Pharmacological Treatment of Post-Traumatic Stress Disorder: Jonathan I. Bisson
Pharmacological Treatment of Post-Traumatic Stress Disorder: Jonathan I. Bisson
001909
Pharmacological treatment
of post-traumatic stress disorder
Jonathan I. Bisson
Abstract Post-traumatic stress disorder (PTSD) causes significant distress and is often associated with markedly
reduced functioning. Recent reviews have consistently recommended trauma-focused psychological
therapies as a first-line treatment for PTSD. Pharmacological treatments have also been recommended
but not as consistently. This article reviews the available trials of the pharmacological treatment of PTSD
and discusses their implications.
Post-traumatic stress disorder (PTSD) is now well Interest in the prevention of its development
established as a discrete psychiatric disorder with following a traumatic event provoked attempts to
evidence of a distinct neurobiology. Its features have discover effective early psychological interventions.
been refined since it was first introduced as a diagnosis One of these, psychological debriefing, has now
in DSM–III (American Psychiatric Association, 1980) been shown to lack evidence of efficacy (Rose et al,
and the past decade has seen an exponential rise in 2005) but trauma-focused cognitive–behavioural
the number of publications relating to it. The disorder interventions for symptomatic individuals have
is characterised by re-experiencing (e.g. nightmares been shown to be efficacious (e.g. Bryant et al, 1998;
and flashbacks), avoidance, numbing of general Ehlers et al, 2003; Bisson et al, 2004).
responsiveness, and hyperarousal (e.g. irritability Of more pertinence here is the possibility of a new
and hypervigilance) following a traumatic event. area of controversy in the management of PTSD,
It has been estimated to have a lifetime prevalence that of the effectiveness or otherwise of pharmaco
of 8% in the USA, is deemed to be chronic if it lasts logical approaches. Clinical practice guidelines
for more than 3 months and runs a course whereby commissioned by the National Institute for Health
around a half recover within 2 years but about a and Clinical Excellence (NICE) recommend that
third continue to have the diagnosis 6 years later medication should be considered a second-line
(Kessler et al, 1995). treatment for PTSD, behind trauma-focused psy
Factors associated with the development of chological treatments such as trauma-focused
PTSD include lack of perceived social support after cognitive–behavioural therapy and eye movement
the event, marked initial distress, high-impact desensitisation and reprocessing (National Collabor
trauma (rape has consistently been associated with ating Centre for Mental Health, 2005). My primary
the highest rates), dissociation at the time, past aim in this article is to critically review the evidence
psychiatric history and female gender (Brewin et for a pharmacological approach to the management
al, 2000; Ozer et al, 2003). Over half of PTSD sufferers of PTSD, to allow readers to understand the evidence
will also have another psychiatric disorder (Kessler on which the NICE guidelines have been based and
et al, 1995). As a diagnosis, PTSD has always been draw their own conclusions regarding the role of
associated with a degree of controversy. Some have medication in PTSD.
criticised the very existence of PTSD, arguing that
it is a Western social construct; others acknowledge
its existence but are concerned by probable over- The neurobiology of PTSD
diagnosis (e.g. Tyrer, 2005).
Aside from the controversy over the diagnosis of Our understanding of the neurobiology of PTSD
PTSD, its management has also been controversial. has been greatly informed by work on memory
Jonathan Bisson is a clinical senior lecturer in psychiatry at Cardiff University (Monmouth House, University Hospital of Wales, Heath
Park, Cardiff CF14 4XW, UK. Email: [email protected]). He leads the local traumatic stress service and is an active researcher in this
field. He was recently co-chair of the Guideline Development Group for the National Institute for Clinical Excellence’s clinical practice
guidelines on post-traumatic stress disorder.
119
Bisson
and fear conditioning. The hippocampus and other Determining the efficacy
areas of the temporal lobe are believed to mediate
conscious memories, for example the exact details
of interventions
of a traumatic event. The amygdala is believed to be
Various levels of evidence can be used to assess the
important in the mediation of unconscious memories,
efficacy of interventions but replicated, multicentre,
for example the autonomic aspects of the classic fear
large-scale randomised controlled trials (RCTs)
response. The amygdala receives information about
should be considered the gold standard. This level
external stimuli and is involved in determining their
of evidence is lacking for most pharmacological ap-
significance. This then triggers emotional responses,
proaches to PTSD treatment, with the notable excep-
including ‘fight, flight or freezing’ and alterations in
tions of paroxetine and sertraline. Nevertheless, there
stress hormones and catecholamines.
have been RCTs (albeit not necessarily to the gold
Connections between the amygdala, hippocampus
standard) of several pharmacological approaches
and medial prefrontal cortex have been implicated
and here I consider the results of those for drugs
in determining the final fear response. Hippocampal
lesions have been associated with a stronger fear that are currently available.
response and smaller hippocampal volume has been The efficacy of the drugs is described in terms
associated with PTSD in several studies, probably of reduction in clinician-assessed severity of PTSD
representing a pre-existing vulnerability to its symptoms using the results of the NICE meta-
development rather than a neurotoxic consequence analysis in this area (National Collaborating Centre
(Gilbertson et al, 2002). Neuroimaging studies of for Mental Health, 2005). In studies that did not
people with PTSD have shown decreased activity include a clinician-rated outcome measure the results
in medial prefrontal and anterior cingulate areas to of the Impact of Event Scale, a self-report measure,
be correlated with increased activity in the amyg are given. Box 1 outlines the statistical terms used
dala (Bremner et al, 1999; Shin et al, 2004). This has in the presentation of the results.
resulted in the proposal that PTSD represents a
failure of medial prefrontal and/or anterior cingulate
networks to regulate amygdala activity, resulting in
hyperreactivity to threat (Bremner, 1999). Box 1 Presentation of results
One of the most enduring neurophysiological
theories in recent times has been that of enhanced • k = number of trials
negative feedback in the hypothalamic–pituitary– • n = total number of participants included in
adrenal axis. Several studies have found low the analysis
cortisol levels in people with PTSD and an opposite • s.m.d. (standardised mean difference): a sta-
response to the dexamethasone suppression test than tistical means of determining the effect size
that seen with severe depression, i.e. there is over of a continuous outcome measure. A value
suppression of cortisol release. However, more recent of 0 represents no difference between the
studies have not consistently supported this finding groups
(Young & Breslau, 2005). The finding of increased
• Effect size: in general it is accepted that effect
plasma catecholamine levels in PTSD sufferers has
sizes of < 0.5 are low, < 0.8 medium and > 0.8
also evoked considerable interest, including the
large (Cohen, 1988)
suggestion that an initial adrenergic (adrenaline
and noradrenaline) surge may be associated with • 95% confidence intervals (95% CIs): these
the laying down of traumatic memories (Pitman, figures represent the range of standardised
1989). mean differences within which we can be
Our improved understanding of the neurobiology 95% confident that the true level of differ-
of PTSD does not appear to have driven most ence falls
studies of the efficacy of pharmacological agents • RR (relative risk): in the prevention studies
in the treatment of the disorder, but it has led to the RR is used instead of the s.m.d. to
the development of hypotheses for the potential describe the efficacy of the drug in pre
effectiveness of some drugs (for example propranolol venting the development of PTSD. This
and hydrocortisone as early interventions, see statistic compares the risk of developing
below). It has also resulted in attempts to determine PTSD for the active drug group with that
the impact of drugs on the neurobiological processes for the placebo group. A relative risk of
themselves. Citalopram, for example, has now 1 represents no difference between the
been shown to influence the acquisition of fear groups
conditioning (Burghardt et al, 2004).
Prevention of PTSD
3
Three small RCTs of early pharmacological inter
ventions to prevent PTSD have been published, all 2
of which are likely to have been underpowered to
detect clinically important differences unless of a 1
very large magnitude. The first was based on the
cortisol findings described above and concerned 0
the administration of intravenous hydrocortisone
Amitriptyline
Mirtazapine
Venlafaxine
Olanzapine
Imipramine
to victims of septic shock on an intensive care unit
Phenelzine
Paroxetine
Fluoxetine
-1
Sertraline
in Switzerland (Schelling et al, 2001). The results
were not statistically significant but those receiving
hydrocortisone tended to be less likely to develop
symptoms of PTSD (k = 1; n = 20; RR = 0.17; 95% CI
0.03–1.17). This has not been replicated in other Fig. 1 Treatment of chronic PTSD: standardised mean
populations, although a case study of four individuals differences with 95% confidence intervals.
with chronic PTSD suggests that it may be worthy
of further investigation (Aerni et al, 2004).
The second study concerned propranolol, a beta-
blocker. It was based on the hypothesis that an In summary, there is not enough evidence to
adrenergic surge beginning almost immediately after advocate the routine prescription of medication to
a traumatic event is associated with the development prevent PTSD. There is some evidence for intravenous
of traumatic memories. Pitman and colleagues (2002) hydrocortisone in people with septic shock, but
hypothesised that, for propranolol to be successful, clearly it is difficult to generalise these results to
individuals would have to start taking it within 6 h other populations. There is also some evidence that
of the trauma. The logistic implications of running a temazepam may help with acute insomnia following
trial with this constraint are daunting, but all credit traumatic events. There has been no research to date
to the researchers in completing a small study of exploring the potential of more commonly used
individuals who were randomly allocated to receive agents such as antidepressants in the immediate or
40 mg propranolol or a placebo four times a day for early aftermath of a traumatic event.
10 days. There was no significant difference in rates
of PTSD between the two groups at 1 month (k = 1;
n = 41; RR = 1.14; 95% CI 0.55–2.35) or 3 months (k = 1;
Treatment of PTSD
n = 41; RR = 1.28; 95% CI 0.69–2.38), with the trend
Much more research has been conducted regarding
being in favour of the placebo group. However,
the efficacy of drugs in the treatment of established
the propranolol group became less physiologically
chronic PTSD (Fig. 1). Perhaps not surprisingly
aroused when they listened to an account of the
the selective serotonin reuptake inhibitors (SSRIs)
traumatic event, which indicates the possibility of
have been investigated more than any other family
some effect but not enough to recommend routine
of drugs, indeed more than any other intervention
prescribing.
in the field. The number of individuals entered
Finally, there has been one small RCT of temazepam
into RCTs of SSRIs outnumbers those included in
given shortly after a traumatic event (Mellman et al,
trauma-focused cognitive–behavioural therapy trials
2002). This is of interest because it has been argued
by over 2:1. There are probably several reasons for
that benzodiazepines may hinder the processing of
this, including the willingness of the pharmaceutical
trauma, but on closer scrutiny such assertions appear
industry to fund studies of drugs with the potential
to be based more on anecdote and, possibly, an anti-
to gain another indication for prescribing. It is a sad
prescribing stance than evidence. From a mean of 14
fact that drugs that have shown some potential but
days after the trauma, individuals in the treatment
have lost their patent are not investigated to the same
arm received 30 mg temazepam daily for 5 days,
degree.
then 15 mg daily for 2 days. There was no statistical
difference in rates of PTSD at the 6-week follow-up
point, although a trend was found in favour of the Selective serotonin reuptake inhibitors
placebo group (k = 1; n = 22; RR = 3.2; 95% CI 0.54– Paroxetine
18.98). The temazepam group had slept significantly
better on the first night, but there was no significant There have been three main well-designed double-
difference between groups at follow-up. blind RCTs of paroxetine. Two of these have been
published (Marshall et al, 2001; Tucker et al, 2001), symptoms as a primary outcome measure. The
the other (SKB 627) has not but the results are within results are less convincing than those for paroxetine
the public domain (National Collaborating Centre and do not reach statistical significance (k = 1; n = 301;
for Mental Health, 2005: p. 69). Paroxetine shows a s.m.d. = −0.28; 95% CI 0.54 to −1.2), but this may be
statistically significant positive effect over placebo explained by insufficient numbers to show a real
(k = 3; n = 1070; s.m.d. = −0.42; 95% CI −0.55 to −0.3). but modest effect.
The tight CIs suggest that this is likely to be an ac-
curate estimate of its efficacy, but the critical question
is how clinically significant this effect is: enough for Tricyclics and monoamine oxidase
it to be granted a licence for PTSD by the UK authori- inhibitors
ties but not enough for it to be recommended in the
NICE guidelines (National Collaborating Centre for The RCTs of tricyclic antidepressants and monoam-
Mental Health, 2005) as a first-line treatment! The ine oxidase inhibitors (MAOIs) are older than those
Guideline Development Group set a priori limits on of SSRIs and their quality is inferior. It is disap-
what they would consider clinically meaningful, and pointing that more trials have not been carried out,
as a result gave only a limited recommendation to particularly given the encouraging results of those
paroxetine as a second-line treatment. This, along that have been published. None of the trials used a
with the widely publicised other potential problems clinician-rated outcome measure and therefore the
associated with paroxetine (Duff, 2004), should result results of the Impact of Event Scale, a self-report
in its cautious use for PTSD. measure, are given.
Sertraline Amitriptyline
One of the most interesting things about sertraline The one study (Davidson et al, 1990) that considered
is that, although it is widely recommended as an the efficacy of amitriptyline was positive but with
effective treatment for PTSD (e.g. Friedman et al, very large confidence intervals, meaning that its true
2000; Stein et al, 2004), PTSD is an indication for effect could be anything between low and very large
its use in the UK in females but not in males. This (k = 1; n = 33; s.m.d. = −0.9; 95% CI −1.62 to −0.18).
suggests that the data presented to the authorities
were not totally convincing. In fact, the NICE figures Imipramine
from four published (Brady et al, 2000; Davidson et al,
The evidence for imipramine (Kosten et al, 1991) is
2001a, 2006; Zohar et al, 2002) and two unpublished
weaker than that for amitriptyline and the effect does
studies (Pfizer 588; Pfizer 589) just fail to achieve
not achieve statistical significance, although the wide
statistical significance, with a trend in favour of
confidence intervals mean that its true effect could
sertraline (k = 6; n = 1123; s.m.d. = −0.26; 95% CI −0.51
be a positive one (k = 1; n = 41; s.m.d. = −0.24; 95% CI
to 0.00). Interestingly, the Guideline Development
−0.86 to 0.38).
Group was aware of the two unpublished studies
of sertraline held by Pfizer (Pfizer 588; Pfizer 589).
Despite several requests the full results were not Phenelzine
forthcoming, although enough information was Phenelzine is the only available MAOI with an
obtained to include the studies in the final meta- evidence base for the treatment of PTSD (Kosten et
analysis (National Collaborating Centre for Mental al, 1991) and, like amitriptyline, although the true
Health, 2005: p. 71). The inclusion of these two magnitude of its effect is not known it appears to be
studies reduced the apparent efficacy of sertraline. efficacious (k = 1; n = 37; s.m.d. = −1.08; 95% CI −1.75
Such experiences encourage close scrutiny of to −0.36).
efficacy claims and beg the question ‘How many
other unpublished trials are there?’. Calls for the
pre-registration of RCTs and an undertaking to Other drugs
place all results in the public domain seem to be Mirtazapine
well founded.
There has been one small RCT (Davidson et al, 2003) of
Fluoxetine mirtazapine which was strongly in favour of the drug
(k = 1; n = 21; s.m.d. = −1.89; 95% CI −3.00 to −0.78). It
Fewer individuals have participated in fluoxetine is important to be cautious when interpreting the true
trials than in trials for the other two SSRIs, and effect of any intervention on the basis of one small
only one trial (Martenyi et al, 2002) used a standard RCT, but these results suggest that mirtazapine is
ised clinician assessment of the severity of PTSD worthy of further investigation.
RR = 0.95; 95% CI 0.79–1.15). The same applies for rule it is important to try to reduce substance use first
sertraline (k = 6; n = 1148; RR = 1.10; 95% CI 0.90–1.33), and then reassess before treating the PTSD, although
mirtazapine (k = 1; n = 29; RR = 1.20; 95% CI 0.29–2.82) some centres have reported success with a combined
and venlafaxine (k = 1; n = 358; RR = 0.83; 95% CI treatment approach. With depression and anxiety
0.62–1.12), although fluoxetine was associated with it often depends which appears to be the primary
a greater drop-out rate than placebo (k = 1; n = 131; disorder. If the PTSD predominates then treatment
RR = 0.51; 95% CI 0.28–0.96). of this first is appropriate and often associated with
Some individual studies have reported adverse a concomitant reduction of depressive and anxiety
effects. One RCT (Davidson et al, 2001a) found that, symptoms (National Collaborating Centre for Mental
compared with placebo, sertraline significantly Health, 2005). For some individuals treatment of
increased insomnia, diarrhoea and nausea, and their depression may help them to benefit more from
decreased appetite. An RCT comparing paroxetine psychological treatment for their PTSD.
with placebo (Tucker et al, 2001) found that nausea,
somnolence, dry mouth, asthenia and abnormal
ejaculation had an incidence of at least 10% and The future
twice that of placebo. In one RCT (Davidson et al,
2003) three people taking mirtazapine withdrew There is clearly an urgent need to identify more
because of adverse effects, including sedation, effective pharmacological approaches for the manage
panic attacks, increased anxiety and irritability. ment of PTSD. Despite the more encouraging picture
Three people taking placebo withdrew because in terms of effectiveness of psychological treatments,
of pain, or lack of efficacy; more people taking not all PTSD sufferers will be able to engage with
mirtazapine had increased appetite and weight these and some would prefer a pharmacological
gain. It is also important to consider the possibility alternative. It is to be hoped that in the future the
of a discontinuation syndrome with the SSRIs, and development of novel agents will be based on an
paroxetine in particular, and to follow the well- improved understanding of the neurobiology of
publicised prescribing details (Duff, 2004). PTSD and translational research, the collaborative
interaction of laboratory and clinical medicine.
Bryant, R. A., Harvey, A. G., Dang, S. T., et al (1998) Treatment of Pitman, R. K. (1989) Post-traumatic stress disorder, hormones,
acute stress disorder: a comparison of cognitive–behavioural and memory. Biological Psychiatry, 26, 221–223.
therapy and supportive counselling. Journal of Consulting and Pitman, R. K., Sanders, K. M., Zusman, R. M., et al (2002) Pilot
Clinical Psychology, 66, 862–866. study of secondary prevention of posttraumatic stress disorder
Burghardt, N. S., Sullivan, G. M., McEwen, B. S., et al (2004) The with propranolol. Biological Psychiatry, 51, 189–192.
selective serotonin reuptake inhibitor citalopram increases Rose, S., Bisson, J., Churchill, R., (2002) Psychological debriefing
fear after acute treatment but reduces fear with chronic treat- for preventing post traumatic stress disorder (PTSD). Cochrane
ment: a comparison with tianeptine. Biological Psychiatry, 55, Database of Systematic Reviews, issue 2. Art. No.: CD000560.
1171–1178. DOI: 10.1002/14651858.CD000560.
Butterfield, M. I., Becker, M. E., Connor, K. M., et al (2001) Olanza- Schelling, G., Briegal, J., Roozendaal, B., et al (2001) The effect
pine in the treatment of post-traumatic stress disorder: a pilot of stress doses of hydrocortisone during septic shock on post
study. International Clinical Psychopharmacology, 16, 197–203. traumatic stress disorder in survivors. Biological Psychiatry,
Cohen, J. (1988) Statistical Power Analysis for the Behavioural 50, 978–985.
Sciences. Lawrence Erlbaum Associates. Shin, L. M., Orr, S. P., Carson, M. A., et al (2004) Regional cerebral
Davidson, J., Kudler, H., Smith, R., et al (1990) Treatment of post blood flow in the amygdala and medial prefrontal cortex during
traumatic stress disorder with amitriptyline and placebo. traumatic imagery in male and female Vietnam veterans with
Archives of General Psychiatry, 47, 259–266. PTSD. Archive of General Psychiatry, 61, 168–176.
Davidson, J. R. T., Rothbaum, B. O., van der Kolk, B. A., et al Stein, M. B., Kline, N. A. & Matloff, J. L. (2002) Adjunctive
(2001a) Multicenter, double-blind comparison of sertraline olanzapine for SSRI-resistant combat-related PTSD: a double-
and placebo in the treatment of posttraumatic stress disorder. blind, placebo-controlled study. American Journal of Psychiatry,
Archive of General Psychiatry, 58, 485–492. 159, 1777–1779.
Davidson, J., Pearlstein, T., Londborg, P., et al (2001b) Efficacy of Stein, D. J., Zungu-Dirwayi, N., Van der Linden, G. J. H., et al
sertraline in preventing relapse of posttraumatic stress dis- (2004) Pharmacotherapy for post traumatic stress disorder
order: results of a 28 week doubleblind, placebo-controlled (PTSD). Cochrane Library, issue 2. WileyInterscience.
study. American Journal of Psychiatry, 158, 1974–1981. Tucker, P., Zaninelli, R., Yehuda, R., et al (2001) Paroxetine in the
Davidson, J. R. T., Weisler, R. H., Butterfield, C. D. C., et al (2003) treatment of chronic posttraumatic stress disorder: results of
Mirtazapine vs placebo in posttraumatic stress disorder: a pilot a placebo-controlled, flexible dosage trial. Journal of Clinical
trial. Society of Biological Psychiatry, 53, 188–191. Psychiatry, 62, 860–868.
Davidson, J., Baldwin, D., Stein, D. J., et al (2006) Treatment Tyrer, P. (2005) From the Editor’s desk. British Journal of Psychiatry,
of posttraumatic stress disorder with venlafaxine extended 186, 552.
release: a 6-month randomized controlled trial. Archives of Young, E. A. & Breslau, N. (2005) Cortisol and catecholamines in
General Psychiatry, 63, 1158–1165. posttraumatic stress disorder: an epidemiologic community
Duff, G. (2004) Safety of Selective Serotonin Reuptake Inhibitor Anti- study. Archives of General Psychiatry, 61, 394–401.
depressants. Committee on Safety of Medicines. http://www. Zohar, J., Amital, D., Miodownik, C., et al (2002) Double-blind
info.doh.gov.uk/doh/embroadcast.nsf/vwDiscussionAll/ placebo-controlled pilot study of sertraline in military
9AA9EC56B07B3B4F80256F61004BAA88 veterans with posttraumatic stress disorder. Journal of Clinical
Ehlers, A., Clark, D. M., Hackmann, A., et al (2003) A randomized Psychopharmacology, 22, 190–195.
controlled trial of cognitive therapy, a self-help booklet, and
repeated assessments as early interventions for posttraumatic
stress disorder. Archives of General Psychiatry, 60, 1024–1032.
Friedman, M. J., Davidson, J. R. T. & Mellman, T. A. (2000) MCQs
Pharmacotherapy. In Effective Treatments for PTSD: Practice
Guidelines from the International Society for Traumatic Stress 1 In the UK, PTSD is an indication for the following
Studies (eds E. B. Foa, T. M. Keane & M. J. Freidman), pp. in men and/or women:
84–105. Guilford Press. a� sertraline
Gilbertson, M. W., Shenton, M. E., Ciszewski, A., et al (2002) b� fluoxetine
Smaller hippocampal volume predicts pathologic vulnerability
to psychological trauma. Nature Neuroscience, 5, 1242–1247.
c� mirtazapine
Hamner, M. B., Faldowski, R. A., Ulmer, H. G., et al (2003) Adjunc- d� imipramine
tive risperidone treatment in post-traumatic stress disorder: a e� amitriptyline.
preliminary controlled trial of effects on comorbid psychotic
symptoms. International Clinical Psychopharmacology, 18, 1–8. 2 The autonomic aspects of the classic fear response
Kessler, R. C., Sonnega, A., Bromet, E., et al (1995) Posttraumatic are believed to be mediated by the:
stress disorder in the National Comorbidity Survey. Archives
of General Psychiatry, 52, 1048–1060. a� frontal cortex
Kosten, T. R., Frank, J. B., Dan, E., et al (1991) Pharmacotherapy for b� cerebellum
posttraumatic stress disorder using phenelzine or imipramine. c� hippocampus
Journal of Nervous and Mental Disease, 179, 366–370. d� amygdala
Marshall, R. D., Beebe, K. L., Oldham, M., et al (2001) Efficacy
e� parietal lobe.
and safety of paroxetine treatment for chronic PTSD: a fixed-
dose, placebo-controlled study. American Journal of Psychiatry,
158, 1982–1988. 3 RCTs have shown the following not to be statistically
Martenyi, F., Brown, E. B., Zhang, H., et al (2002) Fluoxetine significantly superior to placebo for PTSD:
versus placebo in posttraumatic stress disorder. Journal of a� paroxetine
Clinical Psychiatry, 63, 199–205. b� phenelzine
Mellman, T. A., Bustamante, V., David, D., et al (2002) Hypnotic
medication in the aftermath of trauma. Journal of Clinical
c� mirtazapine
Psychiatry, 63, 1183–1184. d� venlafaxine
National Collaborating Centre for Mental Health (2005) Post- e� amitriptyline.
traumatic Stress Disorder: The Management of PTSD in Adults
and Children in Primary and Secondary Care. National Clinical 4 The NICE guidelines for PTSD recommend mirtaza-
Practice Guideline Number 26. Gaskell & British Psychological pine or paroxetine in the following circumstances:
Society.
Ozer, E. J., Best, S. R., Lipsey, T. L., et al (2003) Predictors of post- a� first-line treatment of PTSD
traumatic stress disorder and symptoms in adults: a meta- b� second-line treatment of PTSD
analysis. Psychological Bulletin, 129, 52–73. c� for combined use