The British Journal of Psychiatry (2015)
206, 93–100. doi: 10.1192/bjp.bp.114.148551
Review article
Pharmacotherapy for post-traumatic stress
disorder: systematic review and meta-analysis
Mathew Hoskins, Jennifer Pearce, Andrew Bethell, Liliya Dankova, Corrado Barbui, Wietse A. Tol,
Mark van Ommeren, Joop de Jong, Soraya Seedat, Hanhui Chen and Jonathan I. Bisson
Background
Pharmacological treatment is widely used for post-traumatic
stress disorder (PTSD) despite questions over its efficacy.
Aims
To determine the efficacy of all types of pharmacotherapy,
as monotherapy, in reducing symptoms of PTSD, and to
assess acceptability.
Method
A systematic review and meta-analysis of randomised
controlled trials was undertaken; 51 studies were included.
Results
Selective serotonin reuptake inhibitors were found to be
statistically superior to placebo in reduction of PTSD
symptoms but the effect size was small (standardised mean
Post-traumatic stress disorder (PTSD) is a common mental
disorder with an estimated prevalence of 15.4% in the most
robust epidemiological studies (those using diagnostic interviews
and random samples) of conflict-affected populations,1 and a
12-month prevalence across the world of 3–4%.2 The disorder
may occur in people of any age who have been exposed to one or
more exceptionally threatening or horrifying events. Characteristic
symptoms include re-experiencing, avoidance and hyperarousal.3,4
The disorder is associated with substantial comorbidity, such as
depression, anxiety and substance misuse,5 and significant
economic burden.6 Previous meta-analyses of pharmacological
treatment of PTSD have been inconsistent. The UK’s National
Institute for Health and Care Excellence (NICE) guidelines found
that only paroxetine, mirtazapine, amitriptyline and phenelzine
were significantly superior to placebo.7 Owing to the relatively
small effect sizes and sample sizes, none of these drugs was
included as a first-line treatment for PTSD; all were recommended
as second-line treatment after the initiation of trauma-focused
psychological treatment. The guidelines of the Australian Centre
for Posttraumatic Mental Health (ACPMH), consistent with
NICE, recommended that pharmacological interventions should
not be used in preference to trauma-focused psychological
treatment.8 Other reviews have been more positive about
pharmacological treatment, grouping selective serotonin reuptake
inhibitors (SSRIs) together and rating them as equivalent to
trauma-focused psychological treatments.9,10 A Cochrane review
reported strong benefits,11 but the Institute of Medicine found
inadequate evidence to determine the efficacy of pharmacological
treatment for PTSD.12 There are, however, major differences
between the methodological quality of these reviews, making
direct comparison problematic.13 Given the inconsistent findings of
previous meta-analyses and the increasing number of randomised
controlled trials (RCTs) of pharmacological treatments, the World
Health Organization (WHO) commissioned an update of the
information obtained by the most methodologically robust
systematic reviews published to date: those by NICE, ACPMH
and the Cochrane Collaboration.7,8,11 We reviewed RCTs that
difference 70.23, 95% CI 70.33 to 70.12). For individual
pharmacological agents compared with placebo in two or
more trials, we found small statistically significant evidence
of efficacy for fluoxetine, paroxetine and venlafaxine.
Conclusions
Some drugs have a small positive impact on PTSD symptoms
and are acceptable. Fluoxetine, paroxetine and venlafaxine
may be considered as potential treatments for the disorder.
For most drugs there is inadequate evidence regarding
efficacy for PTSD, pointing to the need for more research in
this area.
Declaration of interest
None.
assessed the efficacy of pharmacological treatment compared with
placebo control groups at reducing traumatic stress symptoms in
individuals experiencing PTSD.
Method
All double-blind, randomised, placebo-controlled and comparative
trials of the pharmacological treatment of PTSD completed from
October 2005 (to ensure all eligible trials not published at the time
of the NICE, Cochrane and ACPMH searches would be included)
were considered in our primary and additional searches, covering
13 separate databases. Trials completed before October 2005 that
were included in the NICE, Cochrane and ACPMH reviews were
also considered. Published and unpublished abstracts and reports
were sought out in any language. Studies were not excluded on the
basis of differences between them such as sample size and
duration. Pharmacotherapy trials in which there was ongoing or
newly initiated trauma-focused psychotherapy or where the
experimental medication served as an augmentation agent to
ongoing pharmacotherapy were excluded. Pharmacotherapy trials
in which there was ongoing supportive counselling were allowed
provided it was not initiated during the course of the treatment,
on the basis that this is common in trials and the limited evidence
for supportive counselling.14 Open label trials were not considered.
Our review followed the Preferred Reporting Items for Systemic
Reviews and Meta-analyses (PRISMA) checklist and reporting
guidance.15
Participants
All studies of participants with PTSD according to ICD or DSM
criteria were eligible.3,4 There was no restriction on the basis of
onset, duration or severity of PTSD symptoms, or on the presence
of comorbid disorders, trauma type, age or gender of participants.
93
Hoskins et al
Interventions
Pharmacological treatments for adults with PTSD, in which the
comparator was a placebo or other medication, were eligible for
inclusion.
studies included in previous systematic reviews were doubleextracted by two independent reviewers, cross-checked for accuracy
and any discrepancies were discussed with a third reviewer.
Risk of bias
Outcome measures
The primary outcomes of interest were clinician-administered
continuous measures of symptom severity such as the Clinician
Administered PTSD Scale. Self-rated PTSD symptom scales were
considered separately. The total number of participants who left
the trial early for any reason was used as a proxy measure of
treatment acceptability.
Search strategy
We conducted a primary bibliographic database search of
Medline, Medline In Process, EMBASE, the Health Management
Information Consortium (HMIC) database, PsycINFO, ASSIA
and CINAHL using the Ovid interface on 22 February 2013. In
order to avoid language bias, we separately searched (using the
same search strategy, and in consultation with regional experts)
the Japanese, Chinese and WHO regional databases (Spanish,
Russian and Portuguese languages). This initial broad search
was intended to identify not only the RCTs of interest but also
reviews of pharmacotherapy for PTSD. The comprehensive search
term used (see online Appendix DS1) was created by amalgamating
the previous search strategies from the NICE, Cochrane and
ACPMH guideline reviews with an updated list of medications.
Additional searches for published and unpublished studies were
made in the National Center for PTSD PILOTS database, the
Cochrane Library, the Controlled Trials Register, Web of
Knowledge, OpenSIGLE and Google Scholar. Reference lists of
all selected studies and reviews were further scrutinised for any
additional RCTs. An expert group was consulted to identify any
additional studies they were aware of. Authors of identified studies
were contacted to request data if outcome information was
missing.
Two reviewers, using the domain-based evaluation method
recommended by the Cochrane Collaboration,16 independently
assessed risk of bias in individual studies for each trial. This
method considers the following domains: random sequence
generation; allocation concealment; masking of participants and
personnel; masking of outcome assessment; incomplete outcome
data; selective reporting; and other sources of bias. Any
discrepancies between reviewers’ decisions were resolved by
discussion with a third reviewer. Risk of bias across studies was
assessed by considering publication bias through the visual
examination of funnel plots.
Statistical analysis
Review Manager 5 software was used to synthesise data using
meta-analysis and to provide forest plots for dichotomous and
continuous data. Confidence intervals of 95% were used for all
analyses. Categorical outcome measures such as leaving the study
early were analysed using relative risk (RR) calculations. For
continuous data, standardised mean differences (SMD) were used.
The degree of heterogeneity between studies was calculated using
the I2 statistic. Where this was less than 30%, indicating a mild
degree of heterogeneity, a fixed effects model was used; a random
effects model was used when I2 was greater than 30%. Data were
analysed from the intention to treat (ITT) sample in the ‘once
randomised always analysed’ fashion where possible, to avoid
effects of bias from completers-only analyses. Analyses were
performed for individual drugs and, in order to maximise the
information available from data synthesis, whenever possible for
classes of drugs (e.g. tricyclic antidepressants, SSRIs) and trauma
type (e.g. combat trauma, sexual trauma, interpersonal violence
trauma, all non-combat trauma).
Study selection
One reviewer transferred the initial search hits and studies
included in the earlier systematic reviews into EndNoteX4
software for Windows. Duplicates were removed. Two reviewers
then independently screened the titles and abstracts. Studies that
were clearly irrelevant were excluded; potentially relevant ones
were assessed for inclusion as full texts. Any discrepancies between
reviewers’ decisions were resolved by discussion with a third
reviewer.
Data extraction and risk of bias assessment
All data from newly identified studies were double-extracted by
two independent reviewers into a standardised table and any
discrepancies were discussed with a third reviewer. Data for
change from baseline to end-point were extracted when available,
otherwise end-point data were used. Continuous data were
extracted for clinician-administered PTSD symptom severity
using the Clinician Administered PTSD Scale as the gold standard;
for self-rated PTSD, the Davidson Trauma Scale was used as the
gold standard. If these scales were not used, data from alternative
scales were extracted. Dichotomous data were extracted for
number of people withdrawing from the trial using total number
of participants in the group as the denominator. One reviewer
entered the outcome data into Review Manager 5 software for
Windows, which was then checked by another reviewer. Data from
94
Results
The database search yielded 13 634 records and an additional 74
were identified from other sources. From these, 4613 duplicates
were removed leaving 9095 records. These were screened and
8064 irrelevant studies were removed. This left 1031 abstracts from
which 896 were removed as ineligible. This left 135 full-text
articles which were reviewed to find 84 not meeting the inclusion
criteria. A total of 51 studies were included in this systematic
review (Fig. 1). Sixteen new studies were found from our database
search.17–32 The remaining 35 were found in previous reviews. An
additional 28 studies were identified from the NICE guidelines, of
which five did not meet our inclusion criteria.33–37 This left 23
studies included from the NICE guidelines (references 38–54 plus
six unpublished studies A–F in Appendix 1). Thirty-five studies
were identified in the Cochrane review, of which 19 were already
included in the NICE review and removed as duplicates. A further
four used completer-only data and were not included;55–58
another allowed concomitant psychotropic medications and was
excluded.59 This left an additional 11 studies from the Cochrane
review,60–70 which were included. There were 12 additional
pharmacotherapy studies identified from the ACPMH guidelines,
of which seven were already present in the above reviews and were
removed as duplicates. A further four did not meet our inclusion
criteria,71–74 leaving one additional study which was included.75
Pharmacotherapy for PTSD
Additional records identified
through other sources
(n = 740
Records identified through
database searching
(n = 13 634)
6
Efficacy of pharmacotherapy
6
Records after removing
duplicates
(n = 9095)
6
Full abstracts screened
(n = 1031)
7
Records excluded
(n = 896)
7
Full-text articles
excluded with reasons
(n = 84)
6
Full-text articles assessed
for eligibility
(n = 135)
6
Studies included in
qualitative synthesis
(n = 51)
6
Studies included in
quantitative synthesis
(meta-analysis)
(n = 41 for efficacy)
(n = 35 for acceptability)
Fig. 1
sufficient information to judge the masking of participants,
personnel and outcome assessors as being of low risk. Incomplete
outcome data were addressed adequately in 15 studies. Thirtyeight of the studies were deemed to be free from selective reporting.
Study search profile.
Description of studies
The characteristics of the 51 RCTs included in this review are
summarised in online Table DS1. Only three of the studies did
not employ a placebo comparator arm.28,65,67 There were 31 SSRI
trials, 14 of which assessed sertraline,21,26,38,42,43,45,54,61,65,67,68,A,C,D
nine assessed fluoxetine,23,40,47,51,52,69,70,75,B seven assessed paroxetine,22,32,50,53,64,E,F one citalopram,68 one escitalopram,27 and one
fluvoxamine.28 There were three tricyclic antidepressant trials,42,49,66
and three monoamine oxidase inhibitor (MAOI) trials.48,49,60
Another six trials assessed other antidepressants,18,44,46,65,67,A
and a further ten trials assessed other agents.17,18,20,24,25,29,30,39,62,63
The average sample size was 130 (range 13–538), the average age of
participants was 41 years (range 18–82) and 54% of participants
were women. The average duration of the trials was 12.4 weeks
(range 4–36). Thirty-four studies were based in the USA, five were
international, four were from Israel and there was one each from
Brazil, China, Iran, South Africa and Turkey. The location was
unclear in three studies. The predominant trauma (450%) was
combat in 13 studies, physical/sexual assault in eight, physical
assault alone in four, sexual assault alone in four, natural
disaster in two and road traffic accidents in two. For 18 studies
participants had been exposed to various traumas with no one
type accounting for over 50%.
Risk of bias assessments
Risk of bias assessments are included in online Table DS1.
Fourteen of the studies included enough information on adequate
random sequence generation to be judged as having a low risk of
bias; the remainder were unclear. Only eight studies included an
adequate description of allocation concealment. All 51 studies
described themselves as ‘double blind’ but only eight provided
Data from 21 studies (n = 3932) were available for inclusion in a
meta-analysis of reduction in severity of PTSD symptoms for
any SSRI v. placebo (Fig. 2). This found a small positive effect
for SSRIs when grouped together. The results of meta-analyses for
individual drugs, which had been tested against placebo in at least
two RCTs, are shown in Table 1. Three drugs were significantly
superior to placebo on either clinician- and self-rated PTSD
symptom severity combined (paroxetine) or clinician-rated PTSD
symptom severity alone (fluoxetine and venlafaxine). We found
insufficient evidence to support the preferential use of individual
agents in either combat-related or non-combat-related trauma
(Table 2).
Discussion
This systematic review found statistically significant evidence on
meta-analysis for three pharmacological agents v. placebo in the
treatment of PTSD (fluoxetine, paroxetine and venlafaxine) but
no evidence for brofaromine, olanzapine, sertraline or topiramate.
Four drugs – amitriptyline, GR205171 (a neurokinin-1 antagonist),
mirtazapine and phenelzine – showed superiority over placebo in
single RCTs, whereas eleven did not: alprazolam, citalopram,
desipramine, escitalopram, imipramine, lamotrigine, nefazadone,
risperidone, tiagabine and valproate semisodium. When metaanalyses were undertaken by class of drug rather than individual
drug, SSRIs were found to perform better than placebo. The
absence of sufficient data precluded meta-analyses of other drug
classes. The absence of difference in numbers of individuals
leaving the study early for any reason suggests that the drugs
included were well tolerated overall.
The effect sizes for pharmacological treatments for PTSD
compared with placebo are low and inferior to those reported
for psychological treatments with a trauma focus over waiting-list
or treatment as usual controls.14 They are, however, similar to
those found for antidepressants for depression compared with
placebo.76 Unfortunately, the absence of a common control
condition and head-to-head pharmacological v. psychological
treatment trials makes comparison of the relative efficacies of
these treatment approaches difficult. This is compounded by the
fact that a significant number of participants in psychological
treatment trials were continuing pre-existing pharmacological
treatment at the same time.
It is well accepted that a well-masked, placebo-controlled trial
is a tougher test for an experimental intervention than a trial with
a waiting-list control. The UK’s NICE guidelines development
group attempted to address this by determining a higher effect size
threshold for psychological treatments than pharmacological ones
(0.8 v. 0.5),7 but it is unclear whether such arbitrary cut-offs may
have introduced bias against either form of treatment. What is
clear is the marked effect of the placebo in several of the trials
reported in this review. For example, in the two venlafaxine
studies the mean reduction in PTSD symptoms of those on
placebo was greater than 40%.18,47 There is a need for RCTs of
specific psychological interventions compared with an adequate
non-specific psychological intervention. It is only through such
trials and direct head-to-head comparisons that the relative
effectiveness of differing treatment approaches could be
established. The current meta-analyses are a later iteration of the
95
Hoskins et al
Table 1
Efficacy and tolerability of individual agents v. placebo
Active drug
SSRIs
Paroxetine
Sertraline
Fluoxetine
MAOIs
Brofaromine
Other antidepressants
Venlafaxine
Antipsychotics
Olanzapine
Other drugs
Topiramate
PTSD symptoms (clinician-rated)
PTSD symptoms (self-reported)
Leaving study early
Four studies,50,53,64,E n = 1134
SMD = 70.43 (95% CI 70.53 to 70.29)*
I 2 = 17%a
Nine studies,21,38,42,54,61,68,A,C,D n = 1441
SMD = -0.13 (95% CI 70.27 to 0.01)
I 2 = 37%
Three studies,23,52,70 n = 771
SMD = 70.24 (95% CI 70.41 to 70.08)*
I 2 = 0%
Three studies,50,53,E n = 1251
SMD = 70.38 (95% CI 70.49 to 70.26)*
I 2 = 0%
Six studies,21,38,42,A,C,D n = 1257
SMD = 70.15 (95% CI 70.35 to 0.05)
I 2 = 68%
Three studies,40,47,52 n = 363
SMD = 70.41 (95% CI 70.98 to 0.15)
I 2 = 64%
Five studies,22,50,53,64,E n = 1307 RR = 0.98
(95% CI 0.71 to 1.34)
I 2 = 52%
Eight studies,21,38,42,54,68,A,C,D n = 1387
RR = 1.14 (95% CI 0.95 to 1.37)
I 2 = 15%
Six studies,23,40,47,52,69,70 n = 989
SMD = 1.02 (95% CI 0.72 to 1.45)
I 2 = 26%
Two studies,48,60 n = 159
SMD = 70.24 (95% CI 70.81 to 0.33)
I 2 = 63%
NA
Two studies,48,60 n = 180
RR = 1.56 (95% CI 0.87 to 2.79)
I 2 = 0%
Two studies,18,A n = 687
SMD = 70.20 (95% CI 70.35 to 70.05)*
I 2 = 0%
Two studies,18,A n = 687
SMD = 70.19 (95% CI 70.4 to 0.01)
I 2 = 0%
One study,18 n = 329
RR = 0.91 (95% CI 0.67 to 1.25)
Two studies,31,39 n = 39
SMD = 70.61 (95% CI 71.27 to 0.05)
I 2 = 53%
Two studies,31,39 n = 39
SMD = 70.50 (95% CI 71.16 to 0.15)
Two studies,31,39 n = 49
RR = 1.15 (95% CI 0.36 to 3.71)
I 2 = 0%
Two studies,29,30 n = 69
SMD = 70.46 (95% CI 70.94 to 0.02)
I 2 = 0%
One study,29 n = 38
SMD = 70.6 (95% CI 71.26 to 0.05)
Two studies,29,30 n = 73
RR = 0.92 (95% CI 0.3 to 2.84)
I 2 = 38%
MAOI, monoamine oxidase inhibitor; NA, not applicable; PTSD, post-traumatic stress disorder; RR, relative risk; SMD, standardised mean difference; SSRI, selective serotonin
reuptake inhibitor.
a. The I 2 statistic is noted only when 41 study as not applicable otherwise.
*P50.05.
evidence used to determine what to recommend for recent WHO
guidelines.77 A WHO guidelines development group examined
this evidence and recommended antidepressants as a second
line of treatment of PTSD when psychological interventions
with known efficacy did not work or were not available. The
Study or subgroup
Brady (2000)38
Brady (2005)61
Connor (1999)40
DavidsonA
Davidson (2001)42
Eli LillyB
Friedman (2007)21
Hertzberg (2000)47
Marshall (2001)50
Marshall (2004)64
Martenyi (2002)51
Martenyi (2007)23
Panahi (2011)26
Pfizer 588C
Pfizer 589D
Shaleve (2011)27
SKB627E
Tucker (2001)53
Tucker (2003)68
Van der Kolk (2007)70
Zohar (2002)54
Total (95% CI)
Experimental
Mean
s.d. Total
733
28.1
94
32.56 15.69
49
10.1
9.8
25
739.4 27.12 173
733
23.76 100
710.42 7.5
323
713.1 27.5
86
47
8
6
738.75 27.2
375
55.6 33.4
25
734.6 28.1
226
742.85 25.5
323
722.7
7.3
35
727.4 27.12
94
713.1 27.12
84
731.12 29.63
23
736.5 26.1
109
735.5 24.58 151
741.82 29.09
23
733.23 22.11
30
718.7
6.7
23
Mean
723.2
32.7
20.5
734.17
726.2
710.59
715.4
42
725.3
62.8
26.8
736.6
717.5
727.9
715.4
727.8
730.8
724.7
738.7
730.95
713.5
Control
s.d.
28.7
28.75
12.6
28.42
23.9
10.21
28.07
11
25.8
40.8
26.1
25.7
7.5
28.42
28.42
20.13
25.37
24.98
29.07
22.6
6.6
2377
Heterogeneity: t2 = 0.03; w2 = 42.90, d.f. = 20 (P = 0.002); I 2 = 53%
Test for overall effect: Z = 4.23 (P50.0001)
Fig. 2
96
Total
93
45
22
179
108
88
83
6
188
27
75
88
35
94
82
23
103
156
10
29
19
1553
recently updated Australian guidelines also concluded that
pharmacological interventions should not be preferentially used
as a routine first treatment of PTSD over trauma-focused
psychological treatments.78 There are various other reasons for
considering the prescription of antidepressants, including
Weight
5.8%
4.1%
2.4%
7.3%
6.1%
6.8%
5.6%
0.8%
8.0%
2.8%
6.3%
6.8%
3.3%
5.9%
5.6%
2.5%
6.2%
7.0%
1.7%
3.0%
2.2%
SMD IV, random, 95% CI
70.34 (70.63, 70.05)
70.01 (70.41, 0.40)
70.91 (71.52, 70.31) 8
70.19 (70.40, 0.02)
70.28 (70.56, 70.01)
0.02 (70.21, 0.26)
0.08 (70.22, 0.38)
0.48 (70.68, 1.64)
70.50 (70.68, 70.32)
70.19 (70.73, 0.36)
70.28 (70.54, 70.02)
70.24 (70.48, 70.01)
70.69 (71.18, 70.21)
0.02 (70.27, 0.30)
0.08 (70.22, 0.39)
70.13 (70.71, 0.45)
70.22 (70.49, 0.05)
70.43 (70.66, 70.21)
70.10 (70.85, 0.64)
70.10 (70.61, 0.41)
8
70.77 (71.40, 70.14)
100.0%
70.23 (70.33, 70.12)
SMD IV, random, 95% CI
7
71
70.5
Favours experimental
Meta-analysis of selective serotonin reuptake inhibitors v. placebo (SMD, standardised mean difference).
0
0.5
1
Favours control
Pharmacotherapy for PTSD
Table 2
Trauma type subanalysis of individual agents v. placebo
Natural
disaster/
accident
All non-combat trauma
combined
Active drug
Combat
Sexual
Interpersonal violence
SSRIs
Paroxetine
NA
NA
NA
Four studies,21,26,54,D n = 447
SMD = 70.26
(95% CI 70.68 to 0.16)
I 2 = 77%a
Two studies,47,52 n = 313
SMD = 70.12
(95% CI 70.73 to 0.50)
I 2 = 37%
One study,38 n = 183
SMD = 70.30
(95% CI 70.59 to 70.01)*
One study,64 n = 52
SMD = 70.19
(95% CI 70.73 to 0.36)
Two studies,61,A n = 446
SMD = 70.15
(95% CI 70.34 to 0.04)
I 2 = 68%
One study,70 n = 59
SMD = 70.10
(95% CI 70.61 to 0.41)
One study,60 n = 114
SMD = 0.01
(95% CI 70.36 to 0.38)
NA
One study,48 n = 55
SMD = 70.58
(95% CI 71.58 to 0.02)
NA
NA
NA
Two studies,18,A n = 687
SMD = 70.20
(95% CI 70.35 to 70.05)*
I 2 = 0%
NA
NA
Sertraline
Fluoxetine
MAOIs
Brofaromine
Other antidepressants
Venlafaxine
NA
Two studies,23,40 n = 458
SMD = 70.52
(95% CI 71.16 to 0.13)
I 2 = 76%
NA
NA
One study,64 n = 52
SMD = 70.19
(95% CI 70.73 to 0.36)
Five studies,42,61,A,C,D n = 1008
SMD = 70.11
(95% CI 70.23 to 0.02)
I 2 = 14%
Three studies,29,40,47 n = 517
SMD = 70.36
(95% CI 70.75 to 0.02)
I 2 = 58%
Antipsychotics
Olanzapine
NA
One study,39 n = 11
SMD = 0.16
(95% CI 71.07 to 1.39)
One study,31 n = 28
SMD = 70.93
(95% CI 71.71 to 70.14)*
NA
Two studies,31,39 n = 39
SMD = 70.61
(95% CI 71.27 to 0.05)
I 2 = 53%
Other drugs
Topiramate
NA
One study,29 n = 38
SMD = 70.39
(95% CI 71.03 to 0.25)
One study,30 n = 32
SMD = 72.38
(95% CI 73.33 to 1.43)*
NA
Two studies,29,30 n = 69
SMD = 70.46
(95% CI 70.94 to 0.02)
I 2 = 0%
MAOI, monoamine oxidase inhibitor; NA, not applicable; SMD, standardised mean difference; SSRI, selective serotonin reuptake inhibitor.
a. The I 2 statistic is noted only when >1 study as not applicable otherwise.
*P<0.05.
concurrent depression, lack of availability of psychological
treatments, failure to respond to or tolerate psychological
treatments and the personal preference of the individual with
PTSD.
The variation in efficacy between different agents is striking
and could be explained by a number of factors. First, there may
be real differences between drugs, even those in the same family.
For example, paroxetine’s superior efficacy over sertraline may
possibly be explained by its increased dopamine receptor activity.
Differences in the pharmacology of phenelzine and brofaromine
are also marked, and grouping all drugs in one class together
seems less desirable than considering each one individually. This
confirms previous observation that class membership does not
confer the same level of efficacy in the treatment of PTSD.11 This
meta-analysis supports this assertion, with the SSRIs paroxetine
and fluoxetine having better evidence of efficacy than sertraline.
It is interesting to note, however, that despite failing to show
superiority over placebo, sertraline showed equivalence to
venlafaxine in one of the studies included.A This may be a result
of the strength of placebo effect varying across studies.
The differences found between paroxetine and sertraline could
be due to chance or lack of power, but it is noteworthy that over
1000 individuals were included in the meta-analyses of both
paroxetine and sertraline, which suggests that power was not the
issue. The same cannot be said for the majority of drugs reviewed,
the evaluation of which was based on single RCTs with fewer than
100 participants. This review added 15 new RCTs to the evidence
previously reported in systematic reviews but added no new trials
for three of the four drugs recommended in the NICE guidelines
(mirtazapine, amitriptyline and phenelzine). Of particular note is
that new evidence resulted in drugs not recommended by NICE
(fluoxetine and venlafaxine) now meeting the requirements laid
down by NICE for recommendation as a second-line treatment.
This review used particular rigour in assessing studies. Most of
the other reviews that have concluded more favourably about
pharmacotherapy grouped drugs from the same class together,10,11
did not include unpublished studies,79,80 and adopted different
inclusion criteria.8,10,79,80 This probably accounts for differences
in conclusions between different meta-analyses despite apparently
having the same raw data available. For example, sertraline
performed significantly better than placebo in two recent metaanalyses,79,80 which did not include the two unpublished studies
included in our review.C,D
Study limitations
There were, however, some important methodological flaws in the
studies identified in this review as illustrated by the risk of bias
assessment undertaken. Clinical and statistical heterogeneity was
apparent in the meta-analyses; this makes interpretation and
generalisation across different trauma populations difficult. A
major issue was that, despite having systematically tried to access
unpublished data on the studies without ITT efficacy data,
sufficient data for analysis were only available from only 41 of
the 51 studies included. This raises the risk of outcome reporting
bias.81 Incorrect definition of the ITT sample population was a
97
Hoskins et al
problem. This is an important principle where data from every
person who is randomised should be included in the analysis of
efficacy. Participants might leave a study because of adverse
effects, failed efficacy or greater symptom severity at baseline;
not including their data in the analysis leads to bias, as a treatment
might appear to be more effective than it is. Another important
issue to consider is that this review considers drug monotherapy
as opposed to drug or placebo in combination with psychological
treatment. This evidence cannot, therefore, be used to consider
whether or not pharmacotherapy augments psychological
treatment for PTSD; many people with the disorder do receive both.
Several of the new studies identified by our search defined
their ITT population as participants who received at least one dose
of the study medication and received at least one post-baseline
assessment. This could exclude some participants from analysis
who had received treatment but not been assessed after the
baseline. The most extreme case was a study of fluoxetine that
defined ITT in this way,23 but measured PTSD symptom severity
only at baseline and end-point, so was actually a completers
sample. We decided to include these studies in our analysis but
acknowledge that this affects the reliability of the results.
Implications
Pharmacological interventions for PTSD can be effective but the
magnitude of effect unfortunately is small, and the clinical
relevance of this small effect is unclear. This review supports the
use of paroxetine, venlafaxine and fluoxetine as pharmacological
interventions for PTSD. For most drugs, there remains inadequate
evidence regarding efficacy for PTSD, pointing to the need
for more research in this area to confirm the utility of
pharmacological treatments for this disorder.
Mathew Hoskins, MRCPsych, Jennifer Pearce, BSc, Andrew Bethell, BSc, Liliya
Dankova, BSc, Cardiff University, Cardiff, UK; Corrado Barbui, MD, Department of
Public Health and Community Medicine, Section of Psychiatry, University of Verona,
Verona, Italy; Wietse A. Tol, PhD, Johns Hopkins Bloomberg School of Public Health,
Baltimore, USA; Mark van Ommeren, PhD, World Health Organization, Geneva,
Switzerland; Joop de Jong, MD, PhD, Vrije Universiteit, Amsterdam, The Netherlands;
Soraya Seedat, MD, Stellenbosch University, Stellenbosch, South Africa; Hanhui
Chen, MD, Shanghai Mental Health Centre, Shanghai Jiaotong University, Shanghai,
China; Jonathan I. Bisson, DM, Cardiff University, Cardiff, UK
Correspondence: Professor Jonathan I. Bisson, Cardiff University, Institute of
Psychological Medicine and Clinical Neurosciences, Hadyn Ellis Building, Maindy
Road, Cathays, Cardiff CF24 4HQ, UK. Email [email protected]
First received 13 Oct 2013, final revision 8 Jun 2014, accepted 16 Jun 2014
Funding
The World Health Organization supported this work to inform the development of Mental
Health Gap Action Programme (mhGAP) guidelines on disorders and problems specifically
related to stress. The views expressed in this article are those of the authors solely and do
not necessarily represent the views, policies or decisions of their employers.
Acknowledgements
We acknowledge Jorge Castro and Keiko Sakurai (World Health Organization interns) for
assistance in multi-language searches.
C. Pfizer588. Unpublished data. Appendix 14 of 2nd consultation draft for
the NICE (2005) PTSD guidelines.
D. Pfizer589. Unpublished data. Appendix 14 of 2nd consultation draft for
the NICE (2005) PTSD guidelines.
E. SKB627 Bryson H, Lawrinson S, Edwards GJ, Grotzinger KM. A 12 week,
double-blind, placebo-controlled, parallel group study to assess the
efficacy and tolerability of paroxetine in patients suffering from posttraumatic stress disorder.
F. SKB650 Bryson H, Dillingham KE, Jeffery PJ. A study of the maintained
efficacy and safety of paroxetine versus placebo in the long-term
treatment of posttraumatic stress disorder.
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The British Journal of Psychiatry (2015)
206, 93–100. doi: 10.1192/bjp.bp.114.148551
Data supplement
Table DS1
Study characteristics
Risk of bias assessment
Duration
of
treatment
Diagnostic criteria,
minimum severity
and duration of illness
Number of
participants n
(% female)
Total leaving
the study n
Predominant
trauma type (%)
Mean duration
of trauma
symptoms
Age, year
Mean (range)
Outcome measures
Adequate
sequence
generation
Allocation
concealment
Blinding of participants,
personnel and
outcome assessors
Incomplete
outcome data
addressed
Free from
selective
reporting
Free from
other bias
CAPSIES
Unclear
Unclear
Unclear
High
High
Unclear
High
Study, location
Design, intervention, dose range and mean
Baker (1995)60
USA
Multicentre, randomised, double-blind, parallel,
placebo-controlled, flexible dose brofaromine up to 150 mg
12 weeks
DSM-III-RCAPS >45MADRS 146 (19)
522
46 months
35
Combat (60)
12.8 years
44 (23–73)
Brady (2000)38
USA
Multicentre, randomised, double-blind, parallel, placebocontrolled, flexible dose sertraline 50–200 mg (133.3 mg)
12 weeks
DSM-III-RCAPS >50>6
months
187 (73)
50
Sexual assault (61)
12 years
40 (18+)
CAPSDTSIESCGI-SCGI-IHRSD
Unclear
Unclear
Unclear
Unclear
Low
Brady (2005)61
USA
Randomised, double-blind, parallel, placebo-controlled, fixed dose
sertraline 50–150 mg
12 weeks
DSM-IVConcurrent
alcoholism
94 (46)
36.7 (18–65)
CAPSHRSD
Alcohol use severity
Low
Unclear
Unclear
High
Low
Unclear
Braun (1990)62
Israel
Randomised, double-blind, cross-over, placebo-controlled, 2 week 5 weeks
titrated placebo washout flexible dose alprazolam
1.5–6 mg (4.65 mg)
DSM-III
13 (0)
6
Combat (40)
37.7
DSM-based PTSD
scaleIESHRSDHRSAVAS
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
High
Physical assault (50)
4.3 years
Butterfield (2001)39
USA
Randomised, double-blind, parallel, placebo-controlled, flexible
dose olanzapine 5–20 mg (14.1 mg)
10 weeks
DSM-IV
15 (93)
4
Rape (53)
43.2 (18–70)
DTSIESSPRINTTOP-8
Unclear
Unclear
Unclear
Low
Low
Carey (2012)31
South Africa
Single centre, randomised, double-blind, parallel, placebocontrolled, flexible dose olanzapine 5–15 mg (9.2 mg)
8 weeks
DSM-IVCAPS >50>3
months
34
(60% female of n = 28)
10
Domestic violence
and criminal violence
40.5
(range 18+ of n = 28)
CAPSDTSMADRSCGISDS
Unclear
Low
Unclear
Unclear
Low
High
Connor (1999)40
USA
Randomised, double-blind, parallel, placebo-controlled, flexible
dose fluoxetine 10–60 mg (30 mg)
12 weeks
DSM-III-R
54 (91)
17
Rape (26)
32 (18–55)
DGRSSIPDTSSDSVS
Low
Low
Unclear
Unclear
Low
Unclear
Connor (2005)17
USA
Responders to open label treatment randomised to double-blind,
placebo-controlled discontinuation phase, flexible dose tiagabine
4–16 mg (10.8 mg)
12 weeks
discontinuation
phase
DSM-IVCGI-S >4
18 (0)
5
18–65
SPRINTSIPCGISDTSHRSDCD-RISCPSQISDI
Unclear
Unclear
Unclear
Unclear
Low
High
32 (18+)
CAPSCGI-SDTSGAF
Unclear
Unclear
Unclear
High
Low
High
CGI-ISI-PTSDCGISHRSDHRSAIESNIEPI
Unclear
Unclear
Unclear
Low
Low
Unclear
A
6 years
Multicentre, randomised, double-blind, placebo-controlled,
parallel flexible dose venlafaxine 37.5-300mg (164.4mg) v.
sertraline 25–200 mg (110.2 mg)
12 weeks
DSM-IVCAPS >60DTS
>40>6 months
538 (65)
218
Non-sexual abuse (26)
Davidson (1990)41
USA
Randomised, double-blind, parallel, placebo-controlled, flexible
dose amitriptyline 50–300 mg (169 mg)
8 weeks
DSM-III
46 (0)
13
Combat (100)
Davidson (2001)42
USA
Multicentre, randomised, double-blind, parallel, placebocontrolled, flexible dose sertraline 20–200 mg (137 mg), relapse
prevention following open label study
28 weeks
DSM-III-RCAPS-2 450
46 months
96 (30)
48
Physical or sexual
assault (52)
13.05 years
43 (21–69)
CGI-SCGI-IIESCAPS
Unclear
Unclear
Unclear
Unclear
Low
High
Davidson (2001)43
USA
Multicentre, randomised, double-blind, parallel, placebocontrolled, flexible dose sertraline 50–200 mg (146.3 mg)
12 weeks
DSM-III-RCAPS-2
45046 months
208 (22)
77
Physical/sexual
assault (62)
12.2 years
37.1 (18–69)
CGI-ICGI-SIESCAPS
Low
Unclear
Unclear
Unclear
Low
High
Davidson (2003)44
USA
Randomised, double-blind, parallel, placebo-controlled, fixed
dose mirtazapine 15–45 mg (38.8 mg)
8 weeks
DSM-IVSIP
29 (0)
6
Mixed
46.5
SPRINTCGI-I
Unclear
Unclear
Unclear
Unclear
Low
High
Davidson (2004)45
USA
Remission data pooled from two double-blind placebo-controlled
12-week flexible dose sertraline comparison trials
12 weeks
DSM-III-RCAPS 450
46 months
384 (75)
127
Physical/sexual assault
38 (18–69)
CGI-SCGI-IDTSIESCAPS-2
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Davidson (2005)82
USA
Six months open label treatment followed by 6 months
randomised, double-blind, placebo-controlled, flexible dose
fluoxetine 10–60 mg (48.6 mg)
6 months
(discontinuation
phase)
MINI criteria
62 (50)
32
Combat (32)
44.1 (18–70)
SPRINTCGI-SDTS
Unclear
Unclear
Unclear
Unclear
High
Unclear
Davidson
USA
18
12.1 years
Multicentre, randomised, double blind, parallel, placebocontrolled, flexible dose venlafaxine 37.5–300 mg (181.7 mg)
24 weeks
DSM-IVCAPS 460
46 months
329 (54)
105
Assault (57)
41.35 (18+)
CAPS-SX17CGI-SGAFHRSD17CD-RISC SVSQ-LES-Q-SFSDS
Low
Unclear
Low
Low
Low
High
Davidson (2007)19
USA
Multicentre, randomised, double blind, parallel, placebocontrolled, flexible dose tiagabine 4–16 mg (11.2 mg)
12 weeks
DSM-IVCAPS
450DTS 450
232 (56)
91
Physical/sexual
assault (53)
13.1 years
42.6 (16–64)
CAPSDTSTOP-8CGI-CCDRSSDSMGSQMADRS
Unclear
Unclear
Unclear
High
High
Unclear
Davis (2001)46
USA
Randomised, double-blind, parallel, placebo-controlled, flexible
dose nefazodone 200–600 mg (435 mg)
12 weeks
DSM-IV
42 (2)
19
Combat (98)
29.9 years
53.8 (32–75)
CAPSHRSAHRSDPTSD
checklistCADSSGAFSCGI
Unclear
Low
Low
Low
Low
High
Davis (2008)20
USA
Randomised, double-blind, parallel, placebo-controlled, flexible
dose divalproex 500–3000 mg (2309 mg)
8 weeks
DSM-IVCAPS 445
85 (2)
17
Combat (95)
24.4 years
55.2 (19–70)
CAPSTOP-8MADRSCGISCGI-IHRSA
Low
Low
Low
Unclear
Low
Low
Eli LillyB
Randomised, double-blind, placebo-controlled, parallel arm,
fixed dose fluoxetine 20 mg v. 40 mg
12 weeks
411 (0)
259
CGI-STOP-8
Unclear
Unclear
Unclear
High
High
High
Friedman (2007)21
USA
Multicentre, randomised, double-blind, parallel, placebocontrolled, flexible dose sertraline 50–200 mg (135 mg)
12 weeks
DSM-III-RCAPS 4546
months
40
Combat (71)
45.5 (18+)
CAPSIESCGI-ICGISDTSHRSAHRSDPSQIDESMISS
Low
Unclear
Low
Unclear
Low
Unclear
Huaihai22
China
Preventative, randomised, double-blind, placebo-controlled,
flexible dose paroxetine 10–20 mg
1 month
DSM-IVHealthy population 53 (41)
0
Natural disaster (100)
36.4 (18+)
PCLPTSD self-rating scale
Unclear
Unclear
Unclear
Low
High
Unclear
Hertzberg (1999)63
USA
Randomised, double-blind, parallel, placebo-controlled, flexible
dose lamotrigine 25–500 mg (380 mg)
12 weeks
DSM-IVSIP
15 (36)
6
Combat (71)
43.4 (29–53)
SIPDGRP
Unclear
Unclear
Unclear
Low
High
High
Hertzberg (2000)47
USA
Randomised, double-blind, parallel, placebo-controlled, flexible
dose fluoxetine 10–60 mg (48 mg)
12 weeks
DSM-III-R
12 (0)
1
Combat (100)
46 (44–48)
DGRPDTSSDSSIP
Unclear
Unclear
Unclear
Unclear
High
Unclear
Katz (1994)48
USA
Multicentre, randomised, double-blind, parallel, placebocontrolled, flexible dose brofaromine 50–150 mg
14 weeks
DSM-III-RCAPS 436
68 (24)
23
Physical assault (38)
39 (22–62)
CAPSCGI
Unclear
Unclear
Unclear
High
High
High
Kosten (1991)49
USA
Multicentre, randomised, double-blind, parallel, placebocontrolled, flexible dose imipramine 50–300 mg (225 mg) v.
phenelzine 15–75 mg (68 mg)
8 weeks
DSM-III
60 (0)
28
Combat (100)
39
IESHRSAHRSDRSDCAS
Unclear
Unclear
Unclear
Low
Low
Unclear
41.8 (18+)
CAPS-2CGI-IDTSTOP8SDSMADRS
Unclear
Unclear
Unclear
High
Low
High
39.8 (18–65)
CAPSCGIIPPDESHRSAHRSD
Unclear
Unclear
Unclear
High
Low
High
High
Davidson (2006)
International
Marshall (2001)
USA
50
169 (21)
Multicentre, randomised, double-blind, parallel, placebocontrolled, fixed dose paroxetine 25 mg v. 50 mg
12 weeks
DSM-IV
563 (57)
208
Physical/sexual
assault (48–54)
Marshall (2004)64
USA
Randomised, double-blind, parallel, placebo-controlled, flexible
dose paroxetine 10–60 mg. Maintenance phase not included
10 weeks
DSM-IV43 months
63 (0)
33
Physical assault
or abuse (48)
Martenyi (2002)52
International
Acute phase, multicentre, randomised, double-blind, parallel,
placebo-controlled, flexible dose fluoxetine 20–80 mg (57.8 mg)
12 weeks
DSM-IVCAPS-DX
450CGI-S 44
301 (19)
139
Combat (47)
Martenyi (2002)51
International
Continuation phase, multicentre, randomised, double-blind,
parallel, placebo-controlled, flexible dose fluoxetine 20–80 mg
(57.8 mg)
24 weeks
DSM-IVCAPS-DX
450CGI-S 44
131 (19)
33
Non-combat (53)
Martenyi (2007)23
USA
Multicentre, randomised, double-blind, parallel, placebocontrolled, fixed dose fluoxetine (20 mg, 40 mg)
12 weeks
DSM-IVCAPS >50, CGI-I >4 411 (71)
64
Sexual assault (78)
Matthew (2011)24
USA
Multicentre, randomised, double blind, parallel, placebocontrolled, fixed dose GR205171 5 mg
8 weeks
DSM-IVCAPS >50CGI-S
>4>3 months
16
Physical/sexual
assault (72)
McRae (2004)65
USA
Randomised, double-blind, parallel arm, flexible dose nefazodone
100–600 mg (463 mg) v. sertraline 50–200 mg (153 mg)
12 weeks
DSM-IVCAPS-S >50 after 37 (0)
placebo run-in>3 months
Padala (2006)25
USA
Randomised, double blind, parallel, placebo-controlled, flexible
dose risperidone 4–6 mg (2.62 mg)
12 weeks
Panahi (2011)26
Iran
Randomised, double blind, parallel, placebo-controlled, flexible
dose sertraline 50–200 mg (140 mg)
10 weeks
Petrakis (2012)32
USA
Pfizer588C
47 (59)
18 years
2.8 years
15.7 years
5.15 years
11.4 years
37.9 (18–65)
TOP-8CAPSCGI-SCGIIMADRSHRSASCL-90-RDES
Low
Low
Unclear
Unclear
Low
38.3 (18–65)
TOP-8CAPSCGI-SCGIIMADRSHRSASCL-90-RDES
Low
Low
Unclear
Low
Low
High
40.7 (18–75)
TOP-8CAPSDTSCGISMADRSHRSADES
Unclear
Unclear
Unclear
Unclear
Low
Low
(18-65)
CAPSDTSCGI-IMADRSCGISSDS
Low
Low
Low
Unclear
High
High
40.3 (18–65)
CAPS-SCGIUnclear
IDTSMADRSHRSATOP-8PSQISDS
Unclear
Unclear
Unclear
Low
High
20 (100)
8
DSM-IV-TRCGI-S >4>6
months
70 (0)
8
Combat (100)
41.3 (19–65)
CAPSTOP-8HRSDHRSA
Unclear
Unclear
Unclear
High
High
Unclear
45.6
IES-RCGI-S
Low
Unclear
Low
Low
Low
Multicentre, randomised, double-blind, parallel, placebo-controlled,
flexible dose paroxetine 10–40 mg (39.7 mg) v. desipramine
25–200 mg (187.2 mg) (naltrexone groups not considered)
DSM-IV529/7 abstinent
? = 88 (9) (n = 44 in
monotherapy groups)
7 (monotherapy)
Combat (92)
Unclear
47.1
CAPSHRSD
Unclear
Unclear
Unclear
Low
Low
Multicentre, randomised placebo-controlled, double-blind, parallel, 74 days
flexible dose trial sertraline (156 mg)
DSM-III-RCAPS-2 >50
193 (75)
50
Physical/sexual assault
Unclear
10.5 years
37
CAPS-2CGI-IIESDTSCGI-S
Unclear
Unclear
Unclear
High
High
High
Pfizer589D
Randomised, double-blind, placebo-controlled, parallel flexible
dose trial sertraline (156 mg)
72 days
DSM-III-R
169 (20)
40
Combat (71)
Reist (1989)66
USA
Multicentre, randomised, double blind, cross-over, placebocontrolled, flexible dose desipramine 50–200 mg (165 mg)
8 weeks
DSM-III-R
27 (0)
9
Combat (100)
18 years
45
CGI-SCGI-IIESDTSCAPS-2
Unclear
Unclear
Unclear
High
High
High
38.4 (28–64)
IESHRSDHRSABDI
Unclear
Unclear
Unclear
High
Low
Saygin (2002)67
Turkey
Randomised, double-blind, parallel arm, flexible dose nefazodone
200–400 mg (332.4 mg) v. sertraline 50–100 mg (68.3 mg)
24 weeks
DSM-IV
60 (0)
6
Earthquake survivors
Unclear
41.5
TOP-8CGI-ICGI-SCGI-SE
Unclear
Unclear
Unclear
High
Low
Unclear
Shalev (2011)27
Israel
Randomised, double-blind, parallel, placebo-controlled, fixed dose
escitalopram 10–20 mg
20 weeks
DSM-IVCAPS 440, no
minimum duration
46 (44)
7
RTA (83)
SKB627E
Randomised, double-blind, parallel, placebo-controlled, flexible
dose paroxetine 20–50 mg
84 days
DSM-IV
322 (53)
38.6 (18–70)
CAPSPSS-SR
Low
Unclear
Low
Unclear
Low
Unclear
18–75
CAPS-2CGI-I
Unclear
Unclear
Unclear
High
High
SKB650F
Randomised, double-blind, placebo-controlled, flexible dose
paroxetine up to 50 mg
252 days
DSM-IVCAPS 450
176 (66)
High
43 (18–82)
CAPS-2DTSMADRSSDS
Unclear
Unclear
Unclear
High
High
High
Spivak (2006)28
Israel
Randomised, double blind, parallel, head-to-head comparator,
fixed dose reboxetine 8 mg v. fluvoxamine 150 mg
8 weeks
DSM-IVCAPS 460
41 month
40 (47)
12
Tucker (2001)53
USA
Multicentre, randomised, double blind, parallel arm, placebocontrolled, flexible dose paroxetine 20–50 mg (27.6 mg)
12 weeks
DSM-IV
323 (66)
152
High
Tucker (2003)68
USA
Randomised, double blind, parallel, placebo-controlled, flexible
dose citalopram 20–50 mg (36.2 mg) v. sertraline 50–200 mg
(134.1 mg)
10 weeks
DSM-IVCAPS >50
59 (72)
14
Tucker (2007)29
USA
Randomised, double blind, parallel, placebo-controlled, flexible
dose topiramate25–400 mg (150 mg)
8 weeks
DSM-IVCAPS >50No
minimum duration
40 (80)
6
Childhood sexual abuse
(34)
41.5 (18–65)
CAPSHRSAHRSDTOP-8CGISCGI-IDTSBISSDSCD-RISC
Low
Unclear
Unclear
Low
Low
Unclear
Van der Kolk (1994)69
USA
Multicentre, randomised, double-blind, parallel arm, placebocontrolled, flexible dose fluoxetine 20–60 mg (40 mg)
5 weeks
DSM-III-R
64 (34)
17
Combat (44)
40.4 (22–55)
CAPSBDHIHRSDDESDESI
Unclear
Unclear
Unclear
High
Low
High
Van der Kolk (2004)70
USA
Multicentre, randomised, double-blind, parallel arm, placebocontrolled, flexible dose fluoxetine 10–60 mg v. EMDR
5 weeks
DSM-IV>12 months
59 (86)
7
Interpersonal victimisation 13.1 years
(72)
34.9 (18–65)
CAPSBDI
Unclear
Unclear
Unclear
Low
Low
Low
Yeh (2010)30
Bra-zil
Randomised, double blind, parallel, placebo-controlled
topiramate 50–200 mg (102.9 mg)
12 weeks
DSM-IV
35 (68)
21
Violence (100)
40.1 (18–62)
CAPSBDICGI
Low
Unclear
Unclear
Low
Low
Unclear
Zohar (2002)54
Israel
Multicentre, randomised, double-blind, parallel arm, placebocontrolled, flexible dose sertraline 50–200 mg (120 mg)
10 weeks
DSM-III-RCAPS-2 450
CGI-S 4446 months
51 (37/42)
20
Combat (32/42)
40 (18+)
CAPS-2CGI-ICGI-SMADRSLOCF
(1 post-baseline assessment)
Unclear
Unclear
Unclear
High
Low
High
24.1 years
144.1 days
46
RTA (100)
14.9 years
Physical abuse/assault (31)
40.1
CAPSTOP-8HRSDHRSA
Low
Unclear
Low
High
Low
40.8 (18–78)
CAPS-2CGI-IDTSTOP8SDSMADRS
Unclear
Unclear
Unclear
High
Low
High
38.5 (18–64)
CAPSIESBDI
Unclear
Unclear
Unclear
High
Low
High
BDHI, Buss–Durkee Hostility Inventory; BDI, Beck Depression Inventory; CADSS, Clinician Administered Dissociative States Scale; CAPS, Clinician Administered PTSD Scale; CAPS-2, CAPS part 2; CAPS-DX, CAPS Diagnosis; CAPS-SX17, CAPS Symptom 17-item; CAS, Covi Anxiety Scale; CDRS-R, Children’s Depression Rating Scale Revised; CD-RISC, Connor–Davidson Resilience Scale; SVS, Sheehan Stress Vulnerability Scale; CGI, Clinical Global Impression (C, change; I, improvement; S, severity);
DES, Dissociative Experiences Scale; DESI, Disorders of Extreme Stress Inventory; DGRP, Duke Global Rating for PTSD; DTS, Davidson Trauma Scale; EMDR, eye movement desensitisation and reprocessing; EPI, Eysenck Personality Inventory; GAF, Global Assessment of Functioning; HRSA, Hamilton Rating Scale for Anxiety; HRSD, Hamilton Rating Scale for Depression; IES, Impact of Events Scale; IPP, Inventory of Personal Problems; LOCF, last observation carried forward; MADRS,
Montgomery–Åsberg Depression Rating Scale; MISS, Mississippi Scale for Combat-Related PTSD; NI, Newcastle Index; PCL, Psychopathy Checklist; PSQI, Pittsburgh Sleep Quality Index; PSS, PTSD Symptoms Scale; PSS-SR, PSS self-rated; QLES Q-SF, Quality of Life Enjoyment and Life Satisfaction Short Form; RSD, Raskin Scale for Depression; RTA, road traffic accident; SCL-90-R, Hopkins 90-item Symptom Checklist Revised; SDS, Sheehan Disability Scale; SI-PTSD, DSM-based PTSD scale;
SIP, Structured Interview for PTSD; SPRINT, Short PTSD Rating Interview scale; TOP-8, Treatment Outcome PTSD Scale; VAS, Visual Analog Scale; VS, Vulnerability to the Effects of Stress Scale.
Appendix DS1
Electronic search strategy
1. Stress Disorders, Traumatic/ or Combat Disorders/ or Stress Disorders,
Post-Traumatic, Acute/ or Stress Disorders, Post-Traumatic/ or Stress,
Psychological/
2. Stress, Psychological/ or Critical Incident Stress/ or Stress Disorders,
Post-Traumatic/
41. animals/ not (animals/ and human$.mp.)
42. animal$/ not (animal$/ and human$/)
43. meta-analysis/
3. Posttraumatic Stress Disorder/ or Emotional Trauma/ or Traumatic
Neurosis/
44. meta-analysis.pt.
4. Posttraumatic Stress Disorder/ or Psychotrauma/
46. or/41–45
5. (post?traumatic$ or post-traumatic$ or stress disorder$ or acute stress
or PTSD or ASD or DESNOS).tw.
47. 25 not 46
6. (combat neuros$ or combat syndrome or concentration camp
syndrome or extreme stress or flash?back$ or flash-back$ or hypervigilan$ or hypervigilen$ or psych$ stress or psych$ trauma$ or
psycho?trauma$ or psycho-trauma$).tw.
45. systematic review/
48. pharmacother*.tw
49. pharmacolog*.tw
50. antipsychotic*.tw
51. Psychopharmacology/
7. (railway spine or (rape adj2 trauma$) or re?experienc$ or re-experienc$
or torture syndrome or traumatic neuros$ or traumatic stress).tw.
52. Benzodiazepines/
8. (trauma$ and (avoidance or grief or horror or death$ or night?mare$ or
night-mare$ or emotion$)).tw.
54. hypnotics/
53. antidepressive agents/
9. grief bereav*.tw
55. sedatives/
10. or/1–9
56. medicat*.tw
11. exp clinical trials/ or cross-over studies/ or random allocation/ or
double-blind method/ or single-blind method/
57. drug*.tw
12. random$.pt.
59. ˆAntidepressive Agents¤
60. ˆMonoamine Oxidase Inhibit ORs¤
13. exp clinical trial/ or crossover procedure/ or double blind procedure/
or single blind procedure/ or randomization/
14. exp clinical trials/ or crossover design/ or random assignment/
15. exp clinical trials/ or double blind method/ or random allocation/
16. random$.mp.
17. (cross-over or cross?over or (clinical adj2 trial$) or single-blind$ or
single?blind$ or doubleblind or double?blind$ or triple-blind or triple?blind).tw.
2
40. or/26-39
58. drug therapy/
61. ˆSelective Serotonin Reuptake InhibitORs¤
62. ˆTricyclic Drugs¤
63. Acetylcarnitine
64. Alaproclate
65. Amersergide
66. Amiflamine
18. randomized controlled trial/
67. Amineptine
19. matched pair analysis/
68. Amitriptyline
20. cohort study.tw
69. Amoxapine
21. case-control.tw
70. Befloxatone
22. before-and-after studies.tw
71. Benactyzine
23. epidemiological studies.tw
72. Beta blockers
24. intervention studies.tw
73. Beta*.tw
25. or/11–24
74. Brofaromine
26. mask*.tw
75. Bupropion
27. blind*.tw
76. Butriptyline
28. ˆlatin square¤.tw
77. Caroxazone
29. placebos/
78. ChlORpoxiten
30. placebo*.tw
79. Cilosamine
31. random*.tw
80. Cimoxatone
32. research design/
81. Citalopram
33. comparative study/
82. Clomipramine
34. evaluation studies/
83. ClORgyline
35. follow-up studies/
84. ClORimipramine
36. prospective studies/
85. Clovoxamine
37. control*.tw
86. Cortisol
38. prospectiv*.tw
87. Deanol
39. volunteer*.tw
88. Demexiptiline
89. Deprenyl
126. Oxaflozane
90. Desipramine
127. Oxaprotiline
91. Dibenzipin
128. Pargyline
92. Diclofensine
129. Paroxetine
93. Dothiepin
130. Phenelzine
94. Doxepin
131. Piribedil
95. Duloxetine
132. Pirlindole
96. Escitalopram
133. Pivagabine
97. Etoperidone
134. Propranol
98. Femoxetine
135. Prosulpride
99. Fluotracen
100. Fluoxetine
101. Fluparoxan
102. Fluvoxamine
103. Hydrocortisone
104. Idazoxan
105. Imipramine
106. Iprindole
107. Iproniazid
108. isocarboxazid
109. Litoxetine
110. Lofepramine
111. Maprotiline
112. Medifoxamine
113. Melitracen
114. Metapramine
115. Mianserin
136. Protriptyline
137. Quinupramine
138. Reboxetine
139. Rolipram
140. Sertraline
141. Setiptiline
142. Teniloxine
143. Tetrindole
144. Thiazesim
145. Thozalinone
146. Tianeptine
147. Toloxatone
148. Tomoxetine
149. Tranylcypromine
150. Trazodone
151. Trimipramine
116. Milnacipran
152. Venlafaxine
117. Minaprine
153. Viloxazine
118. Mirtazapine
154. Viqualine
119. Moclobemide
155. Zimeldine
120. Nefazodone
156. beta blockers
121. Nialamide
157. beta*.tw.
122. Nomifensine
158. cortisol
123. NORtriptyline
159. hydrocortisone
124. Noxiptiline
160. or/48-159
125. Opipramol
161. 10 and 25 and 40 and 46 and 47 and 159
Pharmacotherapy for post-traumatic stress disorder: systematic
review and meta-analysis
Mathew Hoskins, Jennifer Pearce, Andrew Bethell, Liliya Dankova, Corrado Barbui, Wietse A. Tol, Mark
van Ommeren, Joop de Jong, Soraya Seedat, Hanhui Chen and Jonathan I. Bisson
BJP 2015, 206:93-100.
Access the most recent version at DOI: 10.1192/bjp.bp.114.148551
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