Stahl’s Illustrated

Anxiety, Stress, and PTSD

Stephen M. Stahl
University of California, San Diego
 Meghan M. Grady
Neuroscience Education Institute
Nancy Muntner
Illustrations
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PREFACE
These books are designed to be fun, with all concepts illustrated by full-
color images and the text serving as a supplement to figures, images, and
tables. The visual learner will find that this book makes
psychopharmacology concepts easy to master, while the non-visual learner
may enjoy a shortened text version of complex psychopharmacology
concepts. Each chapter builds upon previous chapters, synthesizing
information from basic biology and diagnostics to building treatment plans
and dealing with complications and comorbidities.

Novices may want to approach this book by first looking through all the
graphics, gaining a feel for the visual vocabulary on which our
psychopharmacology concepts rely. After this once-over glance, we suggest
going back through the book to incorporate the images with supporting text.
Learning from visual concepts and textual supplements should reinforce one
another, providing you with solid conceptual understanding at each step
along the way.

Readers more familiar with these topics should find that going back and
forth between images and text provides an interaction with which to vividly
conceptualize complex psychopharmacology. You may find yourself using
this book frequently to refresh your psychopharmacological knowledge. And
you will hopefully refer your colleagues to this desk reference.

This book is intended as a conceptual overview of different topics; we

provide you with a visual-based language to incorporate the rules of
psychopharmacology at the sacrifice of discussing the exceptions to these
rules. A Suggested Readings section at the end gives you a good start for
more in-depth learning about particular concepts presented here.

When you come across an abbreviation you don’t understand, you can refer
to the Abbreviations list in the back. Stahl’s Essential Psychopharmacology,
3rd Edition, and Stahl’s Essential Psychopharmacology: The Prescriber’s
Guide, 3rd Edition, can be helpful supplementary tools for more in-depth
information on particular topics in this book. Now you can also search topics
in psychopharmacology on the Neuroscience Education Institute’s website
(www.neiglobal.com) for lectures, courses, slides, and related articles.

Whether you are a novice or an experienced psychopharmacologist,

hopefully this book will lead you to think critically about the complexities
involved in psychiatric disorders and their treatments.

Best wishes for your educational journey into the fascinating field of
psychopharmacology!
 Contents
Preface
Continuing Medical Education (CME) Information
Objectives
Chapter 1:
Neurobiology of Stress and Anxiety
Chapter 2:
Posttraumatic Stress Disorder (PTSD)
Chapter 3:
Neurotransmitter Systems as Pharmacological Targets for PTSD
Chapter 4:
First-Line Medications for PTSD
Chapter 5:
Second-Line, Adjunct, and Investigational Medications for PTSD
Chapter 6:
Cognitive Behavioral Therapy (CBT) for PTSD
Chapter 7:
Caring for Patients with PTSD
Chapter 8:
Unique Considerations for the Military Population
Summary
Abbreviations
Suggested Readings
Index
CME Posttest
Activity Evaluation
 CME Information
Overview
This book provides an overview of the latest developments in research and clinical treatment of
posttraumatic stress disorder (PTSD). Chapter 1 covers the neurobiology of normal fear and worry and
how genetic and environmental factors may interact to affect these circuits and increase risk for
psychiatric illnesses such as PTSD. Chapter 2 covers the clinical presentation of PTSD, including
comorbidities and suicidality as well as its underlying risk factors and neurobiology. Chapter 3
reviews the major neurotransmitter systems that regulate functioning within anxiety-related brain
circuits, and that are therefore potential targets of pharmacologic action in the treatment of PTSD.
Chapter 4 reviews the mechanisms of action and clinical characteristics of first-line pharmacologic
treatments for PTSD, while Chapter 5 does the same for second-line, adjunct, and investigational
agents, and Chapter 6 explains the methods for several first- and second-line cognitive behavioral
therapies. Chapter 7 reviews diagnostic and treatment strategies for patients with PTSD, including
consideration of comorbidities. Finally, Chapter 8 focuses on risks and complicating factors that are
particularly relevant to the military population, with emphasis on the relationship between PTSD and
the potential long-term effects of mild TBI.

Target Audience
This activity has been developed for prescribers specializing in psychiatry. There are no prerequisites
for this activity. Health care providers in all specialties who are interested in psychopharmacology,
especially primary care physicians, nurses, psychologists, and pharmacists, are welcome for advanced
study.

Statement of Need
A surprisingly high percentage of the population will experience at least one traumatic event in their
lifetime (trauma being defined as a frightening situation in which one experiences or witnesses the
threat of death or injury). Although not all individuals exposed to traumatic events will develop
psychopathology—in fact, most do not—a significant minority will, with potentially devastating
consequences for them and their loved ones.

The following unmet needs regarding anxiety and posttraumatic stress disorder (PTSD) were revealed
following a critical analysis of expert faculty assessment and literature review:
PTSD is increasingly prevalent and associated with significant morbidity and mortality
Neurobiology of stress and anxiety can serve to enhance understanding of anxious symptoms
and their treatment
 Treatments for PTSD continue to be examined, with many options—both pharmacological and
nonpharmacological—available based on individual symptoms

To help fill these unmet needs, quality improvement efforts need to provide education regarding (1)
neurobiology of PTSD; (2) risk factors, both environmental and genetic, for PTSD; and (3) different
therapeutic options available for PTSD and how to develop treatment strategies that maximize
outcomes.

Learning Objectives
After completing this educational activity, participants should be better able to:
Explain the neurobiology of both normal and pathological stress and anxiety
Recognize the environmental and genetic factors that can contribute to the development of
anxiety disorders
Explain the pharmacology of therapeutic agents used in treating posttraumatic stress disorder
(PTSD)
Identify new drugs and methods in development for the treatment of PTSD
Explain the principles and methods involved in cognitive behavioral therapy (CBT) for PTSD
Customize treatment regimens for patients with PTSD based on symptom profile,
comorbidities, and life situations

Accreditation and Credit Designation Statements

The Neuroscience Education Institute is accredited by the Accreditation Council for Continuing
Medical Education to provide continuing medical education for physicians.

The Neuroscience Education Institute designates this educational activity for a maximum of 4.0 AMA
PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their
participation in the activity. Also available will be a certificate of participation for completing this
activity.

Nurses may claim credit for activities approved for AMA PRA Category 1 Credits™ in most states, for
up to 50% of the nursing requirement for recertification. This activity is designated for 4.0 AMA PRA
Category 1 Credits.

Activity Instructions
This CME activity is in the form of a printed monograph and incorporates instructional design to
enhance your retention of the information and pharmacological concepts that are being presented. You
are advised to go through the figures in this activity from beginning to end, followed by the text, and
then complete the posttest and activity evaluation. The estimated time for completion of this activity is
4.0 hours.

Instructions for CME Credit

To receive your certificate of CME credit or participation, please complete the posttest (you must
score at least 70% to receive credit) and activity evaluation found at the end of the monograph and
mail or fax them to the address/number provided. Once received, your posttest will be graded and a
certificate sent if a score of 70% or more was attained. Alternatively, you may complete the posttest
and activity evaluation online and immediately print your certificate. There is a fee for the
posttest (waived for NEI members).

NEI Disclosure Policy

It is the policy of the Neuroscience Education Institute to ensure balance, independence, objectivity,
and scientific rigor in all its educational activities. Therefore, all individuals in a position to influence
or control content development are required by NEI to disclose any financial relationships or apparent
conflicts of interest that may have a direct bearing on the subject matter of the activity. Although
potential conflicts of interest are identified and resolved prior to the activity being presented, it
remains for the participant to determine whether outside interests reflect a possible bias in either the
exposition or the conclusions presented.

These materials have been peer-reviewed to ensure the scientific accuracy and medical relevance of
information presented and its independence from commercial bias. The Neuroscience Education
Institute takes responsibility for the content, quality, and scientific integrity of this CME activity.

Individual Disclosure Statements

Authors
Meghan Grady
Director, Content Development, Neuroscience Education Institute, Carlsbad, CA
No other financial relationships to disclose.

Stephen M. Stahl, MD, PhD

Adjunct Professor, Department of Psychiatry, University of California, San Diego School of Medicine
Honorary Visiting Senior Fellow, University of Cambridge, UK
Grant/Research: Forest, Johnson & Johnson, Novartis, Organon, Pamlab, Pfizer, Sepracor, Shire,
Takeda, Vanda, Wyeth
Consultant/Advisor: Arena, Azur, Bionevia, Boehringer Ingelheim, Bristol-Myers Squibb, CeNeRx,
Dainippon Sumitomo, Eli Lilly, Endo, Forest, Janssen, Jazz, Johnson & Johnson, Labopharm,
Lundbeck, Marinus, Neuronetics, Novartis, Noven, Pamlab, Pfizer, Pierre Fabre, Sanofi-Synthélabo,
Sepracor, Servier, Shire, SK, Solvay, Somaxon, Tetragenix, Vanda
Speakers Bureau: Pfizer, Wyeth

Peer Reviewer
Ronnie Gorman Swift, MD
Professor and Associate Chairman, Department of Psychiatry and Behavioral Sciences, New York
Medical College, Valhalla
Professor of Clinical Public Health, School of Public Health, New York; New York Medical College,
Valhalla Chief of Psychiatry and Associate Medical Director, Metropolitan Hospital Center, New York,
NY
No other financial relationships to disclose.

Design Staff
Nancy Muntner
Director, Medical Illustrations, Neuroscience Education Institute, Carlsbad, CA

No other financial relationships to disclose.

Disclosed financial relationships have been reviewed by the Neuroscience Education Institute CME
Advisory Board to resolve any potential conflicts of interest. All faculty and planning committee
members have attested that their financial relationships do not affect their ability to present well-
balanced, evidence-based content for this activity.

Disclosure of Off-Label Use

This educational activity may include discussion of products or devices that are not currently labeled
for such use by the FDA. Please consult the product prescribing information for full disclosure of
labeled uses.

Disclaimer
The information presented in this educational activity is not meant to define a standard of care, nor is
it intended to dictate an exclusive course of patient management. Any procedures, medications, or
other courses of diagnosis or treatment discussed or suggested in this educational activity should not
be used by clinicians without full evaluation of their patients’ conditions and possible
contraindications or dangers in use, review of any applicable manufacturer’s product information, and
comparison with recommendations of other authorities. Primary references and full prescribing
information should be consulted.
Participants have an implied responsibility to use the newly acquired information from this activity to
enhance patient outcomes and their own professional development. The participant should use his/her
clinical judgment, knowledge, experience, and diagnostic decision-making before applying any
information, whether provided here or by others, for any professional use.

Sponsorship Information
This activity is sponsored by Neuroscience Education Institute.

Support
This activity is supported solely by the sponsor, Neuroscience Education Institute.
Neither the Neuroscience Education Institute nor the authors have received any funds or grants in
support of this educational activity.

Date of Release/Expiration
Release Date: February 2010 CME Credit Expiration Date: January 2013
 Objectives

Explain the neurobiology of both normal and pathological stress and

anxiety
Recognize the environmental and genetic factors that can contribute to
the development of anxiety disorders
Explain the pharmacology of therapeutic agents used in treating
posttraumatic stress disorder (PTSD)
Identify new drugs and methods in development for the treatment of
PTSD
Explain the principles and methods involved in cognitive behavioral
therapy (CBT) for PTSD
Customize treatment regimens for patients with PTSD based on
symptom profile, comorbidities, and life situations
 Chapter 1

Neurobiology of Stress and Anxiety

Anxiety is a normal emotional and neurophysiological reaction to a
perceived threat, and serves the purpose of preparing one to “freeze, take
flight, or fight.” Such a reaction is obviously an appropriate and even
adaptive survival mechanism in the presence of actual threats, allowing one
both to escape the current threat and to avoid future ones through
conditioned fear learning. When the reaction occurs in the absence of a
realistic threat, however—whether because the threat itself is unlikely or
because harm from the perceived threat is unlikely—then it serves no useful
purpose and instead can significantly disrupt one’s ability to function, thus
constituting an anxiety disorder.

There are several anxiety disorders, as defined in the Diagnostic and

Statistical Manual of Mental Disorders (DSM) IV-TR, each with distinct
characteristics, criteria, and symptoms, but all sharing the common core
symptoms of excessive fear and worry. The neurobiological circuits
underlying these core symptoms may thus be involved in all anxiety
disorders, with the different phenotypes reflecting not unique circuitry but
rather divergent malfunctioning within those circuits.

This chapter covers the neurobiology of normal fear and worry and how
genetic and environmental factors may interact to affect these circuits and
increase risk for psychiatric illnesses such as posttraumatic stress disorders
(PTSD), which is the focus of this book.
 SECTION ONE
The Core Symptoms of Anxiety Disorders: Fear and Worry

FIGURE 1.1. The two core symptoms shared by all anxiety disorders are
anxiety or fear coupled with some form of worry. The circuitry mediating
these two features is different, and will be addressed in turn, beginning with
anxiety/fear.

The Amygdala’s Role in Fear and Anxiety

FIGURE 1.2. Anxiety is a state that encompasses both an internal “feeling”
of fear and the physiological expression of that fear. Although separate
circuits mediate these different aspects of anxiety, they share in common a
central role of the amygdala, an almond-shaped limbic structure with
widespread reciprocal connections with both higher and lower brain regions.
As shown in Figures 1.3 through 1.9, the amygdala both regulates and is
regulated by these other brain regions in order to produce (or suppress) a
fear response.

Fear vs. Anxiety

TABLE 1.1.
DESCRIPTION ANATOMICAL
LOCALIZATION
fear Short-term, stimulus-specific Basolateral, central, and medial
response nuclei of amygdala
anxiety Sustained response influencing Basolateral amygdala projections
behavior after the stimulus is to bed nucleus of stria terminalis
removed
 The Amygdala and the Feeling of Fear

FIGURE 1.3. The emotional aspect of fear is regulated by connections

between the amygdala and key areas of the prefrontal cortex, specifically the
orbitofrontal cortex (OFC) and the anterior cingulate cortex (ACC).

The Amygdala and the Physiology of Fear:

Autonomic Output
FIGURE 1.4. The physiological reaction to a fearful stimulus involves
activation of multiple systems, including the autonomic system, as shown
here. Activation of this system is regulated by connections between the
amygdala and the locus coeruleus (LC), and leads to an increase in heart rate
(HR) and blood pressure that is necessary for a fight/flight reaction.

Although acute activation of the autonomic nervous system is important for

survival in response to real threats, chronic activation as part of an anxiety
disorder can lead to increased risk of cardiovascular issues such as
atherosclerosis, cardiac ischemia, hypertension, myocardial infarction (MI),
or even sudden death.

The Amygdala and the Physiology of Fear:

Endocrine Output
FIGURE 1.5. The hypothalamic pituitary adrenal (HPA) axis is responsible
for endocrine output during the fear/stress response, and is regulated by the
amygdala via reciprocal connections with the hypothalamus. During acute
stress, such as exposure to a fearful stimulus, HPA activation increases the
release of glucocorticoids such as cortisol, but only for a short time, until the
perceived danger is gone. An abnormal stress response may occur due to
chronic, unrelenting stress and/or due to stress during critical developmental
periods, and can be associated with increased rates of medical complications
such as coronary artery disease, type 2 diabetes, and stroke.

The role of the HPA axis in anxiety disorders is discussed in more detail in
Figure 1.6 as well as in Figures 2.6 and 2.7.

The HPA Axis

FIGURE 1.6. The central role of the HPA axis in stress processing makes it
logical that it would be involved in the risk for anxiety disorders. The normal
stress response involves activation of the hypothalamus and a resultant
increase in corticotrophin releasing factor (CRF) (A), which in turn
stimulates the release of adrenocorticotrophic hormone (ACTH) from the
pituitary gland (B). ACTH causes glucocorticoid release (cortisol in humans)
from the adrenal gland, which binds to receptors in the hypothalamus,
pituitary, and hippocampus (C). Glucocorticoid binding in the hypothalamus
inhibits CRF release, ending the stress response (D). In addition, the
hippocampus plays a role in inhibiting the stress response (D).

In situations of chronic stress, excessive glucocorticoid release may

eventually lead to hippocampal atrophy, thus preventing it from inhibiting
the HPA axis (E). This could contribute to chronic activation of the HPA axis
(F) and increase risk for an anxiety disorder.

The Amygdala and the Physiology of Fear:

 Breathing Output

FIGURE 1.7. Increases in respiration rate are also an important part of a

fear response and are regulated by connections between the amygdala and
the parabrachial nucleus (PBN). However, when excessive activation occurs,
this can cause shortness of breath, exacerbation of asthma, or a sense of
being smothered—all of which are symptoms of a panic attack.

The Amygdala and the Behavior of Fear

FIGURE 1.8. The emotional and physiological responses to a threat prepare
one to take action in order to escape or combat that threat. The actual motor
response taken—whether fight, flight, or freeze—is regulated in part through
connections between the amygdala and the periaqueductal grey (PAG).

The Hippocampus:
An Internal Fearmonger
FIGURE 1.9. Anxiety can be triggered not only by an external stimulus but
also internally through traumatic memories stored in the hippocampus,
which can activate the amygdala and cause it, in turn, to activate other brain
regions to generate a fear response. This is known as reexperiencing and is a
central feature of posttraumatic stress disorder (PTSD).

Fear Conditioning
FIGURE 1.10. An important part of the normal fear response is the
amygdala’s ability to “remember” stimuli associated with the stressor so that
it can react more efficiently if the stressor is ever reencountered—a process
known as fear conditioning.

Upon acute exposure to a fearful situation, the lateral amygdala integrates

input from several brain regions, including sensory cortex and thalamus,
which provide information about stimuli associated with the fearful
situation; the hippocampus, which provides memories of related fearful or
traumatic experiences; and the ventromedial prefrontal cortex (VMPFC),
which may provide mitigating input to suppress a fear response (A). If a fear
response is in fact generated, then the amygdala restructures existing
synapses to increase the efficiency of glutamatergic neurotransmission in
response to future sensory input associated with the feared stimulus (B,
represented by increased orange glutamate output and at synapses).

The Worry Loop

FIGURE 1.11. Figures 1.2 through 1.10 reviewed the circuitry of fear, one
of the two core symptoms of all anxiety disorders. The second core
symptom, worry, involves different circuitry, as shown in Figure 1.12.

Worry and Obsessions

FIGURE 1.12. Worry, which can include apprehensive expectation,
catastrophic thinking, and obsessions, is hypothetically linked to cortico-
striatal-thalamic-cortical (CSTC) loops. Specifically shown here is a CSTC
loop originating and ending in the dorsolateral prefrontal cortex (DLPFC).
 SECTION TWO
The Path to Anxiety Disorders: A Circuit’s Story

FIGURE 1.13. During acute exposure to stressors, the fear circuits

described in Figures 1.3 through 1.9 are activated (middle), thus producing
reactions that optimize the chances for survival. Once the trauma is
withdrawn, the circuits return to baseline functioning (right). How then
might activation of these circuits lead to the pathological symptoms of
anxiety disorders?

Stress Sensitization in Normal Circuits

FIGURE 1.14. When circuits are repeatedly stressed and put on overload
(middle right), it can lead to a condition known as “stress sensitization,” in
which circuits not only become overly activated but remain overly activated
even when the stressor is withdrawn (right).

A sensitized circuit does not necessarily mean that symptoms will develop,
however. Instead, overloading circuits can potentially result in a loss of
resilience and development of vulnerability to future stressors. Thus,
individuals who have highly stressed and overloaded circuits may be
phenotypically normal but have an increased risk for development of future
anxiety disorders. This is known as a “presymptomatic” state.

Progression from Stress Sensitization

FIGURE 1.15. This figure shows the progression from stress sensitization to
psychiatric symptoms. Stress sensitized circuits at rest are shown on the far
left. In the absence of additional stressors, these overly activated circuits are
clinically silent because they are able to compensate for the excessive
activation. However, they are less efficient in their information processing
than are normal, nonsensitized circuits. Under additional stress or emotional
trauma, stress-sensitized circuits are hypothetically unable to compensate
and begin to show signs of breakdown into subtle prodromal symptoms
(middle left). With further emotional trauma, these failing circuits either do
not compensate when they overly activate or even break down and fail to
activate adequately, leading to the development of subsyndromal symptoms
(middle right). Finally, with continuing emotional trauma, the
malfunctioning circuits break down further; thereafter psychiatric symptoms
not only develop but may persist even after withdrawal of the emotional
trauma (far right).

Is All Stress Bad?

FIGURE 1.16. The experience of life stress can create stress sensitization
and consequently increased risk for psychiatric illness, as shown in Figure
1.15. Interestingly, however, the degree of stress seems to make a difference,
with only severe or overwhelming stress generally leading to sensitization
(far right). In fact, exposure to mild stress in infancy may actually be
protective: studies have shown that animals who have experienced mild
stress in infancy may be less reactive to future stressors (middle) than
animals not previously exposed to stress (left).

Stress Diathesis Model:

A Tale of Two Influences, Part 1
FIGURE 1.17. Exposure to stress isn’t the whole story, however. Psychiatric
symptoms often develop due both to genetic and environmental influences.
This is known as the stress diathesis hypothesis.

Thus, although environmental stressors—such as childhood abuse, divorce,

viruses, or toxins—can increase the risk, or diathesis, of developing a mental
illness, individuals with a normal genome and thus normal circuits may
experience only normal activation of circuits in response to these stressful
events. Such individuals would not express a mental illness, exhibiting
instead a normal phenotype with no adverse behavioral symptoms.

Stress Diathesis Model:

A Tale of Two Influences, Part 2
FIGURE 1.18. However, individuals with a risk gene for mental illness may
experience inefficient information processing in the “biased” circuit in
response to stress, increasing the likelihood of stress sensitization. This does
not necessarily mean that behavioral symptoms will ensue. Genetically
inefficient information processing may be behaviorally “silent” if it is
compensated by overactivation via backup systems. In this case, the
individual may still have a normal behavioral phenotype despite having an
abnormal biological endophenotype. Thus, abnormal circuit activation may
be detectable with functional brain scanning, but clinical interview would
reveal no psychiatric symptoms.

Stress Diathesis Model:

A Tale of Two Influences, Part 3
FIGURE 1.19. An individual with multiple stressors and multiple genetic
risks may not have sufficient backup mechanisms to compensate for
inefficient information processing within a genetically “biased” circuit. The
circuit may either be unsuccessfully compensated by overactivation or it
may break down and not activate at all. In either case, psychiatric symptoms
would be likely to develop.

An Allegorical View of Stress Diathesis

FIGURE 1.20. This representation summarizes the concept of stress
diathesis, which was explained in Figures 1.17 through 1.19. Each
suspension cable is analogous to a gene, while the vehicles that pass over the
bridge represent types of environmental stressors.
 Chapter 2

Posttraumatic Stress Disorder (PTSD)

A surprisingly high percentage of the population will experience at least one
traumatic event in their lifetime (trauma being defined as a frightening
situation in which one experiences or witnesses the threat of death or injury).
Although not all individuals exposed to traumatic events will develop
psychopathology—in fact, most do not—a significant minority will, with
potentially devastating consequences for them and their loved ones.

Posttraumatic stress disorder (PTSD) has a prevalence rate of 7–8%, with

even higher rates for specific subpopulations (e.g., military personnel). It is a
disorder with significant impact on functioning and quality of life and should
be diagnosed and treated according to the best available evidence.

This chapter covers the clinical presentation of PTSD, including

comorbidities and suicidality as well as its underlying risk factors and
neurobiology.
 PTSD:
An Historical Perspective

FIGURE 2.1. The psychological consequences of extremely stressful and

dangerous situations such as warfare have been documented since ancient
Roman times. It was not until the last thirty years, however, that those
consequences were recognized as anything more than weakness of character
in the individuals who suffered from them. Though PTSD is not confined to
war-related traumas, most evolutions of its name and hypothesized etiology
have derived from examination of military experiences.

The first modern conceptualization of posttraumatic stress symptoms was

described in 1678 as nostalgia and attributed to homesickness on the part of
soldiers. Nearly two hundred years later, advances in modern weaponry
contributed to such a large proportion of American Civil War soldiers
exhibiting stress-related ailments—soldier’s heart—that the first military
hospital for the insane was established. Further advances in weapon
technology in the First World War led to the proposed etiology of brain
concussion caused by exploding shells, and hence the term shell shock.
Other conceptualizations of posttraumatic symptoms at that time included
irritable heart (overstimulation of the sympathetic nervous system) and war
neurosis (Freud’s suggestion that soldiers were reconciling their traumatic
experiences in their minds). By the end of World War I posttraumatic stress
was no longer attributed to physical brain injury, and by World War II the
term battle fatigue had emerged, again with the implication that it
represented weakness.

FIGURE 2.1 (CONT.). The first edition of the DSM contained the entry
“gross stress reaction” under the category “transient situational personality
disturbances.” This was not considered a true diagnosis but rather a
temporary state experienced by a “normal” person who had experienced
great or unusual stress. This entry was eliminated from DSM-II, with no
corresponding replacement. Advances in the field of psychiatry, coinciding
with the return of hundreds of thousands of Vietnam War veterans suffering
from posttraumatic stress, ultimately led to the inclusion of PTSD in the
third edition of the DSM, published in 1980. Since then the diagnosis has
been retained, although revisions to criteria have occurred, most notably
with respect to the definition of a traumatic event. Further revisions are
likely, as planning for DSMV is heavily underway and debate in the
literature abounds regarding how PTSD should be defined, described, and
classified.

Criteria Controversies and the Future of PTSD

FIGURE 2.2. The current diagnostic criteria for PTSD (DSM-IV-TR) are
shown here. A diagnosis of PTSD depends on exposure to a traumatic event
(A) and development of symptoms related to that event (B through D). There
is some degree of controversy surrounding each of these criteria groups;
however, most controversy is with respect to criterion A. Debate exists
surrounding the type of qualifying traumatic event, the degree of exposure
required, and even whether a traumatic event should be required at all.
Accordingly, the DSM-V posttraumatic and dissociative disorders subwork
group is considering (1) whether/how to revise A1; (2) whether to retain or
revise A2; (3) whether to revise, reduce, or expand B, C, and D; (4) whether
PTSD should be reclassified with adjustment and dissociative disorders
rather than with anxiety disorders; (5) whether to add any new proposed
trauma-related disorders; and (6) how to create developmentally sensitive
criteria.

Clinical Picture of PTSD

FIGURE 2.3. Characteristic symptoms of PTSD are shown here. Of 17 total
diagnostic symptoms, only 6 are required for a diagnosis; thus it is possible
that two individuals with PTSD could express quite divergent symptom
profiles. Nonetheless, the majority of patients with PTSD will exhibit
anxiety related to reexperiencing of the traumatic event (intrusive thoughts,
dreams, flashbacks), hyperarousal and startle responses (as well as
corresponding worry about experiencing such responses), avoidance
behaviors, feelings of alienation, emotional numbing, anger and irritability,
and sleep difficulties including nightmares.

Common Comorbidities
FIGURE 2.4. It is more common than not for a patient with PTSD to have
at least one comorbid psychiatric disorder, with the most frequent
comorbidities being major depressive disorder, alcohol dependence, drug
abuse, and other anxiety disorders. Chronic pain can also be a frequent
comorbidity, particularly following traumatic events involving injury (see
Figure 2.10).

It is common for patients with PTSD to have a psychiatric history prior to

exposure to a traumatic event; however, it is also common for a comorbid
disorder to be diagnosed subsequent to onset of PTSD. Some argue that the
rates of comorbidity in PTSD are artificially high owing to the degree of
symptom overlap between PTSD and depression/other anxiety disorders.
This is an important consideration warranting further investigation, though
from a clinical practice perspective it may be most important to recognize
the symptoms that patients experience, regardless of the disorder to which
they might be attributed.

Suicide Risk
FIGURE 2.5. Rates of suicide ideation, attempts, and completions are
alarmingly high in PTSD, regardless of the type of trauma experienced.
PTSD is the only anxiety disorder that independently predicts suicidal
behavior, though risk may also be increased in patients with comorbid
disorders, particularly depression. The high rate of suicidal behavior in
PTSD may not be surprising considering the overlap between recognized
risk factors for suicidality, shown here, and the symptoms and associated
features of PTSD. In particular, research shows that disorders characterized
by extreme anxiety and agitation—such as PTSD—as well as those
characterized by poor impulse control—such as substance use disorders,
commonly comorbid with PTSD—are the strongest predictors of suicide
attempts among psychiatric disorders. Although many risk factors for
suicidality are difficult or impossible to address (depicted as “high-hanging”
fruit), certain factors, many of which are relevant to PTSD, can be addressed
(“low-hanging” fruit).

Risk Factors that Predict PTSD

 STRONG MODERATE ???
Psychiatric history Life stress Trauma type
Childhood abuse Lack of social support Small hippocampus
Family psychiatric Other previous trauma Hypocortisolism
history
Other adverse childhood Genetic
experience polymorphisms
Trauma severity

TABLE 2.1. PTSD’s dependence on a causal event creates the complication

of two potential sets of risk factors: those for exposure to a traumatic event
and those for development of PTSD following exposure to a traumatic event.
The risk factors shown here have been documented to predict PTSD, but
some (e.g., psychiatric history) may also be risk factors for trauma exposure.

Early Life Stress as a Risk Factor for PTSD

FIGURE 2.6. Stressful experiences in early life, such as childhood abuse or
neglect, can have long-term negative consequences (see Figures 1.13
through 1.20). At a neurophysiological level, exposure to early life stress can
lead to dysregulation of the HPA axis that may be characterized by either
hypo- or hyperactive stress responses (see Figure 1.6). Specifically,
individuals with a history of early life stress demonstrate exaggerated ACTH
release and reduced cortisol release in response to stressors. Hippocampal
atrophy has also been documented in this population, as has reduced levels
of brain-derived neurotrophic factor (BDNF).

At a phenotypic level, these neurophysiological alterations are associated

with increased risk for development of mental illnesses, most notably major
depressive disorder (MDD) and PTSD.

PTSD and the HPA Axis

FIGURE 2.7. In PTSD, several abnormalities in HPA axis function have
been identified, including increased CRF, downregulation of CRF receptors,
decreased cortisol levels, and increased sensitivity to negative cortisol
feedback. In addition, reduced hippocampal volume has been documented.

Reduced Hippocampal Volume and Stress:

Cause or Effect?
FIGURE 2.8. It is unknown whether reduced hippocampal volume may be a
marker of preexisting vulnerability to stress, a structural consequence of
stress, or both. Reduced hippocampal volume has been found in adult
maltreatment-related PTSD, but not in childhood maltreatment-related
PTSD, suggesting that it is a consequence of stress that occurs over time. On
the other hand, a twin study in combat-related PTSD suggests that smaller
hippocampal volume may be a risk factor for PTSD development.

Genetic Risk Factors

FIGURE 2.9. Isolating specific genetic influences in PTSD can be difficult,
as it, like other mental illnesses, is a complex disorder characterized by
multiple genetic and environmental risk factors (Table 2.1). Several
polymorphisms that may increase risk for PTSD are under investigation.
These include the SLC6A3 9 repeat allele in the dopamine transporter gene,
the “s” allele in the serotonin transporter gene (see Figures 3.3 and 3.4),
Val66Met in the BDNF gene, and multiple polymorphisms in the FKBP5
gene. FKBP5 is a glucocorticoid receptor cochaperone; thus polymorphisms
in its gene could affect HPA axis functionality, which is altered in both child
abuse survivors and individuals with PTSD (Figures 2.6 and 2.7). In fact,
four single nucleotide polymorphisms in the FKBP5 gene seem to interact
with severity of child abuse to predict adult PTSD symptoms. Further
investigation into this and other potential candidate genes is ongoing.

Neuroimaging Findings in PTSD

TABLE 2.2. There is no existing biomarker for assessing risk for,
diagnosing, or charting progression of PTSD. We can still be informed,
however, by neuroimaging and other studies that have shown
neurobiological abnormalities in patients with PTSD. Summarized here is
the current neurobiological evidence, including potential clinical
implications of those findings (those with the strongest evidence are shown
in green). As with reduced hippocampal volume (included here and
discussed in Figure 2.8), it remains unknown whether these neurobiological
changes in PTSD patients reflect risk factors for or consequences of the
disorder.

Relationship Between Trauma Type and PTSD

TABLE 2.3. The majority of people have experienced a traumatic event (as
defined in DSM). In addition, individuals who have experienced a traumatic
event are actually likely to have experienced more than one. The most
frequently experienced traumas are witnessing the death or extreme injury of
another person, being involved in a natural disaster such as fire or flood, and
being involved in a life-threatening accident. Although these are the most
frequent trauma types across genders, men are more likely to experience
them; men are also more likely than women to be threatened with a weapon,
be physically attacked, or engage in combat, and in fact are more likely to
experience a trauma overall. Women are more likely than men to be
molested, raped, or physically abused or neglected as a child.

The majority of individuals exposed to a trauma do not develop PTSD. In

addition, the most commonly experienced traumatic events are not the ones
most associated with PTSD. In fact, although rape is the trauma type with
the lowest lifetime prevalence in men it is associated with the highest
probability of PTSD. Combat, childhood neglect, and childhood physical
abuse are also associated with high probability of PTSD in men. In women,
the trauma types associated with the highest probability of PTSD are
childhood physical abuse, rape, being threatened with a weapon, and
molestation.

Although men are more likely than women to experience a traumatic event,
women are more likely to experience a trauma associated with a high
probability of developing PTSD. Women may also be more likely than men
to meet criteria for PTSD following a traumatic event. Both of these factors
may contribute to the higher rate of PTSD in women than in men.

Although it is interesting to evaluate the relationship between trauma type

and PTSD, it is not currently clear what influence trauma type has on the
risk for exposure to future stressors, the risk for development of PTSD, or
the symptom expression of PTSD.
 PTSD and Chronic Pain

FIGURE 2.10. Many traumatic events that can lead to PTSD (e.g.,
accidents, combat, physical attack) can also result in physical injury, and in
many cases the pain associated with such injury may become chronic. In
fact, PTSD and chronic pain are common comorbidities following a
traumatic event. The extent and nature of the relationship between PTSD and
pain is not known, but there is some evidence that PTSD can drive pain and
that pain can drive PTSD—in other words, that there is a mutual
maintenance relationship between the two.

In theory, if pain occurred in conjunction with a traumatic event, then

subsequent pain could trigger distressing memories of the event that in turn
lead to arousal and avoidance. Arousal can cause muscle tension that may
exacerbate pain; the pain itself may also be so distressing that it leads to
avoidance. This model is supported by a recent longitudinal study in which
reexperiencing and arousal symptoms at the time of a traumatic event
predicted pain at three months; further, reexperiencing and arousal at three
months predicted pain at twelve months. In turn, pain at baseline predicted
arousal at three months, while pain at three months predicted reexperiencing,
arousal, and avoidance at twelve months.
 Chapter 3

Neurotransmitter Systems as Pharmacological Targets for

PTSD
In Chapter 1 we matched the core symptoms of anxiety disorders with the
brain circuits that hypothetically mediate them, and illustrated how those
circuits can become sensitized and increase risk for a psychiatric disorder
such as PTSD. Chapter 3 reviews the major neurotransmitter systems that
regulate functioning within those brain circuits, and that are therefore
potential targets of pharmacologic action in the treatment of PTSD.
 The Neurotransmitters of Fear and Worry

FIGURE 3.1. The major chemical players in amygdala-centered circuits

include serotonin (5HT), gamma-aminobutyric acid (GABA),
norepinephrine (NE), glutamate, corticotrophin releasing factor (CRF), and
other hormones involved in HPA axis function. 5HT, GABA, NE, and
glutamate are also central to functioning in the CSTC loops of worry, as is
dopamine (DA). In addition, voltage-sensitive ion channels are involved in
neurotransmission in all of these circuits. Each of these neurotransmitters
systems are discussed in turn on the following pages.

Serotonergic Pathways
FIGURE 3.2. These are the major serotonergic projections in the brain. As
shown, serotonergic neurons innervate the amygdala and the prefrontal
cortex, two regions essential to anxiety and worry. Serotonin has also been
implicated in other symptoms associated with PTSD, including emotional
numbing, irritability, and suicidality. In fact, many of the pharmacologic
agents used to treat PTSD have as their central mechanism the modulation of
serotonergic neurotransmission (see Chapters 4 and 5). There is some
evidence for altered serotonin neurotransmission in PTSD, including
decreased serum concentrations and decreased density of platelet serotonin
uptake sites. Further evidence implicating serotonin in anxiety and fear
comes from genetic studies looking at the serotonin transporter (SERT) gene
and amygdala reactivity.

SERT Genotype and Amygdala Activation, Part 1

FIGURE 3.3. Genetic research has shown that the type of SERT (serotonin
transporter) one has can affect how active the amygdala is in response to
fearful stimuli. A polymorphism in the gene that codes for SERT yields two
alleles, one long (“l”) and one short (“s”). Carriers of the s allele make fewer
copies of SERT, have lower amounts of SERT reuptake activity, and have
higher amounts of synaptic serotonin. Functional neuroimaging data show
that s carriers also have greater amygdala reactivity to fearful faces (A) than
do those with the l/l variant (B).

SERT Genotype and Amygdala Activation, Part 2

FIGURE 3.4. Another way of saying this may be that the l/l genotype leads
to a “resilient” circuit that can process fearful or stressful stimuli efficiently,
whereas the s genotype leads to a “vulnerable” circuit that overreacts in
response to fearful or stressful stimuli. The relationship between SERT
variants and amygdala reactivity has been demonstrated in multiple studies
as well as a recent meta-analysis, and is further supported by results of a
recent fear-conditioning study in which only s carriers developed
conditioned startle potentiation.

The clinical implications of the SERT variant/amygdala reactivity

relationship are not yet known, however. A recent meta-analysis of SERT
studies found no association between SERT variant and risk for depression,
neither as a main effect nor as an interaction effect between genotype and
stressful life events. Thus, although it has been posited that overactivation of
circuits in s carriers may confer greater risk of developing a mood or anxiety
disorder in the context of multiple life stressors, current evidence does not
support this.
 Potential Targets for Modulating Serotonergic
Neurotransmission, Part 1

FIGURE 3.5. Given the clear link between the 5HT system and amygdala
activity, it is not surprising that many of the pharmacologic agents used to
treat anxiety are primarily serotonergic in mechanism. Shown here and in
Figure 3.6 are some of the potential targets for modulating the serotonin
system. Specific agents that act at these sites are discussed in Chapters 4 and
5.

Serotonin can have its synaptic action terminated by the serotonin

transporter, SERT, which transports serotonin molecules back into the
presynaptic neuron for reuse (see Chapter 4 for agents acting at SERT).
Serotonin can also be destroyed by monoamine oxidase (MAO) enzymes,
which convert serotonin molecules into an inactive derivative (see Figure 5.7
for agents acting at MAO enzymes).
 Potential Targets for Modulating Serotonergic
Neurotransmission, Part 2

FIGURE 3.6. Pre- and postsynaptic serotonin receptors are shown here. On
the presynaptic side, in addition to the 5HT transporter (see Figure 3.5),
there is a key presynaptic 5HT receptor (5HT1B/D) that functions as an
autoreceptor to regulate 5HT release. There are also several postsynaptic
5HT receptors (5HT1A, 5HT1B/D, 5HT2A, 5HT2C, 5HT3, 5HT4, 5HT6,
5HT7, and many others denoted by 5HTX,Y,Z) as shown here.

Noradrenergic Pathways
FIGURE 3.7. These are the major noradrenergic projections in the brain.
Like serotonergic neurons, noradrenergic neurons innervate the amygdala
and the prefrontal cortex, both of which are essential to anxiety and worry.
In addition, noradrenergic neurons originate in the locus coeruleus, which is
responsible for the autonomic output of fear (see Figure 1.4).

Potential Noradrenergic Mechanisms for Novel Anxiolytics

FIGURE 3.8. Noradrenergic hyperactivation can lead to anxiety, panic
attacks, tremors, sweating, tachycardia, hyperarousal, and nightmares. Such
autonomic reactivity at the time of exposure to a traumatic event may be
associated with risk of developing PTSD. Alpha 1 and beta 1 adrenergic
receptors may be specifically involved in these reactions (see Figures 3.10,
5.16, and 5.33).

Potential Targets for Modulating Noradrenergic

Neurotransmission, Part 1
FIGURE 3.9. Shown here and in Figure 3.10 are some of the potential
pharmacologic targets for modulating the noradrenergic system. Specific
agents that act at these sites are discussed in Chapters 4 and 5.

Norepinephrine can have its synaptic action terminated by the

norepinephrine transporter (NET), which transports norepinephrine
molecules back into the presynaptic neuron for reuse (see Chapter 4 for
agents acting at NET). Norepinephrine can also be destroyed by MAO
enzymes, which convert norepinephrine molecules into an inactive
derivative (see Figure 5.7 for agents acting at MAO enzymes).

Potential Targets for Modulating Noradrenergic

Neurotransmission, Part 2
FIGURE 3.10. Pre- and postsynaptic norepinephrine receptors are shown
here. On the presynaptic side, in addition to the NE transporter (see Figure
3.9), there is a key presynaptic NE receptor (alpha 2) that functions as an
autoreceptor to regulate NE release. There are also several postsynaptic NE
receptors (alpha 1, 2A, 2B, and 2C; beta 1, 2, and 3) as shown here. Alpha 1
and beta 1 receptors may be of particular importance to the treatment of
anxiety (see Figures 5.16 and 5.33).

GABA “Pathways”
FIGURE 3.11. GABA is the major inhibitory neurotransmitter in the brain,
regulating and reducing the activity of many neurons, including neurons in
the amygdala and within CSTC loops. GABA therefore plays a key role in
the experience and expression of anxiety, and can potentially be modulated
in order to reduce anxiety. Shown on the following pages are some of the
potential pharmacologic targets for modulating the GABA-ergic system.
Specific agents that act at these sites are discussed in Figures 5.11 and 5.37.

Potential Targets for Modulating GABA-ergic

Neurotransmission
FIGURE 3.12. GABA can have its synaptic action terminated by the GABA
transporter (GAT), which transports GABA molecules back into the
presynaptic neuron for reuse, or by the enzyme GABA transaminase
(GABA-T), which converts GABA in the presynaptic bouton into an inactive
substance.

In addition to the GABA transporter, there are three major types of

postsynaptic GABA receptors: GABA-A, GABA-B, and GABA-C. GABA-
A and -C receptors are ligand-gated ion channels that form part of an
inhibitory chloride channel, while GABA-B receptors are G protein-linked
and can couple with calcium or potassium channels. GABA-A receptors are
particularly relevant to anxiety and to the anxiolytic effects of
benzodiazepines, and are discussed in more detail in Figure 5.10.

Glutamate Pathways
FIGURE 3.13. While GABA is the major inhibitory neurotransmitter in the
brain (Figures 3.11 and 3.12), glutamate is the major excitatory
neurotransmitter. Shown here are the main glutamatergic projections in the
brain. Glutamate is a major player in communication between the prefrontal
cortex (PFC) and other brain regions, and is particularly involved in CSTC
loops.

Unlike GABA, which has had a recognized role in anxiety and its treatment
for some time, glutamate has only recently received focus in this area.
Shown on the following pages are some of the potential targets for
modulating the glutamatergic system. Investigational agents that act at these
sites are discussed in Figure 5.35.

Glutamate Receptors
FIGURE 3.14. Pre- and postsynaptic glutamate receptors are shown here.
The excitatory amino acid transporter (EAAT) clears excess glutamate from
synapses and transports it back into the presynaptic neuron. Metabotropic
glutamate receptors (mGluR) are linked to G-proteins and can occur either
pre- or postsynaptically, with presynaptic mGluRs acting as autoreceptors to
regulate glutamate release. Three other types of postsynaptic glutamate
receptors are linked to ion channels and are named for the agonists that bind
to them: NMDA (N-methyl-D-aspartate), AMPA (alpha-amino-3-hydroxy-5-
methyl-4-isoxazolepropionic acid), and kainate. Glutamate’s actions at
NMDA receptors are dependent in part upon the presence of a cotransmitter,
either glycine or d-serine, which are produced in nearby neurons (glycine) or
glial cells (d-serine).

Voltage-Sensitive Ion Channels

FIGURE 3.15. Excitatory neurotransmission may also be modulated by
targeting voltage-sensitive ion channels, which are integrally involved in the
process of neurotransmission, as shown here (see Figure 5.9 for agents
acting at voltage-sensitive ion channels).

An action potential is sent to the axon terminal via voltage-sensitive sodium

channels (VSSC) along the axon. The sodium released by those channels
triggers a VSSC at the axon terminal to open (A), allowing sodium influx
into the presynaptic neuron (B). This changes the electrical charge of the
voltage-sensitive calcium channel (VSCC) (C), causing it to open and allow
calcium influx (D). As the intraneuronal concentration of calcium increases
(E), the synaptic vesicle is caused to dock and merge with the presynaptic
membrane, leading to neurotransmitter release (F).

CRF and Other Stress Hormones

FIGURE 3.16. The central role of the HPA axis in stress responses (Figure
1.6) makes it logical that it would be involved in anxiety disorders, and this
is in fact substantiated by evidence of HPA axis abnormalities in PTSD
(Figure 2.7). Receptors and neurotransmitters within the HPA axis are
therefore potential targets for pharmacological action in PTSD
(investigational agents acting at these sites are discussed in Figures 5.34 and
5.36).

Dopamine and the PFC

FIGURE 3.17. Dopamine is integral to functioning in the PFC, which is the
brain region responsible (in conjunction with the thalamus and striatum) for
worry symptoms such as apprehensive expectations, catastrophic thinking,
and obsessions. Efficient functioning of the PFC requires a delicate balance
of receptor stimulation, specifically alpha 2 receptors by NE and D1
receptors by DA.

In theory, NE increases incoming salient signals by allowing for increased

connectivity of prefrontal networks, while DA decreases noise by preventing
inappropriate connections from taking place. Cortical pyramidal cell
function is optimal when stimulation of both alpha 2A and D1 receptors is
moderate (top of curve). If stimulation at these receptors is too low (left), all
incoming signals are the same, preventing a person from focusing on one
single task. When stimulation is too high (right), the signals get scrambled as
additional receptors are recruited, again misguiding a person’s attention and
potentially leading to inappropriate worry.

Born Worried? COMT Genotype and PFC Activation

FIGURE 3.18. Dopamine levels in the PFC are regulated in large part by
the enzyme catechol-O-methyl-transferase (COMT). A polymorphism in the
gene that codes for COMT yields two alleles, “met” and “val,” with the
met/met genotype associated with lower COMT activity and thus higher DA
levels. During cognitive tasks, this may be beneficial, allowing for normal
activation (top right), whereas reduced DA with the val genotype may lead
to inefficiency of cognitive information processing, potentially requiring
more effort to perform less well (top left).

In the case of stress responses, however, the beneficial genotype may be

reversed. That is, higher baseline DA levels with the met/met genotype
combined with DA release in response to stress may cumulatively be
excessive and contribute to worry and risk for anxiety disorders (bottom
right). Those with the val genotype, on the other hand, may be less reactive
to stress because COMT can destroy the excess dopamine (bottom left).

Conditioned Fear Extinction:

 COMT

FIGURE 3.19. There is evidence not only that the variant of COMT may
affect risk for anxiety disorders, but also that it may affect the likelihood that
certain treatment will be effective. Specifically, a standard treatment for
many anxiety disorders is exposure therapy, in which a feared stimulus is
repeatedly presented without adverse consequences so that there is a
progressive reduction of the response to the fear stimulus (discussed in more
detail in Figure 6.2). This is known as fear extinction, and is a form of new
learning (that the stimulus is not threatening) rather than elimination of the
old conditioned fear.

In a preliminary study, individuals with the val genotype achieved extinction

of a conditioned fear (measured by startle potentiation) to a fearful face that
had originally been paired with shock (left). Those with the met/met
genotype, on the other hand, did not achieve extinction, suggesting that too
high levels of DA may have prevented efficient information processing in
the PFC (right).
 Chapter 4

First-Line Medications for PTSD1

First-line pharmacologic treatments for PTSD act predominantly on the
serotonergic and, to a lesser extent, the noradrenergic systems. Specifically,
these agents include the selective serotonin reuptake inhibitors (SSRIs) and
the serotonin norepinephrine reuptake inhibitors (SNRIs). In this chapter, the
mechanisms of action of agents within these two pharmacologic classes are
explained, and a brief overview of clinical characteristics of each agent is
provided in turn.

Life-threatening or Dangerous Side Effects

Contraindications

Tips and Pearls

Children and Adolescents

Pregnancy

Cardiac Impairment
Renal Impairment

Hepatic Impairment
 Pharmacological Treatments

FIGURE 4.1. First-line medications for PTSD include the selective

serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake
inhibitors (SNRIs), with only paroxetine and sertraline approved by the Food
and Drug Administration (FDA) for this indication. This figure will be used
throughout the book to indicate where the various pharmacotherapies under
discussion fall in the sequence of selecting treatments for PTSD.

Selective Serotonin Reuptake Inhibitors (SSRIs):

Mechanism of Action, Part 1
FIGURE 4.2. There are six agents within the SSRI class, all of which share
the central feature of serotonin reuptake inhibition (SRI, indicated above in
part A). These agents bind to the serotonin transporter (SERT), preventing
serotonin (5HT) from being taken back up into the presynaptic neuron (B).
However, the onset of action of SSRIs is delayed, suggesting that the
therapeutic effects are actually related to downstream adaptive changes
rather than acute actions at SERT.

Selective Serotonin Reuptake Inhibitors (SSRIs):

Mechanism of Action, Part 2
FIGURE 4.3. The mechanism by which SSRIs may alleviate symptoms of
PTSD is not truly understood. There is evidence that the increase in synaptic
serotonin caused by SSRIs leads to a cascade of events that changes the
expression of critical genes. This can affect synthesis of pre- and
postsynaptic serotonin receptors as well as of other critical proteins. Thus the
ultimate effects of SSRIs may be widespread.

Selective Serotonin Reuptake Inhibitors (SSRIs):

Mechanism of Action, Part 3
FIGURE 4.4. One particular effect of interest is that SSRIs can increase
brain-derived neurotrophic factor (BDNF) levels, which are reduced in
individuals exposed to extreme stress (see Figure 2.6) and may be related to
hippocampal atrophy seen in PTSD (see Figure 2.8). Serotonin can increase
the availability of BDNF by initiating signal transduction cascades that lead
to its release. These actions may be further enhanced by therapeutic agents
that boost serotonin (e.g., SSRIs).

Secondary Pharmacological Properties of SSRIs

FIGURE 4.5. In addition to the shared feature of serotonin reuptake
inhibition, each SSRI has different secondary properties that may contribute
to their therapeutic and side effect profiles. The unique pharmacological and
clinical properties of each of the six SSRIs (Table 4.1) are shown in Figures
4.6 through 4.17.

SSRIs
TABLE 4.1
Agent Approved in PTSD

paroxetine (Paxil, Aropax, Seroxat) Yes

sertraline (Zoloft) Yes

fluoxetine (Prozac, Serafem) No

fluvoxamine (Luvox, Faverin) No

citalopram (Celexa, Cipramil) No

escitalopram (Lexapro, Cipralex) No

 Paroxetine

FIGURE 4.6. Paroxetine is used widely to treat anxiety disorders, and in

fact is approved to treat all five major anxiety disorders, including PTSD.
Paroxetine has anticholinergic effects (M1 muscarinic antagonism), which
may contribute to its anxiolytic efficacy. In addition to this and SRI
(serotonin reuptake inhibition) properties, paroxetine is a weak
norepinephrine reuptake inhibitor (NRI), a nitric oxide synthetase (NOS)
inhibitor, and a potent CYP450 2D6 inhibitor. Paroxetine is a substrate as
well as an inhibitor of 2D6, which can lead to a rapid decline in plasma drug
levels, contributing to the withdrawal symptoms experienced upon sudden
discontinuation.
 Paroxetine: Tips and Pearls

FIGURE 4.7. Dosing and safety information for paroxetine.

Sertraline
FIGURE 4.8. Sertraline is approved to treat multiple anxiety disorders,
including PTSD. It has weak dopamine reuptake inhibition (DRI) properties
and also binds to sigma 1 receptors, in addition to its SRI properties. While
sigma 1 actions are not well understood, they may contribute to anxiolytic
effects and may also be useful in psychotic depression. The actions at DAT
may be weak, but perhaps only a small amount of DAT inhibition is enough
to contribute to improvement of certain symptoms (e.g., concentration
difficulties related to dopamine in the prefrontal cortex).

Sertraline: Tips and Pearls

FIGURE 4.9. Dosing and safety information for sertraline.

Fluoxetine
FIGURE 4.10. Fluoxetine is approved to treat multiple anxiety disorders,
and though not approved has evidence of efficacy in PTSD. It has effects not
only on the serotonin system via serotonin reuptake inhibition (SRI) but also
on the norepinephrine and dopamine systems via weak norepinephrine
reuptake inhibition (NRI) and antagonism at 5HT2C receptors. In brief,
stimulation of 5HT2C receptors inhibits norepinephrine and dopamine
release; thus antagonism of these receptors can lead to norepinephrine and
dopamine release. This may contribute to increased anxiety and insomnia
that is often experienced at initiation of treatment. Fluoxetine also inhibits
CYP450 2D6 and 3A4. Fluoxetine has a long half-life, while its active
metabolite has an even longer half-life; these factors may reduce the
incidence of withdrawal symptoms following sudden discontinuation.

Fluoxetine: Tips and Pearls

FIGURE 4.11. Dosing and safety information for fluoxetine.

Fluvoxamine
FIGURE 4.12. Fluvoxamine is approved to treat obsessive compulsive
disorder and is used off-label to treat other disorders, including PTSD.
Fluvoxamine has secondary actions at sigma 1 receptors (more potently than
sertraline), which may contribute to increased anxiolytic efficacy.
Fluvoxamine is also an inhibitor of both CYP450 3A4 and CYP450 1A2,
and thus may have more drug interactions than other SSRIs.

Fluvoxamine: Tips and Pearls

FIGURE 4.13. Dosing and safety information for fluvoxamine.

Citalopram
FIGURE 4.14. Citalopram is used off-label to treat multiple anxiety
disorders, including PTSD. Citalopram consists of two enantiomers, R and
S. Taken together, this agent is known as racemic citalopram, with mild
antihistamine and CYP450 2D6 inhibitory properties residing in the R
enantiomer. Citalopram may be somewhat inconsistent in therapeutic action
at its lowest dose, potentially requiring a dose increase to optimize treatment
response. This may be due to a recent finding that the R enantiomer may be
active at the serotonin transporter (SERT), interfering with the ability of the
S enantiomer to inhibit SERT. This interference could lead to reduced
inhibition of SERT, reduced synaptic serotonin, and possibly reduced
therapeutic action.

Citalopram: Tips and Pearls

FIGURE 4.15. Dosing and safety information for citalopram.

Escitalopram
FIGURE 4.16. Escitalopram is approved to treat generalized anxiety
disorder and is used off-label to treat PTSD. It is, in essence, citalopram with
the R enantiomer removed, and thus lacks the antihistaminic and CYP450
2D6 inhibitory properties of citalopram, leaving the sole property of
serotonin reuptake inhibition (SRI). Additionally, by removing the R
enantiomer (which can interfere with SERT inhibition of the S enantiomer),
the lowest dose of escitalopram may be more effective than the comparable
dose of citalopram. Because of its truly selective mechanism of action,
escitalopram has the lowest risk of drug interactions of all the SSRIs and
may be the best tolerated as well.

Escitalopram: Tips and Pearls

FIGURE 4.17. Dosing and safety information for escitalopram.

Serotonin Norepinephrine Reuptake Inhibitors (SNRIs):

Mechanism of Action
FIGURE 4.18. The SNRIs combine the serotonin reuptake inhibition (SRI)
of SSRIs with norepinephrine reuptake inhibition (NRI). Thus they bind to
the serotonin transporter, or SERT (A), and the norepinephrine transporter,
or NET (B), preventing reuptake of serotonin and norepinephrine,
respectively. As with the SSRIs, the underlying therapeutic mechanisms for
SNRIs in PTSD are not known but are likely due to downstream effects (see
Figures 4.3 and 4.4).

Of the SNRIs, only venlafaxine has been studied in controlled trials in

PTSD; however, they are all included here as a first-line option due to their
mechanistic similarity to venlafaxine and SSRIs as well as their evidence of
efficacy in other anxiety disorders.

SNRIs
TABLE 4.2.
Agent Approved in PTSD
venlafaxine XR (Effexor XR, Efexor XR) No

desvenlafaxine (Pristiq) No

duloxetine (Cymbalta, Xeristar) No

milnacipran (Savella, Ixel, Toledomin) No

 Venlafaxine

FIGURE 4.19. Venlafaxine is approved to treat multiple anxiety disorders,

and has evidence of efficacy to treat PTSD. Venlafaxine’s property of
serotonin reuptake inhibition (SRI) is moderately potent and present at all
doses, whereas its degree of norepinephrine reuptake inhibition (NRI) is
dependent on dose (though even at high doses it is more serotonergic than
noradrenergic). In addition, venlafaxine is converted to an active metabolite,
desvenlafaxine, by CYP450 2D6. Desvenlafaxine has relatively more
noradrenergic inhibition than the parent drug; thus noradrenergic activity
may be even less with venlafaxine when given concomitantly with a
CYP450 2D6 inhibitor. Discontinuation of venlafaxine may cause
withdrawal reactions, especially after sudden discontinuation. The extended-
release formulation is much better tolerated than the immediate-release
formulation.

Venlafaxine: Tips and Pearls

FIGURE 4.20. Dosing and safety information for venlafaxine.

Desvenlafaxine
FIGURE 4.21. Desvenlafaxine, the active metabolite of venlafaxine, is not
approved to treat any anxiety disorders but may be used off label. It is
formed as a result of CYP450 2D6 but is not itself a substrate for any
CYP450 enzyme; thus its plasma levels should be more consistent than those
of venlafaxine. Although it is more potent at the serotonin transporter than at
the norepinephrine transporter, it has greater norepinephrine reuptake
inhibition (NRI) relative to serotonin reuptake inhibition (SRI) compared to
venlafaxine.

Desvenlafaxine: Tips and Pearls

FIGURE 4.22. Dosing and safety information for desvenlafaxine.

Duloxetine
FIGURE 4.23. Duloxetine is approved to treat generalized anxiety disorder
and is used but not approved to treat PTSD. Like venlafaxine and
desvenlafaxine, duloxetine has greater serotonin reuptake inhibition (SRI)
than norepinephrine reuptake inhibition (NRI); however, both serotonin and
norepinephrine blockade may be present at the low end of the therapeutic
dosing range. Duloxetine is a CYP450 2D6 inhibitor, which may result in
various drug interactions that should be monitored.

Duloxetine: Tips and Pearls

FIGURE 4.24. Dosing and safety information for duloxetine.

Milnacipran
FIGURE 4.25. Milnacipran is neither approved nor widely used to treat
anxiety disorders. It is somewhat different than other SNRIs in that it has the
strongest norepinephrine reuptake inhibition (NRI) relative to serotonin
reuptake inhibition (SRI) among the four approved agents. Some data even
suggest that its actions at the norepinephrine transporter are stronger than
those at the serotonin transporter, while the other SNRIs are generally the
opposite. Milnacipran may be more energizing and activating than some
other SNRIs due to its relatively potent noradrenergic actions, which could
be disadvantageous for patients with anxiety, at least in the short term.

Milnacipran: Tips and Pearls

FIGURE 4.26. Dosing and safety information for milnacipran.
 Chapter 5

Second-Line, Adjunct, and Investigational Medications for

PTSD
In addition to the first-line selective serotonin reuptake inhibitors (SSRIs)
and serotonin norepinephrine reuptake inhibitors (SNRIs), there are many
second-line and adjunct pharmacologic options for PTSD. In this chapter,
the mechanisms of action of such agents are explained and clinical
characteristics are briefly reviewed. Several agents under investigation for
their potential use in PTSD are reviewed as well.
 SECTION ONE
Second-line Medications

FIGURE 5.1. Second-line medications for PTSD include tricyclic

antidepressants (TCAs); monoamine oxidase inhibitors (MAOIs); the alpha
2 delta ligands, gabapentin and pregabalin; and anxiolytic benzodiazepines.

Tricyclic Antidepressants (TCAs):

Mechanism of Action
FIGURE 5.2. Like the SNRIs, the primary mechanisms of action for
tricyclic antidepressants (TCAs) are blockade of the serotonin transporter, or
SERT (B), and the norepinephrine transporter, or NET (A), preventing
reuptake of serotonin and norepinephrine, respectively. Some TCAs are
more selective for serotonergic mechanisms and some are more strongly
noradrenergic, although all TCAs block reuptake of both neurotransmitters
to some extent.

The TCA Family

FIGURE 5.3. TCAs, although considered as efficacious as the SSRIs and
SNRIs for depression, have several unwanted mechanisms that contribute to
a worse tolerability profile. Histamine H1 receptor blockade may relieve
insomnia but can also cause sedation and may lead to weight gain.
Muscarinic M1 receptor blockade causes dry mouth, blurred vision, urinary
retention, and constipation, while muscarinic M3 receptor blockade can
interfere with insulin action. Alpha 1 adrenergic receptor blockade causes
orthostatic hypotension and dizziness. In very high doses, TCAs’ weak
blockade of voltage-sensitive sodium channels in the heart and brain is
thought to be the cause of coma and seizures.

Selections from the TCA Family

FIGURE 5.4. Brief clinical characteristics of select TCAs prescribed for
PTSD.

Monoamine Oxidase Inhibitors (MAOIs):

Mechanism of Action
FIGURE 5.5. The enzyme monoamine oxidase A (MAO-A) metabolizes
serotonin (5HT), norepinephrine (NE), and dopamine (DA) (left panels).
Monoamine oxidase B (MAO-B) also metabolizes DA, but it metabolizes
5HT and NE only at high concentrations (left panels). Thus inhibition of
MAO-A increases 5HT and NE but has little effect on DA (because MAO-B
is still able to metabolize it). In contrast, inhibition of MAO-B does not have
great effect on 5HT or NE, but does increase DA to some extent (though
MAO-A is still available to metabolize it). Combined inhibition of MAO-A
and MAO-B leads to greater increases in each of these neurotransmitters
than inhibition of either enzyme alone (right panels).
 MAOIs, Tyramine, and Hypertensive Crisis
A. Hypertensive Crisis
Defined as diastolic blood pressure > 120 mmHg
Symptoms include: occipital headache that may radiate frontally, palpitation, neck stiffness or
soreness, nausea, vomiting, sweating (sometimes with fever), dilated pupils, photophobia, tachycardia
or bradycardia that can be associated with constricting chest pain

B. Dietary Modifications for Patients on MAO Inhibitors*

Foods to Avoid Foods Allowed

Dried, aged, smoked, fermented, spoiled, or Fresh or processed meat, poultry,

improperly stored meat, poultry, or fish or fish

Broad bean pods All other vegetables

Aged cheeses Processed and cottage cheese,

ricotta cheese, yogurt
Tap and nonpasteurized beers
Canned or bottled beers and
Marmite, sauerkraut
alcohol
Soy products, tofu
Brewer’s and baker’s yeast

*No dietary modifications needed for low doses of transdermal or oral selective MAO-B inhibitors.

TABLE 5.1. Tyramine, an amine present in various foods including cheese,

acts to increase release of norepinephrine. A meal high in tyramine (40 mg or
more), combined with inhibition of MAO-A (which also increases
norepinephrine) can lead to a high accumulation of norepinephrine and
potentially dangerous vasoconstriction and hypertension. In some cases this
can lead to hypertensive crisis, a potentially fatal reaction (see characteristics
in part A). The risk can be controlled by restricting tyramine intake (see
dietary suggestions in part B).
 Drugs to Avoid with MAOIs
C. Drugs to Avoid for Patients on MAO Inhibitors Due to Risk of Hypertensive Crisis

Decongestants: phenylephrine, ephedrine (ma huang, ephedra), pseudoephedrine, phenyl-

propanolamine

Stimulants: amphetamines, methylphenidate

Antidepressants: TCAs, atomoxetine, reboxetine, venlafaxine, desvenlafaxine, duloxetine,

milnacipran, bupropion

Appetite suppressants: sibutramine, phentermine

D. Drugs Contraindicated in Combination with MAO Inhibitors Due to Risk of Serotonin

Syndrome

Antidepressants: fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram,

venlafaxine, desvenlafaxine, duloxetine, milnacipran, TCAs (especially clomipramine)

Other TCA structures: cyclobenzapine, carbamazepine

Appetite suppressants: sibutramine

Opioids: dextromethorphan, meperidine, tramadol, methadone, propoxyphene

TABLE 5.2. Some drugs with noradrenergic actions can also lead to
hypertensive crisis when combined with MAOIs and should be avoided (A).

Combination of MAOIs with agents that inhibit serotonin reuptake can also
be dangerous, as combining two different methods of increasing serotonin
may lead to a dramatic accumulation of serotonin. This can cause excessive
stimulation of postsynaptic serotonin receptors and lead to hyperthermia,
coma, seizures, cardiovascular problems, and death. This is known as the
“serotonin syndrome” and is why the combination of an MAOI with any
drug that has SRI properties is strictly contraindicated (B).
 MAOIs with Reduced Risk of Tyramine Reactions

FIGURE 5.6. MAOIs presumably must inhibit MAO-A in the brain for
therapeutic effects in anxiety disorders. However, they also cause
simultaneous inhibition of MAO-A in the liver and intestinal mucosa, which
creates risk of tyramine reactions.

(A) One mechanism for preserving the effects in the brain while avoiding
effects in the gut is reversible inhibition of MAO-A (RIMA). RIMAs can be
removed from the enzyme by competitors (e.g., norepinephrine). Thus the
accumulation of norepinephrine released by tyramine can displace the
RIMA, allowing norepinephrine to be destroyed and reducing risk of a
tyramine reaction.

(B) A second way to combat this dilemma is with transdermal selegiline. The
selective MAO-B inhibitor must be administered in high doses in order to
inhibit MAO-A as well. Transdermal administration of selegiline delivers the
drug directly into the systemic circulation, hitting the brain in high doses but
avoiding a first pass through the liver and thus reducing risk of a tyramine
reaction.

Selections from the MAOI Family

FIGURE 5.7. Brief clinical characteristics of select MAOIs prescribed for
PTSD.

Alpha 2 Delta Ligands:

Mechanism of Action
FIGURE 5.8. The role of voltage-sensitive calcium channels (VSCCs) in
regulating neurotransmission was illustrated in Figure 3.15. Pathological
anxiety and fear may be caused by overactivation of amygdala circuits; thus
modulating VSCC activity within those circuits may normalize
neurotransmission and reduce symptoms.

Alpha 2 delta ligands bind selectively to VSCCs and actually appear to bind
with higher affinity to VSCCs in the open channel conformation. Thus they
may exert greater effects in situations where neurons have excessive activity,
as hypothesized for amygdala circuits in anxiety disorders, while not
interfering with normal neurotransmission in neurons uninvolved in
mediating the pathological anxiety state.

Alpha 2 Delta Ligands:

Gabapentin and Pregabalin
FIGURE 5.9. Brief clinical characteristics of alpha 2 delta ligands.

Benzodiazepines:
Mechanism of Action

FIGURE 5.10. GABA is the major inhibitory neurotransmitter in the brain

and has multiple receptors (Figures 3.11 and 3.12). Benzodiazepines exert
their anxiolytic actions at GABA-A receptors, as illustrated here.
GABA-A receptors consist of five subunits with a central chloride channel
and have binding sites not only for GABA but also for benzodiazepines.
When a benzodiazepine binds to the GABA-A receptor in the absence of
GABA it has no effect on the GABA channel—chloride conductance is the
same as in the resting state (A). When GABA binds to its site on the GABA-
A receptor, it increases the frequency of opening of the chloride channel,
allowing more chloride to pass through (B). When a benzodiazepine binds to
the GABA-A receptor in the presence of GABA it causes the channel to
open even more frequently than when GABA alone is present (C). This type
of mechanism is termed positive allosteric modulation.

Selections from the Benzodiazepine Family

FIGURE 5.11. Brief clinical characteristics of anxiolytic benzodiazepines.
 SECTION TWO
Adjunct Medications

FIGURE 5.12. Adjunct medications for PTSD include agents that may treat
residual anxiety (e.g., mirtazapine, atypical antipsychotics) as well as those
that target specific symptoms (e.g., alpha 1 antagonists for nightmares,
sedative hypnotics for sleep disturbances) or comorbidities (e.g., naltrexone
and acamprosate for alcohol abuse/dependence).

Sedating Antidepressants, Part 1

FIGURE 5.13. Mirtazapine has multiple mechanisms that may contribute to
its therapeutic profile. It has actions at alpha 2 receptors as well as three 5HT
receptors—2A, 2C, and 3—and also blocks histamine 1 (H1) receptors.

By blocking alpha 2 receptors, mirtazapine increases both serotonin and

norepinephrine; however, because 5HT2A, 2C, and 3 receptors are also
blocked by mirtazapine, the net stimulation falls on 5HT1A receptors. This
further results in release of dopamine, which may be helpful in depression as
well as anxiety. Mirtazapine’s antagonist actions at 5HT2A and 2C receptors
also result in increased release of dopamine and norepinephrine, which may
contribute to anxiolytic, antidepressant, and sleep-restoring properties.
Finally, H1 receptor antagonism may help relieve insomnia and anxiety but
may also cause sedation and contribute to weight gain.

Sedating Antidepressants, Part 2

FIGURE 5.14. At antidepressant doses (150–600 mg/day), trazodone is a
potent antagonist at serotonin 2A receptors and also blocks serotonin 2C
receptors and the serotonin transporter. In addition, its blockade of histamine
1 receptors is largely responsible for its sedative effects, while blockade of
alpha 1 adrenergic receptors may contribute to efficacy for treating
nightmares (see Figure 5.16). At low doses (25–100 mg/night), trazodone
does not adequately block serotonin reuptake but does retain its other
properties and thus can still be sedating.

Sedating Antidepressants, Part 3

FIGURE 5.15. Doxepin is a tricyclic antidepressant that, at antidepressant
doses (150–300 mg/day) inhibits serotonin and norepinephrine reuptake and
is an antagonist at histamine 1, muscarine 1, and alpha 1 adrenergic
receptors. At low doses (1–6 mg/night), however, doxepin is quite selective
for histamine 1 receptors and thus may be used as a hypnotic.

Alpha 1 Antagonists for Nightmares

FIGURE 5.16. Noradrenergic neurons (Figure 3.7) originate in the locus
coeruleus, which is responsible for the autonomic output of fear (Figure 1.4),
and innervate the amygdala and the prefrontal cortex, both of which are
essential to anxiety and worry (Figures 1.2 through 1.8). Alpha adrenergic
blockers may modulate the anxiogenic effects of noradrenergic
hyperactivation (see Figure 3.8). Interestingly, alpha adrenergic receptors are
also involved in sleep responses, and may thus be relevant to the sleep
disturbances and nightmares associated with PTSD.

Prazosin, an alpha 1 adrenergic blocker approved for the treatment of

hypertension, has been used to prevent nightmares in patients with PTSD.
Such use has not been extensively studied, but early clinical data suggest
that it may be efficacious.

Sedative Hypnotics
FIGURE 5.17. Sleep disturbances are common in patients with PTSD.
Implementing good sleep hygiene techniques is important for these patients;
in addition, the use of sedative hypnotics may be beneficial. Zaleplon,
zolpidem, zopiclone, and eszopiclone bind to GABA-A receptors, as do the
benzodiazepines (Figures 5.10 and 5.11), but they do so in a way that does
not generally cause tolerance, dependence, or withdrawal upon
discontinuation. Zaleplon and zolpidem are also selective for GABA-A
receptors containing the alpha 1 subtype, which theoretically could
contribute to the lower risk of tolerance and dependence with these agents.
However, these agents may need to be restricted in PTSD due to the frequent
association of comorbid alcohol and drug abuse.

Adjunct Medications for Sleep-Related Problems

FIGURE 5.18. Brief clinical characteristics of some adjunct medications
prescribed for sleep-related problems.

Atypical Antipsychotics
FIGURE 5.19. Atypical antipsychotics are best known as treatments of
psychosis in schizophrenia and acute mania in bipolar disorder. However,
these agents are increasingly being used to treat other disorders as well,
including depression and anxiety disorders. Pharmacologically this makes
sense, as their shared mechanisms—serotonin 2A antagonism and dopamine
2 antagonism/partial agonism–lead to modulation of the serotonin and
dopamine systems. In addition, each agent has a unique secondary profile
(see above and Figures 5.20 through 5.27) that may further contribute to
therapeutic actions in various disorders.

Risperidone
FIGURE 5.20. In addition to being a serotonin 2A/dopamine 2 antagonist,
risperidone blocks alpha 2 adrenergic receptors, which may contribute to
efficacy for depression. It also blocks alpha 1 adrenergic receptors, which
may contribute to orthostatic hypotension and sedation but could also
potentially be therapeutic for sleep disturbances in PTSD (see Figure 5.16).
Receptor “X” in the icon above represents the unclear actions that some
atypical antipsychotics have on the insulin system, where they change
cellular insulin resistance and increase fasting plasma triglyceride levels.
 Olanzapine

FIGURE 5.21. Olanzapine has widespread actions on the serotonin and

dopamine systems and also blocks muscarinic 1 and 3 receptors, alpha
adrenergic 1 receptors, and histamine 1 receptors. 5HT2C blockade may
contribute to antidepressant effects and improve cognitive problems, but
may also (potentially in concert with H1 antagonism) contribute to weight
gain. Histamine 1, alpha 1 adrenergic, and muscarinic 1 receptor antagonism
can cause sedation. Receptor “X” in the icon above represents the unclear
actions that some atypical antipsychotics have on the insulin system, where
they change cellular insulin resistance and increase fasting plasma
triglyceride levels.
 Quetiapine

FIGURE 5.22. Quetiapine has widespread actions on the serotonin and

dopamine systems and also blocks muscarinic 1 and 3 receptors, alpha
adrenergic 1 and 2 receptors, and histamine 1 receptors. Its active
metabolite, norquetiapine, has unique features (red circles) that most likely
add to quetiapine’s efficacy. The partial 5HT1A agonist feature of quetiapine
and the 5HT2C antagonism and norepinephrine reuptake inhibition of
norquetiapine are hypothetically responsible for its antidepressant and pro-
cognitive effects. Alpha 2 adrenergic antagonism may also be a factor in
antidepressant effects. 5HT2C blockade may contribute to weight gain,
particularly in association with H1 blockade. Histamine 1, alpha 1
adrenergic, and muscarinic 1 receptor antagonism can cause sedation,
though H1 blockade may also improve sleep disturbances. Receptor “X” in
the icon above represents the unclear actions that some atypical
antipsychotics have on the insulin system, where they change cellular insulin
resistance and increase fasting plasma triglyceride levels.
 Aripiprazole

FIGURE 5.23. Aripiprazole functions primarily as a dopamine 2 partial

agonist and is also a 5HT2A antagonist. In addition, it is a 5HT1A partial
agonist, which may contribute to antidepressant and pro-cognitive effects.
The clinical significance of its D3 partial agonist property is unknown, but it
theoretically may contribute to antidepressant effects.
 Ziprasidone

FIGURE 5.24. Ziprasidone has actions on the serotonin, dopamine, and

norepinephrine systems. Its 5HT1D and 5HT2C antagonism as well as
serotonin and norepinephrine reuptake blocking properties could contribute
to potential antidepressant and anxiolytic effects, and 5HT2C antagonism
may enhance cognition as well. At high doses, alpha 1 adrenergic
antagonism could contribute to sedation and hypotension.
 Paliperidone

FIGURE 5.25. Paliperidone is the active metabolite of risperidone (Figure

5.20) and thus has a similar profile. It is a serotonin 2A/dopamine 2
antagonist and also blocks alpha 2 adrenergic receptors, which may
contribute to efficacy for depression. Receptor “X” in the icon above
represents the unclear actions that some atypical antipsychotics have on the
insulin system, where they change cellular insulin resistance and increase
fasting plasma triglyceride levels.
 Iloperidone

FIGURE 5.26. In addition to being a serotonin 2A/dopamine 2 antagonist,

iloperidone is a potent antagonist at alpha 1 adrenergic receptors, which may
contribute to efficacy for treating nightmares. Iloperidone also blocks
serotonin 2C, 6, and 7 receptors as well as alpha 2 adrenergic receptors,
which could contribute to efficacy for depression.
 Asenapine

FIGURE 5.27. Asenapine has widespread actions on the serotonergic,

dopaminergic, and noradrenergic systems and also blocks histamine 1
receptors. The relevance of its actions at many receptors is not yet known,
but serotonin 2C and alpha 2 antagonist properties may contribute to
antidepressant actions, while histamine 1 antagonism may be largely
responsible for its sedative effects.
 Anticonvulsants

FIGURE 5.28. Many anticonvulsants are used in the treatment of mental

illnesses, most frequently in bipolar disorder. They are not well studied in
PTSD, though there are small preliminary studies with lamotrigine and
topiramate. The mechanisms of action of anticonvulsants are unique and not
well understood, but many seem to have effects on the GABA-ergic and
glutamatergic systems. Lamotrigine may work by blocking the alpha subunit
of voltage-sensitive sodium channels; it may also reduce glutamate release
and have actions at other ion channels for calcium and potassium.
Topiramate may interfere with voltage-sensitive sodium and/or calcium
channels in order to enhance GABA and reduce glutamate actions, and is
also a weak inhibitor of carbonic anhydrase.

Lamotrigine and Topiramate

FIGURE 5.29. Brief clinical characteristics of some adjunct medications
prescribed for PTSD.

Alcohol Dependence/Withdrawal Treatments

FIGURE 5.30. Alcohol abuse is one of the most common comorbidities in
PTSD. Two pharmacologic options for treating alcohol abuse/dependence
are naltrexone and acamprosate.

Naltrexone is a mu opioid receptor antagonist that can reduce the pleasurable

effects of drinking and thus both decrease heavy drinking and increase
abstinence. Adherence is an important consideration, however, and may be
enhanced by administering naltrexone as a once monthly intramuscular
injection (naltrexone XR).

Acamprosate is a derivative of the amino acid taurine and, like alcohol, both
reduces excitatory glutamate neurotransmission and enhances GABA
neurotransmission. It is therefore able to “substitute” for alcohol during
withdrawal to mitigate the adverse effects and increase the likelihood of
abstinence.

Naltrexone and Acamprosate

FIGURE 5.31. Brief clinical characteristics of some adjunct medications
prescribed for alcohol dependence/withdrawal.
 SECTION THREE
Investigational

FIGURE 5.32. Several pharmacologic mechanisms are under investigation

for their potential use in PTSD.

Can PTSD Be Prevented?

Beta Blockers
FIGURE 5.33. There is some research to suggest that administration of beta
adrenergic blockers immediately following exposure to trauma could block
fear conditioning before it even occurs. Specifically, blockade of beta
receptors in the ventromedial prefrontal cortex (VMPFC) and hippocampus
may prevent input from reaching the amygdala and thus prevent synaptic
changes that lead to fear conditioning. Though intriguing, this is not yet a
proven treatment strategy.

Can PTSD Be Prevented?

Hydrocortisone
FIGURE 5.34. Another potential preemptive treatment for PTSD is
hydrocortisone. Decreased cortisol levels have been demonstrated in PTSD
patients (Figure 2.7), and in fact low cortisol levels at the time of exposure to
a traumatic event predict development of PTSD (A), so it is reasonable that
administering cortisol immediately following exposure could prevent
development of the disorder (B). There is some empirical support for this
strategy, although as with beta adrenergic blockers it is preliminary.

D-Cycloserine
FIGURE 5.35. Fear conditioning (Figure 1.10) is not readily reversed, but it
can be suppressed through fear extinction, a type of new learning in which
there is a progressive reduction of the response to a feared stimulus when it
is repeatedly presented without adverse consequences. Strengthening of
synapses involved in fear extinction could help enhance the development of
fear extinction learning in the amygdala and reduce symptoms of PTSD. D-
cycloserine is an NMDA receptor co-agonist that may contribute to
extinction of fear responses during exposure therapy (see Figure 6.2) by
increasing the efficiency of glutamate neurotransmission at such synapses.

Potential Targets within the HPA Axis

FIGURE 5.36. The central role of the HPA axis in stress responses (Figure
1.6) and in PTSD (Figure 2.7) is well established. There are several potential
therapeutic targets within the HPA axis under investigation for PTSD.

One such approach is CRF1 receptor antagonists. CRF is elevated in PTSD;

thus blocking its actions may prevent the abnormal stress response and
alleviate symptoms. CRF1 receptors are also present in the brain outside the
HPA axis, and actions there could theoretically have therapeutic effects as
well.

Another approach is glucocorticoid receptor antagonists, which can compete

with cortisol at the glucocorticoid receptor and result in lack of expression of
glucocorticoid genes, again potentially preventing the abnormal stress
response as well as hippocampal atrophy.

A third approach is antagonism of vasopressin 1B receptors. Stimulation of

vasopressin 1B receptors contributes to release of ACTH during stress
reactions; thus blocking these receptors may prevent complications within
the HPA axis. As with CRF1 receptors, vasopressin 1B receptors are present
in the brain outside of the HPA axis and activity there could also
theoretically be therapeutic.
 Neuroactive Steroid:
Ganaxolone

FIGURE 5.37. Neuroactive steroids are another potential novel treatment

option for PTSD. Endogenous neuroactive steroids such as allopregnanolone
and its equipotent stereoisomer, pregnanolone, bind to the delta subtype of
GABA-A receptors (A) to facilitate tonic GABA neurotransmission (B).
Because GABA plays a central role in the experience and expression (or
suppression) of anxiety (Figure 3.11), it is reasonable that reduced activity of
these neurosteroids would be anxiogenic. In fact, some research suggests
that there is a block in the synthesis of these two endogenous neuroactive
steroids in individuals with PTSD.

Ganaxolone is a synthetic, 3-beta-methylated derivative of allopregnanolone

that is currently under development for the treatment of epilepsy. Although it
is not yet being studied in PTSD, there is hope that eventually such research
will be pursued.
 Chapter 6

Cognitive Behavioral Therapy (CBT) for PTSD

Cognitive behavioral therapy (CBT) is a structured form of psychotherapy
that includes both behavioral modification strategies and cognitive therapies.
There are many different types of CBT, all of which are intended to help
patients learn new responses to life situations. Most if not all patients with
PTSD should have CBT as part of their treatment regimen. In this chapter,
the methods for the best-evidenced cognitive and behavioral therapies for
patients with PTSD are explained.

Cognitive Behavioral Therapy (CBT):

First-line Options
FIGURE 6.1. Cognitive behavioral therapy (CBT) for PTSD is designed to
modify the behaviors and thoughts/beliefs that developed in response to
trauma. First-line therapies include exposure therapy and cognitive
restructuring.

Exposure Therapy
FIGURE 6.2. Exposure therapy for PTSD involves exposing the patient to
feared stimuli associated with the traumatic event for repeated and prolonged
periods of time. There are several forms of exposure therapy: imaginal,
which involves repeatedly recounting traumatic memories; in vivo, which is
exposure to feared stimuli in real life; and interoceptive, which involves
experiencing feared physical sensations. Combining multiple types of
exposure therapy is generally most effective.

Exposure therapy can target reexperiencing symptoms (by reducing fear

associated with thinking about the trauma) and avoidance behaviors (by
reducing fear associated with confronting trauma-related stimuli that are not
actually dangerous), as well as reduce general hyperarousal. In addition, by
increasing the patient’s perceived control over fear, this can facilitate
processing of the traumatic memory (help patients “make sense” of it).

Cognitive Restructuring
FIGURE 6.3. Cognitive restructuring is a process by which patients learn to
evaluate and modify inaccurate and unhelpful thoughts (e.g., “It was my
fault I was raped”). Adjusting how one thinks about a traumatic event can
presumably alter one’s emotional response to it, and in fact cognitive
restructuring particularly seems to help address emotions such as shame and
guilt. It can be used alone but is often used as an adjunct to exposure
therapy.

There are six main steps of cognitive restructuring: (1) identify a distressing
event/thought; (2) identify and rate (0–100) emotions related to the
event/thought; (3) identify automatic thoughts associated with the emotions,
rate the degree to which one believes them, and select one to challenge; (4)
identify evidence in support of and against the thought; (5) generate a
response to the thought using the evidence for/against (even though
<evidence for>, in fact <evidence against>) and rate the degree of belief in
the response; (6) rerate emotion related to the event/thought.

Cognitive Behavioral Therapy (CBT):

Second-line Options
FIGURE 6.4. Second-line CBT options include stress inoculation training
(SIT) and eye movement desensitization and reprocessing therapy (EMDR).
Two additional strategies include dialectical behavior therapy (DBT), which
may be useful as an adjunct, and acceptance and commitment therapy
(ACT).

Stress Inoculation Training

FIGURE 6.5. There are other therapies that may be considered second-line.
Stress inoculation training (SIT) is an anxiety management approach in
which patients learn techniques such as relaxation, assertive communication
skills, thought stopping (distracting oneself from distressing thoughts), and
guided self-dialogue (replacing irrational negative internal dialogue with
rational thoughts).

Eye Movement Desensitization and Reprocessing

FIGURE 6.6. Another second-line strategy, eye movement desensitization
and reprocessing (EMDR), is a technique in which patients recount
traumatic experiences while focusing on a moving object (e.g., the
therapist’s finger), with the intention that this facilitates the processing of the
traumatic memory. There is empirical support for this approach, though not
as much as for exposure therapy and cognitive restructuring.

Dialectical Behavior Therapy

FIGURE 6.7. Dialectical behavior therapy (DBT) is designed to address
destructive behaviors and emotion regulation in borderline personality
disorder, but has been used in other disorders including PTSD. DBT stresses
validation, balance between acceptance and change, and mindfulness (being
present with the moment and aware of both your emotions and your
thoughts). Because DBT teaches patients to be aware in the moment and
accept unpleasant emotions, it may be particularly useful as an adjunct for
patients who dissociate during exposure therapy.

Acceptance and Commitment Therapy

FIGURE 6.8. A similar therapy, acceptance and commitment therapy
(ACT), involves acceptance of thoughts and anxiety as experiences that a
person can have while still living a life in accordance with one’s values.

Cognitive Behavioral Therapy (CBT):

Adjunct Options
FIGURE 6.9. Seeking safety therapy and motivational interviewing may be
used for patients with comorbid substance dependence/abuse.

Seeking Safety Therapy

FIGURE 6.10. Seeking safety therapy is a technique specifically developed
for individuals with substance abuse and trauma histories. It is an integrated
treatment approach in which both PTSD and substance abuse are addressed
simultaneously, with the main goal being to help patients attain safety in
their lives (in terms of relationships, thought processes, behaviors, and
emotions). Seeking safety offers 25 treatment topics based on four content
areas: cognitive, behavioral, interpersonal, and case management. The
treatment can be customized for each individual patient, using whatever
combination of treatment topics that best suits the patient’s needs. A clinician
guide and client handouts are available for each treatment topic.

Motivational Interviewing
FIGURE 6.11. Motivational interviewing is patient-focused counseling with
the direct goal of enhancing one’s motivation to change by helping explore
and resolve ambivalence (e.g., “I want to stop smoking, but I’m afraid I’ll
gain weight”). It was originally developed to help individuals with problem
drinking but can be used in the treatment of patients with other forms of
substance abuse and dependence. With motivational interviewing the
clinician is a facilitator, helping the patient identify, articulate, and resolve
his or her own ambivalence without direct persuasion, confrontation, or
coercion.
 Chapter 7

Caring for Patients With PTSD

Treatment of PTSD includes both nonpharmacological and pharmacological
options, with many patients likely benefiting from a combination of the two.
PTSD can be a very difficult disorder to treat, and outcomes in general may
not be as positive as those for other anxiety disorders or for depression,
particularly with respect to pharmacological treatments. Most patients with
PTSD also have at least one comorbid disorder, further complicating the
clinical picture.

This chapter reviews diagnostic and treatment strategies for patients with
PTSD, including consideration of comorbidities. Prior to beginning any
treatment for PTSD, it is important to fully inform the patient about the
disorder and its treatments, including realistic expectations of treatment
outcomes.
 Screening and Assessment
ASSESSMENT TOOLS NOTES
Primary Care Posttraumatic Stress 4-item self-administered tool; yes–no measure; each item
Disorder Screen assesses one dimension of PTSD (reexperiencing,
(PC-PTSD) avoidance, numbing, hyperarousal); 2 or more yes answers
warrants further evaluation Used by military branches
Posttraumatic Stress Disorder 19-item self-administered tool; 0–4 point scale; based on
Checklist DSM-IV criteria; civilian and military versions;
(PCL) recommended cutoff score of 50, though some suggest it
could be lower Used by military branches
Posttraumatic Diagnostic Scale 4-part self-administered tool; parts 1 and 2 assess trauma
(PDS) history while parts 3 and 4 assess for PTSD symptoms and
functional impairment, respectively; part 3 uses a 0–3 point
scale, is based on DSM-IV criteria, and has a cutoff score
of 15
Davidson Trauma Scale 17-item self-administered tool; both frequency and severity
(DTS) are rated for each item; 0–4 point scale; based on DSM-IV
criteria; cutoff score of 40
SPAN 4-item self-administered tool; derived from Davidson
Trauma Scale; cutoff score of 5 or more
Trauma Questionnaire (TQ), Evaluate for presence of traumatic event
Stressful Life Events Screening
Questionnaire (SLESQ)

TABLE 7.1. This table gives an overview of screening and assessment tools
available to clinicians for PTSD. The tools included here are self-
administered, have documented validity, and are relatively easy to
implement in clinical practice. The most commonly used clinician-rated
scale in multicenter medication trials is the Clinician-Administered PTSD
Scale, part 2 (CAPS-2, not shown).
 Screening for Suicidality
Psychiatric illnesses Comorbid affective disorders, substance abuse, Cluster B
personality disorders, etc.
History Prior suicide attempts, aborted attempts or self harm; medical
diagnoses, family history of suicide / attempts / mental illness
Individual strengths Coping skills; personality traits; past responses to stress; capacity
/ vulnerabilities for reality testing; tolerance of psychological pain
Psychosocial Acute and chronic stressors; changes in status; quality of support;
situation religious beliefs
Suicidality Past and present suicidal ideation, plans, behaviors, intent;
methods
Warning signs Emotions (serious depression; acute agitation, anxiety, insomnia;
feeling overwhelmed or that there is no way out)
Behaviors (withdrawal from friends and activities, increase in
substance use, impulsiveness, putting self in danger, giving away
possessions, finalizing personal affairs, any unusual behavior)
Expressions (death themes in letters, notes; talking or hinting
about suicide; stating a desire to die)

TABLE 7.2. This table summarizes factors to evaluate when screening

patients for suicide risk. Suicide assessment should not be rushed and should
be repeatedly periodically. It is not uncommon for patients to be untruthful
when responding to questions about suicidal ideation and intent; thus
responses should not merely be taken at face value. Instead, the other factors
listed here as well as intuition should be used when making clinical
decisions.

Assessing for Comorbid Disorders and Complications

FIGURE 7.1. Because of the high rates of comorbid disorders in patients
with PTSD, which can affect the selection and sequence of treatment, it is
important to assess for such disorders prior to determining a treatment plan.
Physical illnesses may also affect clinical decisions and should be evaluated;
common problems in patients with PTSD include headaches, irritable bowel
syndrome, and chronic pain. In addition, it is important to assess for life
factors that may either help or hinder treatment, such as abusive
relationships, marital discord, financial difficulties, life demands, and
support systems.

Cognitive Behavioral Therapy (CBT)

FIGURE 7.2. Shown here is a summary of the first-line, second-line, and
adjunctive cognitive behavioral therapy (CBT) and psychotherapy options
described in Chapter 6. CBT should typically be included in the management
of any patient with PTSD, but the particular therapy used will vary
depending on the particular patient and requires consideration of comorbid
disorders, life factors, and the patient’s readiness to accept treatment.

Pharmacological Treatments
FIGURE 7.3. Shown here is a summary of the first-line, second-line, and
adjunctive medication options for PTSD. First-line medications include the
selective serotonin reuptake inhibitors and serotonin norepinephrine
reuptake inhibitors, with only paroxetine and sertraline approved by the
Food and Drug Administration (FDA) for this indication. There is limited
evidence for any other medications as monotherapy for PTSD, and in fact
even first-line treatments often leave patients with residual symptoms. SSRIs
and SNRIs were covered in detail in Chapter 4, while second-line, adjunct,
and investigational options were covered in Chapter 5.

Treating PTSD and Comorbid Substance Use/Abuse

FIGURE 7.4. The approach to treatment for patients with comorbid PTSD
and substance dependence/abuse may vary depending on the degree of
dependence or addiction. Patients with significant problems with substance
dependence/abuse may need to address that first before beginning PTSD
treatment, particularly cognitive behavioral therapy. Other patients may be
able to address both simultaneously or begin treatment for PTSD first. For
patients with nicotine dependence it may be best to address PTSD symptoms
prior to attempting smoking cessation. In all cases, substance use should be
carefully monitored during treatment, and any increase in substance use
should be managed promptly.

Specific pharmacologic treatments for substance dependence/abuse that may

be used as adjuncts to PTSD treatment include naltrexone and acamprosate
for alcohol use, methadone and buprenorphine for opiate dependence, and
bupropion, varenicline, and nicotine replacement for nicotine dependence.
Non-pharmacological strategies include seeking safety therapy, motivational
interviewing, and support groups.

Treating PTSD and Comorbid Depression

FIGURE 7.5. In general, first-line pharmacological treatments for
depression are the same as those for anxiety disorders, with first-line options
generally being selective serotonin reuptake inhibitors (SSRI) and serotonin
norepinephrine reuptake inhibitors (SNRI). Bupropion, a norepinephrine and
dopamine reuptake inhibitor (NDRI), is a first-line option for depression as
well and may particularly help patients with fatigue and cognitive
symptoms. In addition, there are many other second-line, adjunct, and
ancillary treatment options for depression, many of which overlap with those
for PTSD. In general there is a larger body of evidence for effectiveness of
pharmacological treatments in depression than there is in PTSD.

Cognitive behavioral therapy (CBT) can also be an important part of

depression treatment. Combining pharmacological and cognitive behavioral
therapy may be particularly important for patients with comorbid depression
and PTSD in order to reach a positive outcome.

Treating PTSD and Comorbid Anxiety Disorders

FIGURE 7.6. There is quite a bit of overlap between both the
pharmacological and non-pharmacological treatment options for PTSD and
other anxiety disorders, and in many cases symptoms of comorbid anxiety
disorders will improve with PTSD treatment, particularly if symptoms of the
comorbid disorder are functionally related to PTSD. If the disorders are truly
distinct, however, then cognitive behavioral techniques will likely need to be
targeted to each disorder. Cognitive behavioral therapies can either be
simultaneous or sequential, depending on the needs of the patient.

With respect to pharmacological options, the main difference between

treatment for PTSD and other anxiety disorders is that benzodiazepines have
well established efficacy in generalized anxiety disorder and panic disorder,
whereas there is a lack of evidence for their use in PTSD. However, they
should still be used with caution in patients with PTSD and comorbid
anxiety.

Treating PTSD and Comorbid Sleep Problems

FIGURE 7.7. Most patients with PTSD have problems with insomnia,
typically manifested as difficulty initiating or maintaining sleep. For some
patients sleep difficulties can resolve with PTSD treatment, but it is not
uncommon for insomnia to remain a problem even after other symptoms
have resolved. For these patients it may be necessary to address insomnia
directly.

When selecting treatment for insomnia, it is important to determine both the

underlying cause, if possible, as well as contributing factors. For example,
many patients with PTSD will feel a sense of heightened danger at night;
furthermore, depending on the particular trauma history, the bedroom itself
may be considered a dangerous environment. These patients may therefore
keep the light on or have television or music playing for comfort, all of
which are contrary to good sleep hygiene. Thus, in addition to addressing
fears associated with sleeping, patients should be educated on proper sleep
hygiene.

If insomnia persists, medication may be necessary. There are many

pharmacologic options available, including sedating antidepressants,
quetiapine, and sedative hypnotics. Alpha 1 antagonists may help reduce
nightmares, while alpha 2 delta ligands can improve slow-wave sleep.
 Treating PTSD and Comorbid Chronic Pain

FIGURE 7.8. There is limited research on the treatment of comorbid PTSD

and chronic pain. When determining a treatment plan for chronic pain it is
important to assess not only pain severity, location, distribution, and triggers,
but also attitudes and beliefs about pain, existing coping methods, and
functional impairments.

Several cognitive behavioral therapies that are used for PTSD can also be
applied to the treatment of chronic pain, including exposure therapy (both in
vivo exposure to pain-related activities and interoceptive exposure to feared
physical sensations) and acceptance and commitment therapy. Exercise can
also be beneficial for reducing chronic pain and may be therapeutic for
arousal symptoms as well.

Multiple pharmacologic options for PTSD are also treatments for chronic
pain. These include the first-line serotonin norepinephrine reuptake
inhibitors (SNRIs), tricyclic antidepressants (TCAs), and gabapentin and
pregabalin. Other antidepressants and anticonvulsants are also often used to
treat chronic pain. Opiates are frequently prescribed, but such use should be
cautious due to the risk of dependence and addiction; this may be a
particular concern for PTSD patients, who already have heightened risk for
substance abuse and dependence.
 Chapter 8

Unique Considerations for the Military Population

By virtue of their occupation, individuals in the military are at heightened
risk for exposure to traumatic events. This has become particularly apparent
in recent years, as the wars in Afghanistan and Iraq have contributed to
drastic increases in the rates of PTSD, depression, and suicide among service
members. There has also been a rise in the rates of traumatic brain injuries
(TBI), as advances in protective equipment have increased the chances of
survival from injuries that previously would have been fatal. This chapter
focuses on risks and complicating factors that are particularly relevant to the
military population, with emphasis on the relationship between PTSD and
the potential long-term effects of mild TBI.

Military Personnel:
A Population at Risk
FIGURE 8.1. The experience of combat can involve having one’s own life
threatened, observing death or injury of others, being unable to protect
others from harm, or being the agent of killing or harm to others. In addition,
deployed troops witness the often devastating effects of war on civilians and
their communities.

The high rates of exposure to trauma combined with the separation from
loved ones during deployment, and the difficulty of readjusting to life
following deployment (particularly for reserves), create a uniquely elevated
risk of PTSD for service members. Alcohol and drug abuse are also common
in the military population and can complicate the presentation of PTSD as
well as increase risk for suicidal behavior. The ready access to weapons and
training in how to use them are additional concerns for individuals with
suicidal ideation, plans, or intent.

Impact of the Iraq and Afghanistan Wars

FIGURE 8.2. Recognition of these unique considerations for the military
population is particularly important in light of the wars in Iraq and
Afghanistan, which have contributed to drastic rises in the rates of mental
illnesses in the military, most notably PTSD and depression, as well as
unprecedented numbers of completed suicides. In fact, as many as a fifth of
services members returning from Iraq may have a mental health problem;
this may increase to one in four for those who have deployed three or more
times. One factor that may make service members in these wars more
vulnerable is that the dangers they face on a daily basis are unexpected and
unpredictable: instead of a front line, they have improvised explosive
devices and roadside bombs. Prolonged and frequent deployments are also
common and can compound the effects of separation from family and
difficulties with reintegration as well as potentially increase the likelihood of
exposure to combat (see Figure 8.3). Relative lack of public support for the
wars in Iraq and Afghanistan can negatively impact troop morale and may be
an important modifying factor as well.

More Combat Exposure Increases Risk of PTSD

FIGURE 8.3. Risk for development of PTSD may increase with greater
exposure to combat (e.g., being shot at, knowing someone who was killed,
killing another individual). In fact, a linear relationship between number of
firefights and PTSD prevalence has been shown among soldiers and Marines
deployed either to Iraq or to Afghanistan.

Barriers to Care:
Ongoing Stigma and Limited Resources
FIGURE 8.4. A core concern with respect to service members exposed to
trauma is the ongoing stigma associated with mental illness and with
individuals who receive such diagnoses. Despite destigmatization and
education programs on mental illness that have been implemented in the
various branches of the military, there may still be a significant proportion of
service members who doubt that PTSD is a real illness that can result from
military service. This stigma and lack of support for individuals with trauma-
related mental illness can significantly limit and/or undermine the quality of
care that they receive, if they are even willing to seek care at all.

Further complicating the diagnosis and treatment of service members with

mental illnesses is the fact that there is a major shortage of mental health
staffing within the army. Other medical professionals within the army do not
have extensive mental health training; thus access to qualified mental health
professionals is a considerable problem.

Physical Symptoms as a Common Presentation of PTSD in

Veterans
FIGURE 8.5. Service members with PTSD may be likely to present with a
number of physical symptoms. Physical symptoms including chronic pain
can be a common comorbidity to PTSD following injury (Figure 2.10), but
may also be associated with PTSD even in the absence of injury. Studies of
veterans of the Gulf war and of the Iraq war demonstrate that PTSD is
independently associated with diminished general health and greater number
of physical symptoms such as abdominal, muscle, joint, and head pain. In
fact, among combat veterans seeking treatment for PTSD, as many as two-
thirds have a preexisting chronic pain diagnosis. In particular,
temporomandibular joint disorders (TMJ) and chronic widespread pain are
commonly comorbid with PTSD. It is therefore important to evaluate for
PTSD in service members and veterans presenting with physical complaints.

Mild Traumatic Brain Injury (TBI)

TABLE 8.1. An additional complication for both the differential diagnosis
and treatment of PTSD is the high rate of traumatic brain injury (TBI)
among service members involved in the Iraq and Afghanistan wars. TBI is
defined as a physical or mechanical brain injury causing temporary or
permanent impairment of brain function. It can be either open (foreign object
penetrating the brain) or closed (blunt force, acceleration/deceleration). Mild
TBI is generally defined as an alteration in level of consciousness or a loss
of consciousness that lasts up to 30 minutes, with normal computerized
tomography (CT) and/or magnetic resonance imaging (MRI) scans and a
Glasgow Coma Scale (GCS) score of 13–15 (see above). TBIs are the most
frequent physical injury among personnel serving in the current wars, and
are typically closed, resulting from explosion or blast injury.

Mild TBI and PTSD:

Can They Co-occur?
FIGURE 8.6. There has been controversy over whether it is possible for
both PTSD and TBI to result from the same trauma, in large part because
TBI generally involves amnesia of the traumatic injury, while PTSD
presumably requires recollection of the traumatic event. Examination of
large-scale populations has led to the general acceptance that they can co-
occur, with divergence in comorbidity rates related to the severity of the
TBI. Specifically, severe TBI may actually be protective against PTSD,
whereas mild TBI may increase risk, perhaps because resulting cognitive
deficits impair the ability to process emotional information related to the
trauma.

That both PTSD and TBI could result from the same trauma is not surprising
when one considers that the brain regions most vulnerable to TBI are also
those associated with symptoms of PTSD (areas shaded in green).

Mild TBI and Persistent Postconcussive Syndrome (PPCS)

FIGURE 8.7. The majority of individuals who suffer a mild TBI experience
acute disorientation, confusion, agitation, and anterograde and retrograde
amnesia. Fatigue, headaches, dizziness, sleep disturbances, seizures, and
irritability/anger may also occur and often resolve over several days to
weeks. A significant minority, however, may experience persistent symptoms
that can include the above as well as additional cognitive impairments
(memory, attention, concentration, and executive function) and emotional
symptoms (apathy, emotional lability, and disinhibition). This constellation
of symptoms is termed persistent postconcussive syndrome (PPCS).

PPCS Symptoms:
Are They Really Postconcussive?
FIGURE 8.8. Although ideally TBI would be diagnosed immediately
following injury or blast exposure and using the Glasgow Coma Scale (see
Table 8.1), in reality, at least for veterans of Iraq and Afghanistan, the
diagnosis is often done retrospectively, months after an injury or exposure to
a blast. Further, the diagnosis is typically based on a single positive response
to one of three screening questions: (1) did you lose consciousness? (2) were
you dazed, confused, or seeing stars? or (3) do you not remember the injury?
The problem with this method is that TBI is not the only possible cause of
these things—in particular, feeling dazed or confused during a traumatic
event may simply be dissociation due to acute stress. Yet almost two-thirds
of reported cases of mild TBI among Iraq and Afghanistan war veterans have
been identified based on a positive response to that question. Thus many
individuals diagnosed with persistent postconcussive syndrome may never
have had concussion to begin with.

PPCS and PTSD:

Symptom Overlap
FIGURE 8.9. In fact, many individuals diagnosed with persistent
postconcussive syndrome (PPCS) may actually have PTSD. There is a great
deal of overlap between symptoms of PPCS and those of PTSD (and of other
illnesses as well), making it difficult to determine the underlying cause even
in individuals with well-documented history of TBI. The shared
symptomatology between PTSD and persistent symptoms of TBI may be
explained by the overlap in implicated brain regions shown in Figure 8.6.

PPCS or PTSD?
FIGURE 8.10. When one considers both the symptom overlap and the fact
that most cases of mild TBI in service members are not well-substantiated, it
seems likely that there is a large overestimate of the number of individuals
with ongoing complications related to brain injury (and a corresponding
underestimate of individuals with PTSD). In an analysis of service members
reporting mild TBI compared to those with no injury, only persistent
headache was associated with loss of consciousness after accounting for
PTSD and depression, and no physical health outcomes were associated with
altered mental status (dazed/confused or no memory of injury).

Although this section has focused on the military population, it should be

noted that TBI does, of course, occur in the civilian population as well.
Interestingly, only 3–5% of civilians with mild TBI experience PPCS. In the
military population, the estimate based on the current screening process is
ten times that.

Treating PTSD in Patients Who Have Had TBI

FIGURE 8.11. General treatment recommendations for PTSD in patients
who have experienced a TBI are the same as those for PTSD alone; this is
true for both pharmacological and non-pharmacological treatments. One
should be aware, however, that patients with TBI may be more sensitive to
the effects of medications (both therapeutic and side effects) as well as to
any potential drug interactions. For patients with comorbid PTSD and TBI it
is best to avoid medications with anticholinergic and sedative effects as well
as those that can lower the seizure threshold. Antipsychotics and
benzodiazepines in particular are not generally recommended in patients
with TBI.

Due to increased sensitivity to medication effects, it is recommended to start

at low doses, titrate slowly, monitor vigilantly, and use as few medications as
possible. Adherence may be a particular concern for this population:
cognitive symptoms may affect one’s ability to remember the medication
schedule, while impaired concentration, low frustration tolerance, and
physical symptoms may impede participation in cognitive behavioral
therapy.
 Treating PPCS in Patients with PTSD

FIGURE 8.12. Individual with postconcussive symptoms may require

treatment for impaired cognitive functioning. Cognitive rehabilitation
therapy can be used to address problems with attention, memory, and
functional communication. Cognitive restructuring may be beneficial for
patients who incorrectly attribute symptoms or normal sensations to the
brain injury.

Pharmacological treatments for cognition may be used, although this is not

well studied in patients with history of TBI and should be done cautiously.
Examples of cognitive enhancers include stimulants, cholinesterase
inhibitors, and modafinil. Because of the abuse potential of stimulants, these
should be used cautiously in patients with PTSD.
 Summary

Anxiety and fear are normal responses to stressors

The emotional, behavioral, and physical manifestations of anxiety and
fear are mediated in large part by amygdala-centered circuits
Pathological anxiety may develop when repeated stressors and genetic
vulnerabilities combine and lead to stress-sensitization within those
circuits
Posttraumatic stress disorder (PTSD) is a particularly prevalent disorder
with significant functional consequences
First-line treatment options for PTSD include cognitive behavioral
therapy (CBT—exposure, cognitive restructuring), selective serotonin
reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors
There are also many second-line and adjunct treatment options
(pharmacological and non-pharmacological)
Most patients with PTSD have at least one comorbid disorder, which
can affect treatment decisions
Military personnel face unique circumstances that put them at particular
risk for PTSD
 Abbreviations

5HT .............. serotonin

ACC ............. anterior cingulate cortex
ACT ............. acceptance and commitment therapy
ACTH ........... adrenocorticotrophin hormone
AMPA ........... alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
BDNF ........... brain-derived neurotrophic factor
CBT .............. cognitive behavioral therapy
COMT .......... catechol-O-methyl-transferase
CR ............... controlled-release
CRF .............. corticotrophin releasing factor
CSTC ............ cortico-striatal-thalamic-cortical
CT ................ computerized tomography
DA ............... dopamine
DBT .............. dialectical behavioral therapy
DLPFC ........... dorsolateral prefrontal cortex
DRI ............... dopamine reuptake inhibition
DSM ............. Diagnostic and Statistical Manual of Mental Disorders
EAAT ............ excitatory amino acid transporter
EMDR ........... eye movement desensitization and reprocessing
FDA.............. Food and Drug Administration
GABA .......... gamma-aminobutyric acid
GABA-T ........ gamma-aminobutyric transaminase
GAT ............. gamma-aminobutyric transporter
GCS ............. Glasgow Coma Scale
HPA .............. hypothalamic pituitary adrenal
IR ................. immediate-release
MAO ............ monoamine oxidase
MAOI ........... monoamine oxidase inhibitor
mGluR .......... metabotropic glutamate receptor
MRI .............. magnetic resonance imaging
NaSSA ......... noradrenergic and specific serotonergic antidepressant
NDRI ............ norepinephrine and dopamine reuptake inhibitor
NE ............... norepinephrine
NET .............. norepinephrine transporter
NMDA ......... N-methyl-D-aspartate
NOS ............ nitric oxide synthetase
NRI .............. norepinephrine reuptake inhibition
OFC ............. orbitofrontal cortex
PAG ............. periaqueductal grey
PBN ............. parabrachial nucleus
PFC .............. prefrontal cortex
PPCS ............ persistent postconcussive syndrome
PTSD ............ posttraumatic stress disorder
RIMA ............ reversible inhibitor of monoamine oxidase
SERT ............. serotonin transporter
SIT ............... stress inoculation therapy
SNRI ............ serotonin norepinephrine reuptake inhibitor
SRI ............... serotonin reuptake inhibition
SSRI ............. selective serotonin reuptake inhibitor
TBI ............... traumatic brain injury
TCA ............. tricyclic antidepressant
VMPFC ......... ventromedial prefrontal cortex
VSCC ........... voltage-sensitive calcium channel
VSSC ............ voltage-sensitive sodium channel
XR ................ extended-release
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 Index

acamprosate, 104, 122–3, 148, 149

acceptance and commitment therapy (ACT), 135, 139, 147, 153
accidents, and risk of PTSD, 36
adherence, to medication by PTSD patients with traumatic brain injury, 167
adjunctive medications, for PTSD, 104, 148
adrenal gland, 8
adrenocorticotrophic hormone (ACTH), 8, 32, 55, 128
adverse childhood experience, as risk factor for PTSD, 30. See also childhood abuse
Afghanistan war, 157–8
alcohol abuse: and acamprosate, 122–3, 149; comorbidity of with PTSD, 28, 122, 149; and diazepam,
103; and military populations, 156; and naltrexone, 122–3, 149
allopregnanolone, 129
alpha 1 adrenergic receptors: and anxiety, 49; blockade of and side effects of tricyclic antidepressants,
92; and noradrenergic hyperactivation, 47; and trazodone, 106
alpha 1 antagonists, 104, 108, 149, 152
alpha 2 delta ligands, 90, 100–1, 152
alpha 2 receptors, and mirtazapine, 105
alprazolam, 103
American Civil War, 24
amitriptyline, 93
amnesia, and traumatic brain injury, 162
AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), 53
amygdala: and fear response, 3, 5, 6–7, 9, 10, 12, 125, 127; and neuroimaging findings in PTSD, 35;
and noradrenergic projections, 46; serotonin transporter genotype and, 42–3; and worry, 3
anger, as symptom of PTSD, 27
anterior cingulate cortex (ACC), and emotional aspects of fear, 5
anticholinergic effects, of paroxetine, 66
anticonvulsants, 120–1
antidepressants: and MAOIs, 97; sedating forms of, 105–7. See also tricyclic antidepressants
antipsychotics, and traumatic brain injury, 167. See also atypical antipsychotics
anxiety: definition of, 1, 4; GABA and experience and expression of, 50, 52; and GABA-A receptors,
51; and glutamate, 52; and hippocampus, 11; neuroanatomy of compared to fear, 4; role of
amygdala in, 3; and stress inoculation training, 136. See also anxiety disorders
anxiety disorders: and citalopram, 74; comorbidity of with PTSD, 28, 151; COMT and risk of, 58; as
defined in DSM-IV-TR, 1; and desvenlafaxine, 82; and diazepam, 103; fear and worry as core
symptoms of, 2; and fluoxetine, 70; and lorazepam, 103; and milnacipran, 86; neurobiology of,
15–22; and paroxetine, 66; and presymptomatic state, 16; and risk of cardiovascular issues, 6; and
sertraline, 68; and venlafaxine, 80. See also anxiety; generalized anxiety disorder
anxiolytics, noradrenergic mechanisms for novel forms of, 47. See also benzodiazepines
appetite suppressants, and MAOIs, 97
aripiprazole, 115
arousal, and relationship between chronic pain and PTSD, 38. See also hyperarousal
asenapine, 119
assessment, of PTSD: for comorbid disorders and complications, 146; screening tools for, 144. See
also diagnosis
asthma, 9
atypical antipsychotics: as adjuncts, 104, 148; characteristics of specific agents, 112–19; mechanisms
of action, 111. See also antipsychotics
atypical depression, and phenelzine, 99
autism: and aripiprazole, 115; and risperidone, 112
automatic thoughts, and cognitive restructuring, 134
autonomic nervous system, and physiology of fear, 6
avoidance: and diagnostic criteria for PTSD, 26, 27; and relationship between chronic pain and PTSD,
38

battle fatigue, 24
behavior, and neurophysiology of fear, 10
benzodiazepines: clinical characteristics of selected forms, 103; and GABA-A receptors, 51;
mechanism of action, 102; second-line forms of, 90, 148; and traumatic brain injury, 167;
treatment of PTSD and comorbid anxiety disorder with, 151
beta blockers, 125
beta 1 receptors, 47, 49
bipolar depression: and olanzapine, 113; and quetiapine, 114
bipolar disorder: and anticonvulsants, 120; and atypical antipsychotics, 111–16
blood pressure, 6. See also hypertension
borderline personality disorder, and dialectical behavior therapy, 138
brain-derived neurotrophic factor (BDNF), 31, 34, 63
buprenorphine, 149
bupropion, 149, 150

calcium, and voltage-sensitive ion channels, 54, 100

cardiac impairment. See special populations
cardiovascular issues, anxiety disorders and risk of, 6
catechol-O-methyl-transferase (COMT), 57–8
childhood abuse, as risk factor for PTSD, 30, 31, 34, 36, 37. See also adverse childhood experience
children. See adverse childhood experience; infants; special populations
cholinesterase inhibitors, 168
chronic pain, comorbidity of with PTSD, 28, 38, 146, 153, 160
citalopram, 65, 74–5
Clinician-Administered PTSD Scale (CAPS-2), 144
clonazepam, 103
cognitive behavioral therapy, for PTSD: and acceptance and commitment therapy, 139; and anxiety
disorders, 151; and chronic pain, 153; and cognitive restructuring, 134; for depression, 150; and
dialectical behavior therapy, 138; and exposure therapy, 133; and eye movement desensitization
and reprocessing, 137; and motivational interviewing, 142; overview of, 131–2, 135, 140, 147;
and seeking safety therapy, 141; and stress inoculation training, 136; and traumatic brain injury,
167
cognitive impairments: and adherence to medication, 167; and persistent postconcussive syndrome,
163, 168
cognitive rehabilitation therapy, 168
cognitive restructuring, 132, 134, 147, 168
combat, as risk factor for PTSD, 36, 37, 156, 158
comorbidity, and PTSD: and anxiety disorders, 151; and chronic pain, 28, 38, 146, 153; and
depression, 150; and physical illnesses, 146; prevalence of, 28, 146; and sleep problems, 152; and
substance abuse, 149
computerized tomography (CT), and traumatic brain injury, 161
conditioned fear extinction, 58
coronary artery disease, 7
cortico-striatal-thalamic-cortical (CSTC) loops, 14, 52, 55
corticotrophin releasing factor (CRF), 8, 32, 40
cortisol, 7, 32, 126
CRF 1 receptor antagonists, 124, 128
D-cycloserine, 124, 127
CYP450 enzymes: and desvenlafaxine, 82; and duloxetine, 84; and fluoxetine, 70; and fluvoxamine,
72; and paroxetine, 66
Davidson Trauma Scale (DTS), 144
decongestants, and MAOIs, 97
depression: and amitriptyline, 93; and aripiprazole, 115; and cognitive behavioral therapy, 150;
comorbidity of with PTSD, 150; and desipramine, 93; and doxepin, 107; lorazepam for anxiety
associated with, 103; and nortriptyline, 93; and trazodone, 106. See also atypical depression;
major depressive disorder; manic depressive disorder; psychotic depression; treatment-resistant
depression
desipramine, 93
desvenlafaxine, 79, 80, 82–3
diabetes, 7
diabetic peripheral neuropathic pain, and pregabalin, 101
diagnosis, of PTSD, 26, 27. See also assessment; differential diagnosis; screening
Diagnostic and Statistical Manual of Mental Disorders (DSM), 1, 25, 26
dialectical behavior therapy (DBT), 135, 138, 147
diazepam, 103
dietary modifications, for patients on MAOIs, 96
differential diagnosis, of PTSD and traumatic brain injury (TBI), 161
dopamine: fluoxetine and release of, 70; and functioning in prefrontal cortex, 56–7; and monoamine
oxidase enzymes, 95. See also dopamine reuptake inhibition; dopamine transporter gene
dopamine reuptake inhibition (DRI), and sertraline, 68
dopamine transporter gene, 34
dorsal anterior cingulate cortex (dACC), and neuroimaging studies of PTSD, 35
dorsolateral prefrontal cortex (DLPFC), and obsessions, 14
dosages and dosage range for:
acamprosate, 123; alprazolam, 103; amitriptyline, 93; arpiprazole, 115; asenapine, 119; citalopram, 75;
clonazepam, 103; desipramine, 93; desvenlafaxine, 83; diazepam, 103; doxepin, 107; duloxetine,
85; escitalopram, 77; eszopiclone, 110; fluoxetine, 71; fluvoxamine, 73; gabapentin, 101;
iloperidone, 118; imipramine, 93; lamotrigine, 121; lorazepam, 103; milnacipran, 87; mirtazapine,
105; moclobemide, 99; naltrexone, 123; nortriptyline, 93; paliperidone, 117; paroxetine, 67;
phenelzine, 99; prazosin, 110; pregabalin, 101; quetiapine, 114; risperidone, 112; selegiline, 99;
sertraline, 69; topiramate, 121; trancypromine, 99; trazodone, 106; venlafaxine, 81; zaleplon, 110;
ziprasidone, 116; zolpidem, 110
doxepin, 107
drug interactions: and duloxetine, 84; and escitalopram, 76; and fluvoxamine, 72; and MAOIs, 97; and
traumatic brain injury in PTSD patients, 167
duloxetine, 79, 84–5

early life stress, as risk factor for PTSD, 31

education, on mental illness in military, 159
emotions: and cognitive restructuring, 134; and fear, 5, 10; PTSD and emotional numbing, 27; and
symptoms of persistent postconcussive syndrome, 163
endocrine system, and neurobiology of fear, 7
escitalopram, 65, 76–7
eszopiclone, 109, 110
excitatory amino acid transporter (EAAT), 53
exercise, and chronic pain, 153
exposure therapy: applications and techniques of, 133; and chronic pain, 153; and conditioned fear
extinction, 58; and dialectical behavior therapy, 138; as first-line therapy for PTSD, 132, 147
extended-release formulation, of venlafaxine, 80
eye movement desensitization and reprocessing (EMDR), 135, 137, 147

family psychiatric history, as risk factor for PTSD, 30

fear: amygdala and neurophysiology of, 3, 5, 6–7, 9, 10, 12; as core symptom of anxiety disorders, 2;
and hippocampus, 11; and locus coeruleus, 46; neuroanatomy of compared to anxiety, 4; and
neurotransmitters, 40. See also fear conditioning; fear extinction
fear conditioning: amygdala and stress response, 12; and beta blockers, 125; and catechol-O-methyl-
transferase, 58; and D-cycloserine, 127; and SERT genotype, 43
fear extinction, 127
fibromyalgia, and pregabalin, 101
fight/flight reaction, 6
FKBP5 gene, 34
fluoxetine, 65, 70–1
fluvoxamine, 65, 72–3
Freud, Sigmund, 24
functional brain scanning, and stress diathesis model, 20

GABA (gamma-aminobutyric acid): and amygdala-centered neurocircuits, 40; and anticonvulsants,

120; and benzodiazepines, 102; key role of in experience and expression of anxiety, 50; potential
targets for modulating, 51. See also GABA transaminase; GABA transporter
GABA-A receptors, 51, 102
GABA-B receptors, 51
gabapentin, 101, 153
GABA transaminase (GABA-T), 51
GABA transporter (GAT), 51
ganaxolone, 129
gender, and trauma types resulting in PTSD, 36, 37
generalized anxiety disorder: and alprazolam, 103; and duloxetine, 84; and escitalopram, 76
genetics: and risk factors for PTSD, 30, 34; and serotonin transporter gene, 42–3; and stress diathesis
hypothesis, 19–22
Glascow Coma Scale (GCS), 161, 164
glucorticoid receptor antagonists, 128
glucocorticoids, 7, 8
glutamate, 40, 52–3
glycine, 53
gross stress reaction, 25
Gulf war, 160

headaches, and PTSD, 146

heart rate (HR), 6
hepatic impairment. See special populations
hippocampal atrophy: and chronic stress, 8, 33; and PTSD, 30–3, 35, 63
hippocampus: and beta blockers, 125; fear and fear conditioning, 11, 125; and inhibition of stress
response, 8; and neuroimaging findings in PTSD, 35; small size of as risk factor in PTSD, 30. See
also hippocampal atrophy
histamine 1 receptors, 92, 106
hydrocortisone, 124, 126
hyperarousal: and diagnostic criteria for PTSD, 26, 27; and exposure therapy, 133. See also arousal
hypertension: MAOIs and crisis of, 96; and prazosin, 110. See also blood pressure
hypnotics, and sedation, 109
hypocortisolism, 30
hypothalamic pituitary adrenal (HPA) axis: early life stress and dysregulation of, 31; and physiology
of fear, 7; and PTSD, 31, 55, 128; and stress responses, 8, 54

iloperidone, 118
imaginal exposure, 133
imipramine, 93
impulse control, and suicide risk in PTSD, 29
infants, and exposure to stress, 18
information processing: and stress diathesis model, 20; and stress sensitized circuits, 17
insomnia: comorbidity of with PTSD, 152; and eszopiclone, 110; and tricyclic antidepressants, 92; and
zaleplon, 110; and zolpidem, 110. See also sleep disturbances
interoceptive exposure, 133
investigational medications, 124
in vivo exposure, 133
Iraq war, 157–8, 160
irritability, and symptoms of PTSD, 27
irritable bowel syndrome, 146

kainate, 53

lamotrigine, 104, 120, 121, 148

locus coeruleus (LC): and noradrenergic projections, 46; and physiology of fear, 6
lorazepam, 103

magnetic resonance imaging (MRI), and traumatic brain injury, 161

MAOIs. See monoamine oxidase inhibitors
major depressive disorder: comorbidity of with PTSD, 28; and mirtazapine, 105; and
neurophysiological alterations from early life stress, 31; and nortriptyline, 93; and selegiline, 99;
and tranylcypromine, 99. See also depression
mania: and aripiprazole, 115; and olanzapine, 113; and quetiapine, 114; and ziprasidone, 116. See also
bipolar disorder
manic depressive disorder, and doxepin, 107
mental health professionals, limited access to in military, 159
metabotropic glutamate receptors (mGluR), 53
methadone, 149
met/met genotype, 57, 58
military population: barriers to mental health care for, 159; impact of Iraq and Afghanistan wars on
mental health of, 157; increase in prevalence of PTSD in, 155; and persistent postconcussive
syndrome, 163–8; physical symptoms as common presentation of PTSD in, 160; and risk factors
for PTSD, 156; and traumatic brain injury, 161–3. See also combat; warfare
milnacipran, 79, 86–7
mindfulness, and dialectical behavior therapy, 138
mirtazapine, 104, 105, 148
moclobemide, 99
modafinil, 168
monoamine oxidase (MAO) enzymes: and dopamine, 95; and norepinephrine, 48, 95; and serotonin,
44, 95; and tyramine reactions to MAOIs, 98
monoamine oxidase inhibitors (MAOIs): clinical characteristics of, 99; and drug interactions, 97;
mechanism of action, 94–5; and tyramine reactions, 96, 98
motivational interviewing, 140, 142, 147, 149
muscarinic M1 receptor blockade, and tricyclic antidepressants, 92
naltrexone, 104, 122–3, 148, 149
natural disasters, and risk of PTSD, 36, 37
neuroactive steroids, 129
neurobiology: of fear and worry, 2–14; and neurocircuits in anxiety disorders, 15–22. See also
amygdala; hippocampus; hypothalamic pituitary adrenal (HPA) axis; locus coeruleus;
neurotransmitters; prefrontal cortex
neuroimaging studies, of PTSD, 35
neurotransmitters: of fear and worry, 40; and GABA pathways, 50–1; and glutamate pathways, 52–3;
and noradrenergic pathways, 46–9; and serotonergic pathways, 41–5; and voltage-sensitive ion
channels, 54. See also dopamine; GABA; norepinephrine; serotonin
nicotine dependence, 149
nightmares: and alpha 1 antagonists, 108, 152; and symptoms of PTSD, 27; and trazodone, 106
nitric oxide synthetase (NOS) inhibitors, 66
NMDA (N-methyl-D-aspartate), 53
noradrenergic pathways. See norepinephrine
norepinephrine: and circuits of fear and worry, 40; and monoamine oxidase enzymes, 95; and potential
mechanisms for novel anxiolytics, 47; potential targets for modulating neurotransmission of, 48–
9; and prefrontal cortex, 56
norepinephrine reuptake inhibition (NRI): and desvenlafaxine, 82; and duloxetine, 84; and fluoxetine,
70; and milnacipran, 86; and paroxetine, 66; and serotonin norepinephrine reuptake inhibitors, 78;
and venlafaxine, 80
norepinephrine transporter (NET), 48, 91
nortriptyline, 93

obsessions, and worry, 14

obsessive-compulsive disorder, and fluvoxamine, 72
olanzapine, 113
opiate dependence, and PTSD, 149, 153
opioids, and MAOIs, 97
orbitofrontal cortex (OFC), and emotional aspects of fear, 5

pain. See chronic pain

paliperidone, 117
panic attacks, symptoms of, 9
panic disorder: and alprazolam, 103; and clonazepam, 103
parabrachial nucleus (PBN), and fear response, 9
paroxetine, 65, 66–7, 148
periaqueductal grey (PAG), and fear response, 10
persistent postconcussive syndrome (PPCS), 163–6, 168
pharmacological treatments, for PTSD: overview of adjunct medications, 104; overview of first-line
medications, 59–60; overview of investigational medications, 124; overview of second-line
medications, 89–90. See also alpha 2 delta ligands; anticonvulsants; antidepressants;
antipsychotics; benzodiazepines; dosages and dosage range; drug interactions; monoamine
oxidase inhibitors; selective serotonin reuptake inhibitors; serotonin norepinephrine reuptake
inhibitors; side effects; special populations; stimulants; specific medications
phenelzine, 99
physical attack, and risk of PTSD, 36
physical illnesses, as comorbid with PTSD, 146
physical symptoms, and presentation of PTSD in veterans, 160
postherpetic neuraligia, and alpha 2 delta ligands, 101
postsynaptic GABA receptor, 51
postsynaptic glutamate receptor, 53
postsynaptic norepinephrine receptor, 49
postsynaptic serotonin receptors, 45
Posttraumatic Diagnostic Scale (PDS), 144
posttraumatic stress disorder (PTSD): acceptance and commitment therapy for, 139; adjunct
medications for, 104, 148; and alcohol abuse, 122; and anticonvulsants, 120; and anxiety
disorders, 28, 151; assessment tools for, 144; beta blockers and prevention of, 125; and chronic
pain, 28, 38, 153, 160; clinical picture of, 27; and cognitive restructuring, 134; common
comorbidities in, 28, 122; criteria controversies and future of, 26; and depression, 150; diagnostic
criteria for, 26; and dialectical behavior therapy, 138; and duloxetine, 84; and early life stress, 31;
and escitalopram, 76; exposure therapy for, 133; and eye movement desensitization and
reprocessing, 137; and genetics, 34; and hippocampal volume, 30, 31, 32, 33, 35, 63; historical
perspective on, 24–5; and HPA axis, 32, 55, 128; hydrocortisone and prevention of, 126; and
hyperarousal, 26, 27, 133; investigational medications for, 124; and military population, 155–68;
and monoamine oxidase inhibitors, 99; and motivational interviewing, 142; and neuroactive
steroids, 129; neuroimaging findings in, 35; and noradrenergic hyperactivation, 47; overview of
cognitive behavioral therapy for, 131–2, 135, 140, 147; overview of first-line medications for, 59–
60, 148; overview of second-line medications for, 89–90, 148; and persistent postconcussive
syndrome (PPCS), 168; and prazosin, 108; prevalence of, 23, 36, 155; and quetiapine, 114; and
reexperiencing symptoms, 11, 26, 27, 133; risk factors for, 30–1, 33, 34; and risperidone, 112; and
serotonin, 41; and serotonin norepinephrine reuptake inhibitors, 78; sleep disturbances and
nightmares in, 108, 109, 152; and stress inoculation training, 136; and substance abuse, 149; and
suicide risk, 29; and types of trauma, 36–7; and venlafaxine, 80
Posttraumatic Stress Disorder Checklist (PCL), 144
prazosin, 108, 110
prefrontal cortex (PFC): COMT genotype and activation of, 57; and dopamine, 56–7; and glutamate
pathways, 52; and noradrenergic projections, 46
pregabalin, 101, 153
pregnancy. See infants; special populations
pregnanolone, 129
presymptomatic states, and anxiety disorders, 16
presynaptic norepinephrine receptor, 49
presynaptic serotonin receptor (5HT1B/D), 45
prevalence: of mental health issues in military population, 157; of PTSD, 23, 36, 155
prevention, of PTSD by administration of medications after exposure to trauma, 125–6
Primary Care Posttraumatic Stress Disorder Screen (PC-PTSD), 144
prodromal symptoms, 17
psychiatric history, and risk of suicide in PTSD, 145
psychosocial situation, and risk of suicide in PTSD, 145
psychotic depression: and doxepin, 107; and sertraline, 68
PTSD. See posttraumatic stress disorder

quetiapine, 114

rape, and risk of PTSD, 36, 37

reexperiencing: and diagnostic criteria for PTSD, 26, 27; and exposure therapy, 133; and
hippocampus, 11; and relationship between PTSD and chronic pain, 38
renal impairment. See special populations
R enantiomer, of citalopram, 74, 76
respiration rate, and fear response, 9
reversible inhibition of MAO-A (RIMA), 98
risk factors: and prediction of PTSD, 30, 31, 33, 34; for PTSD in military population, 156, 158; for
suicide in PTSD, 29, 145
risperidone, 112
rostral anterior cingulate cortex (rACC), 35

safety. See side effects; suicide and suicidal ideation

schizophrenia, and atypical antipsychotics, 111–19
screening: and assessment tools for PTSD, 144; for risk of suicide in PTSD, 145
sedation: and antidepressants, 105–7; and hypnotics, 109
seeking safety therapy, 140, 141, 147, 149
seizures and seizure disorders: and anticonvulsants, 121; and clonazepam, 103; and gabapentin, 101;
and pregabalin, 101
selective serotonin reuptake inhibitors (SSRIs): as first-line medications for PTSD, 60, 148;
mechanisms of action, 61–3; secondary pharmacological properties of, 64; and specific agents, 65
selegiline, 98, 99
S enantiomer, of citalopram, 74
serotonin: fear and worry circuits, 40; and monoamine oxidase enzymes, 95; potential
pharmacological targets for modulating, 44–5; and PTSD, 41. See also serotonin receptors;
serotonin reuptake inhibition; serotonin syndrome; serotonin transporter
serotonin norepinephrine reuptake inhibitors (SNRIs): and chronic pain, 153; as first-line medications
for PTSD, 60, 148; mechanisms of action, 78; and specific agents, 79
serotonin (5HT2C) receptors, and fluoxetine, 70
serotonin reuptake inhibition (SRI): and desvenlafaxine, 82; and duloxetine, 84; and escitalopram, 76;
and fluoxetine, 70; and milnacipran, 86; and paroxetine, 66; and serotonin norepinephrine
reuptake inhibitors, 78; and venlafaxine, 80. See also selective serotonin reuptake inhibitors
(SSRIs)
serotonin syndrome, and MAOIs, 97
serotonin transporter (SERT): and citalopram, 74; and genetic risk factors for PTSD, 34; and genetics
of amygdala response to fearful stimuli, 42–3; and mechanism of action of SSRIs, 61; and
modulation of serotonergic neurotransmission, 44–5; and tricyclic antidepressants, 91
sertraline, 65, 68–9, 148
shell shock, 24
side effects: of citalopram, 75; of desvenlafaxine, 83; of duloxetine, 85; of escitalopram, 77; of
fluoxetine, 71; of fluvoxamine, 73; of milnacipran, 87; of olanzapine, 113; of paroxetine, 67; of
quetiapine, 114; of risperidone, 112; of sertraline, 69; of tricyclic antidepressants, 92; of
venlafaxine, 81
sigma 1 receptors, 68, 72
SLC6A3 9 repeat allele, 34
sleep disturbances: and alpha 1 antagonists, 108; and diagnosis of PTSD, 27; and risperidone, 112; and
sedative hypnotics, 109; treatment of PTSD and comorbid, 152. See also insomnia; nightmares
smoking cessation, 149
social support, and risk factors for PTSD, 30
sodium, and voltage-sensitive ion channels, 54
SPAN, 144
special populations: and citalopram, 75; and desvenlafaxine, 83; and duloxetine, 85; and escitalopram,
77; and fluoxetine, 71; and fluvoxamine, 73; and milnacipran, 87; and paroxetine, 67; and
sertraline, 69; and venlafaxine, 81. See also infants; military population
startle responses, and diagnosis of PTSD, 27
stigma, as barrier to mental health care in military, 159
stimulants: and MAOIs, 97; and PTSD patients with postconcussive symptoms, 168
stress: exposure to in infancy, 18; and hippocampal volume, 33; and HPA activation, 7, 8; and
neurobiology of sensitization to, 16–18; as risk factor for PTSD, 30, 31
stress diathesis model, 19–22
Stressful Life Events Screening Questionnaire (SLESQ), 144
stress inoculation training (SIT), 135, 136, 147
stroke, 7
substance abuse: comorbidity of with PTSD, 28, 149; and military populations, 156; and risk of
suicide in PTSD, 29; and seeking safety therapy, 141. See also alcohol abuse
subsyndromal symptoms, 17
suicide and suicidal ideation: and military populations, 156, 157; risk of in PTSD patients, 29, 145
support groups, and comorbid PTSD and substance abuse, 149

temporomandibular joint disorders (TMJ), 160

threat with weapon, and risk of PTSD, 36, 37
topiramate, 104, 120, 121, 148
transdermal administration, of selegiline, 98
transient situational personality disturbances, 25
tranylcypromine, 99
trauma: definition of, 23; and diagnostic criteria for PTSD, 26; relationship between type of and
PTSD, 36–7
traumatic brain injury (TBI), 155, 161–3, 167
Trauma Questionnaire (TQ), 144
trazodone, 106
treatment-resistant depression: and olanzapine, 113; and quetiapine, 114
tricyclic antidepressants (TCAs): and chronic pain, 153; clinical characteristics of select forms of, 93;
mechanism of action, 91; side effects of, 92. See also antidepressants
tyramine, and MAOIs, 96, 98

val genotype, 57, 58

Val66Met (BDNF gene), 34
varenicline, 149
vasopressin 1B receptors, 128
venlafaxine, 78, 79, 80–1
ventromedial prefrontal cortex (VMPC), and fear conditioning, 12, 125
veterans. See combat; military population; warfare
Vietnam War, 25
voltage-sensitive ion channels, 40, 54, 100

warfare, and historical perspective on PTSD, 24. See also combat; military population
warning signs, of suicide in PTSD, 145
withdrawal symptoms: and fluoxetine, 70; and paroxetine, 66; and venlafaxine, 80. See also alcohol
abuse
World War I and World War II, 24
worry and worry loop, 2, 13, 14, 40

zaleplon, 109, 110

ziprasidone, 116
zolpidem, 109, 110
zopiclone, 109
 CME Posttest

To receive your certificate of CME credit or participation, please complete the posttest (you must
score at least 70% to receive credit) and activity evaluation answer sheet found on the last page and
return it by mail or fax it to 760-931-8713. Once received, your posttest will be graded and, along with
your certificate (if a score of 70% or more was attained), returned to you by mail. Alternatively, you
may complete these items online and immediately print your certificate at www.neiglobal.com/cme.
There is a $40 fee for the posttest (waived for NEI members).

Please circle the correct answer on the answer sheet provided.

1. The emotional, physiological, and behavioral expressions of fear and anxiety are hypothetically
regulated by circuitry centered around the:
A. Amygdala
B. Hippocampus
C. Hypothalamus
D. Prefrontal cortex

2. Individuals with PTSD demonstrate dysregulation of the HPA axis characterized by:
A. Increased CRF and glucocorticoids
B. Decreased CRF and glucocorticoids
C. Increased CRF and decreased glucocorticoids
D. Decreased CRF and increased glucocorticoids

3. Which of the following scenarios is consistent with the stress-diathesis model?

A. An individual with normal genes and an abusive childhood has inefficiently functioning
brain circuits and a normal phenotype (i.e., no mental illness)
B. An individual with a risk gene and a normal childhood has inefficiently functioning brain
circuits and a normal phenotype
 C. An individual with both a risk gene and an abusive childhood has inefficiently functioning
brain circuits and a mental illness
D. A and C
E. A, B, and C

4. Although each first-line medication option for PTSD has a unique pharmacological profile, they all
share what common central mechanism?
A. Dopamine reuptake inhibition
B. GABA reuptake inhibition
C. Serotonin reuptake inhibition
D. Norepinephrine reuptake inhibition

5. A 24-year-old male passenger suffers mild injuries in a head-on car accident in which the driver of
the other vehicle dies. A beta blocker could theoretically be promising for individuals like this man
because they have preliminarily been shown to:
A. Block formation of fear conditioning immediately following trauma
B. Reverse fear conditioning during exposure therapy
C. Facilitate fear extinction immediately following trauma
D. Facilitate fear extinction during exposure therapy

6. A man who was bitten by a dog as a child is beginning cognitive restructuring therapy to treat his
PTSD. He identifies walking down the sidewalk past a person with their dog on a leash as a highly
distressing situation, rating his fear during such an encounter as 80/100. He states that he strongly
believes any dog is likely to escape its leash and try to attack him. The next step in cognitive
restructuring would be for him to:
A. Put himself in a situation in which he encounters a dog on a leash
B. Identify evidence for and against the thought that the dog would escape and attack him
C. Practice techniques such as breathing exercises while thinking about encountering a dog on a
leash

7. A young woman has just been diagnosed with PTSD and is ready to begin medication treatment.
Which of the following has the most evidence of efficacy as a first-line treatment in PTSD?
A. Alprazolam
B. Duloxetine
C. Pregabalin
 D. Sertraline

8. A patient presents with comorbid PTSD and substance abuse. Her care provider recommends
seeking safety therapy as an initial treatment strategy prior to beginning any other CBT or
medication. This means that:
A. PTSD will be addressed first
B. Substance abuse will be addressed first
C. PTSD and substance abuse will be addressed simultaneously

9. A 29-year-old woman has a history of childhood abuse and has suffered from depression and PTSD
for many years without seeking treatment. She has just started taking a selective serotonin reuptake
inhibitor. Based on general rates of remission with medications, symptoms of which disorder
would be expected to improve the most?
A. Depression
B. PTSD
C. Depression and PTSD have comparable remission rates

10. A 22-year-old soldier has headaches, dizziness, irritability, and concentration problems six months
after a blast injury in which he briefly lost consciousness. Both PTSD and persistent
postconcussive syndrome are part of the differential diagnosis. According to existing data, which
of these symptoms remains associated with brain injury after accounting for PTSD?
A. Headache
B. Dizzinesss
C. Irritability
D. Concentration problems
 Stahl’s Illustrated: Anxiety, Stress, and PTSD
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Posttest Answer Sheet (score of 70% or higher required for CME credit)
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2. ABCD
3. ABCDE
4. ABCD
5. ABCD
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A. Increased
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A. Change my practice
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C. Do nothing as current practice reflects activity’s recommendations
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14. I commit to making the following change(s) in my practice as a result of participating in this
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A. Educate PTSD patients and their families on PTSD, its neurobiological and environmental
contributors, and the scientific rationale for various treatment options
B. Encourage patients with PTSD to participate in cognitive behavioral therapy
 C. Assess for comorbidities and complications prior to making treatment recommendations as
well as periodically during treatment
D. A and B
E. A and C
F. B and C
G. All of the changes (A, B, and C)
H. I am already doing all of the above

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 Table of Contents
Title
Copyright
Preface
Contents
Continuing Medical Education (CME) Information
Objectives
Chapter 1: Neurobiology of Stress and Anxiety
Chapter 2: Posttraumatic Stress Disorder (PTSD)
Chapter 3: Neurotransmitter Systems as Pharmacological Targets for PTSD
Chapter 4: First-Line Medications for PTSD
Chapter 5: Second-Line, Adjunct, and Investigational Medications for PTSD
Chapter 6: Cognitive Behavioral Therapy (CBT) for PTSD
Chapter 7: Caring for Patients with PTSD
Chapter 8: Unique Considerations for the Military Population
Summary
Abbreviations
Suggested Readings
Index
CME Posttest
Activity Evaluation