitors significantly affect ziprasidone
augmentation with a benzodiazepine or plasma levels
conventional antipsychotic, either orally or • Little potential to affect metabolism of
intramuscularly drugs cleared by CYP450 enzymes
• Rather than raise the dose above these • May enhance the effects of
levels in partial responders, consider antihypertensive drugs
augmentation with a mood stabilizing • May antagonize levodopa, dopamine
anticonvulsant, such as valproate or agonists
lamotrigine • May enhance QTc prolongation of other
• Children and elderly should generally be drugs capable of prolonging QTc interval
dosed at the lower end of the dosage
spectrum Other Warnings/
• Ziprasidone intramuscular can be given
Precautions
short-term, both to initiate dosing with oral
• Ziprasidone prolongs QTc interval more
ziprasidone or another oral antipsychotic
than some other antipsychotics
and to treat breakthrough agitation in
patients maintained on oral antipsychotics

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(continued) ZIPRASIDONE

• Use with caution in patients with • Children and adolescents using ziprasidone
conditions that predispose to hypotension may need to be monitored more often than
(dehydration, overheating) adults and may tolerate lower doses better
• Priapism has been reported
• Dysphagia has been associated with
antipsychotic use, and ziprasidone should Pregnancy
be used cautiously in patients at risk for • Risk Category C [some animal studies
aspiration pneumonia show adverse effects, no controlled studies
in humans]
Do Not Use
• Psychotic symptoms may worsen during
• If patient is taking agents capable of
pregnancy and some form of treatment
significantly prolonging QTc interval (e.g.,
may be necessary
pimozide, thioridazine, selected
• Ziprasidone may be preferable to
antiarrhythmics, moxifloxacin,
anticonvulsant mood stabilizers if
sparfloxacin)
treatment is required during pregnancy
• If there is a history of QTc prolongation or
cardiac arrhythmia, recent acute Breast Feeding
myocardial infarction, uncompensated • Unknown if ziprasidone is secreted in
heart failure human breast milk, but all psychotropics
• If there is a proven allergy to ziprasidone assumed to be secreted in breast milk
✽ Recommended either to discontinue drug
or bottle feed
SPECIAL POPULATIONS • Infants of women who choose to breast
feed while on ziprasidone should be
Renal Impairment monitored for possible adverse effects
• No dose adjustment necessary
• Not removed by hemodialysis
• Intramuscular formulation should be used THE ART OF PSYCHOPHARMACOLOGY
with caution
Potential Advantages
Hepatic Impairment • Some cases of psychosis and bipolar
• No dose adjustment necessary disorder refractory to treatment with other
Cardiac Impairment antipsychotics
• Ziprasidone is contraindicated in patients ✽ Patients concerned about gaining weight
with a known history of QTc prolongation, ✽ Patients with diabetes
• Patients requiring rapid relief of symptoms
recent acute myocardial infarction, and
(intramuscular injection)
uncompensated heart failure
• Patients switching from intramuscular
• Should be used with caution in other cases
ziprasidone to an oral preparation
of cardiac impairment because of risk of
orthostatic hypotension Potential Disadvantages
Elderly • Patients noncompliant with twice daily
dosing
• Some patients may tolerate lower doses
better ✽ Patients noncompliant with dosing with
food

Primary Target Symptoms

Children and Adolescents • Positive symptoms of psychosis
• Not officially recommended for patients • Negative symptoms of psychosis
under age 18 • Cognitive symptoms
• Clinical experience and early data suggest • Unstable mood (both depression and
ziprasidone may be safe and effective for mania)
behavioral disturbances in children and • Aggressive symptoms
adolescents

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ZIPRASIDONE (continued)

• Less sedation than some antipsychotics,

more than others (at moderate to high
Pearls doses)
✽ QTc prolongation fears are often ✽ More activating than some other
exaggerated and not justified since QTc antipsychotics at low doses
prolongation with ziprasidone is not dose- • One of the least expensive atypical
related and few drugs have any potential to antipsychotics within recommended
increase ziprasidone’s plasma levels therapeutic dosing range
✽ Efficacy may be underestimated since • Anecdotal reports of utility in treatment-
ziprasidone is mostly under-dosed resistant cases, especially when adequately
(<120 mg/day) in clinical practice dosed
✽ Well-accepted in clinical practice when ✽ One of only 2 atypical antipsychotics with
wanting to avoid weight gain because less a short-acting intramuscular dosage
weight gain than most other atypical formulation
antipsychotics
✽ May not have diabetes or dyslipidemia
risk, but monitoring is still indicated

Suggested Reading
Bantick RA, Deakin JF, Grasby PM. The 5- Taylor D. Ziprasidone in the management of
HT1A receptor in schizophrenia: a promising schizophrenia : the QT interval issue in
target for novel atypical neuroleptics? J context. CNS Drugs 2003;17:423–30.
Psychopharmacol 2001;15:37–46.
Yatham LN. Efficacy of atypical antipsychotics
Gunasekara NS, Spencer CM, Keating GM. in mood disorders. J Clin Psychopharmacol
Spotlight on ziprasidone in schizophrenia and 2003;23(3 Suppl 1):S9–14.
schizoaffective disorder. CNS Drugs
2002;16:645–52.
Keck PE Jr, McElroy SL, Arnold LM.
Ziprasidone: a new atypical antipsychotic.
Expert Opin Pharmacother 2001;2:1033–42.

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0521011698s10.qxd 9/2/04 2:49 PM Page 521

ZOLPIDEM
THERAPEUTICS • Agents with antihistamine actions (e.g.,
diphenhydramine, tricyclic antidepressants)
Brands • Ambien
see index for additional brand names Tests
• None for healthy individuals
Generic? No

Class SIDE EFFECTS

• Non-benzodiazepine hypnotic; alpha 1
How Drug Causes Side Effects
isoform selective antagonist of GABA-A/
• Actions at benzodiazepine receptors that
benzodiazepine receptors
carry over to the next day can cause
Commonly Prescribed For daytime sedation, amnesia, and ataxia
(bold for FDA approved) • Long-term adaptations of zolpidem not well
• Short-term treatment of insomnia studied, but chronic studies of other alpha
1 selective non-benzodiazepine hypnotics
suggest lack of notable tolerance or
dependence developing over time
How The Drug Works
• Binds selectively to a subtype of the Notable Side Effects
benzodiazepine receptor, the alpha 1 ✽ Sedation
isoform ✽ Dizziness, ataxia
• May enhance GABA inhibitory actions that ✽ Dose-dependent amnesia
provide sedative hypnotic effects more ✽ Hyper-excitability, nervousness
selectively than other actions of GABA • Rare hallucinations
• Boosts chloride conductance through • Diarrhea, nausea
GABA-regulated channels • Headache
• Inhibitory actions in sleep centers may
provide sedative hypnotic effects
Life Threatening or
How Long Until It Works Dangerous Side Effects
• Generally takes effect in less than an hour • Respiratory depression, especially when
taken with other CNS depressants in
If It Works overdose
• Improves quality of sleep
• Effects on total wake-time and number of Weight Gain
nighttime awakenings may be decreased
over time

If It Doesn’t Work • Reported but not expected

• If insomnia does not improve after Sedation
7–10 days, it may be a manifestation of a
primary psychiatric or physical illness such
as obstructive sleep apnea or restless leg
syndrome, which requires independent • Many experience and/or can be significant
evaluation in amount
• Increase the dose
• Improve sleep hygiene What To Do About Side Effects
• Switch to another agent • Wait
• To avoid problems with memory, only take
Best Augmenting Combos zolpidem if planning to have a full night’s
for Partial Response or sleep
Treatment-Resistance • Lower the dose
• Generally, best to switch to another agent • Switch to a shorter-acting sedative
• Trazodone hypnotic

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ZOLPIDEM (continued)

• Administer flumazenil if side effects are How to Stop

severe or life-threatening • Although rebound insomnia could occur,
this effect has not generally been seen with
Best Augmenting Agents for Side therapeutic doses of zolpidem
Effects • If taken for more than a few weeks, taper
• Many side effects cannot be improved with to reduce chances of withdrawal effects
an augmenting agent
Pharmacokinetics
• Short elimination half-life (approximately
DOSING AND USE 2.5 hours)

Usual Dosage Range

• 10 mg/day at bedtime for 7–10 days Drug Interactions
• Increased depressive effects when taken
Dosage Forms with other CNS depressants
• Tablet 5 mg • Sertraline may increase plasma levels of
zolpidem
How to Dose • Rifampin may decrease plasma levels of
• 10 mg/day at bedtime zolpidem

Dosing Tips Other Warnings/

✽ Zolpidem is not absorbed as quickly if Precautions
taken with food, which could reduce onset • Insomnia may be a symptom of a primary
of action disorder, rather than a primary disorder
• Patients with lower body weights may itself
require only a 5 mg dose • Some patients may exhibit abnormal
• Zolpidem should generally not be thinking or behavioral changes similar to
prescribed in quantities greater than a those caused by other CNS depressants
1-month supply (i.e., either depressant actions or
• Risk of dependence may increase with disinhibiting actions)
dose and duration of treatment • Some depressed patients may experience a
✽ However, treatment with alpha 1 selective worsening of suicidal ideation
non-benzodiazepine hypnotics may cause • Use only with extreme caution in patients
less tolerance or dependence than with impaired respiratory function or
benzodiazepine hypnotics obstructive sleep apnea
• Zolpidem should only be administered at
Overdose bedtime
• No fatalities reported with zolpidem • Temporary memory loss may occur at
monotherapy; sedation, ataxia, confusion, doses above 10 mg/night
hypotension, respiratory depression, coma
Do Not Use
Long-Term Use • If there is a proven allergy to zolpidem
• Not generally intended for long-term use
• Increased wakefulness during the latter
part of night (wearing off) or an increase in SPECIAL POPULATIONS
daytime anxiety (rebound) may occur
Renal Impairment
Habit Forming • No dose adjustment necessary
• Zolpidem is a Schedule IV drug • Patients should be monitored
• Some patients may develop dependence
and/or tolerance; risk may be greater with Hepatic Impairment
higher doses • Recommended dose 5 mg
• History of drug addiction may increase risk • Patients should be monitored
of dependence

522
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(continued) ZOLPIDEM

Cardiac Impairment THE ART OF PSYCHOPHARMACOLOGY

• No available data
Potential Advantages
Elderly • Patients who require long-term treatment
• Recommended initial dose: 5 mg
Potential Disadvantages
• Elderly may have increased risk for falls,
• More expensive than some other sedative
confusion
hypnotics

Primary Target Symptoms

Children and Adolescents • Time to sleep onset
• Safety and efficacy have not been • Total sleep time
established • Nighttime awakenings
• Long-term effects of zolpidem in
children/adolescents are unknown
• Should generally receive lower doses and Pearls
be more closely monitored
✽ One of the most popular sedative
hypnotic agents in psychopharmacology
• Zolpidem has been shown to increase the
Pregnancy total time asleep and to reduce the amount
• Risk category B [animal studies do not of nighttime awakenings
show adverse effects, no controlled studies ✽ May be preferred over benzodiazepines
in humans] because of its rapid onset of action, short
• Infants whose mothers took sedative duration of effect, and safety profile
hypnotics during pregnancy may • Clearance of zolpidem may be slightly
experience some withdrawal symptoms slower in women than in men
• Neonatal flaccidity has been reported in • May not be ideal for patients who desire
infants whose mothers took sedative immediate hypnotic onset and eat just prior
hypnotics during pregnancy to bedtime
• Not a benzodiazepine itself, but binds to
Breast Feeding benzodiazepine receptors
• Some drug is found in mother’s breast milk • May have fewer carryover side effects than
✽ Recommended either to discontinue drug some other sedative hypnotics
or bottle feed • May cause less dependence than some
other sedative hypnotics, especially in
those without a history of substance abuse

Suggested Reading
Holm KJ, Goa KL. Zolpidem: an update of its Soyka M, Bottlender R, Moller HJ.
pharmacology, therapeutic efficacy and Epidemiological evidence for a low abuse
tolerability in the treatment of insomnia. Drugs potential of zolpidem. Pharmacopsychiatry
2000;59:865–89. 2000;33:138–41.
Rush CR. Behavioral pharmacology of Toner LC, Tsambiras BM, Catalano G, Catalano
zolpidem relative to benzodiazepines: a review. MC, Cooper DS. Central nervous system side
Pharmacol Biochem Behav 1998;61:253–69. effects associated with zolpidem treatment.
Clin Neuropharmacol 2000;23:54–8.

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0521011698s10.qxd 9/2/04 2:49 PM Page 525

ZONISAMIDE
THERAPEUTICS If It Doesn’t Work (for conditions
Brands • Zonegran other than epilepsy)
• May only be effective in patients who fail to
• Excegran
respond to agents with proven efficacy, or
see index for additional brand names
it may not work at all
Generic? Not in U.S. • Consider increasing dose or switching to
another agent with better demonstrated
efficacy
Class Best Augmenting Combos
• Anticonvulsant, voltage-sensitive sodium for Partial Response or
channel modulator; T-type calcium channel Treatment-Resistance
modulator; structurally a sulfonamide
• Zonisamide is itself a second-line
Commonly Prescribed For augmenting agent to numerous other
agents in treating conditions other than
(bold for FDA approved)
epilepsy, such as bipolar disorder, chronic
• Adjunct therapy for partial seizures in
neuropathic pain, and migraine
adults with epilepsy
• Bipolar disorder Tests
• Chronic neuropathic pain
• Consider baseline and periodic monitoring
• Migraine
of renal function
• Parkinson’s disease
• Psychotropic drug-induced weight gain
• Binge-eating disorder
SIDE EFFECTS
How Drug Causes Side Effects
How The Drug Works • CNS side effects theoretically due to
• Unknown excessive actions at voltage-sensitive ion
• Modulates voltage-sensitive sodium channels
channels by an unknown mechanism • Weak inhibition of carbonic anhydrase may
• Also modulates T-type calcium channels lead to kidney stones
• Blocks glutamate release • Serious rash theoretically an allergic
• Facilitates dopamine and serotonin release reaction
• Inhibits MAO-B
• Inhibits carbonic anhydrase Notable Side Effects
How Long Until It Works
✽ Sedation, depression, difficulty
concentrating, agitation, irritability,
• Should reduce seizures by 2 weeks psychomotor slowing, dizziness, ataxia
• Onset of action as well as convincing • Headache
therapeutic efficacy have not been • Nausea, anorexia, abdominal pain, vomiting
demonstrated for uses other than • Kidney stones
adjunctive treatment of partial seizures • Elevated serum creatinine and blood urea
nitrogen
If It Works
• The goal of treatment is complete
remission of symptoms (e.g., seizures, Life Threatening or
pain, mania, migraine) Dangerous Side Effects
• Would currently only be expected to work • Rare serious rash (Stevens Johnson
in a subset of patients for conditions other syndrome, toxic epidermal necrolysis)
than epilepsy as an adjunctive treatment to (sulfonamide)
agents with better demonstration of • Rare oligohidrosis and hyperthermia
efficacy (pediatric patients)
• Rare blood dyscrasias (aplastic anemia;
agranulocytosis)
• Sudden hepatic necrosis

525
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ZONISAMIDE (continued)

• Sudden unexplained deaths have occurred • No evidence from controlled trials of

(unknown if related to zonisamide use) increasing response over 400 mg/day
• However, some patients may tolerate and
Weight Gain respond to doses up to 600 mg/day
• Little experience with doses greater than
600 mg/day
• Reported but not expected • Side effects may increase notably at doses
✽ Patients may experience weight loss greater than 300 mg/day
• For intolerable sedation, can give most of
Sedation the dose at night and less during the day

Overdose
• No fatalities; bradycardia, hypotension,
• Many experience and/or can be significant respiratory depression
in amount
• Dose-related Long-Term Use
• Can wear off with time but may not wear • Safe
off at high doses • Consider periodic monitoring of blood urea
nitrogen and creatinine
What To Do About Side Effects
• Wait Habit Forming
• Wait • No
• Wait
• Take more of the dose at night to reduce How to Stop
daytime sedation • Taper
• Lower the dose • Epilepsy patients may seize upon
• Switch to another agent withdrawal, especially if withdrawal is
abrupt
Best Augmenting Agents for Side • Rapid discontinuation may increase the
Effects risk of relapse in bipolar patients
• Many side effects cannot be improved with • Discontinuation symptoms uncommon
an augmenting agent
Pharmacokinetics
• Plasma elimination half-life approximately
DOSING AND USE 63 hours
• Metabolized in part by CYP450 3A4
Usual Dosage Range • Partially eliminated renally
• 100–600 mg/day in 1–2 doses

Dosage Forms Drug Interactions

• Capsule 25 mg, 50 mg, 100 mg • Agents that inhibit CYP450 3A4 (such as
nefazodone, fluvoxamine, and fluoxetine)
How to Dose may decrease the clearance of zonisamide,
• Initial 100 mg/day; after 2 weeks can and increase plasma zonisamide levels,
increase to 200 mg/day; dose can be possibly requiring lower doses of
increased by 100 mg/day every 2 weeks if zonisamide
necessary and tolerated; maximum dose • Agents that induce CYP450 3A4 (such as
generally 600 mg/day; maintain stable dose carbamazepine) may increase the clearance
for at least 2 weeks before increasing dose of zonisamide and decrease plasma
zonisamide levels, possibly requiring
higher doses of zonisamide
Dosing Tips • Enzyme-inducing antiepileptic drugs
✽ Most clinical experience is at doses up to (carbamazepine, phenytoin, phenobarbital,
400 mg/day and primidone) may decrease plasma
levels of zonisamide

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(continued) ZONISAMIDE

• Theoretically, zonisamide may interact with

carbonic anhydrase inhibitors to increase
the risk of kidney stones Children and Adolescents
• Cases of oligohidrosis and hyperthermia
have been reported
Other Warnings/ • Not approved for use in children
Precautions • Use in children for the expert only, with
• Depressive effects may be increased by close monitoring, after other options have
other CNS depressants (alcohol, MAOIs, failed
other anticonvulsants, etc.)
• Use with caution when combining with
other drugs that predispose patients to Pregnancy
heat-related disorders, including carbonic • Risk category C [some animal studies
anhydrase inhibitors and anticholinergics show adverse effects, no controlled studies
✽ Life-threatening rashes have developed in in humans]
association with zonisamide use; • Use in women of childbearing potential
zonisamide should generally be requires weighing potential benefits to the
discontinued at the first sign of serious mother against the risks to the fetus
rash • Taper drug if discontinuing
• Patient should be instructed to report any • Seizures, even mild seizures, may cause
symptoms of hypersensitivity immediately harm to the embryo/fetus
(fever; flu-like symptoms; rash; blisters on • Lack of convincing efficacy for treatment of
skin or in eyes, mouth, ears, nose, or conditions other than epilepsy suggests
genital areas; swelling of eyelids, risk/benefit ratio is in favor of
conjunctivitis, lymphadenopathy) discontinuing zonisamide during pregnancy
• Patients should be monitored for signs of for these indications
unusual bleeding or bruising, mouth sores,
infections, fever, and sore throat, as there Breast Feeding
may be an increased risk of aplastic anemia • Unknown if zonisamide is secreted in
and agranulocytosis with zonisamide human breast milk, but all psychotropics
assumed to be secreted in breast milk
Do Not Use
• If there is a proven allergy to zonisamide or
✽ Recommended either to discontinue drug
or bottle feed
sulfonamides • If drug is continued while breast feeding,
infant should be monitored for possible
adverse effects
SPECIAL POPULATIONS • If child becomes irritable or sedated, breast
feeding or drug may need to be
Renal Impairment discontinued
• Zonisamide is primarily renally excreted
• Use with caution
• May require slower titration
THE ART OF PSYCHOPHARMACOLOGY
Hepatic Impairment
Potential Advantages
• Use with caution
• Treatment-resistant conditions
• May require slower titration
• Patients who wish to avoid weight gain
Cardiac Impairment
Potential Disadvantages
• No specific recommendations
• Poor documentation of efficacy for off-label
Elderly uses
• Some patients may tolerate lower doses • Patients noncompliant with twice daily
better dosing
• Elderly patients may be more susceptible
Primary Target Symptoms
to adverse effects
• Seizures

527
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ZONISAMIDE (continued)

• Numerous other symptoms for off-label • Early studies suggest possible utility in
uses Parkinson’s disease
• Patients with a history of kidney stones • Preclinical studies suggest possible utility
in neuropathic pain
• Early studies suggest some therapeutic
Pearls potential for mood stabilizing
• Well studied in epilepsy • Chronic intake of caffeine may lower brain
✽ Much off-label use is based upon zonisamide concentrations and attenuate
its anticonvulsant effects
theoretical considerations rather than
clinical experience or compelling efficacy ✽ Due to reported weight loss in some
studies patients in trials with epilepsy, some
• Early studies suggest efficacy in binge- patients with psychotropic-induced weight
eating disorder gain are treated with zonisamide
• Early studies suggest possible efficacy in • Utility for this indication is not clear nor
migraine has it been systematically studied

Suggested Reading
Chadwick DW, Marson AG. Zonisamide add-on Jain KK. An assessment of zonisamide as an
for drug-resistant partial epilepsy. Cochrane anti-epileptic drug. Expert Opin Pharmacother.
Database Syst Rev. 2002;(2):CD001416. 2000;1:1245–60.
Glauser TA, Pellock JM. Zonisamide in Leppik IE. Three new drugs for epilepsy:
pediatric epilepsy: review of the Japanese levetiracetam, oxcarbazepine, and zonisamide.
experience. J Child Neurol. 2002;17:87–96. J Child Neurol. 2002;17 Suppl 1:S53–7.

528
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ZOPICLONE
THERAPEUTICS • Agents with antihistamine actions (e.g.,
diphenhydramine, tricyclic antidepressants)
Brands • Imovane
see index for additional brand names Tests
• None for healthy individuals
Generic? No

Class SIDE EFFECTS

• Non-benzodiazepine hypnotic; alpha 1
How Drug Causes Side Effects
isoform selective antagonist of GABA-A/
• Actions at benzodiazepine receptors that
benzodiazepine receptors
carry over to the next day can cause
Commonly Prescribed For daytime sedation, amnesia, and ataxia
(bold for FDA approved) ✽ Long-term adaptations of zopiclone, a
• Short-term treatment of insomnia mixture of an active S enantiomer and an
inactive R enantiomer, have not been well
studied, but chronic studies of the active
isomer eszopiclone suggest lack of notable
How The Drug Works tolerance or dependence developing over
• May bind selectively to a subtype of the time
benzodiazepine receptor, the alpha 1
isoform Notable Side Effects
• May enhance GABA inhibitory actions that ✽ Sedation
provide sedative hypnotic effects more ✽ Dizziness, ataxia
selectively than other actions of GABA ✽ Dose-dependent amnesia
• Boosts chloride conductance through ✽ Hyper-excitability, nervousness
GABA-regulated channels • Dry mouth, loss of appetite, constipation,
• Inhibitory actions in sleep centers may bitter taste
provide sedative hypnotic effects • Impaired vision
How Long Until It Works
• Generally takes effect in less than an hour Life Threatening or
Dangerous Side Effects
If It Works • Respiratory depression, especially when
• Improves quality of sleep taken with other CNS depressants in
• Effects on total wake-time and number of overdose
nighttime awakenings may be decreased
over time Weight Gain
If It Doesn’t Work
• If insomnia does not improve after 7–10
days, it may be a manifestation of a • Reported but not expected
primary psychiatric or physical illness such Sedation
as obstructive sleep apnea or restless leg
syndrome, which requires independent
evaluation
• Increase the dose • Many experience and/or can be significant
• Improve sleep hygiene in amount
• Switch to another agent
What To Do About Side Effects
Best Augmenting Combos • Wait
for Partial Response or • To avoid problems with memory, only take
Treatment-Resistance zopiclone if planning to have a full night’s
• Generally, best to switch to another agent sleep
• Trazodone • Lower the dose

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ZOPICLONE (continued)

• Switch to a shorter-acting sedative Pharmacokinetics

hypnotic • Metabolized by CYP450 3A4
• Administer flumazenil if side effects are • Terminal elimination half-life approximately
severe or life-threatening 3.5–6.5 hours

Best Augmenting Agents for Side

Effects Drug Interactions
• Many side effects cannot be improved with • Increased depressive effects when taken
an augmenting agent with other CNS depressants
• Theoretically, inhibitors of CYP450 3A4,
such as nefazodone and fluvoxamine, could
DOSING AND USE increase plasma levels of zopiclone
Usual Dosage Range
• 7.5 mg at bedtime Other Warnings/
Precautions
Dosage Forms • Insomnia may be a symptom of a primary
• Tablet 7.5 mg scored disorder, rather than a primary disorder
itself
How to Dose • Some patients may exhibit abnormal
• No titration, take dose at bedtime thinking or behavioral changes similar to
those caused by other CNS depressants
(i.e., either depressant actions or
Dosing Tips disinhibiting actions)
• Zopiclone should generally not be • Some depressed patients may experience a
prescribed in quantities greater than a worsening of suicidal ideation
1-month supply • Use only with extreme caution in patients
• Risk of dependence may increase with with impaired respiratory function or
dose and duration of treatment obstructive sleep apnea
• However, chronic treatment with alpha 1 • Zopiclone should only be administered at
selective non-benzodiazepine hypnotics bedtime
may cause less tolerance or dependence
than benzodiazepine hypnotics Do Not Use
• If patient has myasthenia gravis
Overdose • If patient has severe respiratory
• Can be fatal; clumsiness, mood changes, impairment
sedation, weakness, breathing trouble, • If patient has had a stroke
unconsciousness • If there is a proven allergy to zopiclone

Long-Term Use
• Not generally intended for use past SPECIAL POPULATIONS
4 weeks
Renal Impairment
Habit Forming • Increased plasma levels
• Some patients may develop dependence • May need to lower dose
and/or tolerance; risk may be greater with
higher doses Hepatic Impairment
• History of drug addiction may increase risk • Increased plasma levels
of dependence • Recommended dose 3.75 mg

How to Stop Cardiac Impairment

• Rebound insomnia may occur the first • Dosage adjustment may not be necessary
night after stopping
• If taken for more than a few weeks, taper Elderly
to reduce chances of withdrawal effects • May be more susceptible to adverse effects

530
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(continued) ZOPICLONE

• Initial dose 3.75 mg at bedtime; can THE ART OF PSYCHOPHARMACOLOGY

increase to usual adult dose if necessary
and tolerated
Potential Advantages
• Those who require long-term treatment

Potential Disadvantages
Children and Adolescents • More expensive than some other sedative
• Safety and efficacy have not been hypnotics
established
• Long-term effects of zopiclone in Primary Target Symptoms
children/adolescents are unknown • Time to sleep onset
• Should generally receive lower doses and • Nighttime awakenings
be more closely monitored • Total sleep time

Pregnancy Pearls
• Risk category C [some animal studies ✽ May be preferred over benzodiazepines
show adverse effects, no controlled studies because of its rapid onset of action, short
in humans] duration of effect, and safety profile
• Infants whose mothers took sedative • Zopiclone does not appear to be a highly
hypnotics during pregnancy may dependence-causing drug, at least not in
experience some withdrawal symptoms patients with no history of drug abuse
• Neonatal flaccidity has been reported in • Rebound insomnia does not appear to be
infants whose mothers took sedative common
hypnotics during pregnancy • Not a benzodiazepine itself, but binds to
benzodiazepine receptors
Breast Feeding • May have fewer carryover side effects than
• Some drug is found in mother’s breast milk some other sedative hypnotics
✽ Recommended either to discontinue drug • The active enantiomer of zopiclone,
or bottle feed eszopiclone, has received an approvable
letter from the United States Food and
Drug Administration

Suggested Reading
Fernandez C, Martin C, Gimenez F, Farinotti R. Noble S, Langtry HD, Lamb HM. Zopiclone. An
Clinical pharmacokinetics of zopiclone. Clin update of its pharmacology, clinical efficacy
Pharmacokinet 1995;29:431–41. and tolerability in the treatment of insomnia.
Drugs 1998;55:277–302.
Hajak G. A comparative assessment of the
risks and benefits of zopiclone: a review of 15
years’ clinical experience. Drug Saf 1999;
21:457–69.

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0521011698s10.qxd 9/2/04 2:49 PM Page 533

ZOTEPINE
THERAPEUTICS • Perhaps 5–15% of schizophrenic patients
can experience an overall improvement of
Brands • Lodopin greater than 50–60%, especially when
• Zoleptil receiving stable treatment for more than a
see index for additional brand names year
• Such patients are considered super-
Generic? No
responders or “awakeners” since they may
be well enough to be employed, live
independently, and sustain long-term
Class relationships
• Atypical antipsychotic (serotonin-dopamine • Many bipolar patients may experience a
antagonist) reduction of symptoms by half or more
• Continue treatment until reaching a plateau
Commonly Prescribed For of improvement
(bold for FDA approved) • After reaching a satisfactory plateau,
• Schizophrenia continue treatment for at least a year after
• Other psychotic disorders first episode of psychosis
• Mania • For second and subsequent episodes of
psychosis, treatment may need to be
indefinite
How The Drug Works • Even for first episodes of psychosis, it may
• Blocks dopamine 2 receptors, reducing be preferable to continue treatment
positive symptoms of psychosis indefinitely to avoid subsequent episodes
• Blocks serotonin 2A receptors, causing • Treatment may not only reduce mania but
enhancement of dopamine release in also prevent recurrences of mania in
certain brain regions and thus reducing bipolar disorder
motor side effects and possibly improving
cognitive and affective symptoms If It Doesn’t Work
• Interactions at a myriad of other • Consider trying one of the first-line atypical
neurotransmitter receptors may contribute antipsychotics (risperidone, olanzapine,
to zotepine’s efficacy quetiapine, ziprasidone, aripiprazole,
✽ Specifically inhibits norepinephrine amisulpride)
uptake • If 2 or more antipsychotic monotherapies
do not work, consider clozapine
How Long Until It Works • If no first-line atypical antipsychotic is
• Psychotic symptoms can improve within effective, consider higher doses or
1 week, but it may take several weeks for augmentation with valproate or lamotrigine
full effect on behavior as well as on • Some patients may require treatment with
cognition and affective stabilization a conventional antipsychotic
• Classically recommended to wait at least • Consider noncompliance and switch to
4–6 weeks to determine efficacy of drug, another antipsychotic with fewer side
but in practice some patients require up to effects or to an antipsychotic that can be
16–20 weeks to show a good response, given by depot injection
especially on cognitive symptoms • Consider initiating rehabilitation and
psychotherapy
If It Works • Consider presence of concomitant drug
• Most often reduces positive symptoms in abuse
schizophrenia but does not eliminate them
• Can improve negative symptoms, as well Best Augmenting Combos
as aggressive, cognitive, and affective for Partial Response or
symptoms in schizophrenia Treatment-Resistance
• Most schizophrenic patients do not have a • Augmentation of zotepine has not been
total remission of symptoms but rather a systematically studied
reduction of symptoms by about a third • Valproic acid (valproate, divalproex,
divalproex ER)

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ZOTEPINE (continued)

• Other mood stabilizing anticonvulsants monitoring for the rapid onset of polyuria,
(carbamazepine, oxcarbazepine, polydipsia, weight loss, nausea, vomiting,
lamotrigine) dehydration, rapid respiration, weakness
• Lithium and clouding of sensorium, even coma
• Benzodiazepines • EKGs may be useful for selected patients
(e.g., those with personal or family history
Tests of QTc prolongation; cardiac arrhythmia;
✽ Although risk of diabetes and recent myocardial infarction;
dyslipidemia with zotepine has not been uncompensated heart failure; or those
systematically studied, monitoring as for all taking agents that prolong QTc interval
other atypical antipsychotics is suggested such as pimozide, thioridazine, selected
Before starting an atypical antipsychotic antiarrhythmics, moxifloxacin, sparfloxacin,
✽ Weigh all patients and track BMI during etc.)
treatment • Patients at risk for electrolyte disturbances
• Get baseline personal and family history of (e.g., patients on diuretic therapy) should
obesity, dyslipidemia, hypertension, and have baseline and periodic serum
cardiovascular disease potassium and magnesium measurements
✽ Get waist circumference (at umbilicus), • Patients with suspected hematologic
blood pressure, fasting plasma glucose, abnormalities may require a white blood
and fasting lipid profile cell count before initiating treatment
• Determine if the patient is • Monitor liver function tests in patients with
• overweight (BMI 25.0–29.9) established liver disease
• obese (BMI ≥30) • Should check blood pressure in the elderly
• has pre-diabetes (fasting plasma glucose before starting and for the first few weeks
100–125 mg/dl) of treatment
• has diabetes (fasting plasma glucose
>126 mg/dl)
• has hypertension (BP >140/90 mm Hg) SIDE EFFECTS
• has dyslipidemia (increased total
cholesterol, LDL cholesterol, and How Drug Causes Side Effects
triglycerides; decreased HDL cholesterol) • By blocking alpha 1 adrenergic receptors, it
• Treat or refer such patients for treatment, can cause dizziness, sedation, and
including nutrition and weight hypotension
management, physical activity counseling, • By blocking histamine 1 receptors in the
smoking cessation, and medical brain, it can cause sedation and weight
management gain
• By blocking dopamine 2 receptors in the
Monitoring after starting an atypical
striatum, it can cause motor side effects
antipsychotic
• By blocking dopamine 2 receptors in the
✽ BMI monthly for 3 months, then quarterly pituitary, it can cause elevations in
✽ Blood pressure, fasting plasma glucose, prolactin
fasting lipids within 3 months and then
• Mechanism of weight gain and possible
annually, but earlier and more frequently
increased incidence of dyslipidemia and
for patients with diabetes or who have
diabetes of atypical antipsychotics is
gained >5% of initial weight
unknown
• Treat or refer for treatment and consider
switching to another atypical antipsychotic Notable Side Effects
for patients who become overweight,
• Atypical antipsychotics may increase the
obese, pre-diabetic, diabetic, hypertensive,
risk for diabetes and dyslipidemia, although
or dyslipidemic while receiving an atypical
the specific risks associated with zotepine
antipsychotic
are unknown
✽ Even in patients without known diabetes, • Agitation, anxiety, depression, asthenia,
be vigilant for the rare but life threatening
headache, insomnia, sedation,
onset of diabetic ketoacidosis, which
hypo/hyperthermia
always requires immediate treatment, by

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(continued) ZOTEPINE

• Constipation, dry mouth, dyspepsia, weight DOSING AND USE

gain
• Tachycardia, hypotension, sweating,
Usual Dosage Range
blurred vision • 75–300 mg/day in 3 divided doses
• Rare tardive dyskinesia
Dosage Forms
• Dose-related hyperprolactinemia
• Tablet 25 mg, 50 mg, 100 mg

Life Threatening or How to Dose

Dangerous Side Effects • Initial 75 mg/day in 3 doses; can increase
• Rare neuroleptic malignant syndrome every 4 days; maximum 300 mg/day in
• Rare seizures (risk increases with dose, 3 doses
especially over 300 mg/day)
• Blood dyscrasias
• Dose-dependent QTc prolongation Dosing Tips
• Slow initial titration can minimize
Weight Gain hypotension
• No formal studies, but some patients may
do well on twice daily dosing rather than
• Many experience and/or can be significant 3 times daily dosing
in amount ✽ Dose-related QTc prolongation, so use
with caution, especially at high doses
Sedation
Overdose
• Can be fatal, especially in mixed overdoses;
seizures, coma
• Many experience and/or can be significant
in amount Long-Term Use
• Can be used to delay relapse in long-term
What To Do About Side Effects treatment of schizophrenia
• Wait
• Wait Habit Forming
• Wait • No
• For motor symptoms, add an
anticholinergic agent How to Stop
• Take more of the dose at bedtime to help • Slow down-titration (over 6 to 8 weeks),
reduce daytime sedation especially when simultaneously beginning
• Weight loss, exercise programs, and a new antipsychotic while switching (i.e.,
medical management for high BMIs, cross-titration)
diabetes, dyslipidemia • Rapid discontinuation may lead to rebound
• Reduce the dose psychosis and worsening of symptoms
• Switch to a first-line atypical antipsychotic • If antiparkinson agents are being used,
they should be continued for a few weeks
Best Augmenting Agents for Side after zotepine is discontinued
Effects
• Benztropine or trihexyphenidyl for motor Pharmacokinetics
side effects • Metabolized by CYP450 3A4 and CYP450
• Sometimes amantadine can be helpful for 1A2
motor side effects • Active metabolite norzotepine
• Benzodiazepines may be helpful for
akathisia
• Many side effects cannot be improved with Drug Interactions
an augmenting agent • Combined use with phenothiazines may
increase risk of seizures

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ZOTEPINE (continued)

• Can decrease the effects of levodopa, increasing zotepine plasma levels (e.g.,
dopamine agonists diazepam, CYP450 1A2 inhibitors and
• Epinephrine may lower blood pressure CYP450 3A4 inhibitors)
• May interact with hypotensive agents due
to alpha 1 adrenergic blockade Do Not Use
• May enhance QTc prolongation of other • If patient has epilepsy or family history of
drugs capable of prolonging QTc interval epilepsy
• Plasma concentrations increased by • If patient has gout or history of
diazepam, fluoxetine nephrolithiasis
• Zotepine may increase plasma levels of • If patient is taking other CNS depressants
phenytoin • If patient is taking high doses of other
• May increase risk of bleeding if used with antipsychotics
anticoagulants • If patient is taking agents capable of
• Theoretically, dose may need to be raised if significantly prolonging QTc interval (e.g.,
given in conjunction with CYP450 1A2 pimozide; thioridazine; selected
inducers (e.g., cigarette smoke) antiarrhythmics such as quinidine,
• Theoretically, dose may need to be lowered disopyramide, amiodarone, and sotalol;
if given in conjunction with CYP450 1A2 selected antibiotics such as moxifloxacin
inhibitors (e.g., fluvoxamine) in order to and sparfloxacin)
prevent dangers of dose-dependent QTc • If there is a history of QTc prolongation or
prolongation cardiac arrhythmia, recent acute
• Theoretically, dose may need to be lowered myocardial infarction, uncompensated
if given in conjunction with CYP450 3A4 heart failure
inhibitors (e.g., fluvoxamine, nefazodone, • If patient is pregnant or breast feeding
fluoxetine) in order to prevent dangers of • If there is a proven allergy to zotepine
dose-dependent QTc prolongation

Other Warnings/ SPECIAL POPULATIONS

Precautions Renal Impairment
• Not recommended for use with sibutramine • Recommended starting dose 25 mg twice a
• Use cautiously in patients with alcohol day; recommended maximum dose
withdrawal or convulsive disorders generally 75 mg twice a day
because of possible lowering of seizure
threshold Hepatic Impairment
• If signs of neuroleptic malignant syndrome • Recommended starting dose 25 mg twice a
develop, treatment should be immediately day; recommended maximum dose
discontinued generally 75 mg twice a day
• Because zotepine may dose-dependently • May require weekly monitoring of liver
prolong QTc interval, use with caution in function during the first few months of
patients who have bradycardia or who are treatment
taking drugs that can induce bradycardia
(e.g., beta blockers, calcium channel Cardiac Impairment
blockers, clonidine, digitalis) • Drug should be used with caution
• Because zotepine may dose-dependently • Zotepine produces a dose-dependent
prolong QTc interval, use with caution in prolongation of QTc interval, which may be
patients who have hypokalemia and or enhanced by the existence of bradycardia,
hypomagnesemia or who are taking drugs hypokalemia, congenital or acquired long
than can induce hypokalemia and/or QTc interval, which should be evaluated
magnesemia (e.g., diuretics, stimulant prior to administering zotepine
laxatives, intravenous amphotericin B, • Use with caution if treating concomitantly
glucocorticoids, tetracosactide) with a medication likely to produce
• Because zotepine dose-dependently prolonged bradycardia, hypokalemia,
prolongs QTc interval, use with caution in slowing of intracardiac conduction, or
patients taking any agent capable of prolongation of the QTc interval

536
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(continued) ZOTEPINE

• Avoid zotepine in patients with a known THE ART OF PSYCHOPHARMACOLOGY

history of QTc prolongation, recent acute
myocardial infraction, and uncompensated
Potential Advantages
heart failure • Norepinephrine reuptake blocking actions
have theoretical benefits for cognition
Elderly (attention) and for depression
• Recommended starting dose 25 mg twice a
day; recommended maximum dose
Potential Disadvantages
generally 75 mg twice a day • Patients not compliant with 3 times daily
dosing
• Patients requiring rapid onset of
antipsychotic action
Children and Adolescents • Patients with uncontrolled seizures
• Not recommended under age 18
Primary Target Symptoms
• Positive symptoms of psychosis
Pregnancy • Negative symptoms of psychosis
• Insufficient data in humans to determine • Cognitive functioning
risk • Depressive symptoms
• Zotepine is not recommended during
pregnancy
Pearls
Breast Feeding ✽ Zotepine inhibits norepinephrine
• Zotepine is not recommended during reuptake, which may have implications for
breast feeding treatment of depression, as well as for
• Immediate postpartum period is a high-risk cognitive symptoms of schizophrenia
time for relapse of psychosis, so may • Risks of diabetes and dyslipidemia not
consider treatment with another well-studied for zotepine, but known
antipsychotic significant weight gain suggests the need
for careful monitoring during zotepine
treatment
• Not as well investigated in bipolar disorder,
but its mechanism of action suggests
efficacy in acute bipolar mania

Suggested Reading
Ackenheil M. [The biochemical effect profile of Stanniland C, Taylor D. Tolerability of atypical
zotepine in comparison with other antipsychotics. Drug Saf 2000; 22 (3):
neuroleptics]. Fortschr Neurol Psychiatr 1991; 195–214.
59 Suppl 1: 2–9.
Fenton M, Morris S, De-Silva P, Bagnall A,
Cooper SJ, Gammelin G, Leitner M. Zotepine
for schizophrenia. Cochrane Database Syst
Rev 2000; (2): CD001948.

537
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0521011698s10.qxd 9/2/04 2:49 PM Page 539

ZUCLOPENTHIXOL
THERAPEUTICS and/or an atypical antipsychotic for mood
stabilization and maintenance
Brands • Clopixol
• Clopixol-Acuphase If It Doesn’t Work
see index for additional brand names • Consider trying one of the first-line atypical
antipsychotics (risperidone, olanzapine,
Generic? No quetiapine, ziprasidone, aripiprazole,
amisulpride)
• Consider trying another conventional
Class antipsychotic
• Conventional antipsychotic (neuroleptic, • If 2 or more antipsychotic monotherapies
thioxanthene, dopamine 2 antagonist) do not work, consider clozapine

Commonly Prescribed For Best Augmenting Combos

(bold for FDA approved) for Partial Response or
• Acute schizophrenia (oral, acetate injection) Treatment-Resistance
• Maintenance treatment of schizophrenia • Augmentation of conventional
(oral, decanoate injection) antipsychotics has not been systematically
• Bipolar disorder studied
• Aggression • Addition of a mood stabilizing
anticonvulsant such as valproate,
carbamazepine, or lamotrigine may be
How The Drug Works helpful in both schizophrenia and bipolar
• Blocks dopamine 2 receptors, reducing mania
positive symptoms of psychosis • Augmentation with lithium in bipolar mania
may be helpful
How Long Until It Works • Addition of a benzodiazepine, especially
• For injection, psychotic symptoms can short-term for agitation
improve within a few days, but it may take
1–2 weeks for notable improvement Tests
• For oral formulation, psychotic symptoms ✽ Since conventional antipsychotics are
can improve within 1 week, but may take frequently associated with weight gain,
several weeks for full effect on behavior before starting treatment, weigh all patients
and determine if the patient is already
If It Works overweight (BMI 25.0–29.9) or obese
• Most often reduces positive symptoms in (BMI ≥30)
schizophrenia but does not eliminate them • Before giving a drug that can cause weight
• Most schizophrenic patients do not have a gain to an overweight or obese patient,
total remission of symptoms but rather a consider determining whether the patient
reduction of symptoms by about a third already has pre-diabetes (fasting plasma
• Continue treatment in schizophrenia until glucose 100–125 mg/dl), diabetes (fasting
reaching a plateau of improvement plasma glucose >126 mg/dl), or
• After reaching a satisfactory plateau, dyslipidemia (increased total cholesterol,
continue treatment for at least a year after LDL cholesterol and triglycerides;
first episode of psychosis in schizophrenia decreased HDL cholesterol), and treat or
• For second and subsequent episodes of refer such patients for treatment, including
psychosis in schizophrenia, treatment may nutrition and weight management, physical
need to be indefinite activity counseling, smoking cessation, and
• Reduces symptoms of acute psychotic medical management
mania but not proven as a mood stabilizer ✽ Monitor weight and BMI during treatment
or as an effective maintenance treatment in ✽ While giving a drug to a patient who has
bipolar disorder gained >5% of initial weight, consider
• After reducing acute psychotic symptoms evaluating for the presence of pre-diabetes,
in mania, switch to a mood stabilizer diabetes, or dyslipidemia, or consider
switching to a different antipsychotic

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ZUCLOPENTHIXOL (continued)

• Should check blood pressure in the elderly Weight Gain

before starting and for the first few weeks
of treatment
• Monitoring elevated prolactin levels of
• Many experience and/or can be significant
dubious clinical benefit
in amount
• Some people may lose weight

SIDE EFFECTS Sedation

How Drug Causes Side Effects
• By blocking dopamine 2 receptors in the
striatum, it can cause motor side effects • Many experience and/or can be significant
• By blocking dopamine 2 receptors in the in amount
pituitary, it can cause elevations in • Acetate formulation may be associated with
prolactin an initial sedative response
• By blocking dopamine 2 receptors
excessively in the mesocortical and
What To Do About Side Effects
mesolimbic dopamine pathways, especially • Wait
at high doses, it can cause worsening of • Wait
negative and cognitive symptoms • Wait
(neuroleptic-induced deficit syndrome) • For motor symptoms, add an
• Anticholinergic actions may cause anticholinergic agent
sedation, blurred vision, constipation, dry • Reduce the dose
mouth • For sedation, take at night
• Antihistaminic actions may cause sedation, • Switch to an atypical antipsychotic
weight gain • Weight loss, exercise programs, and
• By blocking alpha 1 adrenergic receptors, it medical management for high BMIs,
can cause dizziness, sedation, and diabetes dyslipidemia
hypotension
Best Augmenting Agents for Side
• Mechanism of weight gain and any
possible increased incidence of diabetes or
Effects
dyslipidemia with conventional • Benztropine or trihexyphenidyl for motor
antipsychotics is unknown side effects
• Sometimes amantadine can be helpful for
Notable Side Effects motor side effects
✽ Extrapyramidal symptoms • Benzodiazepines may be helpful for
✽ Tardive dyskinesia (risk increases with akathisia
duration of treatment and with dose) • Many side effects cannot be improved with
✽ Priapism an augmenting agent
✽ Galactorrhea, amenorrhea
• Rare lens opacity
• Sedation, dizziness DOSING AND USE
• Dry mouth, constipation, vision problems
• Hypotension Usual Dosage Range
• Weight gain • Oral 20–60 mg/day
• Acetate 50–150 mg every 2–3 days
• Decanoate 150–300 mg every 2–4 weeks
Life Threatening or
Dangerous Side Effects Dosage Forms
• Rare neuroleptic malignant syndrome • Tablet 10 mg, 25 mg, 40 mg
• Rare neutropenia • Acetate 50 mg/mL (equivalent to
• Rare respiratory depression zuclopenthixol 45.25 mg/mL),
• Rare agranulocytosis 100 mg/2 mL (equivalent to zuclopenthixol
• Rare seizures 45.25 mg/mL)

540
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(continued) ZUCLOPENTHIXOL

• Decanoate 200 mg/mL (equivalent to Long-Term Use

zuclopenthixol 144.4 mg/mL), 500 mg/mL • Zuclopenthixol decanoate is intended for
(equivalent to zuclopenthixol 361.1 mg/mL) maintenance treatment
• Some side effects may be irreversible (e.g.,
How to Dose tardive dyskinesia)
• Oral: initial 10–15 mg/day in divided doses;
can increase by 10–20 mg/day every Habit Forming
2–3 days; maintenance dose can be • No
administered as a single nighttime dose;
maximum dose generally 100 mg/day How to Stop
• Injection should be administered • Slow down-titration of oral formulation
intramuscularly in the gluteal region in the (over 6 to 8 weeks), especially when
morning simultaneously beginning a new
• Acetate generally should be administered antipsychotic while switching (i.e., cross-
every 2–3 days; some patients may require titration)
a second dose 24–48 hours after the first • Rapid oral discontinuation may lead to
injection; duration of treatment should not rebound psychosis and worsening of
exceed 2 weeks; maximum cumulative symptoms
dosage should not exceed 400 mg; • If antiparkinson agents are being used,
maximum number of injections should not they should be continued for a few weeks
exceed 4 after zuclopenthixol is discontinued
• Decanoate: initial dose 100 mg; after
1–4 weeks administer a second injection of Pharmacokinetics
100–200 mg; maintenance treatment is • Metabolized by CYP450 2D6
generally 100–600 mg every 1–4 weeks • For oral formulation, elimination half-life
approximately 20 hours
• For acetate, rate limiting half-life
Dosing Tips approximately 32 hours
• For decanoate, rate limiting half-life
• Onset of action of the intramuscular
approximately 17–21 days with multiple
acetate formulation following a single
doses
injection is generally 2–4 hours; duration of
action is generally 2–3 days
• Zuclopenthixol acetate is not intended for
long-term use, and should not generally be Drug Interactions
used for longer than 2 weeks; patients • Theoretically, concomitant use with
requiring treatment longer than 2 weeks CYP450 2D6 inhibitors (such as paroxetine
should be switched to a depot or oral and fluoxetine) could raise zuclopenthixol
formulation of zuclopenthixol or another plasma levels and require dosage reduction
antipsychotic • CNS effects may be increased if used with
• When changing from zuclopenthixol other CNS depressants
acetate to maintenance treatment with • If used with anticholinergic agents, may
zuclopenthixol decanoate, administer the potentiate their effects
last injection of acetate concomitantly with • Combined use with epinephrine may lower
the initial injection of decanoate blood pressure
• The peak of action for the decanoate is • Zuclopenthixol may block the
usually 4–9 days, and doses generally have antihypertensive effects of drugs such as
to be administered every 2–3 weeks guanethidine, but may enhance the actions
of other antihypertensive drugs
Overdose • Using zuclopenthixol with metoclopramide
• Sedation, convulsions, extrapyramidal or piperazine may increase the risk of
symptoms, coma, hypotension, shock, extrapyramidal symptoms
hypo/hyperthermia • Zuclopenthixol may antagonize the effects
of levodopa and dopamine agonists

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ZUCLOPENTHIXOL (continued)

• Some patients taking a neuroleptic and Hepatic Impairment

lithium have developed an encephalopathic • Use with caution
syndrome similar to neuroleptic malignant
syndrome Cardiac Impairment
• Use with caution
Other Warnings/ Elderly
Precautions • Some patients may tolerate lower doses
• If signs of neuroleptic malignant syndrome better
develop, treatment should be immediately • Maximum acetate dose 100 mg
discontinued
• Use with caution in patients with epilepsy,
glaucoma, urinary retention Children and Adolescents
• Decanoate should not be used with
• Safety and efficacy have not been
clozapine because it cannot be withdrawn
established in children under age 18
quickly in the event of serious adverse
• Preliminary open-label data show that oral
effects such as neutropenia
zuclopenthixol may be effective in reducing
• Possible antiemetic effect of zuclopenthixol
aggression in mentally impaired children
may mask signs of other disorders or
overdose; suppression of cough reflex may
cause asphyxia
• Use only with great caution if at all in Pregnancy
Parkinson’s disease or Lewy Body • Not recommended for use during
dementia pregnancy
• Observe for signs of ocular toxicity • Psychotic symptoms may worsen during
(pigmentary retinopathy and lenticular and pregnancy and some form of treatment
corneal deposits) may be necessary
• Avoid undue exposure to sunlight • Atypical antipsychotics may be preferable
• Avoid extreme heat exposure to conventional antipsychotics or
• Do not use epinephrine in event of anticonvulsant mood stabilizers if
overdose as interaction with some pressor treatment is required during pregnancy
agents may lower blood pressure
Breast Feeding
Do Not Use • Some drug is found in mother’s breast milk
• If patient is taking a large concomitant ✽ Recommended either to discontinue drug
dose of a sedative hypnotic or bottle feed
• If patient is taking guanethidine or a similar • Infants of women who choose to breast
acting compound feed should be monitored for possible
• If patient has CNS depression, is adverse effects
comatose, or has subcortical brain damage
• If patient has acute alcohol, barbiturate, or
opiate intoxication THE ART OF PSYCHOPHARMACOLOGY
• If patient has narrow angle-closure
glaucoma Potential Advantages
• If patient has phaeochromocytoma, • Non-compliant patients (decanoate)
circulatory collapse, or blood dyscrasias • Emergency use (acute injection)
• In case of pregnancy
• If there is a proven allergy to Potential Disadvantages
zuclopenthixol • Children
• Elderly
• Patients with tardive dyskinesia
SPECIAL POPULATIONS Primary Target Symptoms
Renal Impairment • Positive symptoms of psychosis
• Use with caution • Negative symptoms of psychosis

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(continued) ZUCLOPENTHIXOL

• Aggressive symptoms atypical antipsychotics where antipsychotic

responses of individual patients can
occasionally vary greatly from one atypical
Pearls antipsychotic to another
• Zuclopenthixol depot may reduce risk of • Patients with inadequate responses to
relapse more than some other depot atypical antipsychotics may benefit from a
conventional antipsychotics, but it may trial of augmentation with a conventional
also be associated with more adverse antipsychotic such as zuclopenthixol or
effects from switching to a conventional
• Can combine acute injection with depot antipsychotic such as zuclopenthixol
injection in the same syringe for rapid • However, long-term polypharmacy with a
onset and long duration effects when combination of a conventional
initiating treatment antipsychotic such as zuclopenthixol with
• Zuclopenthixol may have serotonin 2A an atypical antipsychotic may combine
antagonist properties, but these have never their side effects without clearly
been systematically investigated for augmenting the efficacy of either
atypical antipsychotic properties at low • Although a frequent practice by some
doses prescribers, adding 2 conventional
• Patients have very similar antipsychotic antipsychotics together has little rationale
responses to any conventional and may reduce tolerability without clearly
antipsychotic, which is different from enhancing efficacy

Suggested Reading
Coutinho E, Fenton M, Adams C, Campbell C. Fenton M, Coutinho ES, Campbell C.
Zuclopenthixol acetate in psychiatric Zuclopenthixol acetate in the treatment of
emergencies: looking for evidence from acute schizophrenia and similar serious mental
clinical trials. Schizophr Res 2000;46:111–8. illnesses. Cochrane Database Syst Rev
2000;(2):CD000525.
Coutinho E, Fenton M, Quraishi S.
Zuclopenthixol decanoate for schizophrenia
and other serious mental illnesses. Cochrane
Database Syst Rev 2000;(2):CD001164.

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0521011698emt.qxd 9/2/04 2:51 PM Page 545

Index by Drug Name

Abilify (aripiprazole), 25 amisulpride, 7
Absenor (valproate), 499 Amitrip (amitriptyline), 13
Aclonium (gabapentin), 201 Amitriptilin (amitriptyline), 13
Acuilix (moclobemide), 307 Amitriptylin (amitriptyline), 13
Adapin (doxepine), 145 amitriptyline, 13
Adderrall (d,l amphetamine), 115 Amitriptylinum (amitriptyline), 13
Adderrall XR (d,l-amphetamine), 115 Amitrol (amitriptyline), 13
Adepil (amitriptyline), 13 Amizepin (carbamazepine), 47
Adipress (clonidine), 81 Amizol (amitriptyline), 13
Adofen (fluoxetine), 175 amoxapine, 19
Adumbran (oxazepam), 341 Anafranil (clomipramine), 69
AH3 N (hydroxyzine), 219 Anafranil 75 (clomipramine), 69
Aiglonyl (sulpiride), 435 Anafranil Retard (clomipramine), 69
Alased (haloperidol), 213 Anatensoi Decanoaat (fluphenazine), 185
Albium (lorazepam), 265 Anatensol (fluphenazine), 185
Aldazine (thioridazine), 447 Anatensol Concentraat (fluphenazine), 185
Alemoxan (clozapine), 91 Anatensol Decanoate (fluphenazine), 185
Alepam (oxazepam), 341 Ancholactil (chlorpromazine), 57
Alertec (modafinil), 313 Aneural (maprotiline), 277
Aleviatin (zonisamide), 525 Aneurol (diazepam), 109
Alimoral (sulpiride), 435 Anexate (flumazenil), 167
Aliseum (diazepam), 109 Anform (pemoline), 357
Allegron (nortriptyline), 329 Ansilor (lorazepam), 265
Almazine (lorazepam), 265 Ansiolin (diazepam), 109
Aloperidin (haloperidol), 213 Ansised (buspirone), 43
Aloperidin Decanoate (haloperidol), 213 Ansium (diazepam), 109
Alpralid (alprazolam), 1 Ansium (sulpiride), 435
Alpralid (triazolam), 483 Antalon (pimozide), 377
Alpraz (alprazolam), 1 Antelepsin (clonazepam), 75
alprazolam, 1 Anten (doxepin), 145
alprazolam XR, 1 Antenex (diazepam), 109
Alprox (alprazolam), 1 Antideprin (imipramine), 223
AltiAlprazolam (alprazolam), 1 Antiparkin (selegiline), 423
Alti-Clonazepam (clonazepam), 75 Antoderin (oxazepam), 341
Alti-Desipramine (desipramine), 103 Anxial (buspirone), 43
Alti-Doxepin (doxepin), 145 Anxidin (clorazepate), 87
Alti-Trazodone (trazodone), 477 Anxiolit (oxazepam), 341
Alti-Triazolam (triazolam), 483 Anxiolit Plus (oxazepam), 341
Alti-Valproic (valproate), 499 Anxiron (buspirone), 43
Alupram (diazepam), 109 Apaurin (diazepam), 109
Alzam (alprazolam), 1 Apilepsin (valproate), 499
Alzon (alprazolam), 1 Apo-Alprax (alprazolam), 1
Ambien (zolpidem), 521 Apo-Amitriptyline (amitriptyline), 13
Ambo-neural (selegiline), 423 Apo-Buspirone (buspirone), 43
Amboneural (selegiline), 423 Apo-Carbamazepine (carbamazepine), 47
Amilin (amitriptyline), 13 Apo-Clomipramine (clomipramine), 69
Amilit (amitriptyline), 13 Apo-Clonazepam (clonazepam), 75
Aminazins (chlorpromazine), 69 Apo-Clonidine (clonidine), 81
Amindan (selegiline), 423 Apo-Clorazepate (clorazepate), 87
Amineurin (amitriptyline), 13 Apo-Desipramine (desipramine), 103
Aminuerin retard (amitriptyline), 13 Apo-Diazepam (diazepam), 109
Amioxid (amitriptyline), 13 Apo-Doxepin (doxepin), 145

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Apo-Fluoxetine (fluoxetine), 175 Benzotran (oxazepam), 341

Apo-Fluphenazine (fluphenazine), 185 Berk-Dothiepin (dothiepin), 139
Apo-Haloperidol (haloperidol), 213 Besitran (sertraline), 429
Apo-Imipramine (imipramine), 223 Bespar (buspirone), 43
Apo-Lorazem (lorazepam), 265 Betamaks (sulpiride), 435
Apo-Oxepam (oxazepam), 341 Betamed (diazepam), 109
Apo-Perphenazine (perphenazine), 365 Betapam (diazepam), 109
Apo-Selegiline (selegiline), 423 Bialzepam (diazepam), 109
Apo-Thioridazine (thioridazine), 447 Bikalm (zolpidem), 521
Apo-Trazodone (trazodone), 477 Bioperidolo (haloperidol), 213
Apo-Triazo (triazolam), 483 Bioxetin (fluoxetine), 175
Apo-Trifluoperazine (trifluoperazine), 487 Biron (buspirone), 43
Apo-Trimip (trimipramine), 493 Biscasil (chlorpromazine), 57
Apoh-Hydroxyzine (hydroxyzine), 219 Biston (see carbamazepine), 47
Apollonset (diazepam), 109 Bortalium (diazepam), 109
Aponal (doxepin), 145 bupropion, 37
Apozepam (diazepam), 109 bupropion SR, 37
Aremis (sertraline), 429 bupropion XL, 37
Aricept (donepezil), 133 Buscalm (buspirone), 43
Arima (moclobemide), 307 Buspar (buspirone), 43
Aripax (lorazepam), 265 BuSpar (buspirone), 43
aripiprazole, 25 Buspimen (buspirone), 43
Arminol (sulpiride), 435 Buspisal (buspirone), 43
Arol (moclobemide), 307 buspirone, 43
Aropax (paroxetine), 351 Buteridol (haloperidol), 213
Asendin (amoxapine), 19 Calmoflorine (sulpiride), 435
Asendis (amoxapine), 19 Camcolit (lithium), 247
Asepin (triazolam), 483 Caprysin (clonidine), 81
Aspam (diazepam), 109 Carbabeta (carbamazepine), 47
Atarax (hydroxyzine), 219 Carbagamma (carbamazepine), 47
Atarviton (diazepam), 109 carbamazepine, 47
Atensine (diazepam), 109 Carbapin (carbamazepine), 47
Aterax (hydroxyzine), 219 Carbatrol (carbamazepine), 47
Ativan (lorazepam), 265 Carbium (carbamazepine), 47
atomoxetine, 31 Carbolith (lithium), 247
Atretol (carbamazepine), 47 Carbolithium (lithium), 247
Audium (diazepam), 109 Carbymal (carbamazepine), 47
Audilex (clorazepate), 87 Cardilac (fluphenazine), 185
Aurorix (moclobemide), 307 Carpaz (carbamazepine), 47
Avant (haloperidol), 213 Cassadan (alprazolam), 1
Aventyl (nortriptyline), 329 Catanidin (clonidine), 81
Avoxin (fluvoxamine), 195 Catapres (clonidine), 81
Axoren (buspirone), 43 Catapres-TTS (clonidine), 81
Azene (clorazepate), 87 Cedrol (zolpidem), 521
Azepa (carbamazepine), 47 Celexa (citalopram), 63
Azepal (carbamazepine), 47 Cenilene (fluphenazine), 185
Azona (trazodone), 477 Centedrin (d,l-methylphenidate), 121
Azor (alprazolam), 1 Cereen (haloperidol), 213
Azutranquil (oxazepam), 341 Championyl (sulpiride), 435
Barclyd (clonidine), 81 Chlorazin (chlorpromazine), 57
Beconerv neu (flurazepam), 191 chlordiazepoxide, 53
Belivon (risperidone), 411 Chlorpromazin (chlorpromazine), 57
Belpax (amitriptyline), 13 Chlorpromazina HCl (chlorpromazine), 57
Belseren (clorazepate), 87 chlorpromazine, 57
Benpon (nortriptyline), 329 Cibalith S-Lithonate (lithium), 247
Bentapam (diazepam), 109 Cidoxepin (doxepin), 145
Benzopin (diazepam), 109 Cipram (citalopram), 63

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Cipramil (citalopram), 63 Defobin (chlordiazepoxide), 53

Cisordinol (zuclopenthixol), 539 Deftan (lofepramine), 253
citalopram, 63 Degranol (carbamazepine), 47
clomipramine, 69 Delepsine (valproate), 499
clonazepam, 75 Delgian (maprotiline), 277
Clonazepamum (clonazepam), 75 Demolox (amoxapine), 19
clonidine, 81 Deniban (amisulpride), 7
Clonisin (clonidine), 81 Depacon (valproate), 499
Clonistada (clonidine), 81 Depakene (valproate), 499
Clopixol (zuclopenthixol), 539 Depakine Chrono (valproate), 499
Clopixol Acuphase (zuclopenthixol), 539 Depakine (LA) (valproate), 499
Clopixol Conc (zuclopenthixol), 539 Depakine Zuur (valproate), 499
Clopress (clomipramine), 69 Depakote (valproate), 499
clorazepate, 87 Depakote ER (valproate), 499
Clordezalin (chlorpromazine), 57 Depakote sprinkle (valproate), 499
Clorpres (clonidine), 81 Deparkin (valproate), 499
clozapine, 91 Depex (sulpiride), 435
Clozaril (clozapine), 91 Depixol (flupenthixol), 181
Coaxil (tianeptine), 461 Depixol-Conc (flupenthixol), 181
Cognex (tacrine), 439 Deprakine (valproate), 499
Cognitiv (selegiline), 423 Depral (sulpiride), 435
Combipres (clonidine), 81 Depramine (imipramine), 223
Complutine (diazepam), 109 Deprax (trazodone), 477
Concerta (d,l-methylphenidate), 121 Deprenon (fluoxetine), 175
Concordin (protriptyline), 391 Deprenyl (selegiline), 423
Concordine (protriptyline), 391 Depressase (maprotiline), 277
Consta (risperidone), 411 Deprex (fluoxetine), 175
Contemnol (lithium), 247 Deprilan (selegiline), 423
Control (lorazepam), 265 Deprilept (maprotiline), 277
Convulex (valproate), 499 Deprimyl (lofepramine), 253
Convulsofin (valproate), 499 Deprinocte (estazolam), 163
Cosmopril (selegiline), 423 Deprinol (imipramine), 223
Cylert (pemoline), 357 Deptran (doxepin), 145
Cymbalta (duloxetine), 151 Deroxat (paroxetine), 351
d-amphetamine, 97 Desconex (loxapine), 271
d,l-amphetamine, 115 Desidox (doxepin), 145
d-methylphenidate, 127 desipramine, 103
d,l-methylphenidate, 121 Desisulpid (sulpiride), 435
Dalcipran (milnacipran), 295 Desitriptylin (amitriptyline), 13
Dalmane (flurazepam), 191 Desyrel (trazodone), 477
Dalmadorm (flurazepam), 191 Devidon (trazodone), 477
Dalparan (zolpidem), 521 Dexamphetamine (d-amphetamine), 97
Dapotum (fluphenazine), 185 Dexamphetamine sulfate (d-amphetamine), 97
Dapotum Acutum (fluphenazine), 185 Dexedrine (d-amphetamine), 97
Dapotum D (fluphenazine), 185 Dexedrine Spansuler (d-amphetamine), 97
Dapotum Depot (fluphenazine), 185 Dexmethylphenidate (d-methylphenidate), 127
Daprimen (amitriptyline), 13 Dextro Stat ( d-amphetamine), 97
Darkene (flunitrazepam), 171 D-Pam (diazepam), 109
Darleton (sulpiride), 435 Denion (diazepam), 109
Deadyn (pemoline), 357 Diaceplex (diazepam), 109
Decafen (fluphenazine), 185 Diaceplex simple (diazepam), 109
Decanoate (haloperidol), 213 Diapam (diazepam), 109
Decazate (fluphenazine), 185 Diaquel (diazepam), 109
Decentan (perphenazine), 365 Diastat (diazepam), 109
Decentan (fluphenazine), 185 Diazemuls (diazepam), 109
Decentan-Depot (perphenazine), 365 diazepam, 109
Defanyl (amoxapine), 19 Dicepin B6 (diazepam), 109

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Digton (sulpiride), 435 Efexir (venlafaxine), 505

Diligan (hydroxyzine), 219 Efexor (venlafaxine), 505
Dinalexin (fluoxetine), 175 Efexor XL (venlafaxine), 505
Dipromal (valproate), 499 Effexor (venlafaxine), 505
Discimer (trifluoperazine), 487 Effexor XR (venlafaxine), 505
Distedon (diazepam), 109 Effiplen (buspirone), 43
divalproex (valproate), 499 Egibren (selegiline), 423
Divial (lorazepam), 265 Eglonyl (sulpiride), 435
Dixarit (clonidine), 81 Elavil (amitriptyline), 13
Dixibon (sulpiride), 435 Elavil Plus (amitriptyline), 13
Dizac (diazepam), 109 Eldepryl (selegiline), 423
Dobren (sulpiride), 435 Elenium (chlordiazepoxide), 53
Dobupal (venlafaxine), 505 Eliwel (amitriptyline), 13
Dogmatil (sulpiride), 435 Elopram (citalopram), 63
Dogmatyl (sulpiride), 435 Elroquil N (hydroxyzine), 219
Dolmatil (sulpiride), 435 Elperil (thioridazine), 447
Domical (amitriptyline), 13 Emdalen (lofepramine), 253
Dominans (nortriptyline), 329 Endep (amitriptyline), 13
Domnamid (estazolam), 163 Enimon (sulpiride), 435
DOM-trazodone (trazodone), 477 Epial (carbamazepine), 47
donepezil, 133 Epilim (valproate), 499
Doneurin (doxepin), 145 Epitol (carbamazepine), 47
Donix (lorazepam), 265 Epitomax (topiramate), 465
Dopress (Dothiepin), 139 Equilid (sulpiride), 435
Doral (quazepam), 397 Equitam (lorazepam), 265
Dorken (clorazepate), 87 Ergenyl (valproate), 499
Dorm (lorazepam), 265 Eridan (diazepam), 109
Dormalin (quazepam), 397 Erocap (fluoxetine), 175
Dormapam (temazepam), 443 Ergocalm (lorazepam), 265
Dorme (quazepam), 397 escitalopram, 157
Dormicum (midazolam), 291 Esculid (diazepam), 109
Dormodor (flurazepam), 191 Esilgan (estazolam), 163
Dothep (Dothiepin), 139 Esipride (sulpiride), 435
dothiepin, 139 Eskalith (lithium), 247
Doxal (doxepin), 145 Eskalith CR (lithium), 247
Doxedyn (doxepin), 145 Eskazine (trifluoperazine), 487
doxepin, 145 Esparon (alprazolam), 1
Dozic (haloperidol), 213 estazolam, 163
Drenian (diazepam), 109 Ethipam (diazepam), 103
Dresent (sulpiride), 435 Ethipramine (imipramine), 223
Ducene (diazepam), 109 Euhypnos (temazepam), 443
duloxetine, 151 Euipnos (temazepam), 443
Dumirox (fluvoxamine), 195 Eurosan (diazepam), 109
Dumozolam (triazolam), 483 Eutimil (paroxetine), 351
Dumyrox (fluvoxamine), 195 Eutimox (fluphenazine), 185
Duraclon (clonidine), 81 Evacalm (diazepam), 109
Duradiazepam (diazepam), 109 Everiden (valproate), 499
Duralith (lithium), 247 Exan (buspirone), 43
Duraperidol (haloperidol), 213 Excegran (zonisamide), 525
Durazepam (oxazepam), 341 Exelon (rivastigmine), 417
Durazolam (lorazepam), 265 Exogran (zonisamide), 525
Dutonin (nefazodone), 323 Exostrept (fluoxetine), 175
Dynalert (pemoline), 357 Fardalan (sulpiride), 435
Dynamin (pemoline), 357 Fargenor (chlordiazepoxide), 53
Eclorion (sulpiride), 435 Faustan (diazepam), 109
Edronax (reboxetine), 407 Faverin (fluvoxamine), 195
Efectin (venlafaxine), 505 Felicium (fluoxetine), 175

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Felison (flurazepam), 191 gabapentin, 201

Fenactil (chlorpromazine), 57 Gabitril (tiagabine), 457
Fentazin (perphenazine), 365 galantamine, 207
Fevarin (fluvoxamine), 195 Gamanil (lofepramine), 253
Fidelan (sulpiride), 435 Gamibetal Plus (diazepam), 109
Finlepsin (carbamazepine), 47 Gamonil (lofepramine), 253
Flaracantyl (thioridazine), 447 Gen-Alprazolam (alprazolam), 1
Flonital (fluoxetine), 175 Gen-Clomipramine (clomipramine), 69
Floxyfral (fluvoxamine), 195 Gen-Triazolam (triazolam), 483
Fluanxol (flupenthixol), 181 Gen-Valproic (valproate), 499
Fluanxol Depot (flupenthixol), 181 Geodon (ziprasidone), 515
Fluanxol Depot 2% (flupenthixol), 181 Gewakalm (diazepam), 103
Fluanxol Depot 10% (flupenthixol), 181 Gladem (sertraline), 429
Fluanxol LP 20 mg/mL (flupenthixol), 181 Gnostorid (oxazepam), 341
Fluanxol LP 100 mg/mL (flupenthixol), 181 Gobanal (diazepam), 109
Fluanxol Retard (flupenthixol), 181 Haemiton (clonidine), 81
Fluctin (fluoxetine), 175 Halcion (triazolam), 483
Fluctine (fluoxetine), 175 Haldol (haloperidol), 213
Fludecate (fluphenazine), 185 Haldol decanoas (haloperidol), 213
Flufenazin (fluphenazine), 185 Haldol Decanoat (haloperidol), 213
Flufenazin dekanoat (fluphenazine), 185 Haldol Decanoate (haloperidol), 213
Flufenazin Enantat (fluphenazine), 185 Haldol Decanoato (haloperidol), 213
flumazenil, 167 Haldol Depot (haloperidol), 213
Fluni OPT (flunitrazepam), 171 Haldol L.A. (haloperidol), 213
Flunimerck (flunitrazepam), 171 Haloneural (haloperidol), 213
Fluninoc (flunitrazepam), 171 Haloper (haloperidol), 213
Flunipam (flunitrazepam), 171 haloperidol, 213
Flunitrax (flunitrazepam), 171 Haloperidol Decanoat (haloperidol), 213
flunitrazepam, 171 Haloperidol decanoato (haloperidol), 213
Flunox (flurazepam), 191 Haloperin (haloperidol), 213
Fluocim (fluoxetine), 175 Haloperin depotinjektio (haloperidol), 213
Fluoxeren (fluoxetine), 175 Harmomed (dothiepin), 139
fluoxetine, 175 Harmoned (diazepam), 109
Fluoxifar (fluoxetine), 175 Helex (alprazolam), 1
Fluoxin (fluoxetine), 175 Helogaphen (chlordiazepoxide), 53
Flupam (flunitrazepam), 171 Hermolepsin (carbamazepine), 47
flupenthixol, 181 Herphonal (trimipramine), 493
fluphenazine, 185 Hexafene (hydroxyzine), 219
flurazepam, 191 Hexalid (diazepam), 109
Fluscand (flunitrazepam), 171 Hibanil (chlorpromazine), 57
Flutepam (flurazepam), 191 Hibernal (chlorpromazine), 57
Flutin (fluoxetine), 175 Hipnodane (quazepam), 397
Flutraz (flunitrazepam), 171 Hipnosedon (flunitrazepam), 171
Fluval (fluoxetine), 175 Histilos (hydroxyzine), 219
fluvoxamine, 195 Huberplex (chlordiazepoxide), 53
Fluxadir (fluoxetine), 175 Hydoic acid (valproate), 499
Fluxonil (fluoxetine), 175 Hydophen (clomipramine), 69
Focalin (d-methylphenidate), 121 Hydroxyzin (hydroxyzine), 219
Foille (trifluoperazine), 487 hydroxyzine, 219
Fokalepsin (carbamazepine), 47 Hydroxyzinum (hydroxyzine), 219
Fondur (fluoxetine), 175 Hypam (triazolam), 483
Fontex (fluoxetine), 175 Hypnocalm (flunitrazepam), 171
Fonzac (fluoxetine), 175 Hypnodorm (flunitrazepam), 171
Fortunan (haloperidol), 213 Hypnor (flunitrazepam), 171
Frontal (alprazolam), 1 Hypnorex retard (lithium), 247
Frosinor (paroxetine), 351 Hypnovel (midazolam), 291
Frosnor (paroxetine), 351 Hyton Asa (pemoline), 357

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Idom (dothiepine), 139 Lentotran (chlordiazepoxide), 53

Iktoviril (clonazepam), 75 Leponex (clozapine), 91
Ilman (flunitrazepam), 171 Leptilin (valproate), 499
Imavate (imipramine), 223 Leukominerase (lithium), 247
Imipramin (imipramine), 223 Levanxol (temazepam), 443
imipramine, 223 levetiracetam, 243
Imipramiin (imipramine), 223 Lexapro (escitalopram), 157
Imovane (zopiclone), 529 Li-450 (lithium), 247
Inadalprem (lorazepam), 265 Librax (chlordiazepoxide), 53
Insom (flunitrazepam), 171 Libraxin (chlordiazepoxide), 53
Ipnovel (midazolam), 291 Librium (chlordiazepoxide), 53
Iremofar (hydroxyzine), 219 Lidanil (mesoridazine), 287
Iremo Sedofren (trifluoperazine), 487 Lidone (molindone), 319
isocarboxazid, 229 Li-Liquid (lithium), 247
Ivadal (zolpidem), 521 Lilly Fluoxetine (fluoxetine), 175
Ixel (milnacipran), 295 Limbatril (chlordiazepoxide), 53
Janimine (imipramine), 223 Limbatril F (chlordiazepoxide), 53
Januar (oxazepam), 341 Limbitrol (chlordiazepoxide), 53
Jardin (dothiepin), 139 Limbitrol F (chlordiazepoxide), 53
Jatroneural (trifluoperazine), 487 Limbitryl (chlordiazepoxide), 53
Jatrosom (tranylcypromine), 471 Limbitryl Plus (chlordiazepoxide), 53
Jatrosom N (tranylcypromine), 471 Liskonum (lithium), 247
Jatrosom N (trifluoperazine), 487 Litarex (lithium), 247
Julap (selegiline), 423 Lithane (lithium), 247
Jumex (selegiline), 423 Lithiofor (lithium), 247
Jumexal (selegiline), 423 Lithionit (lithium), 247
Kainever (estazolam), 163 Lithiucarb (lithium), 247
Kalma (alprazolam), 1 lithium, 247
Kanopan 75 (maprotiline), 277 Lithium carbonicum (lithium), 247
Karbazin (carbamazepine), 47 Lithium-aspartat (lithium), 247
Keppra (levetiracetam), 243 Lithium citrate syrup (lithium), 247
Kinabide (selegiline), 423 Lithium-Duriles (lithium), 247
Klarium (diazepam), 109 Lithiumkarbonat (lithium), 247
Klofelins (clonidine), 81 Lithiumorotat (lithium), 247
Klonipin (clonazepam), 75 Lithizine (lithium), 247
Klopoxid (chlordiazepoxide), 53 Lithobid (lithium), 247
Kloproman (chlorpromazine), 57 Lithonate (lithium), 247
Klorproman (chlorpromazine), 57 Lithostat (lithium), 247
Klotriptyl (chlordiazepoxide), 53 Lito (lithium), 247
Klozapol (clozapine), 91 Litoduron (lithium), 247
Labileno (lamotrigine, 235 Lodopin (zotepine), 533
Ladose (fluoxetine), 175 lofepramine, 253
Lamictal (lamotrigine), 235 loflazepate, 259
Lamictin (lamotrigine), 235 Lomesta (lorazepam), 265
lamotrigine, 235 Lonseren (pipothiazine), 383
Lamra (diazepam), 109 Lorabenz (lorazepam), 265
Lanexat (flumazenil), 167 Lorafen (lorazepam), 265
Largactil (chlorpromazine), 57 Loram (lorazepam), 265
Largatrex (chlorpromazine), 57 Lorans (lorazepam), 265
Laroxyl (amitriptyline), 13 Lorapam (lorazepam), 265
Laubeel (lorazepam), 265 lorazepam, 265
Lauracalm (lorazepam), 265 Lorenin (lorazepam), 265
Lebopride (sulpiride), 435 Loridem (lorazepam), 265
Lelptilan (valproate), 499 Lorien (fluoxetine), 175
Lelptilanil (valproate), 499 Lorivan (lorazepam), 265
Lentizol (amitriptyline), 13 Lorsedal (lorazepam), 265
Lentolith (lithium), 247 Lorsifar (lorazepam), 265

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Lorsilan (lorazepam), 265 Merlit (lorazepam), 265

Lorzem (lorazepam), 265 mesoridazine, 287
Lovan (fluoxetine), 175 Metadate CD (d,l-methylphenidate), 121
Loxapac (loxapine), 271 Metadate ER (d,l-methylphenidate), 121
loxapine, 271 Metamidol (diazepam), 109
Loxitane (loxapine), 271 Methylin (d,l-methylphenidate), 121
Ludiomil (maprotiline), 277 Methylin ER (d,l-methylphenidate), 121
Lullan (perospirone), 361 Methylphenidate (d,l-methylphenidate), 121
Lustral (sertraline), 429 Metylyl (desipramine), 103
Luvox (fluvoxamine), 195 Mialin (alprazolam), 1
Lyogen (fluphenazine), 185 midazolam, 291
Lyogen Depot (fluphenazine), 185 Milithin (lithium), 247
Lyoridin Depot (fluphenazine), 185 milnacipran, 295
Lyorodin (fluphenazine), 185 Mipralin (imipramine), 223
Lyrica (pregabalin), 387 Mirbanil (sulpiride), 435
Majorpin (zotepine), 533 Mirenil (fluphenazine), 185
Mallorol (thioridazine), 447 Mirenil Prolongatum (fluphenazine), 185
Maludil (maprotiline), 277 Mirfat (clonidine), 81
Mandro-Zep (diazepam), 109 Mirfudorm (oxazepam), 341
Manerix (moclobemide), 307 Mirpan (maprotiline), 277
Maniprex (lithium), 247 mirtazapine, 301
Mapro Gry (maprotiline), 277 Moban (molindone), 319
Mapro Tablinen (maprotiline), 277 Mocloamine (moclobemide), 307
Maprolu (maprotiline), 277 moclobemide, 307
Maprolu-50 (maprotiline), 277 modafinil, 313
Maprostad (maprotiline), 277 Modalina (trifluoperazine), 487
Maprotibene (maprotiline), 277 Modecate (fluphenazine), 185
Maprotilin (maprotiline), 277 Modiodal (modafinil), 313
maprotiline, 277 Moditen (fluphenazine), 185
Marax (hyroxyzine), 219 Moditen Action Prolongee (fluphenazine), 185
Mareen 50 (doxepin), 145 Moditen Depot (fluphenazine), 185
Mariastel (sulpiride), 435 Moditen Enanthate (fluphenazine), 185
Marplan (isocarboxazid), 229 Modium (lorazepam), 265
Martimil (nortriptyline), 329 molindone, 319
Masmoran (hydroxyzine), 219 Molipaxin (trazodone), 477
Maveral (fluvoxamine), 195 Motipress (nortriptyline), 329
Maximed (protriptyline), 391 Motival (nortriptyline), 329
Mazepine (carbamazepine), 47 Motivan (paroxetine), 351
Maxivalet (amitriptyline), 13 Movergan (selegiline), 423
Medipam (diazepam), 109 Moverin (selegiline), 423
Medopam (oxazepam), 341 Moxadil (amoxapine), 19
Mefurine (thioridazine), 447 Multipax (hydroxyzine), 219
Megaphen (chlorpromazine), 37 Multum (chlordiazepoxide), 53
Meilax (loflazepate), 259 Murelax (oxazepam), 341
Meleril (thioridazine), 447 Mutan (fluoxetine), 175
Melipramin (imipramine), 223 Mylproin (valproate), 499
Melipramine (imipramine), 223 Nailin (nortriptyline), 329
Mellaril (thioridazine), 447 Nalin (nortriptyline), 329
Melleretten (thioridazine), 447 Namenda (memantine), 283
Melleril (thioridazine), 447 Nansius (clorazepate), 87
Melzine (thioridazine), 447 Napoton (chlordiazepoxide), 53
Memac (donepezil), 133 Narcozep (flunitrazepam), 171
memantine, 283 Nardelzine (phenelzine), 371
Menfazona (nefazodone), 323 Nardil (phenelzine), 371
Menrium (chlordiazepoxide), 53 Narol (buspirone), 43
Mepizin (oxazepam), 341 Navane (thiothixene), 453
Meresa (sulpiride), 435 Navicalm (hydroxyzine), 219

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Nefadar (nefazodone), 323 Novo-Hydroxyzine (hydroxyzine), 219

nefazodone, 323 Novo-Lorazem (lorazepam), 265
Nefirel (nefazodone), 323 Novo-Maprotiline (maprotiline), 277
Neodorm SP (temazepam), 443 Novo-Peridol (haloperidol), 213
Neo Gnostoride (chlordiazepoxide), 53 Novoprotect (amitriptyline), 13
Neoride (sulpiride), 435 Novo-Selegine (selegiline), 423
Neurol (alprazolam), 1 Novo-Trazodone (trazodone), 477
Neurolepsin (lithium), 247 Novo-Trimipramine (trimipramine), 493
Neurolithium (lithium), 247 Novo-Triolam (triazolam), 483
Neurolytril (diazepam), 109 Novo-Valproic (valproate), 499
Neurontin (gabapentin), 201 Novodorm (triazolam), 483
Neurotol (carbamazepine), 47 Nozepams (oxazepam), 341
Neurotop (carbamazepine), 47 Nu-Alpraz (alprazolam), 1
Nevropromazine (chlorpromazine), 57 Nu-Carbamazepine (carbamazepine), 47
Nicoflox (fluoxetine), 175 Nu-Clonidine (clonidine), 81
Nifalin (lorazepam), 265 Nu-Loraz (lorazepam), 265
Nilium (flunitrazepam), 171 Nu-Trazodone (trazodone), 477
Niotal (zolpidem), 521 Nu-Trimipramine (trimipramine), 493
Nipolept (zotepine), 533 Nuctalon (estazolam), 163
Nivalin (galantamine), 207 Nufarol (sulpiride), 435
Noam (diazepam), 109 Nulans (lorazepam), 265
Noan-Gap (lorazepam), 265 Nycoflox (fluoxetine), 175
Noctazepam (oxazepam), 341 Nylipark (sulpiride), 435
Noctran (clorazepate), 87 Oasil (chlordiazepoxide), 53
Nocturne (temazepam), 443 olanzapine, 335
Nomapam (temazepam), 443 olanzapine-fluoxetine combination, 335
Noneston (sulpiride), 435 Olasek (olanzapine), 335
Nopress (nortriptyline), 329 Omaha (sulpiride), 435
Nordotol (carbamazepine), 47 Omca (fluphenazine), 185
Norebox (reboxetine), 407 Omiryl (sulpiride), 435
Norestran (sulpiride), 435 Omnali Esteve (chlordiazepoxide), 53
Norfenazin (nortriptyline), 329 Omnipress (amoxapine), 19
Noriel (flunitrazepam), 171 Oniria (quazepam), 397
Noriline (nortriptyline), 229 Opamin (oxazepam), 341
Noripam (oxazepam), 341 Opamox (oxazepam), 341
Noritren (nortriptyline), 329 Opiran (pimozide), 377
Norkotral N (oxazepam), 341 Orap (pimozide), 377
Norkotral Tema (temazepam), 443 Orfidal (lorazepam) Orfilept (valproate), 499
Normison (temazepam), 443 Orfiril (valproate), 499
Normum (sulpiride), 435 Orfiril Retard (valproate), 499
Norpramin (desipramine), 103 Ormodon (temazepam), 443
Northiaden (dothiepin), 139 Orsanil (thioridazine), 447
Nortimil (desipramine), 103 Orthon (fluoxetine), 175
Nortix (nortriptyline), 329 Ox-Pam (oxazepam), 341
Nortrilen (nortriptyline), 329 Oxa-Puren (oxazepam), 341
Nortriptilin (nortriptyline), 329 Oxabenz (oxazepam), 341
nortriptyline, 329 Oxahexal (oxazepam), 341
Nova-Pam (chlordiazepoxide), 53 Oxaline (oxazepam), 341
Novazam (diazepam), 109 Oxanid (oxazepam), 341
Novhepar (lorazepam), 265 Oxapam (oxazepam), 341
Novo-Alprazol (alprazolam), 1 Oxapax (oxazepam), 341
Novo-Carbamaz (carbamazepine), 47 Oxaphar (oxazepam), 341
Novo-Clonidine (clonodine), 81 Oxascand (oxazepam), 341
Novo-Clopamine (clomipramine), 69 oxazepam, 341
Novo-clopate (clorazepate), 87 oxcarbazepine, 345
Novo-Doxepin (doxepin), 145 Oxepam (oxazepam), 341
Novo-fluoxetine (fluoxetine), 175 Oxepam Expidet (oxazepam), 341

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Oxyperazine (trifluoperazine), 487 Plenur (lithium), 247

Ozodeprin (sulpiride), 435 Plurimen (selegiline), 423
Paceum (diazepam), 109 PMS-carbamazepine (carbamazepine), 47
Pacinol (fluphenazine), 185 PMS-Clonazepam (clonazepam), 75
Pacium (diazepam), 109 PMS-Desipramine (desipramine), 103
Pamelor (nortriptyline), 329 PMS-Fluoxetine (fluoxetine), 175
Panix (alprazolam), 1 PMS-fluphenazine (fluphenazine), 185
Pantrop Retard (chlordiazepoxide), 53 PMS-Fluphenazine Decanoate (fluphenazine), 185
Paracefan (clonidine), 81 PMS-Haloperidol (haloperidol), 213
Paratil (sulpiride), 435 PMS-Hydroxyzine (hydroxyzine), 219
Parkinyl (selegiline), 423 PMS-Lithium (lithium), 247
Parmodalin (trifluoperazine), 487 PMS-Methylphenidate (d,l-methylphenidate), 121
Parmodalin (tranylcypromine), 471 PMS-Trazodone (trazodone), 477
Parnate (tranylcypromine), 471 Podium (diazepam), 109
paroxetine, 351 Poldoxin (doxepin), 145
paroxetine CR, 351 Polysal (amitriptyline), 13
Parstelin (trifluoperazine), 487 Portal (fluoxetine), 175
Parstelin (tranylcypromine), 471 Pragmarel (trazodone), 477
Pasrin (buspirone), 43 Praxiten (oxazepam), 341
Pax (diazepam), 109 pregabalin, 387
Paxal (alprazolam), 1 Priadel (lithium), 247
Paxam (clonazepam), 75 Prisdal (citalopram), 63
Paxil (paroxetine), 351 Procythol (selegiline), 423
Paxil CR (paroxetine CR), 351 Pro Dorm (lorazepam), 265
Paxium (chlordiazepoxide), 53 Prolixin (fluphenazine), 185
Paxtibi (nortriptyline), 329 Prolixin Decanoate (fluphenazine), 185
Pazolan (alprazolam), 1 Prolixin enanthate (fluphenazine), 185
Pefanium / Pefanic (chlordiazepoxide), 53 Prolongatum (fluphenazine), 185
pemoline, 357 Pronervon T (temazepam), 443
Peratsin (perphenazine), 365 Propam (diazepam), 109
Peratsin Dekanoaatti (perphenazine), 365 Propaphenin (chlorpromazine), 57
Peratsin Enantaati (perphenazine), 365 Propymal (valproate), 499
Perfenazin (perphenazine), 365 Prosedar (quazepam), 397
Peridol (haloperidol), 213 ProSom (estazolam), 163
Permitil (fluphenazine), 185 Prosulpin (sulpiride), 435
perospirone, 361 Prothiaden (dothiepin), 139
perphenazine, 365 Protiaden (dothiepin), 139
Pertofrane (desipramine), 103 protriptyline, 391
Pertofrin (desipramine), 103 Provigil (modafinil), 313
Phasal (lithium), 247 Proxam (oxazepam), 341
phenelzine, 371 Prozac (fluoxetine), 175
Piefol (trifluoperazine), 487 Prozil (chlorpromazine), 57
pimozide, 377 Prozin (chlorpromazine), 57
Piportil (pipothiazine), 383 Prozyn (fluoxetine), 175
Piportil Depot (pipothiazine), 383 Pryleugan (imipramine), 223
Piportil L4 (pipothiazine), 383 Psicocen (sulpiride), 435
Piportil Longum-4 (pipothiazine), 383 Psicofar (chlordiazepoxide), 53
Piportil palmitate (pipothiazine), 383 Psiquiwas (oxazepam), 341
Piportyl palmitat (pipothiazine), 383 Psychopax (diazepam), 109
pipothiazine, 383 Psymoin (maprotiline), 277
Pipotiazine (pipothiazine), 383 Punktyl (lorazepam), 265
Pirium (pimozide), 377 Purata (oxazepam), 341
Placidia (lorazepam), 265 Q-Med Hydroxyzine (hydroxyzine), 219
Placil (clomipramine), 69 Quait (lorazepam), 265
Placinoral (lorazepam), 265 Quastil (sulpiride), 435
Planum (temazepam), 443 quazepam, 397
Plegomazin (chlorpromazine), 57 Quazium (quazepam), 397

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quetiapine, 401 Roipnol (flunitrazepam), 171

Quiedorm (quazepam), 397 Romazicon (flumazenil), 167
Quilibrex (oxazepam), 341 Ronal (flunitrazepam), 171
Quilonum (lithium), 247 Ronyl (pemoline), 357
Quilonum Retard (lithium), 247 Ropan (flunitrazepam), 171
Quinolorm (lithium), 247 Rubifen (d,l-methylphenidate), 121
Quinolorm Retard (lithium), 247 Rulivan (nefazodone), 323
Quiridil (sulpiride), 435 Sanval (zolpidem), 521
Quitaxon (doxepin), 145 Sanzur (fluoxetine), 175
Radepur (chlordiazepoxide), 53 Sapilent (trimipramine), 493
Razolam (alprazolam), 1 Sarafem (fluoxetine), 175
reboxetine, 407 Saroten (amitriptyline), 13
Redomex (amitriptyline), 13 Saroten Retard (amitriptyline), 13
RedomexDiffucaps (amitriptyline), 13 Sarotex (amitriptyline), 13
Regepar (selegiline), 423 Sartuzin (fluoxetine), 175
Relanium (diazepam), 109 Sebor (lorazepam), 265
Relaxedans (chlordiazepoxide), 53 Securit (lorazepam), 265
Relax Sedans (chlordiazepoxide), 53 Sedacoroxen (imipramine), 223
Reliberan (chlordiazepoxide), 53 Sedans (chlordiazepoxide), 53
Remdue (flurazepam), 191 Sedapon (lorazepam), 265
Remeron (mirtazapine), 301 Sedazin (lorazepam), 265
Remergil (mirtazapine), 301 Sedex (flunitrazepam), 171
Remestan (temazepam), 443 Sedizepan (lorazepam), 265
Reminyl (galantamine), 207 Seduxen (chlordiazepoxide), 53
Reneuron (fluoxetine), 175 Seduxen (diazepam), 109
Repazine (chlorpromazine), 57 Seledat (selegiline), 423
Reposium (temazepam), 443 Selegam (selegiline), 423
Reseril (nefazodone), 323 selegiline, 423
Restful (sulpiride), 435 Selepam (quazepam), 397
Restoril (temazepam), 443 Selepar (selegiline), 423
Retinyl (maprotiline), 277 Selepark (selegiline), 423
Reval (diazepam), 109 Seletop 5 (selegiline), 423
Rexer (mirtazapine), 301 Selgene (selegiline), 423
Rho-Doxepin (doxepin), 145 Selpar (selegiline), 423
Rho-Haloperidol (haloperidol), 213 Senior 20 (pemoline), 357
RHO-Fluphenazine Decanoate (fluphenazine), 185 Sensaval (nortriptyline), 329
Rho-Trimine (trimipramine), 493 Sensival (nortriptyline), 329
Ridazine (thioridazine), 447 Sepatrem (selegiline), 423
Rilamir (triazolam), 483 Serol (fluoxetine), 175
Rimarix (moclobemide), 307 Serad (sertraline), 429
Riminyl (galantamine), 207 Serafem (fluoxetine), 175
Risolid (chlordiazepoxide), 53 Seralgan (citalopram), 63
risperidone, 411 Serax (oxazepam), 341
Risperdal (risperidone), 411 Seren (chlordiazepoxide), 53
Risperin (risperidone), 411 Serenace (haloperidol), 213
Rispolept (risperidone), 411 Serenase (haloperidol), 213
Rispolin (risperidone), 411 Serenase (lorazepam), 265
Ritalin (d,l-methylphenidate), 121 Serenase Decanoat (haloperidol), 213
Ritalin LA (d,l-methlyphenidate), 121 Serenase Depot (haloperidol), 213
Ritalin SR (d,l-methylphenidate), 121 Serenelfi (haloperidol), 213
Ritaline (d,l-methylphenidate), 121 Serentil (mesoridazine), 287
rivastigmine, 417 Serepax (oxazepam), 341
Rivatril (clonazepam), 75 Seresta (oxazepam), 341
Rivotril (clonazepam), 75 Sereupin (paroxetine), 351
Rocam (midazolam), 291 Serlain (sertraline), 429
Rohipnol (flunitrazepam), 171 Seronil (fluoxetine), 175
Rohypnol (flunitrazepam), 171 Seropram (citalopram), 63

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Seroquel (quetiapine), 401 Stelium (trifluoperazine), 487

Seroxal (paroxetine), 351 Stelminal (amitriptyline), 13
Seroxat (paroxetine), 351 Stephadilat (fluoxetine), 175
Serpax (oxazepam), 341 Stesolid (diazepam), 109
Sertofren (desipramine), 103 Stilnoct (zolpidem), 521
sertraline, 429 Stilnox (zolpidem), 521
Serzone (nefazodone), 323 Stimul (pemoline), 357
Setous (zotepine), 523 Strattera (atomoxetine), 31
Sevinol (fluphenazine), 185 Stressigal (buspirone), 43
Sevium (haloperidol), 213 Sulamid (amisulpride), 7
SK-Pramine (imipramine), 223 Sulp (sulpiride), 435
Sibason (diazepam), 109 Sulparex (sulpiride), 435
Sicorelax (diazepam), 109 Sulpiphar (sulpiride), 435
Sigacalm (oxazepam), 341 Sulpirid (sulpiride), 435
Sigaperidol (haloperidol), 213 sulpiride, 435
Signopam (temazepam), 443 Sulpiryd (sulpiride), 435
Sinequan (doxepin), 145 Sulpitil (sulpiride), 435
Sinquan (doxepin), 145 Sulpivert (sulpiride), 435
Sinquane (doxepin), 145 Sulpril (sulpiride), 435
Siqualone (fluphenazine), 185 Suprium (sulpiride), 435
Siqualone decanoat (fluphenazine), 185 Surmontil (trimipramine), 493
Siqualone Enantat (fluphenazine), 185 Suxidina (oxazepam), 341
Sirtal (carbamazepine), 47 Sylador (haloperidol), 213
Sobile (oxazepam), 341 Symbyax (olanzapine-fluoxetine combination), 335
Sobril (oxazepam), 341 Synedil (sulpiride), 435
Socian (amisulpride), 7 Synedil Fort (sulpiride), 435
Softramal (clorazepate), 87 Syneudon 50 (amitriptyline), 13
Solarix (moclobemide), 307 tacrine, 439
Solian (amisulpride), 7 Tafil (alprazolam), 1
Solidon (chlorpromazine), 57 Tagonis (paroxetine), 351
Solis (diazepam), 109 Tardotol (carbamazepine), 47
Somagerol (lorazepam), 265 Taro-Carbamazepine (carbamazepine), 47
Somapam (temazepam), 443 Tatanka (alprazolam), 1
Somatarax (hydroxyzine), 219 Tatig (sertraline), 429
Somniton (triazolam), 483 Tavor (lorazepam), 265
Somnium (lorazepam), 265 Tazepam (oxazepam), 341
Somnol (flurazepam), 191 Tegretal (carbamazepine), 47
Somnubene (flunitrazepam), 171 Tegretol (carbamazepine), 47
Sonata (zaleplon), 511 Tegretol LP (carbamazepine), 47
Songar (triazolam), 483 Teledomin (milnacipran), 295
Sovigen (zolpidem), 521 Temador (temazepam), 443
Sporalon (trifluoperazine), 487 Temaze (temazepam), 443
Stablon (tianeptine), 461 temazepam, 443
Stalleril (thioridazine), 447 Temesta (lorazepam), 265
Spasmilan (buspirone), 43 Temodal (quazepam), 397
Spasmo Praxiten (oxazepam), 341 Temporal Slow (carbamazepine), 47
Stamoneurol (sulpiride), 435 Temporol (carbamazepine), 47
Staurodorm (flurazepam), 191 Temtabs (temazepam), 443
Staurodorm Neu (flurazepam), 191 Tenox (temazepam), 443
Stazepine (carbamazepine), 47 Tenso-Timelets (clonidine), 81
Stedon (diazepam), 109 Tensispes (buspirone), 43
Stelabid (trifluoperazine), 487 Tensium (diazepam), 109
Stelabid forte (trifluoperazine), 487 Tensopam (diazepam), 109
Stelabid mite (trifluoperazine), 487 Tepavil (sulpiride), 435
Stelazine (trifluoperazine), 487 Tepazepam (diazepam), 109
Stelbid (trifluoperazine), 487 Tepazepam (sulpiride), 435
Stelbid forte (trifluoperazine), 487 Teperin (amitriptyline), 13

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Teralithe (lithium), 247 Triazoral (triazolam), 483

Terfluoperazine (perphenazine), 365 Trifluo perazin (trifluoperazine), 487
Terflurazine (trifluoperazine), 487 trifluoperazine, 487
Terfluzin (trifluoperazine), 487 Trilafon (perphenazine), 365
Teril (see carbamazepine), 47 Trilafon decanoaat (perphenazine), 365
Texapam (temazepam), 443 Trilafon dekanoat (perphenazine), 365
Thaden (dothiepin), 139 Trilafon Depot (perphenazine), 365
thioridazine, 447 Trilafon enantat(e) (perphenazine), 365
thiothixene, 453 Trilafon enantato (perphenazine), 365
Thombran (trazodone), 477 Trilafon enenthaat (perphenazine), 365
Thorazine (chlorpromazine), 57 Trileptal (oxcarbazepine), 345
Thymal (lorazepam), 265 Trilifan (perphenazine), 365
tiagabine, 457 Trilifan retard (perphenazine), 365
tianeptine, 451 trimipramine, 493
Timelit (lofepramine), 253 Trimonil (carbamazepine), 47
Tymelyt (lofepramine), 253 Trimonil Retard (carbamazepine), 47
Timonil (carbamazepine), 47 Trion (triazolam), 483
Tingus (fluoxetine), 175 Tripamine Surmontil (trimipramine), 493
Tirodil (thioridazine), 447 Triptafen (perphenazine), 365
Titus (lorazepam), 265 Triptil (protriptyline), 391
Tofranil (imipramine), 223 Triptyl (amitriptyline), 13
Tofranil-PM (imipramine), 223 Triptyl Depot (amitriptyline), 13
Tofranil pamoata (imipramine), 223 Trisedyl (trifluoperazine), 487
Toledomin (milnacipran), 295 Trittico (trazodone), 477
Tolid (lorazepam), 265 Tropargal (nortriptyline), 329
Tonirem (temazepam), 443 Tropium (chlordiazepoxide), 53
Topamac (topiramate), 465 Trycam (triazolam), 483
Topamax (topiramate), 465 Tydamine (trimipramine), 493
Topimax (topiramate), 465 Tryptanol (amitriptyline), 13
topiramate, 465 Tryptine (amitriptyline), 13
T-Pam (temazepam), 443 Tryptizol (amitriptyline), 13
Tradon (pemoline), 357 Ucerax (hydroxyzine), 219
Tramensan (trazodone), 477 Umbrium (diazepam), 109
Trankilium (lorazepam), 265 Unilan (alprazolam), 1
Trankimazin (alprazolam), 1 Unisedil (diazepam), 109
Tranquase (diazepam), 109 Unitranxene (clorazepate), 87
Tran-Quil (lorazepam), 265 U-Pan (lorazepam), 265
Tranquipam (lorazepam), 265 Uskan (oxazepam), 341
Tranquirit (diazepam), 109 Valaxona (diazepam), 109
Tranquo (oxazepam), 341 Valclair (diazepam), 109
Tranquo/Tablinen (diazepam), 109 Valclair (chlordiazepoxide), 53
Transene (clorazepate), 87 Valcote 250 (valproate), 499
Tranxene (clorazepate), 87 Valdorm (flurazepam), 191
Tranxilen (clorazepate), 87 Valeans (alprazolam), 1
Tranxilium (clorazepate), 87 Valinil (diazepam), 109
tranylcypromine, 471 Valiquid (diazepam), 109
Tranzen (clorazepate), 87 Valiquid o.3 (diazepam), 109
Travin (buspirone), 43 Valirem (sulpiride), 435
Trazepam (oxazepam), 341 Valium (diazepam), 109
trazodone, 477 Valocordin Diazepam (diazepam), 109
Trazolan (trazodone), 477 Valparine (valproate), 499
Tremorex (selegiline), 423 Valpro (valproate), 499
Trepiline (amitriptyline), 13 valproate, 499
Tresleen (sertraline), 429 valproic acid (valproate), 499
Trevilor (venlafaxine), 505 Valsera (flunitrazepam), 171
Trewilor (venlafaxine), 505 Vandral (venlafaxine), 505
triazolam, 483 Vatran (diazepam), 109

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Venefon (imipramine), 223 Vesadol (haloperidol), 213

venlafaxine, 505 Vesalium (haloperidol), 213
venlafaxine XR, 505 Zactin (fluoxetine), 175
Versed (midazolam), 291 Zafrionil (haloperidol), 213
Vertigo (sulpiride), 435 zaleplon, 511
Vesparax (hydroxyzine), 219 zelapon (selegiline), 423
Vesparax mite (hydroxyzine), 219 Zemorcon (sulpiride), 435
Vesparax Novum (hydroxyzine), 219 Zeptol (carbamazepine), 47
Vigiten (lorazepam), 265 Zerenal (dothiepin), 139
Vincosedan (diazepam), 109 ziprasidone, 515
Visergil (thioridazine), 447 Ziprexa (olanzapine), 335
Vistaril (hydroxyzine), 219 Zispin (mirtazapine), 301
Vivacti (protriptyline), 391 Zoleptil (zotepine), 533
Vival (diazepam), 109 Zoloft (sertraline), 429
Vivapryl (selegiline), 423 zolpidem, 521
Vividyl (nortriptyline), 229 Zonalon (doxepin), 145
Vivol (diazepam), 109 Zonegran (zonisamide), 525
Volital (pemoline), 357 zonisamide, 525
Vulbegal (flunitrazepam), 171 Zopax (alprazolam), 1
Vulpral (valproate), 499 zopiclone, 529
Wellbatrin (bupropion), 37 Zopite (zotepine), 533
Wellbutrin (bupropion), 37 zotepine, 533
Wellbutrin SR (bupropion SR), 37 Z-Pam (temazepam), 443
Wellbutrin XL (bupropion XL), 37 zuclopenthixol, 539
Xanax (alprazolam), 1 Zuledin (chlorpromazine), 57
Xanax XR (alprazolam XR), 1 Zyban (bupropion), 37
Xanor (alprazolam), 1 Zymocomb (sulpiride), 435
Xepin (doxepin), 145 Zyprexa (olanzapine), 335

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Index by Use
Bold for FDA approved

Aggression phenelzine, 371

clozapine, 91 pregabalin, 387
zuclopenthixol, 539 reboxetine, 407
sertraline, 429
Alcohol withdrawal tiagabine, 457
chlordiazepoxide, 53 tianeptine, 461
clonidine, 81 tranylcypromine, 471
clorazepate, 87 trazodone, 477
diazepam, 109 trifluoperazine, 487
lorazepam, 265 trimipramine, 493
oxazepam, 341 venlafaxine, 505

Alzheimer disease Attention deficit/hyperactivity disorder

donepezil, 133 atomoxetine, 31
galantamine, 207 bupropion, 37
memantine, 283 chlorpromazine (hyperactivity), 57
rivastigmine, 417 clonidine, 81
tacrine, 439 d,l-amphetamine, 115
d,l-methylphenidate, 121
Anxiety d-amphetamine, 97
alprazolam, 1 d-methylphenidate, 127
amitriptyline, 13 haloperidol (hyperactivity), 213
amoxapine, 19 modafinil, 313
buspirone, 43 pemoline, 357
chlordiazepoxide, 53 reboxetine, 407
citalopram, 63
clomipramine, 69 Behavioral problems
clonazepam, 75 aripiprazole, 25
clonidine, 81 chlorpromazine, 57
clorazepate, 87 haloperidol, 213
desipramine, 103 olanzapine, 335
diazepam, 109 quetiapine, 401
dothiepin, 139 risperidone, 411
doxepin, 145 ziprasidone, 515
duloxetine, 151
escitalopram, 157 Bipolar depression
fluoxetine, 175 amoxapine, 19
fluvoxamine, 195 aripiprazole, 25
gabapentin (adjunct), 201 bupropion, 37
hydroxyzine, 219 fluoxetine, 175
imipramine, 223 lamotrigine, 235
isocarboxazid, 229 lithium, 247
lofepramine, 253 olanzapine, 335
loflazepate, 259 olanzapine-fluoxetine combination, 175, 335
lorazepam, 265 quetiapine, 401
maprotiline, 277 risperidone, 411
mirtazapine, 301 valproate (divalproex), 499
moclobemide, 307 ziprasidone, 515
nefazodone, 323
nortriptyline, 329 Bipolar disorder
oxazepam, 341 alprazolam (adjunct), 1
paroxetine, 351 amoxapine, 19

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aripiprazole, 25 rivastigmine, 417

bupropion, 37 tacrine, 439
carbamazepine, 47
chlorpromazine, 57 Depression
clonazepam (adjunct), 75 amisulpride, 7
doxepin, 145 amitriptyline, 13
fluoxetine, 175 amoxapine, 19
flupenthixol, 181 atomoxetine, 31
fluphenazine, 185 bupropion, 37
gabapentin (adjunct), 201 buspirone (adjunct), 43
haloperidol, 213 citalopram, 63
lamotrigine, 235 clomipramine, 69
levetiracetam, 243 d,l-amphetamine, 115
lithium, 247 d,l-methylphenidate, 121
lorazepam (adjunct), 265 d-amphetamine, 97
loxapine, 271 desipramine, 103
molindone, 319 d-methylphenidate, 127
olanzapine, 335 dothiepin, 139
olanzapine-fluoxetine combination, 175, 335 doxepin, 145
oxcarbazepine, 345 duloxetine, 151
perphenazine, 365 escitalopram, 157
pipothiazine, 383 fluoxetine, 175
quetiapine, 401 flupenthixol, 181
risperidone, 411 fluvoxamine, 195
thiothixene, 453 imipramine, 223
topiramate (adjunct), 465 isocarboxazid, 229
trifluoperazine, 487 lithium (adjunct), 247
valproate (divalproex), 499 lofepramine, 253
ziprasidone, 515 maprotiline, 277
zonisamide, 525 milnacipran, 295
zotepine, 533 mirtazapine, 301
zuclopenthixol, 539 moclobemide, 307
modafinil (adjunct), 313
Bipolar maintenance nefazodone, 323
aripiprazole, 25 nortriptyline, 329
lamotrigine, 235 olanzapine, 335
lithium, 247 paroxetine, 351
olanzapine, 335 phenelzine, 371
olanzapine-fluoxetine combination, 175, 335 protriptyline, 391
quetiapine, 401 reboxetine, 407
risperidone, 411 selegiline, 423
valproate (divalproex), 499 sertraline, 429
ziprasidone, 515 sulpiride, 435
tianeptine, 461
Bulimia nervosa/binge eating tranylcypromine, 471
fluoxetine, 175 trazodone, 477
topiramate, 465 trimipramine, 493
zonisamide, 525 venlafaxine, 505

Cataplexy syndrome Drug-induced amnesia

clomipramine, 69 midazolam, 291
imipramine, 223
Enuresis
Dementia imipramine, 223
donepezil, 133
galantamine, 207
memantine, 283

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Excessive sleepiness in narcolepsy, Intractable hiccups

obstructive sleep apnea/hypopnea syndrome, chlorpromazine, 57
shift work sleep disorder
modafinil, 313 Mania
alprazolam (adjunct), 1
Fibromyalgia aripiprazole, 25
amitriptyline, 13 chlorpromazine, 57
duloxetine, 151 clonazepam (adjunct), 75
milnacipran, 295 lamotrigine, 235
pregabalin, 387 levetiracetam, 243
lithium, 247
Generalized anxiety disorder lorazepam (adjunct), 265
alprazolam, 1 olanzapine, 355
citalopram, 63 quetiapine, 401
duloxetine, 151 risperidone, 411
escitalopram, 157 valproate (divalproex), 499
fluoxetine, 175 ziprasidone, 515
fluvoxamine, 195 zotepine, 533
mirtazapine, 301
paroxetine, 351 Migraine
pregabalin, 387 topiramate, 465
sertraline, 429 valproate (divalproex), 499
tiagabine (adjunct), 457
venlafaxine, 505 Muscle spasm
diazepam, 109
Hypertension lorazepam, 265
clonidine, 81
Narcolepsy
Insomnia d,l-amphetamine, 115
alprazolam, 1 d,l-methylphenidate, 121
amitriptyline, 13 d-amphetamine, 97
amoxapine, 19 d-methylphenidate, 127
clomipramine, 69 modafinil, 313
clonazepam, 75
desipramine, 103 Nausea/vomiting
diazepam, 109 chlorpromazine, 57
dothiepin, 139 hydroxyzine, 219
doxepin, 145 perphenazine, 365
estazolam, 163
flunitrazepam, 171 Neuropathic pain/chronic pain
flurazepam, 191 amitriptyline, 13
hydroxyzine, 219 amoxapine, 19
imipramine, 223 carbamazepine, 47
lofepramine, 253 clomipramine, 69
lorazepam, 265 clonidine (adjunct), 81
maprotiline, 277 desipramine, 103
nortriptyline, 329 dothiepin, 139
quazepam, 397 doxepin, 145
temazepam, 443 duloxetine, 151
trazodone, 477 gabapentin, 201
triazolam, 483 imipramine, 223
trimipramine, 493 lamotrigine, 235
zaleplon, 511 levetiracetam, 243
zolpidem, 521 lofepramine, 253
zopiclone, 529 maprotiline, 277
memantine, 283
milnacipran, 295

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nortriptyline, 329 Posttraumatic stress disorder

pregabalin, 387 citalopram, 63
tiagabine, 457 clonidine, 81
topiramate, 465 escitalopram, 157
trimipramine, 493 fluoxetine, 175
valproate (divalproex), 499 fluvoxamine, 195
zonisamide, 525 mirtazapine, 301
nefazodone, 323
Neutropenia paroxetine, 351
lithium, 247 sertraline, 429
venlafaxine, 505
Nicotine addiction
bupropion, 37 Premenstrual dysphoric disorder
citalopram, 63
Obsessive-compulsive disorder escitalopram, 157
citalopram, 63 fluoxetine, 175
clomipramine, 69 paroxetine, 351
escitalopram, 157 sertraline, 429
fluoxetine, 175 venlafaxine, 505
fluvoxamine, 195
paroxetine, 351 Pruritus
sertraline, 429 doxepin, 145
venlafaxine, 505 hydroxyzine, 219

Panic disorder Psychosis

alprazolam, 1 alprazolam (adjunct), 1
citalopram, 63 amisulpride, 7
clonazepam, 75 aripiprazole, 25
escitalopram, 157 carbamazepine (adjunct), 47
fluoxetine, 175 chlorpromazine, 57
fluvoxamine, 195 clonazepam (adjunct), 75
isocarboxazid, 229 clozapine, 41
lorazepam, 265 flupenthixol, 181
mirtazapine, 301 fluphenazine, 185
nefazodone, 323 haloperidol, 213
paroxetine, 351 lamotrigine (adjunct), 235
phenelzine, 371 lorazepam (adjunct), 265
pregabalin, 387 loxapine, 271
reboxetine, 407 mesoridazine, 287
sertraline, 429 molindone, 319
tranylcypromine, 471 olanzapine, 335
venlafaxine, 505 perospirone, 361
perphenazine, 365
Parkinson’s disease pimozide, 377
selegiline, 423 pipothiazine, 383
zonisamide, 525 quetiapine, 401
risperidone, 411
Peripheral neuropathic pain sulpiride, 435
pregabalin, 387 thioridazine, 447
thiothixene, 453
Porphyria trifluoperazine, 487
chlorpromazine, 57 valproate (divalproex) (adjunct), 499
ziprasidone, 515
Postherpetic neuralgia zotepine, 533
gabapentin, 201 zuclopenthixol, 539

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Reversal of benzodiazepine effects oxcarbazepine, 345

flumazenil, 167 pregabalin (adjunct), 387
tiagabine, 457
Schizophrenia topiramate, 465
amisulpride, 7 valproate (divalproex), 499
aripiprazole, 25 zonisamide, 525
carbamazepine (adjunct), 47
chlorpromazine, 57 Sexual dysfunction
clozapine, 91 bupropion, 37
flupenthixol, 181
haloperidol, 213 Social anxiety disorder
lamotrigine (adjunct), 235 citalopram, 63
loxapine, 271 clonidine, 81
mesoridazine, 287 escitalopram, 157
molindone, 319 fluoxetine, 175
olanzapine, 335 fluvoxamine, 195
perospirone, 361 isocarboxazid, 229
perphenazine, 365 moclobemide, 307
pipothiazine, 383 paroxetine, 351
quetiapine, 401 phenelzine, 371
risperidone, 411 pregabalin, 387
sulpiride, 435 sertraline, 429
thioridazine, 447 tranylcypromine, 471
thiothixene, 453 venlafaxine, 505
trifluoperazine, 487
valproate (divalproex) (adjunct), 499 Stress urinary incontinence
ziprasidone, 515 duloxetine, 151
zotepine, 533
zuclopenthixol, 539 Tetanus
chlorpromazine, 57
Sedation-induction
hydroxyzine, 219 Tourette’s syndrome
midazolam, 291 clonidine, 81
haloperidol, 213
Seizure disorders pimozide, 377
carbamazepine, 47
clonazepam, 75 Trigeminal neuralgia
clorazepate (adjunct), 87 carbamazepine, 47
diazepam, 109
gabapentin, 201 Weight gain
lamotrigine, 235 topiramate, 465
levetiracetam, 243 zonisamide, 525
lorazepam, 265

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Index by Class
Alzheimer Treatments tianeptine, 461
donepezil, 133 tranylcypromine, 471
galantamine, 207 trazodone, 477
memantine, 283 trimipramine, 493
rivastigmine, 417 venlafaxine, 505
tacrine, 439
Antipsychotics
Anticonvulsants amisulpride, 7
carbamazepine, 47 aripiprazole, 25
clonazepam, 75 chlorpromazine, 57
clorazepate (adjunct), 87 clozapine, 91
diazepam, 109 flupenthixol, 181
gabapentin, 201 fluphenazine, 185
lamotrigine, 235 haloperidol, 213
levetiracetam, 243 loxapine, 271
lorazepam, 265 mesoridazine, 287
oxcarbazepine, 345 molindone, 319
pregabalin, 387 olanzapine, 335
tiagabine, 457 perospirone, 361
topiramate, 465 perphenazine, 365
valproate (divalproex), 499 pimozide, 377
zonisamide, 525 pipothiazine, 383
quetiapine, 401
Antidepressants risperidone, 411
amitriptyline, 13 sulpiride, 435
amoxapine, 19 thioridazine, 447
atomoxetine, 31 thiothixene, 453
bupropion, 37 trifluoperazine, 487
citalopram, 63 ziprasidone, 515
clomipramine, 69 zotepine, 533
desipramine, 103 zuclopenthixol, 539
dothiepin, 139
doxepin, 145 Anxiolytics
duloxetine, 151 alprazolam, 1
escitalopram, 157 amitriptyline, 13
fluoxetine, 175 amoxapine, 19
fluvoxamine, 195 buspirone, 43
imipramine, 223 chlordiazepoxide, 53
isocarboxazid, 229 citalopram, 63
lofepramine, 253 clomipramine, 69
maprotiline, 277 clonazepam, 75
milnacipran, 295 clonidine, 81
mirtazapine, 301 clorazepate, 87
moclobemide, 307 desipramine, 103
nefazodone, 323 diazepam, 109
nortriptyline, 329 dothiepin, 139
paroxetine, 351 doxepin, 145
phenelzine, 371 duloxetine, 151
protriptyline, 391 escitalopram, 157
reboxetine, 407 fluoxetine, 175
selegiline, 423 fluvoxamine, 195
sertraline, 429 gabapentin (adjunct), 201

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hydroxyzine, 219 Mood Stabilizers

imipramine, 223 alprazolam (adjunct), 1
isocarboxazid, 229 amoxapine, 19
lofepramine, 253 aripiprazole, 25
loflazepate, 259 bupropion, 37
lorazepam, 265 carbamazepine, 47
maprotiline, 277 chlorpromazine, 57
mirtazapine, 301 clonazepam (adjunct), 75
moclobemide, 307 doxepin, 145
nefazodone, 323 fluoxetine, 175
nortriptyline, 329 flupenthixol, 181
oxazepam, 341 fluphenazine, 185
paroxetine, 351 gabapentin (adjunct), 201
phenelzine, 371 haloperidol, 213
pregabalin, 387 lamotrigine, 235
reboxetine, 407 levetiracetam (adjunct), 243
sertraline, 429 lithium, 247
tiagabine (adjunct), 457 lorazepam (adjunct), 265
tianeptine, 461 loxapine, 271
tranylcypromine, 471 molindone, 319
trazodone, 477 olanzapine, 335
trifluoperazine, 487 olanzapine-fluoxetine combination, 175, 335
trimipramine, 493 oxcarbazepine, 345
venlafaxine, 505 perphenazine, 365
pipothiazine, 383
Attention Deficit Hyperactivity Disorder pregabalin (adjunct), 387
Treatments quetiapine, 401
atomoxetine, 31 risperidone, 411
bupropion, 37 thiothixene, 453
chlorpromazine, 57 topiramate (adjunct), 465
clonidine, 81 trifluoperazine, 487
d-amphetamine, 97 valproate (divalproex), 499
d,l-amphetamine, 115 ziprasidone, 515
d,l-methylphenidate, 121 zonisamide (adjunct), 525
d-methylphenidate, 127 zotepine, 533
haloperidol, 213 zuclopenthixol, 539
modafinil, 313
pemoline, 357 Neuropathic/Chronic Pain Treatments
reboxetine, 407 amitriptyline, 13
amoxapine, 19
Cognitive Enhancers carbamazepine, 47
atomoxetine, 31 clomipramine, 69
bupropion, 37 clonidine (adjunct), 81
clonidine, 81 desipramine, 103
d-amphetamine, 97 dothiepin, 139
d,l-amphetamine, 115 doxepin, 145
d,l-methylphenidate, 121 gabapentin, 201
d-methylphenidate, 127 imipramine, 223
donepezil, 133 lamotrigine, 235
galantamine, 207 levetiracetam, 243
memantine, 283 lofepramine, 253
modafinil, 313 maprotiline, 277
pemoline, 357 memantine, 283
reboxetine, 407 milnacipran, 295
rivastigmine, 417 nortriptyline, 329
tacrine, 439 pregabalin, 387
tiagabine, 457

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topiramate, 465 Stimulants

trimipramine, 493 d-amphetamine, 97
valproate (divalproex), 499 d,l-amphetamine, 115
zonisamide, 525 d,l-methylphenidate, 121
d-methylphenidate, 127
Sedative Hypnotics pemoline, 357
estazolam, 163
flunitrazepam, 171 Wake-Promoting Agents
flurazepam, 191 d-amphetamine, 97
midazolam, 291 d,l-amphetamine, 115
quazepam, 397 d,l-methylphenidate, 121
temazepam, 443 d-methylphenidate, 127
trazodone, 477 modafinil, 313
triazolam, 483 pemoline, 357
zaleplon, 511
zolpidem, 521
zopiclone, 529

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Abbreviations
5HT serotonin
ACH acetylcholine
ACHE acetylcholinesterase
ADHD attention deficit hyperactivity disorder
ALT alanine aminotransferase
ALPT total serum alkaline phosphatase
AST aspartate aminotransferase
BID twice a day
BMI body mass index
BuChE butyrylcholinesterase
CMI clomipramine
CNS central nervous system
CYP450 cytochrome P450
De-CMI desmethyl-clomipramine
DA dopamine
dl deciliter
DLB dementia with Lewy bodies
ECG electrocardiogram
EEG electroencephalogram
EKG electrocardiogram
EPS extrapyramidal side effects
ERT estrogen replacement therapy
FDA Food and Drug Administration
FSH follicle-stimulating hormone
GAD generalized anxiety disorder
GI gastrointestinal
HDL high-density lipoprotein
HMG CoA beta-hydroxy-beta-methylglutaryl Coenzyme A
HRT hormone replacement therapy
IM intramuscular
IV intravenous
LDL low-density lipoprotein
LH luteinizing hormone
Lb pound
MAO monoamine oxidase
MAOI monoamine oxidase inhibitor
mCPP meta-chloro-phenyl-piperazine
mg milligram
mL milliliter
mm Hg millimeters of mercury
MDD major depressive disorder

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NE norepinephrine
NMDA N-methyl-d-aspartate
OCD obsessive-compulsive disorder
ODV O-desmethylvenlafaxine
PET positron emission tomography
PK pharmacokinetic
PMDD premenstrual dysphoric disorder
PMS premenstrual syndrome
PTSD posttraumatic stress disorder
QD once a day
QHS once a day at bedtime
QID four times a day
RIMA reversible inhibitor of monoamine oxidase A
SNRI dual serotonin and norepinephrine reuptake inhibitor
SSRI selective serotonin reuptake inhibitor
TCA tricyclic antidepressant
TID three times a day
TSH thyroid stimulating hormone

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FDA Use-In-Pregnancy Ratings

Category A: Controlled studies show no risk: adequate, well-controlled studies in pregnant
women have failed to demonstrate risk to the fetus

Category B: No evidence of risk in humans: either animal findings show risk, but human findings
do not; or, if no adequate human studies have been performed, animal findings are
negative

Category C: Risk cannot be ruled out: human studies are lacking, and animal studies are either
positive for fetal risk or lacking as well. However, potential benefits may outweigh
risks

Category D: Positive evidence of risk: investigational or postmarketing data show risk to the
fetus. Nevertheless, potential benefits may outweigh risks

Category X: Contraindicated in pregnancy: studies in animals or humans, or investigational or

postmarketing reports, have shown fetal risk that clearly outweighs any possible
benefit to the patient

571