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Pharmacological interventions for preventing post-traumatic stress

disorder (PTSD) (Review)
Amos T, Stein DJ, Ipser JC
Amos T, Stein DJ, Ipser JC.

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD).
Cochrane Database of Systematic Reviews 2014, Issue 7. Art. No.: CD006239.
DOI: 10.1002/14651858.CD006239.pub2.
www.cochranelibrary.com
Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review)

Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews
TABLE OF CONTENTS
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
SUMMARY OF FINDINGS.............................................................................................................................................................................. 4
BACKGROUND.............................................................................................................................................................................................. 6
OBJECTIVES.................................................................................................................................................................................................. 7
METHODS..................................................................................................................................................................................................... 7
RESULTS........................................................................................................................................................................................................ 12
Figure 1.................................................................................................................................................................................................. 13
Figure 2.................................................................................................................................................................................................. 15
Figure 3.................................................................................................................................................................................................. 16
DISCUSSION.................................................................................................................................................................................................. 20
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 22
ACKNOWLEDGEMENTS................................................................................................................................................................................ 22
REFERENCES................................................................................................................................................................................................ 23
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 28
DATA AND ANALYSES.................................................................................................................................................................................... 45
Analysis 1.1. Comparison 1 Propranolol versus placebo, Outcome 1 Treatment efficacy................................................................ 45
Analysis 1.2. Comparison 1 Propranolol versus placebo, Outcome 2 Sensitivity analysis - observed cases................................... 45
Analysis 2.1. Comparison 2 Hydrocortisone versus placebo, Outcome 1 Treatment efficacy.......................................................... 46
Analysis 2.2. Comparison 2 Hydrocortisone versus placebo, Outcome 2 Sensitivity analysis - observed cases............................. 46
APPENDICES................................................................................................................................................................................................. 47
HISTORY........................................................................................................................................................................................................ 49
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 49
DECLARATIONS OF INTEREST..................................................................................................................................................................... 49
SOURCES OF SUPPORT............................................................................................................................................................................... 50
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 50
INDEX TERMS............................................................................................................................................................................................... 51
Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) i

Informed decisions.
[Intervention Review]
Pharmacological interventions for preventing post-traumatic stress

disorder (PTSD)
Taryn Amos1, Dan J Stein1, Jonathan C Ipser1
1Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa
Contact address: Taryn Amos, Department of Psychiatry and Mental Health, University of Cape Town, Education Centre, Valkenberg
Hospital, Private Bage X1, Observatory, Cape Town, 7925, South Africa. tarynamos@gmail.com.
Editorial group: Cochrane Common Mental Disorders Group

Publication status and date: New, published in Issue 7, 2014.
Citation: Amos T, Stein DJ, Ipser JC. Pharmacological interventions for preventing post-traumatic stress disorder (PTSD). Cochrane
Database of Systematic Reviews 2014, Issue 7. Art. No.: CD006239. DOI: 10.1002/14651858.CD006239.pub2.
ABSTRACT
Background
Post-traumatic stress disorder (PTSD) is a debilitating disorder which, after a sufficient delay, may be diagnosed amongst individuals who
respond with intense fear, helplessness or horror to traumatic events. There is some evidence that the use of pharmacological interventions
immediately after exposure to trauma may reduce the risk of developing of PTSD.
Objectives
To assess the effects of pharmacological interventions for the prevention of PTSD in adults following exposure to a traumatic event.
Search methods
We searched the Cochrane Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR-Studies and CCDANCTR-References)
(to 14 February 2014). This register contains relevant reports of randomised controlled trials from the following bibliographic databases:
CENTRAL (all years); EMBASE (1974 to date); MEDLINE (1950 to date) and PsycINFO (1967 to date). We identified unpublished trials by
searching the National Institute of Health (NIH) Reporter, the metaRegister of Controlled Trials database (mRCT) and the WHO International
Clinical Trials Registry Platform (to December 2013). We scanned the reference lists of articles for additional studies. We placed no
constraints on language and setting.
Selection criteria
We restricted studies to randomised controlled trials (RCTs) of pharmacological interventions compared with placebo for the prevention
of PTSD in adults.
Data collection and analysis

Two authors (TA and JI) independently assessed trials for eligibility and inclusion based on the review selection criteria. We independently
extracted sample, methodological, outcome and 'Risk of bias' data, as well as the number of side effects, from each trial and entered
these into a customised data extraction form. We contacted investigators for missing information. We calculated summary statistics for
continuous and dichotomous variables (if provided). We did not undertake subgroup analyses due to the small number of included studies.
Main results
We included nine short-term RCTs (duration 12 weeks or less) in the analysis (345 participants; age range 18 to 76 years). Participants
were exposed to a variety of traumas, ranging from assault, traffic accidents and work accidents to cardiac surgery and septic shock.
Seven studies were conducted at single centres. The seven RCTs included four hydrocortisone studies, three propranolol studies (of which
one study had a third arm investigating gabapentin), and single trials of escitalopram and temazepam. Outcome assessment measures
Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) 1

Informed decisions.
included the Clinician-Administered PTSD Scale (CAPS), the 36-Item Short-Form Health Survey (SF-36) and the Center for Epidemiological
Studies – Depression Scale (CES-D).
In four trials with 165 participants there was moderate quality evidence for the efficacy of hydrocortisone in preventing the onset of PTSD
(risk ratio (RR) 0.17; 95% confidence interval (CI) 0.05 to 0.56; P value = 0.004), indicating that between seven and 13 patients would need
to be treated with this agent in order to prevent the onset of PTSD in one patient. There was low quality evidence for preventing the
onset of PTSD in three trials with 118 participants treated with propranolol (RR 0.62; 95% CI 0.24 to 1.59; P value = 0.32). Drop-outs due to
treatment-emergent side effects, where reported, were low for all of the agents tested. Three of the four RCTs of hydrocortisone reported
that medication was more effective than placebo in reducing PTSD symptoms after a median of 4.5 months after the event. None of the
single trials of escitalopram, temazepam and gabapentin demonstrated evidence that medication was superior to placebo in preventing
the onset of PTSD.
Seven of the included RCTs were at a high risk of bias. Differential drop-outs between groups undermined the results of three studies, while
one study failed to describe how the allocation of medication was concealed. Other forms of bias that might have influenced study results
included possible confounding through group differences in concurrent medication and termination of the study based on treatment
response.
Authors' conclusions
There is moderate quality evidence for the efficacy of hydrocortisone for the prevention of PTSD development in adults. We found
no evidence to support the efficacy of propranolol, escitalopram, temazepam and gabapentin in preventing PTSD onset. The findings,
however, are based on a few small studies with multiple limitations. Further research is necessary in order to determine the efficacy of
pharmacotherapy in preventing PTSD and to identify potential moderators of treatment effect.
PLAIN LANGUAGE SUMMARY
Medications to prevent post-traumatic stress disorder (PTSD): a review of the evidence
Who may be interested in this review?
- People affected by PTSD and their families.

- Professionals working in adult mental health services.
- General practitioners.
- Charities that support victims of trauma or members of the armed forces.
Why is this review important?
PTSD is a condition experienced by some people after traumatic experiences such as warfare or domestic violence. People with PTSD
experience symptoms of intense fear, helplessness and horror. Research suggests that changes in stress hormones in the brain may
contribute to PTSD. Giving people medications which work in the brain soon after traumatic events may be able to prevent PTSD from
developing.
Previous reviews have shown that talking therapy (cognitive behavioural therapy - CBT) is effective in preventing PTSD. This is the first
review of medication as a preventative treatment for PTSD.
What questions does this review aim to answer?
- Is medication an effective preventative treatment for PTSD compared to placebo (dummy pills)?
- Is medication an acceptable treatment (do people stop medication due to side effects)?
Which studies were included in the review?
We searched databases to find all studies comparing medication with placebo for the prevention of PTSD, published up until February
2014. To be included in the review, studies had to be randomised controlled trials. Studies were included if they had adult participants
aged over 18 who had experienced traumatic events but did not have a diagnosis of PTSD at the time of starting medication.
We included nine studies with a total of 345 participants in the review. Seven out of the nine studies had a high risk of bias due to problems
with the research design.
What does the evidence from the review tell us?
There was moderate quality evidence that hydrocortisone (a steroid medication) prevented PTSD.
There was moderate quality evidence that hydrocortisone reduced the severity of PTSD symptoms.

Informed decisions.
There was no evidence that propranolol (a beta-blocker), escitalopram (a type of antidepressant), temazepam (a tranquillizer) or
gabapentin (an anticonvulsant) prevented PTSD.
All medications were acceptable, with low numbers of people dropping out due to side effects; however not all studies provided
information on this.
What should happen next?
The review authors do not feel there is sufficient evidence yet to recommend any medication as a preventative treatment for PTSD. The
review authors recommend that future high quality research is needed to provide stronger evidence for the effectiveness of medications
in preventing PTSD.

SUMMARY OF FINDINGS
Summary of findings for the main comparison. Propranolol compared to placebo for preventing post-traumatic stress disorder (PTSD)
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Propranolol compared to placebo for preventing post-traumatic stress disorder (PTSD)
Patient or population: adult participants (18 years and older) who have been exposed to any traumatic events, but who did not meet the diagnostic criteria for PTSD at
study recruitment
Better health.
Informed decisions.
Trusted evidence.
Settings: in- and outpatients
Intervention: propranolol
Comparison: placebo
Outcomes Illustrative comparative risks* (95% CI) Relative effect No of partici- Quality of the Comments
(95% CI) pants evidence
Assumed risk1 Corresponding risk (studies) (GRADE)
Placebo Propranolol
Treatment efficacy Study population RR 0.62 118 ⊕⊕⊝⊝

CAPS, CIDI (0.24 to 1.59) (3 studies) low2
Follow-up: median 3 100 per 1000 62 per 1000
months (24 to 159)
Moderate
200 per 1000 124 per 1000

(48 to 318)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is
based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CAPS: Clinician-Administered PTSD Scale; CI: confidence interval; CIDI: Comprehensive International Diagnostic Interview; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1The assumed risk in the control group is based on an estimated event rate of 10% and 20%, as per Norris 2007.
2Approximately five times as many drop-outs prior to the follow-up assessment were observed in the propranolol than in the placebo groups in one study (29.4% versus 5.9% of
the respective samples). Another study provided little information on how allocation was concealed and whether/how blinding of the outcome was performed.
4
Summary of findings 2. Hydrocortisone compared to placebo for preventing post-traumatic stress disorder (PTSD)
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Hydrocortisone compared to placebo for preventing post-traumatic stress disorder (PTSD)
Patient or population: adult participants (18 years and older) who have been exposed to any traumatic events, but who did not meet the diagnostic criteria for PTSD at
study recruitment
Settings: in- and outpatients
Intervention: hydrocortisone
Comparison: placebo
Better health.
Informed decisions.
Trusted evidence.
Outcomes Illustrative comparative risks* (95% CI) Relative effect No of partici- Quality of the Comments
(95% CI) pants evidence
Assumed risk1 Corresponding risk (studies) (GRADE)
Placebo Hydrocortisone
Treatment efficacy Study population RR 0.17 165 ⊕⊕⊕⊝

CAPS, SCID-IV, PTSS-10Q-I (0.05 to 0.56) (4 studies) moderate123
Follow-up: median 4.5 months 100 per 1000 17 per 1000
(5 to 56)
Moderate
200 per 1000 34 per 1000

(10 to 112)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is
based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CAPS: Clinician-Administered PTSD Scale; CI: confidence interval;PTSS-10Q-I: Post-Traumatic Stress Syndrome 10-Questions Inventory; RR: risk ratio; SCID-IV: Structured
Clinical Interview for DSM-IV
GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1The assumed risk in the control group is based on an estimated event rate of 10% and 20%, as per Norris 2007.
2Half of the trials reported administering higher levels of norepinephrine to patients on placebo than medication, which may have confounded the evidence of a treatment effect.
In a third trial, the differential proportion of drop-outs between interventions suggests possible attrition bias.
3Few participants and few events and thus wide confidence intervals.
5
Informed decisions.
BACKGROUND suggest that cognitive behavioural therapy (CBT) is likely to be

beneficial for the prevention of PTSD development in adults and
Description of the condition children (Bisson 2010; Gillies 2012; Mueser 2008; Van Emmerik
2008), with other psychological interventions being less well
Post-traumatic stress disorder (PTSD) is a widespread condition
supported (Mayou 2000; Rose 2002; Ruzek 2001; Turpin 2005).
that has been recognised in the fourth edition of the Diagnostic
The relatively large body of evidence for the short- and long-
and Statistical Manual (DSM-IV) as a pathological response to
term efficacy of medication treatment for PTSD indicates that
severe trauma (APA 1994). To fulfil the DSM-IV criteria for PTSD, an
medication may be effective in preventing PTSD; the most
individual must have been exposed to a traumatic event; have at
evidence of efficacy currently existing for the selective serotonin
least one re-experiencing, three avoidance and two hyperarousal
reuptake inhibitors (SSRIs), with promising initial findings for the
phenomena; and have had the symptoms for at least one month,
selective noradrenergic reuptake inhibitor venlafaxine and the
with the symptoms causing clinically important distress or reduced
atypical antipsychotic risperidone (Ipser 2011). Nevertheless, a
day-to-day functioning. PTSD is labelled as acute for the first three
recent multi-arm randomised controlled trial (RCT) of the SSRI
months and chronic if it lasts beyond three months (Bisson 2010).
escitalopram failed to observe a reduction in the onset of PTSD
There is evidence that PTSD is associated with substantial relative to placebo at five or nine months post-trauma exposure
reductions in quality of life, a high co-morbidity of psychiatric (Shalev 2012). A similar lack of evidence of efficacy was observed
and medical disorders, marked functional impairment and high for the antidepressants imipramine and fluoxetine in reducing
economic costs (Erbes 2007; Schnurr 2009; Solomon 1997). A ASD symptoms in paediatric burn victims (Robert 2008), despite
nationally representative mental health survey, the National initial promising findings in this population in a RCT of imipramine
Comorbidity Survey, discovered that between 50% and 60% of (Robert 1999).
people in the United States are exposed to trauma during their
Several additional classes of medication may be useful in the
lifetimes, with a lifetime incidence of PTSD of 10.4% for women
prevention of PTSD. Findings from controlled trials of the beta-
and 5% for men (Kessler 1995). A more recent replication of this
adrenergic antagonists, such as propranolol (Brunet 2008), and
survey discovered that as many as 3.5% of those interviewed had
glucocorticoids such as hydrocortisone (Delahanty 2012; Schelling
developed PTSD within the previous 12 months (Kessler 2005).
2001), are promising and support suggestions that cortisol
Higher prevalence rates have been found in African countries, with
administration after trauma may be a useful approach in preventing
a reported PTSD lifetime prevalence in four post-conflict settings of
PTSD (Schelling 1999; Schelling 2001). While benzodiazepines are
37.4% in Algeria, 28.4% in Cambodia, 15.8% in Ethiopia and 17.8%
widely used in acute trauma settings, the rationale for their use
in Gaza (de Jong 2001).
in treating trauma has been undermined by the negative findings
Reviews of retrospective and prospective studies have been of a non-randomised controlled trial of clonazepam or alprazolam
conducted to identify predictive factors distinguishing between (Gelpin 1996). Early administration of temazepam following life-
people who subsequently develop PTSD and those who do not threatening incidents actually resulted in a larger proportion of
(Brewin 2000; Ozer 2003). The general finding is that proximal participants developing PTSD in a small randomised, placebo-
factors, such as social support and trauma intensity, are more controlled trial (Mellman 2002). A randomised controlled trial of
strongly implicated in the subsequent development of PTSD than gabapentin did not provide evidence for the efficacy of anxiolytic
more distal factors (such as history of family psychopathology). anticonvulsants in preventing PTSD (Stein 2007).
While peri-traumatic stress dissociation may predict development
of PTSD (Ozer 2003), more than half of individuals who go on to
How the intervention might work
develop PTSD are not diagnosed with acute stress disorder (ASD) Abnormal cortical secretion resulting from disruptions in HPA
(Bryant 2003). axis functioning in PTSD has been widely documented (Meewisse
2007), with reports of lower urinary and plasma cortisol in PTSD
A range of mechanisms have been proposed to account for the suggesting that administering cortical steroids to individuals at
development of PTSD. These include hypotheses focusing on: risk of PTSD might prove beneficial in preventing the onset of
cognitive attributions about the treatment event (Massad 2006; the disorder (Yehuda 1990; Yehuda 2008). Although the precise
Nickerson 2013); re-consolidation of negative memories (Besnard mechanism through which glucocorticoids might prevent PTSD
2012; Pitman 1989); abnormalities associated with exposure to is not clear, animal and human studies have identified complex
trauma in neurotransmitter (Krystal 2009); neuroendocrine (van effects of cortisol administration on memory for emotionally
Zuiden 2013; Yehuda 2006) and neurobiological factors (e.g. arousing events (de Quervain 2009). Specifically, high levels of
glucocorticoid-associated hippocampal atrophy systems (Bremner glucocorticoids appear to improve the initial consolidation of
2004; Sapolsky 2000), and epigenetic mechanisms in which gene- memory for traumatic events, but have detrimental effects on
environment factors place certain individuals at greater risk of the subsequent recall of these events. Additionally, a substantial
developing PTSD (Heinzelmann 2013). A number of sophisticated body of evidence reviewed by de Quervain 2009 indicates that
models have been developed in order to integrate cognitive- the effects of glucocorticoids on traumatic memory are modulated
affective and neurobiological factors (Shalev 2006), which may by noradrenergic release in response to stress (Nicholson 2013),
constitute a focus for prevention interventions or management of particularly in the basolateral amygdala (BLA). The reduced
PTSD. incidence of PTSD in a case-control (Schelling 1999) and a
randomised controlled trial (Schelling 2001) of hydrocortisone
Description of the intervention in patients being treated for septic shock has accordingly been
There are many approaches to PTSD prevention, the most explained in terms of the steroid redressing the low levels of cortisol
common of which is psychotherapy. Controlled clinical trials

Informed decisions.
in combination with elevated levels of noradrenaline typically We also included cluster-randomised control trials and studies with
found in this patient population. multiple treatment groups in the analysis.
According to Pitman's translational model of PTSD pathogenesis Types of participants

(Pitman 1989; Pitman 2005), agents that block the effect of
Participant characteristics
stress hormones in the brain might be expected not only to
reduce the emotional salience of aversive events, but also to We included in the review adult participants (18 years and older)
disrupt the resulting over-consolidation of traumatic memories who have been exposed to any traumatic events, but who did not
and reinforcement of those memory traces through rehearsal of meet the diagnostic criteria for post-traumatic stress disorder at
the events. This is consistent with the finding in a controlled study recruitment.
pilot study that administration of propranolol, an agent that
acts to block post-synaptic beta-adrenergic receptors in the BLA, Co-morbidities
reduced psychophysiological reactivity to mental imagery (Pitman These individuals may or may not have been diagnosed with acute
2002), as well as PTSD rate and symptom severity in a non- stress disorder, or with comorbid psychopathological disorders.
randomised trial in motor vehicle accident or assault victims (Vaiva
2003). Questions remain, however, regarding the relevance of the Setting
adrenalin consolidation hypothesis for indirect trauma (Ozer 2003),
as well as the possible harmful effects of beta-blockers such as We placed no restrictions on setting.
propranolol in reducing the intensity of memory for traumatic
Subsets of participants
events in the reconsolidation of traumatic memories (McCleery
2004). We also included trials that included a subset of participants that
met the review inclusion criteria in the analysis, provided data for
While the GABAergic system may also be involved in PTSD this subset could be extracted from the study report.
development, early work has not supported the use of
benzodiazepines such as clonazepam, alprazolam and temazepam Types of interventions
for PTSD prevention (Gelpin 1996; Mellman 2002). The
We considered any pharmacological interventions, administered
anteretrograde amnesia induced by benzodiazepines and evidence
with the express intent to prevent the onset of PTSD, compared with
from animal studies of their possible potentiation of the acquisition
a placebo.
of fear responses (Hebert 1996; Lumley 2000) could explain
the increased rates of PTSD observed following early use of Experimental interventions
benzodiazepines in controlled trials (Gelpin 1996; Mellman 2002).
The risk of dependency associated with these medications might We grouped specific pharmacological interventions according to
also make them a less suitable option. medication class. These included the following:
Why it is important to do this review • Antipsychotics

• Benzodiazepines
Despite the vast body of evidence on the treatment of PTSD,
• Beta-blockers
little is known about the use of pharmacological interventions
for the prevention of PTSD. A number of Cochrane systematic • Selective serotonin reuptake inhibitors (SSRIs)
reviews have been published in this area, but these have been • Serotonin and norepinephrine reuptake inhibitors (SNRIs)
restricted to psychological debriefing interventions (Rose 2002), • Tricyclic antidepressants (TCAs)
multiple session early psychological interventions (Roberts 2010), • Mono-amine oxidase inhibitors (MAOIs)
and psychosocial interventions (De Silva 2009; Peñalba 2009).
• Other medications
A systematic review of randomised controlled clinical trials of
medication for the prevention of PTSD would therefore help Comparator interventions
to characterise the extent to which pharmacotherapy can be
considered as a viable alternative to psychotherapy as a secondary • Placebo
prevention strategy in the treatment of PTSD.
We placed no restrictions on timing, dose, duration and co-
OBJECTIVES interventions.
To assess the effects of pharmacological interventions for the Types of outcome measures
prevention of PTSD in adults following exposure to a traumatic Primary outcomes
event.
1. Treatment efficacy: we determined treatment efficacy from the
METHODS number of participants who developed PTSD after a minimum
period of three months after the traumatic event (APA 1994).
Criteria for considering studies for this review We determined diagnosis according to the relevant DSM-IV
criteria (APA 1994), as implemented in scales such as the
Types of studies Clinician-Administered PTSD Scale (CAPS) (Blake 1995), and the
We considered all randomised controlled trials (RCTs) for inclusion Comprehensive International Diagnostic Interview (CIDI) (WHO
irrespective of publication status or language. 1997). We also accepted outcomes from studies assigning a
probable diagnosis of PTSD using the Posttraumatic Stress

Informed decisions.
Symptom 10 Questionnaire Inventory (PTSS-10), given evidence • High probability of publication bias.
that this measure has moderate to high (77%) sensitivity and
excellent (97.5%) specificity in diagnosing clinically confirmed We classified the quality of evidence for each outcome according to
cases of PTSD (Weisaeth 1989). the following categories:
2. Treatment acceptability: we included the total proportion of • High quality: further research is very unlikely to change our
participants who withdrew from the RCTs due to treatment- confidence in the estimate of effect.
emergent side effects in the analysis as a surrogate measure • Moderate quality: further research is likely to have an important
of treatment acceptability, in the absence of other more direct impact on our confidence in the estimate of effect and may
indicators of acceptability. change the estimate.
• Low quality: further research is very likely to have an important
Secondary outcomes impact on our confidence in the estimate of effect and is likely
3. Reduction in PTSD symptoms: we assessed PTSD symptoms and, to change the estimate.
where available, symptom cluster response, using validated scales • Very low quality: we are very uncertain about the estimate.
such as the CAPS (Blake 1995) and the PTSS-10.
Timing of outcome assessment
4. Reduction in comorbid symptom responses measured by:
We included data for outcomes from validated measures in the
a. depression scales, such as the Hamilton Depression Scale
review. We determined treatment efficacy from the number of
(Hamilton 1959), and the Beck Depression Inventory (Beck 1961);
participants who developed PTSD after a minimum period of three
b. anxiety scales, such as the Hamilton Anxiety Scale (Hamilton
months after the traumatic event (APA 1994). For studies that
1960).
assessed outcomes at multiple time points (Delahanty 2012; Hoge
5. Quality of life measures, such as the MOS 36-Item Short-Form 2012; Pitman 2002; Shalev 2012; Stein 2007; Zohar 2011a), we
Health Survey (SF-36) (Ware 1992). synthesised data at the first time point that occurred at least three
months after the index traumatic event, consistent with the DSM-IV
6. Measures of functional disability, such as the Sheehan Disability criteria for chronic PTSD (APA 1994).
Scale (Sheehan 1996).
Search methods for identification of studies
7. Side effects: we described the most common drug-related side
CCDAN's Specialised Register (CCDANCTR)
effects for both the included and excluded studies (defined as those
occurring in at least 20% of the participants given medication), as The Cochrane Depression, Anxiety and Neurosis Group (CCDAN)
well as significant differences in the rate of occurrence of treatment- maintain two clinical trials registers at their editorial base in
emergent side effects between medication and control groups, as Bristol, UK, a references register and a studies-based register. The
part of the narrative review. CCDANCTR-References Register contains over 35,000 reports of
randomised controlled trials in depression, anxiety and neurosis.
Main outcomes of 'Summary of findings' tables Approximately 60% of these references have been tagged to
We compiled 'Summary of findings' tables to summarise the individual, coded trials. The coded trials are held in the CCDANCTR-
best evidence for all relevant outcomes (i.e. experimental versus Studies Register and records are linked between the two registers
comparator interventions), and these consisted of the following six through the use of unique Study ID tags. Coding of trials is based
elements using a fixed format (Higgins 2011a): on the EU-Psi coding manual. Reports of trials for inclusion in
the Group's registers are collated from routine (weekly), generic
• A list of all important outcomes, both desirable and undesirable. searches of MEDLINE (January 1950 to date), EMBASE (January
• A measure of the typical burden of these outcomes (e.g. 1974 to date) and PsycINFO (January 1967 to date); quarterly
illustrative risk, or illustrative mean, on control intervention). searches of the Cochrane Central Register of Controlled Trials
• Absolute and relative magnitude of effect (if both are (CENTRAL) and review-specific searches of additional databases.
appropriate). Reports of trials are also sourced from international trials registers
c/o the World Health Organization's trials portal (ICTRP), drug
• Numbers of participants and studies addressing these
companies and the handsearching of key journals, conference
outcomes.
proceedings and other (non-Cochrane) systematic reviews and
• A grade of the overall quality of the body of evidence for each meta-analyses. Details of CCDAN's generic search strategies can be
outcome. found on the Group's website.
• Space for comments.
Electronic searches
Evidence for downgrading studies was based on five factors. If we
found a reason for downgrading the evidence, we classified the We searched the CCDANCTR (Studies and References) (initially to
evidence as 'serious' (downgrading the quality rating by one level) April 2012) on condition alone (due to the ever-increasing list of
or 'very serious' (downgrading the quality grade by two levels): pharmacological interventions used to prevent and treat PTSD).
• Limitations in the design and implementation of the trial. Search terms used were: (PTSD or posttrauma* or post-trauma* or
"post trauma*" or "combat disorder*" or "stress disorder*").
• Indirectness of evidence.
• Unexplained heterogeneity or inconsistency of results. The Trials Search Co-ordinator (TSC) performed a final (more
• Imprecision of results. precise) update search on the CCDANCTR in February 2014,

Informed decisions.
appending terms for prevention: ("early intervention" or prevent* sheets for any discrepancies. If these discrepancies could not be
or prophyla*). addressed by both review authors, we approached an additional
All non-pharmacological (including omega-3) and/or paediatric review author (DS) for further clarification. Where information was
studies were weeded out, together with those already identified by missing, we contacted the investigators by email in an attempt to
the author team. obtain this information.
Earlier searches were also conducted by CCDAN's TSC on MEDLINE We obtained the following information from each trial:
(March 2011), using terms for PTSD in addition to a sensitive list of
drug terms. These searches were instigated when the CCDANCTR • Description of the trials, including the primary researcher, the
was out of date, due to a change over of staff at the editorial base year of publication, source of funding, and the setting and/or
(Appendix 1). location.
• Characteristics of the interventions, including the dose of
The review authors additionally ran their own searches medication, the period over which it was administered and the
on PubMed, PsycINFO and EMBASE (March 2011) (Appendix name of the particular medication tested.
2). We located ongoing or unpublished trials (December • Characteristics of trial methodology, including the diagnostic
2013) using the metaRegister of Controlled Trials database (e.g. DSM-IV (APA 1994)) and exclusionary criteria employed,
(mRCT) (http://www.controlled-trials.com), as well as the WHO the screening instrument used (e.g. the Structured Clinical
clinical trials portal (ICTRP) (http://apps.who.int/trialsearch/) Interview for DSM-IV (SCID) (Spitzer 1996)) for both the primary
and the National Institutes of Health (NIH) Reporter database and comorbid diagnoses, the presence of comorbid major
(http://projectreporter.nih.gov/reporter.cfm). We selected the NIH depressive disorder (MDD), the use of a placebo run-in, whether
ClinicalTrials.gov register as one of the databases searched through a minimal severity criterion was employed and the number of
the mRCT interface. We entered the search terms 'posttraumatic centres involved.
stress disorder' OR 'post traumatic stress disorder' OR 'PTSD' as
• Characteristics of participants, including the number of
search queries for these databases.
participants randomised to the treatment and control groups,
We conducted a systematic review search on OVID MEDLINE (April their age and gender distributions, whether they have been
2012) (Appendix 3). treated with the medication in the past (treatment naivety),
whether they have a history of trauma, the number of
Searching other resources participants in the sample with MDD, the type of trauma to which
they were exposed, and the average time between trauma and
Reference lists
treatment.
We scanned the bibliographies of all identified trials for additional • Outcome measures employed (primary and secondary), and
studies. summary continuous (means and standard deviations) and
dichotomous (number of responders) data. We included
Personal communication additional information, such as the number of total drop-outs
We also obtained published and unpublished trials from key per group as well as the number that dropped out due to
researchers, as identified by the frequency with which they are side effects. We kept records of whether the data reflected the
cited in the bibliographies of RCTs and open-label studies. intention-to-treat (ITT) with last observation carried forward
(LOCF) or completer/observed cases (OC) sample, and the
Data collection and analysis minimal period required for inclusion of participants in the LOCF
analyses. We also recorded other methods of estimating the
Selection of studies outcome for participants who dropped out of the study, such as
Two authors (TA and JI) independently assessed RCTs identified the mixed-effects (ME) model.
from the search for inclusion based on information included in
the title and abstract. We subsequently scanned full-text articles Main comparisons
agreed upon as potentially eligible. The authors independently We planned the following comparisons, based on the protocol
collated the data listed under Data extraction and management for this review (with the post hoc addition of beta-blockers, see
from RCTs which they both regarded as satisfying the inclusion Differences between protocol and review):
criteria specified in the Criteria for considering studies for this
review section. We listed studies for which additional information • Antipsychotics versus placebo
was required in order to determine their suitability for inclusion in • Benzodiazepines versus placebo
the review in the Studies awaiting classification table, pending the • Beta-blockers versus placebo
availability of this information. We resolved any disagreements in
• Selective serotonin reuptake inhibitors (SSRIs) versus placebo
the trial assessment and data collation procedures by discussion
with a third review author (DS). • Serotonin and norepinephrine reuptake inhibitors (SNRIs)
versus placebo
Data extraction and management • Tricyclic antidepressants (TCAs) versus placebo
We designed spreadsheet forms for the purpose of recording • Mono-amine oxidase inhibitors (MAOIs) versus placebo
descriptive information, summary statistics of the outcome • Other medications versus placebo
measures and associated commentary. Two review authors (TA and
JI) compiled these forms and independently extracted data. Once Agents tested in the trials included in this review were
the data extraction process was complete, we rechecked both data the beta-blocker propranolol, the steroid hydrocortisone,

Informed decisions.
the SSRI escitalopram, the anticonvulsant gabapentin and PTSD Scale (CAPS) for symptom severity. In cases in which a range of
the benzodiazepine temazepam. Accordingly, we restricted scales were employed for each outcome, such as in the assessment
comparisons for the treatment and control groups to the following: of comorbid depression on the Montgomery–Åsberg Depression
Rating Scale (MADRS) and Hamilton Depression Scale (HAM-D),
• Benzodiazepines versus placebo we determined the standardised mean difference (SMD). The SMD
• Beta-blockers versus placebo standardises the differences between the means of the treatment
• SSRIs versus placebo and control groups in terms of the variability observed in the trial.
• Other medications (hydrocortisone, gabapentin) versus placebo
Unit of analysis issues
Assessment of risk of bias in included studies Cluster-randomised trials
We assessed the risk of bias of each included study using The In cluster-randomised trials, groups of individuals rather than
Cochrane Collaboration 'Risk of bias' tool (Higgins 2011a). We individuals are randomised to different interventions. Analysing
considered the following six domains: treatment response in cluster-randomised trials without taking
these groups into account is potentially problematic, as
1. Random sequence generation: referring to a random number participants within any one cluster often tend to respond in a
table or using a computer random number generator? similar manner, and thus their data can no longer be assumed
2. Allocation concealment: was the medication sequentially to be independent of one another. Cluster-randomised trials also
numbered, sealed or placed in opaque envelopes? face additional risk of bias issues including (a) recruitment bias, (b)
3. Blinding of participants, personnel and outcome assessors for baseline imbalance, (c) loss of clusters and (d) non-comparability
each main outcome or class of outcomes: was knowledge of with trials in which allocation of treatment is randomly assigned on
the allocated treatment or assessment adequately prevented the individual level (Higgins 2011a). No cluster-randomised trials
during the study? were eligible for inclusion in this review. To prevent unit of analysis
4. Incomplete outcome data for each main outcome or class of errors in future updates of this review, we planned to divide the
outcomes: were missing or excluded outcome data adequately effective sample size of each comparison group in trials that did
addressed? not adjust for clustering by the design effect metric (Higgins 2011b),
5. Selective outcome reporting: were the reports of the study free with the intraclass correlation coefficient (ICC) that is incorporated
of suggestion of selective outcome reporting? within the design effect set equivalent to the median ICC from
published cluster-randomised pharmacotherapy RCTs for anxiety
6. Other sources of bias: was the study apparently free of other
disorders.
problems that could put it at a 'high' risk of bias.
Studies with multiple treatment groups
We extracted relevant information from each study report, where
provided. We made a judgement on the risk of bias for each domain Studies with more than two intervention arms pose difficulties
within and across studies, based on the following three categories: in the analysis of prevention data. We assessed such studies as
'low' risk of bias, 'unclear' risk of bias and 'high' risk of bias. follows:
Two independent review authors (TA and JI) assessed the risk of Continuous data
bias in selected studies. We discussed any disagreements with We pooled mean values, standard deviations and number of
a third review author (DJ). Where necessary, we contacted the participants for each intervention group across treatment arms and
authors of the studies for further information. All risk of bias data compared them against the control group (Higgins 2011a).
are presented graphically and described in the text.
Dichotomous data
Measures of treatment effect
We combined experimental intervention groups into a single group
Categorical data for comparison against the control group, or divided out the shared
We calculated risk ratio of response to treatment and number intervention groups approximately evenly among the comparisons
needed to treat to benefit (NNTB) for the dichotomous outcomes (Higgins 2011a).
of interest. We used risk ratio instead of odds ratio, as odd ratios
Cross-over trials
are less easily interpreted. Odds ratios also tend to overestimate
the size of the treatment effect relative to risk ratios, especially We only included cross-over trials in the calculation of summary
when the occurrence of the outcome of interest is common (as statistics when it was (a) possible to extract medication and
anticipated in this review, with an expected response greater than placebo/comparator data from the first treatment period, or (b)
20%) (Deeks 2011). The NNTB is based on the risk ratio and is when the inclusion of these data from both treatment periods was
computed with respect to an assumed incidence of PTSD following justified through a wash-out period of sufficient duration as to
trauma exposure in the control group of 10% and 20% (Norris 2007). minimise the risk of carry-over effects. We assessed the minimum
The NNTB provides a measure of the number of people who require wash-out period required on the basis of the plasma half-life of
treatment with medication, relative to a control, before a single the particular agent, as determined by consulting the Lundbeck
additional person in the medication group responds to treatment. Psychotropics website (Lundbeck 2003).
Continuous data For cross-over trials in which the wash-out period was regarded as
adequate, we only included data from both periods when it was
We calculated mean differences (MD) for continuous summary data
possible to determine the standard error of the mean difference
derived from the same scale, such as the Clinician-Administered
Informed decisions.
in response between groups (Elbourne 2002). We obtained the Data synthesis

summary statistics required to derive the standard error of interest
We obtained categorical and continuous treatment effects from
from the trial report, or for trials for which this information was
a random-effects model. Random-effects analytic models include
missing, we imputed them through averaging the relevant statistic
both within-study sampling error and between-study variation
from other included cross-over trials with comparable control
in determining the precision of the confidence interval around
conditions.
the overall effect size, whereas fixed-effect modelling approaches
Dealing with missing data take only within-study variation into account. We expressed the
outcomes in terms of an average effect size for each subgroup, as
All analyses of dichotomous data were intention-to-treat (ITT). well as by means of 95% confidence intervals. We included a small
We used the total number of participants randomised to the sample bias corrected version of the Cohen's D effect size estimate,
different comparison groups as the denominator in comparisons Hedges' g, as well as its 95% confidence intervals in the narrative
of treatment efficacy. We only included data from trials which review of study results that could not be synthesised (provided
provided information on the original group size (prior to drop- these data were normally distributed - see paragraph below), to aid
outs) in the analysis of treatment efficacy. In trial reports in in the interpretability of the magnitude of the medication effect. We
which multiple forms of data imputation were conducted, we gave calculated this statistic using the compute.es package within the R
preference to the inclusion of summary statistics for continuous statistical computing language (Del Re 2013).
outcome measures derived from mixed-effects models (ME),
followed by last observation carried forward (LOCF) and observed Evidence that data from individual studies were skewed was
cases (OC) summary statistics (in that order). This is in line with grounds for excluding the study from quantitative analysis. For
evidence that ME methods are more robust to bias than LOCF the purposes of this review, the following constituted evidence
analyses (Verbeke 2000). If data on studies, outcomes, summary of skewness: cases in which the difference between the observed
data, participants or study-level characteristics were missing, we mean and the lowest possible value or highest possible value on
contacted the original investigators. the scale is less than twice as large as the standard deviation (Deeks
2011), or where data are reported as skewed by the authors. For
Assessment of heterogeneity future updates of this review we plan to obtain individual patient
We assessed heterogeneity by means of the Chi2 test of data (where possible) for the purpose of normalising the data by
heterogeneity to assess whether observed differences in results means of log transformation techniques.
are compatible with chance alone. A low P value (or a large
Subgroup analysis and investigation of heterogeneity
Chi2 test relative to its degree of freedom) provides evidence of
heterogeneity of intervention effects (variation in effect estimates We planned subgroup analyses to assess the degree to
beyond chance). We also assessed heterogeneity against a P value which methodological differences between trials might have
of 0.10. If the Chi2 test had a P value of less than 0.10, we interpreted systematically influenced differences observed in the primary
this as evidence of heterogeneity, given the low power of the Chi2 treatment outcomes (Thompson 1994). Current guidelines
test when the number of trials is small (Deeks 2011). In addition, recommend at least 10 studies per characteristic used for stratifying
we used the I2 statistic, reported by RevMan, to quantify the subgroups (Deeks 2011). Accordingly, we did not conduct subgroup
inconsistency of the trial results within each analysis (Higgins 2003). analyses to determine the effect on the primary outcomes of
Thresholds for the interpretation of I2 can be misleading, since the whether trials were conducted at single or multiple treatment
importance of inconsistency depends on several factors. A rough centres, were funded by pharmaceutical companies or included
guide for interpretation was followed: participants with major depression.
• 0% to 40%: might not be important; Sensitivity analysis

• 30% to 60%: may represent moderate heterogeneity; Sensitivity analyses are designed to test the robustness of
• 50% to 90%: may represent substantial heterogeneity; review authors' conclusions to methodological assumptions made
• 75% to 100%: considerable heterogeneity. in conducting meta-analyses. We planned to assess whether
treatment response varies as a function of the use of treatment
Assessment of reporting biases response versus non-response as an outcome statistic. We regarded
We planned to inspect funnels plots visually for evidence of this comparison as necessary in light of evidence that treatment
reporting bias for the treatment efficacy and PTSD symptom response may result in less consistent outcome statistics than non-
reduction outcomes. Funnel plots provide a graphical illustration response (Deeks 2002), when the control group event rate is higher
of the effect estimates of an intervention from individual studies than 50%. No control group event rate was higher than 50% of the
against some measure of the precision of that estimate. However, ITT sample for any of the studies included in this review, obviating
we decided not to generate funnel plots as this would not have the need for this analysis.
been informative, given the small number of studies included in
The dichotomous outcome of treatment response in this review is
the meta-analyses of these outcomes. For the same reason, we also
calculated as the proportion of participants diagnosed with PTSD
decided to forgo additional planned Eggers' regression tests (Egger
at follow-up out of the total randomised sample. This effectively
1997), to confirm evidence of reporting bias from the funnel plots
counts drop-outs in the comparison groups as responders to
for the PTSD symptom reduction outcome. Future updates of the
medication or placebo. We assessed the effect of the decision to use
review will employ Egger's regression test if there are at least 10
the randomised sample instead of the more commonly reported
studies providing data on this outcome (Sterne 2011).
completer sample in a post hoc sensitivity analysis (e.g. Analysis 2.2
and Analysis 1.2).

Informed decisions.
Summary of findings • Moderate quality: further research is likely to have an important

impact on our confidence in the estimate of effect and may
We presented the main findings of the review, for the primary
change the estimate.
outcome of treatment efficacy, in Summary of findings for the
main comparison and Summary of findings 2 using GRADEpro • Low quality: further research is very likely to have an important
3.6 software (http://ims.cochrane.org/gradepro). 'Summary of impact on our confidence in the estimate of effect and is likely
findings' tables present the main findings of a review in a to change the estimate.
transparent and simple tabular format. In particular, they provide • Very low quality: we are very uncertain about the estimate.
key information concerning the quality of evidence, the magnitude
of effect of the interventions examined and the sum of available RESULTS
data on the main outcomes (Higgins 2011a).
Description of studies
We assessed five factors that decrease the quality level of a body of Results of the search
evidence:
We found a total of 3992 study reports through the search process
• Limitations in the design and implementation. (CCDANCTR 2012, OVID MEDLINE 87, mRCT 285, NIH Reporter 941,
• Indirectness of evidence. WHO Trials 667). We scanned each title and abstract (if provided)
• Unexplained heterogeneity or inconsistency of results. for eligibility. Seventy-one studies initially seemed relevant, but
further inspection excluded 50 of these, leaving 21 studies that
• Imprecision of results.
potentially met the inclusion criteria. After independent reviewing
• High probability of publication bias. of the full text for these studies, 12 failed to meet inclusion
We classified the quality of evidence for each outcome according to criteria, leaving nine RCTS eligible for inclusion in the review (see
the following categories: Characteristics of included studies and Figure 1). Two of the nine
eligible studies were identified (prior to the final updated search of
• High quality: further research is very unlikely to change our the CCDANCTR) through searching reference lists (Hoge 2012), and
confidence in the estimate of effect. from editorial feedback on the review (Shalev 2012).

Informed decisions.
Figure 1. Flow diagram.

Informed decisions.
Figure 1. (Continued)
Included studies Interventions

Design The nine RCTs included four hydrocortisone studies (steroid)
(Delahanty 2012; Schelling 2001; Weis 2006; Zohar 2011a), three
The review includes nine short-term RCTs of PTSD prevention.
propranolol studies (beta-blocker) (Hoge 2012; Pitman 2002; Stein
A placebo comparison group was employed in each study, with
2007) (with Stein 2007 investigating the anxiolytic anticonvulsant
one study having two medication arms (i.e. propranolol and
gabapentin) and single studies of temazepam (benzodiazepine)
gabapentin) (Stein 2007). Each study was published in English and
(Mellman 2002) and escitalopram (SSRI) (Shalev 2012). The
supported by a grant and/or pharmaceutical company.
duration of treatment for all pharmacological interventions ranged
Participants from a single dose of hydrocortisone (Zohar 2011a) to a 12-
week intervention for escitalopram (Shalev 2012). Dosages of
Three hundred and forty-five participants were included across the hydrocortisone ranged from 40 mg/day (Delahanty 2012) to 140
nine eligible studies. The average sample size was 38 and ranged mg/day (Zohar 2011a), with propranolol administered in doses
from 20 (Schelling 2001) to 64 (Weis 2006). Each study consisted ranging from 120 mg/day (Stein 2007) to 240 mg/day (Hoge 2012).
of both males and females, with a mean age of approximately 40 The maximum dose of temazepam administered at bedtime was
years. Females accounted for 49% of the total proportion of the 30 mg, while a 10 mg table of escitalopram was administered
sample. The participants in each study were exposed to a range twice daily in Shalev 2012. In Stein 2007, the maximal daily dosage
of trauma types, including assault (Delahanty 2012; Hoge 2012; of gabapentin was 400 mg. The interventions were administered
Mellman 2002), injury (Delahanty 2012; Hoge 2012; Stein 2007; by psychologists (Pitman 2002), psychiatrists (Schelling 2001;
Zohar 2011a), traffic or work accidents (Delahanty 2012; Hoge 2012; Shalev 2012; Zohar 2011a), mental health professionals (Delahanty
Pitman 2002; Shalev 2012; Zohar 2011a), terrorist attack (Shalev 2012), and nursing staff (Stein 2007; Weis 2006), as well as multi-
2012), cardiac surgery (Weis 2006), and septic shock (Schelling disciplinary teams of investigators (Mellman 2002).
2001).
Interventions were administered in the majority of studies within
Participants who were exposed to a traumatic event were assessed the first 12 hours after the traumatic event (Hoge 2012; Pitman
according to DSM-IV criteria in six studies (Delahanty 2012; Hoge 2002; Zohar 2011a), and occurred during the course of the
2012; Pitman 2002; Schelling 2001; Shalev 2012; Zohar 2011a), and traumatic event in two studies (Schelling 2001; Weis 2006).
the additional three studies used specified structured or semi- Medication was only administered within two days after the
structured measurements (Mellman 2002; Stein 2007; Weis 2006). trauma in Stein 2007, and after an average of 14.3 days and
19.8 days in the case of the trials of temazepam (Mellman
Setting 2002) and escitalopram (Shalev 2012), respectively. Interventions
Countries in which studies were conducted included the United occurred concurrently with administration of the study medication
States of America (e.g. Boston, San Diego) (Delahanty 2012; Hoge in some studies, including the stress hormones epinephrine
2012; Mellman 2002; Pitman 2002; Stein 2007), Germany (Schelling and norepinephrine in patients who had undergone cardiac
2001; Weis 2006), and Israel (Shalev 2012; Zohar 2011a). Seven surgery with cardiopulmonary bypass (Weis 2006), and a course
studies were single-centre trials (Delahanty 2012; Hoge 2012; of antibiotics, fluid resuscitation, mechanical ventilation and
Mellman 2002; Schelling 2001; Shalev 2012; Weis 2006; Zohar norepinephrine in patients treated for septic shock (Schelling
2011a), and two studies did not provide sufficient information 2001). Patients in Schelling 2001 were also sedated with infusions
to determine how many centres were recruited from (Pitman of the benzodiazepine midazolam and the opioid fentanyl.
2002; Weis 2006). Patient recruitment settings included intensive Participants in Pitman 2002 received supportive counselling from
care unit (ICU) wards (Delahanty 2012; Weis 2006), trauma the study nurse as appropriate during the course of the study.
centres (Mellman 2002; Schelling 2001; Stein 2007), and hospital
emergency departments (Hoge 2012; Pitman 2002; Shalev 2012; Outcomes
Zohar 2011a). The dichotomous outcome of number of participants diagnosed
with PTSD, as well as the secondary outcome of reduction in
PTSD symptom severity, were assessed for each group using the

Informed decisions.
Clinician-Administered PTSD Scale (CAPS) (Delahanty 2012; Hoge Ongoing studies

2012; Mellman 2002; Pitman 2002; Shalev 2012; Zohar 2011a),
We identified three ongoing randomised, placebo-controlled
the Post-Traumatic Stress Syndrome 10-Questions Inventory
studies of medication for the prevention of PTSD (Zohar 2009;
(PTSS-10Q-I) (Weis 2006), and the Structured Clinical Interview for
Zohar 2010; Zohar 2011b). These RCTs are being conducted by
DSM-IV (SCID-IV) (Schelling 2001) (see Characteristics of included
the same group, and assess the effectiveness of hydrocortisone
studies). The only study to use different measures of categorical
(Zohar 2011b), oxytocin (Zohar 2010), and escitalopram (Zohar
PTSD diagnosis and symptom severity was Stein 2007, in which the
2009) in preventing the onset of PTSD. The investigators of these
Comprehensive International Diagnostic Interview (CIDI) and the
studies require that participants are exposed to a traumatic event,
Posttraumatic Stress Disorder Checklist - Civilian Version (Weathers
with exposure to trauma assessed within six hours after the
2001) were used for these purposes, respectively. The follow-up
traumatic event in two studies (Zohar 2010; Zohar 2011b). All
assessments ranged from as early as two weeks after the trauma
participants are required to be 18 years and older to meet study
(Zohar 2011a) to a median of 31 months after the event (Schelling
criteria. The CAPS will be employed for PTSD diagnosis and/or
2001).
symptom severity assessment in both RCTs for which information
Quality of life was assessed using the 36-item Medical Outcomes on outcome assessment was available (Zohar 2009; Zohar 2010).
Study Short Form Survey (SF-36) (Delahanty 2012; Weis 2006).
Studies awaiting classification
Depression was assessed using the Center for Epidemiological
Studies – Depression Scale (CES-D) (Delahanty 2012; Stein 2007), as Placebo-controlled studies to be assessed for inclusion in the
well as visual analogue scales (VAS) in Zohar 2011a. Zohar 2011a review, pending additional information, include a RCT on the
was the only study in which anxiety symptoms was reported as efficacy of hydrocortisone in 92 high-risk survivors of cardiac
being assessed, using visual analogue scales. surgery, with primary outcomes including immunologic markers,
health care-related quality of life and PTSD (Azad 2007), as well as a
Excluded studies flexible dose trial of 10 mg to 40 mg of paroxetine over 12 weeks in a
We excluded six studies from the review. Exclusions were based on recently deployed military veteran sample (Marx 2006). In addition,
study design (Gelpin 1996; Vaiva 2003), and sample characteristics a 12-week placebo-controlled RCT of escitalopram for participants
(Davidson 2000; Martenyi 2002; Martenyi 2006; Schelling 2004) (see presenting with ASD criteria (A1 and A2 criteria and at least one
Characteristics of excluded studies). additional criterion) after a traumatic injury that occurred in the
prior three weeks, was discontinued (Simon 2005).
Ongoing studies
Risk of bias in included studies
Three studies are listed as ongoing: Zohar 2009; Zohar 2010; Zohar
2011b (see Characteristics of ongoing studies and Figure 1). We assessed the risk of bias using The Cochrane Collaboration's
'Risk of bias' tool for allocation concealment, blinding, incomplete
Studies awaiting classification outcome data, selective reporting and other potential sources of
bias. We classified seven of the included studies as being at high
Three trials were awaiting classification (Azad 2007; Marx 2006;
risk for at least one type of bias (see Figure 2 and Figure 3).
Simon 2005) (see Characteristics of studies awaiting classification
and Figure 1).
Figure 2. 'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages
across all included studies.

Informed decisions.
Figure 3. 'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Informed decisions.
Figure 3. (Continued)
Allocation as blinded in the study report (Schelling 2001; Shalev 2012; Stein
2007; Zohar 2011a), or through correspondence with the trial
Randomisation
investigators (Delahanty 2012; Hoge 2012). We classified Mellman
All included studies described the sequence generation as 2002 as being at 'high' risk, as no information on blinding of the
randomised. Schelling 2001 employed random permutation assessors was available for this study, while we rated the risk of
blocking of participants, while Shalev 2012 utilised an equipoise- bias as 'unclear' for two studies that described the study design as
stratified randomisation scheme, in which participants were "double-blinded" (Pitman 2002; Weis 2006).
given the option of requesting not to be assigned to two of
the four interventions assessed (prolonged exposure, cognitive Incomplete outcome data
therapy, escitalopram versus placebo, waiting list control). A central Three studies failed to provide sufficient information to determine
research pharmacy is described as setting up and maintaining whether the medication and placebo group were comparable with
the randomisation schedule in Stein 2007. Group assignment respect to drop-out proportions, or in terms of the demographic
was via a computer-generated randomisation list in Weis 2006 and clinical characteristics of those who withdrew (Hoge 2012;
and Zohar 2011a, while Mellman 2002 made reference to a Pitman 2002; Schelling 2001), garnering them a rating of 'unclear'
predetermined randomisation schedule. Delahanty 2012 employed risk. Substantially higher proportions of participants withdrew
a random number table to generate the randomisation schedule. from the medication than the placebo groups in Stein 2007
We classified these seven studies as 'low' risk, with the risk of (propanolol: 29.4%; gabapentin: 28.6%; placebo: 5.9%), Shalev
selection bias being designated as 'unclear' in the remaining 2012 (escitalopram: 26%; placebo: 60.9%) and Zohar 2011a
studies. (hydrocortisone: 40%; placebo: 20%), earning these studies a 'high'
risk rating. Studies classified as being at 'low' risk included two
Allocation concealment
RCTs that failed either to detect differences in attrition rates for
Eight of the studies provided sufficient information to be the comparison groups, or in between-group comparisons of the
considered at 'low' risk for selection bias resulting from failure to characteristics of those who withdrew (Delahanty 2012; Weis 2006),
conceal the agents provided to the study participants. Medication and one study in which no participants withdrew prior to follow-up
was prepared by a central pharmacy in three studies (Hoge 2012; (Mellman 2002). We rated the remaining three studies as being at
Mellman 2002; Stein 2007). In Schelling 2001, all syringes of 'unclear' risk with regard to attrition bias.
hydrocortisone and placebo were labelled "study medication",
while the medication and placebo were prepared by Lundbeck Selective reporting
Pharmaceutical and supplied to clinicians by a research associate It was unclear as to whether selective reporting took place in
in Shalev 2012. Weis 2006 described the preparation of the any of the included studies, either because the protocol was not
study agents in vials by a study nurse who was not involved available for the study (Delahanty 2012; Mellman 2002; Pitman
in the care of patients participating in the trial. Delahanty 2012 2002; Schelling 2001; Shalev 2012; Stein 2007; Weis 2006; Zohar
described the use of identical pills/blister packs to conceal the 2011a), or because where the protocol was available, insufficient
allocation of group assignment from the study investigators. information was provided on the planned outcomes to be assessed
Hydrocortisone or placebo were given intravenously in numbered, (Hoge 2012).
identical intravenous bags in Zohar 2011a. We assigned Pitman
2002 a rating of 'high' risk for selection bias, as no information Other potential sources of bias
regarding allocation concealment was provided in the study report.
Various methodological factors may have impacted on study
Blinding findings, including the use of concurrent medication (Schelling
2001; Weis 2006) and psychological treatments during the study
Blinding of participants and personnel (Pitman 2002); employment of invasive medical procedures in
We classified all of the studies included in the review as being some trials (Schelling 2001; Weis 2006); failure to identify the
at 'low' risk of performance bias, as they either described index trauma through specification of the DSM-IV PTSD criterion
themselves as "double-blinded" (Delahanty 2012; Pitman 2002; A (Delahanty 2012; Mellman 2002; Schelling 2001; Stein 2007;
Weis 2006; Zohar 2011a), or participants and personnel were Weis 2006); and industry funding of the trial (Schelling 2001;
explicitly described as blinded in the study report (Schelling 2001; Shalev 2012). We reserved ratings of 'high' risk of bias for
Shalev 2012; Stein 2007), or through correspondence with the trial three studies (Mellman 2002; Schelling 2001; Weis 2006), with all
investigators (Hoge 2012; Mellman 2002). others being classified as being at 'low' risk. In Mellman 2002,
termination of follow-up was dependent on the clinical assessment
Blinding of outcome assessors of PTSD-related symptoms, with only 50% of cases followed up
at the planned six-week assessment point. For both Schelling
We classified six of the studies included in the review as being
2001 and Weis 2006 participants receiving placebo required
at 'low' risk of detection bias, as they were explicitly described
higher norepinephrine doses than participants on hydrocortisone.
Informed decisions.
Although the difference in dosage of norepinephrine was Comparison 2: Beta-blockers versus placebo
not statistically significant in Schelling 2001, the investigators
Primary outcomes
conceded that this may be an alternative explanation of higher
PTSD onset in the placebo group, as previous studies have 2.1 Treatment efficacy: number of participants who developed PTSD
documented higher urinary excretion of norepinephrine in PTSD
Evidence for the efficacy of the beta-blocker propranolol was
patients.
assessed in three studies with 118 participants (Hoge 2012; Pitman
Effects of interventions 2002; Stein 2007). There was low quality evidence of an effect of
medication on the number of patients diagnosed with PTSD at
See: Summary of findings for the main comparison Propranolol follow-up (risk ratio (RR) 0.62; 95% CI 0.24 to 1.59; number needed
compared to placebo for preventing post-traumatic stress disorder to treat to benefit (NNTB) = 14 to 27; see Analysis 1.1).
(PTSD); Summary of findings 2 Hydrocortisone compared to
placebo for preventing post-traumatic stress disorder (PTSD) 2.2 Treatment acceptability: number of participants who withdrew
due to treatment-emergent side effects
See: 'Summary of findings' for the main comparisons of There were insufficient data to conduct a meta-analysis for
propranolol versus placebo (Summary of findings for the main this outcome. No participants in Stein 2007 reported stopping
comparison) and hydrocortisone versus placebo (Summary of medication during the first week of the two-week medication
findings 2). intervention due to treatment-emergent side effects. Neither Hoge
2012 nor Pitman 2002 provided data on the number of participants
Comparison 1: Benzodiazepines versus placebo
who withdrew during the treatment phase of the studies.
Primary outcome
Secondary outcomes
1.1 Treatment efficacy: number of participants who developed post-
traumatic stress disorder (PTSD) 2.3 Reduction in PTSD symptoms
The single trial of temazepam reported a higher proportion We did not synthesise PTSD symptom severity outcome data
of individuals on medication with a diagnosis of PTSD (6/11; provided for two of the propranolol randomised controlled trials
55%) at the final assessment than in the placebo group (3/11; (RCTs) (Hoge 2012; Pitman 2002), due to evidence that the scores
27%) (Mellman 2002). A post hoc Fisher's exact test of the data were not normally distributed. Taken individually, neither of these
provided by the investigators indicates that this difference was not trials demonstrated an effect of medication. Pitman 2002 failed
statistically significant (odds ratio (OR) 3.03, P value = 0.387). to detect a significant difference in mean score between the
propranolol and placebo groups on the CAPS at either one month
1.2 Treatment acceptability: number of participants who withdrew (mean (SD) 27.6 (15.7) versus 35.5 (21.5), respectively) or three
due to treatment-emergent side effects months follow-up (21.1 (12.5) versus 20.5 (21.7), respectively).
All patients completed the intervention and were assessed at Similarly, no differences were observed for scores on the CAPS
follow-up in Mellman 2002. in participants receiving placebo or propranolol in Hoge 2012,
after either one month (mean (SD) 28.5 (27.1) versus 28.5
Secondary outcomes (21.5), respectively) or three months (19 (25.8) versus 21.2 (26.1),
1.3 Reduction in PTSD symptoms
respectively). Although Stein 2007 did observe an overall reduction
in mean Posttraumatic Stress Disorder Checklist–Civilian Version
Total symptom severity scores on the Clinician-Administered PTSD (PCL-C) scores over time, these did not differ by comparison group
Scale (CAPS) decreased from 62.7 (standard deviation (SD) 24.1) at (F < 1).
baseline in the medication group and 56.7 (SD 17.8) in the placebo
group to 53.3 (SD 19.1) and 44.1 (SD 26.1) at the final assessment, 2.4 Reduction in comorbid symptom responses
respectively. There was no evidence that temazepam was more There were insufficient data to conduct a meta-analysis for
effective than placebo in reducing symptom severity (P value = 0.5; this outcome. Stein 2007 reported that a generalised estimating
Hedges' g = 0.39, 95% confidence interval (CI) -0.48 to 1.25). equation (GEE) analysis of changes in depressive symptoms on the
1.4 Reduction in comorbid symptom responses
Center for Epidemiological Studies – Depression Scale (CES-D) over
time failed to find an effect of propranolol.
There were no data to determine the effect of medication on
comorbid depression or anxiety symptoms. 2.5 Quality of life
1.5 Quality of life

There were no data to determine the effect of medication on quality
of life.
There were no data to determine the effect of medication on quality
of life. 2.6 Functional impairment
1.6 Functional impairment

functional disability.
functional disability. 2.7 Side effects
1.7 Side effects Stein 2007 reported that home nurse visits during the first three
days of treatment did not detect symptoms, such as postural
There were no data to determine treatment-emergent side effects. hypotension, which required the discontinuation of medication.

Informed decisions.
Hoge 2012 reported minimal side effects for either hydrocortisone There were no data to determine the effect of medication on
or placebo, with one incident of a fall (without serious injury) being treatment-emergent side effects .
attributed to the medication intervention. Pitman 2002 did not
provide data on treatment-emergent side effects . Comparison 4: Other medications versus placebo
Primary outcome
Comparison 3: Selective serotonin reuptake inhibitors (SSRIs)
versus placebo 4.1 Treatment efficacy: number of participants who developed PTSD
Primary outcomes We observed evidence for the efficacy of hydrocortisone in

preventing the onset of PTSD in a combined sample of 165
3.1 Treatment efficacy: number of participants who developed participants across four studies (RR 0.17; 95% CI 0.05 to 0.56;
PTSD see Analysis 2.1). The size of the medication effect translates
There was no evidence in the single trial of escitalopram that to a number needed to treat to benefit (NNTB) of between
medication was more effective than placebo in preventing the seven and 13 patients. We deemed the quality of the evidence
onset of PTSD, with 13/21 (61.9%) of participants receiving to be moderate. We conducted an additional post hoc analysis
medication and 10/18 (55.6%) in the placebo group meeting excluding Schelling 2001 and Weis 2006. We considered this
diagnostic criteria at the five-month assessment (P value > necessary given the observation of potential bias introduced
0.05) (Shalev 2012). Similar results were reported for the nine through greater administration of norepinephrine to septic shock
months post-trauma assessment (8/19 (42.1%) versus 8/17 (47.1%), and cardiac surgery patients receiving placebo than hydrocortisone
respectively). in these respective RCTs. The combined analysis of PTSD
prevention proportions excluding these studies still favoured the
3.2 Treatment acceptability: number of participants who withdrew hydrocortisone intervention (RR 0.12; 95% CI 0.02 to 0.94).
The administration of the anticonvulsant agent gabapentin, in Stein
Of the 23 participants randomised to 12 weeks of treatment with 2007, was associated with PTSD in two of 10 participants (20%) at
escitalopram or placebo, more than twice as many participants in four months after physical injury was sustained, compared to four
the escitalopram arm (13; 56.5%) withdrew prior to the end of the of 16 participants (25%) on placebo, a statistically non-significant
study than in the placebo arm (6; 26.1%). These participants were difference.
not contacted to ascertain reasons for study withdrawal (personal
communication, Dr. Shalev; 4 December 2013). 4.2 Treatment acceptability: number of participants who withdrew
Secondary outcomes
No data were provided on the proportion of participants who
3.3 Reduction in PTSD symptoms withdrew from treatment due to side effects in the majority of
There were insufficient data to conduct a meta-analysis for hydrocortisone trials (Schelling 2001; Weis 2006; Zohar 2011a).
this outcome. Clinician-rated total symptom severity scores on Delahanty 2012 observed that one of the 13 participants receiving
the CAPS at the five-month assessment were similar in the hydrocortisone who discontinued between randomisation and
escitalopram and placebo groups (mean (SD): 48.71 (29.63) versus the one-month assessment complained of dizziness. It was not
47.11 (20.13), respectively; Hedges' g = 0.06, 95% CI -0.58 to 0.7) possible to contact any of the remaining 20 participants (31.3%)
and nine-month post-trauma assessments (47.16 (26.71) versus across both comparison groups who withdrew prior to the three-
45.71 (26.14), respectively; Hedges' g = 0.05, 95% CI -0.61 to 0.72). month assessment. Although the number of participants who
Similarly, no statistically significant differences were observed in withdrew as a result of treatment-emergent side effects was
comparisons across groups on the re-experiencing, hyperarousal not reported in the single trial of gabapentin (Stein 2007), the
and avoidance PTSD symptom cluster subscales of the CAPS. investigators noted that "subjective reporting by subjects indicated
Finally, participants' own ratings of their PTSD symptoms, as that study medications were well tolerated" (p927).
assessed using the PTSD Symptom Scale – Self-Report Version
Secondary outcomes
(PSS-SR), did not differ by group at either time point.
4.3 Reduction in PTSD symptoms
Data were not available for this outcome for two of the
There were no data to determine the effect of medication on hydrocortisone RCTs (Weis 2006; Zohar 2011a). In addition, data
comorbid depression or anxiety symptoms. from the PTSS-10Q-I at the three-month assessment in Schelling
2001 was not normally distributed and therefore studies could not
3.5 Quality of life
be pooled in the analysis. Delahanty 2012, Weis 2006 and Zohar
There were no data to determine the effect of medication on quality 2011a demonstrated the superiority of hydrocortisone compared
of life. to placebo in reducing PTSD symptom severity, with substantial
differences being observed on the CAPS in Delahanty 2012
3.6 Functional impairment after three months (mean of 19.4 versus 31.3, respectively), and
There were no data to determine the effect of medication on on the Post-Traumatic Stress Syndrome 10-Questions Inventory
functional disability. (PTSS-10Q-I) after six months in Weis 2006 (median of 15.5 versus
25.5, respectively). Zohar 2011a reported a significant group
3.7 Side effects difference favouring hydrocortisone at both two weeks and three
months after a single dose administration (P value < 0.25 and P
value < 0.2, respectively). Finally, Schelling 2001 was not able to

Informed decisions.
detect differences on the PTSS-10Q-I after a median of 31 months Sensitivity analyses

post-intervention between the hydrocortisone and control groups
Use of an intention-to-treat (ITT) versus observed cases sample
(median of 27 and 36 points, respectively).
in calculating response to treatment
Stein 2007 reported that symptoms of PTSD did not decline Effect estimates for the hydrocortisone versus placebo
over time in the gabapentin compared to the placebo group. No comparisons were similar, regardless of whether the effect estimate
additional data on this outcome were provided in the study report. was calculated based on the proportion of participants who
developed PTSD at follow-up out of the ITT (RR 0.17; 95% CI 0.05
to 0.56) or observed cases sample (RR 0.20; 95% CI 0.06 to 0.64)
There were insufficient data to conduct a meta-analysis of the Analysis 2.2. We observed a similar finding with respect to the
effect of hydrocortisone or gabapentin on comorbid depression propranolol versus placebo comparison (ITT sample: RR 0.62; 95%
or anxiety symptoms. Based on a series of repeated-measures CI 0.24 to 1.59; observed cases sample: RR 0.73; 95% CI 0.29 to 1.84)
ANCOVA analyses of outcomes assessed at one and three months Analysis 1.2.
post-injury, Delahanty 2012 reported that participants treated with
hydrocortisone demonstrated reduced symptoms of depression on Publication bias
the CES-D compared to the control group (F(1,18) = 7.7, P value = The greatest number of studies in any comparison in this review
0.01) over time. Rates of major depressive disorder (MDD) assessed was equal to four (Analysis 2.1). We regarded this as insufficient
using the Comprehensive International Diagnostic Interview (CIDI) to warrant conducting qualitative or quantitative tests that would
in Stein 2007 were similar in the gabapentin and placebo groups inform the assessment of publication bias.
four months after the traumatic event (gabapentin: 2/10; placebo:
4/16). DISCUSSION
4.5 Quality of life
Summary of main results
There were insufficient data to conduct a meta-analysis for this
The largest number of randomised controlled trials (RCTs)
outcome. Delahanty 2012 reported improvements in quality of life
investigating the effectiveness of medication in preventing the
assessed using the SF-36 scale over multiple time points (F(1,18)
onset of post-traumatic stress disorder (PTSD) are for the steroid
= 5.3, P value = 0.03). Similarly, Weis 2006 reported improvements
hydrocortisone and the beta-blocker propranolol. We observed
in the hydrocortisone group compared to placebo on the SF-36
evidence of moderate quality for the efficacy of hydrocortisone in
physical and mental summary scores, with statistically significant
preventing PTSD in four studies following exposure to a traumatic
increases observed in the medication group on seven of the eight
event (see Summary of findings 2). Assuming a baseline onset
subscales of this instrument.
of PTSD of 10% to 20% for studies that assessed participants
4.6 Functional impairment a median of four and a half months after trauma exposure,
this translates to having to treat seven to 13 patients with
There were no data to determine the effect of either hydrocortisone hydrocortisone in order for the agent to prevent the onset of
or gabapentin on functional disability. PTSD in one patient. A synthesis of the low quality results from
three RCTs of propranolol did not support the ability of this agent
4.7 Side effects
to prevent the onset of PTSD (see Summary of findings for the
There were no differences in the number of side effects main comparison). This was despite promising findings from a
between the medication and placebo groups in the trials that series of three open-label studies employing symptom provocation
reported these. With regard to hydrocortisone, Schelling 2001 paradigms, in which the repeated administration of propranolol
reported that one individual receiving medication experienced an was associated with reduced numbers of participants diagnosed
intestinal haemorrhage that was treated conventionally (personal with PTSD (Brunet 2011). The solitary trials of escitalopram,
communication); treatment was reported in Zohar 2011a as being temazepam and gabapentin failed to demonstrate that short-term
"well tolerated with no noticeable side effects" (p800); Weis 2006 interventions employing these medications affect the onset of
declared the number of patients in their study as being "too small PTSD.
to detect these [side] effects" (p282); and data on side effects were
Where provided, drop-outs due to side effects of medication were
not reported in Delahanty 2012. Information on side effects was not
comparable between the medication and placebo interventions,
reported for the trial of gabapentin, though all medications tested
suggesting that the agents were well tolerated. This may be due to
in this study were described as being very well tolerated, based on
a variety of factors, including (a) the short duration of treatment for
subjective patient report (Stein 2007).
many of the trials of hydrocortisone and propranolol in particular,
Heterogeneity with Zohar 2011a, for instance, administering hydrocortisone at
a single session, (b) the fact that treatment often took place at
We found no evidence of heterogeneity for trials of hydrocortisone least partly in a controlled environment, such as within trauma
(Chi2 = 0.43, P value = 0.93, I2 = 0%, see Analysis 2.1) and propranolol centres, where medication response and adherence could be
(Chi2 = 0.18, P value = 0.91, I2 = 0%, see Analysis 1.1), when closely monitored, and dosages adjusted accordingly, and (c) that
investigating the efficacy of treatment in preventing PTSD onset. dosages were in the low range for agents that were administered
over extended periods, such as the administration of 20 mg/day
Subgroup analyses of escitalopram over 12 weeks (Shalev 2012). Conclusions that
There were insufficient studies to conduct a subgroup analysis medications are well tolerated should be regarded as preliminary,
(fewer than 10). however, given that data on treatment-emergent side effects were

Informed decisions.
often not reported, regardless of whether these led to study We judged the evidence for the efficacy of hydrocortisone in
withdrawal. preventing PTSD to be of moderate quality (see Summary of
findings 2). Accordingly, further research is likely to have an
Reductions in PTSD symptom severity were observed in three of the important impact on our confidence in the estimate of this
four studies of hydrocortisone, with null findings reported for all agent's treatment effect, and may even change that estimate. The
of the propranolol studies, as well as for the trials of escitalopram, low quality rating of the corresponding estimate for propranolol
gabapentin and temazepam. A narrative review indicates that indicates that the size of the non-significant effect of this agent
hydrocortisone may improve quality of life (Delahanty 2012; Weis in preventing PTSD is likely to change. This reflects shortcomings
2006), and possibly reduce symptoms of depression (Delahanty in the data set contributing to this outcome, including the small
2012), in individuals who have been treated within 12 hours of the number of studies, missing data and small samples included in
traumatic event. these studies. These shortcomings are likely to be equally pertinent
with respect to the null findings for the trials of escitalopram,
Overall completeness and applicability of evidence temazepam and gabapentin. Another potential explanation for the
Completeness of evidence observation that the outcomes assessed in this review appeared
to be relatively insensitive to the effects of medications may be
Reviews of the body of evidence for pharmacotherapy of PTSD the relatively low background rate of PTSD in the samples that
have concluded that selective serotonin reuptake inhibitors constituted the evidence base for this review, as discerned from
(SSRIs) are first-line medication agents for the treatment of the proportion of individuals in the placebo groups who were
PTSD (Ipser 2011), with promising findings for the selective diagnosed with chronic PTSD (31.6%).
noradrenergic reuptake inhibitor (SNRI) venlafaxine and the
atypical antipsychotic risperidone. Despite a comprehensive The absence of any evidence that the benzodiazepine temazepam
search, we were only able to find a single trial testing the efficacy of prevents PTSD or reduces PTSD symptoms is consistent with prior
a SSRI medication (escitalopram) in preventing PTSD. The efficacy negative findings reported for a non-randomised controlled trial
of other medication classes that are frequently considered for of clonazepam or alprazolam (Gelpin 1996). Nevertheless, the
treating PTSD in the prevention of the onset of this disorder, such limitations of the temazepam study (its small size (N = 21), the
as the tricyclic antidepressants (TCAs) and mono-amine oxidase fact that assessments of PTSD were conducted less than three
inhibitors (MAOIs), has also not been investigated. months after the trauma event, that in one half of the cases the
intervention was terminated when clinical judgement indicated the
Limited data were available to assess the effect of medication on initiation of other medication treatment, and that participants were
comorbid symptoms of depression and anxiety, as well as quality not required to endorse the Diagnostic and Statistical Manual (DSM-
of life. None of the included studies assessed post-treatment IV) criterion A for PTSD) suggest that conclusive evidence regarding
changes in functional ability. Additionally, the paucity of studies the efficacy of benzodiazepines in preventing PTSD awaits further
and missing data hampered our ability to assess the degree to controlled studies.
which methodological differences between studies might have
systematically influenced differences observed in the primary Potential biases in the review process
treatment outcome. Accordingly, our conclusions are limited to a
small range of drugs and many of our review questions remain We minimised overall bias in this review process through
unanswered. conducting an extensive search for studies meeting rigorous
methodological inclusion criteria, and through repeated attempts
Applicability of evidence to obtain missing data from the trial investigators. Nevertheless,
the small number of eligible studies compromised our ability
The outcomes of this review may be generalisable to a diverse range to assess the extent to which biases, with respect to which
of settings. Studies were conducted in the United States of America studies were published, might have influenced the review findings.
(Delahanty 2012; Mellman 2002; Pitman 2002; Stein 2007), Germany Furthermore, the post hoc addition of propranolol may have also
(Schelling 2001; Weis 2006), and Israel (Zohar 2011a), in both out- introduced bias as a result of the small number of trials we found,
and inpatient settings, with interventions targeting both males and and may be susceptible to publication bias, though this was not
females across a wide age range. Differences in treatment delivery, tested for. It is also noteworthy that all seven included RCTs
as well as the background and training of study investigators and that provided information on the number of sites recruited from
outcome assessors, increases the likelihood that the findings of were classified as single-site studies. Single-site RCTs may provide
this review are applicable to a range of developed and developing biased estimates of treatment effect, as a recent meta-analysis
nation contexts. demonstrated that the size of these estimates are larger than those
observed with multi-centre trials (Dechartres 2011).
Quality of the evidence
We included nine studies with 345 participants in the review. Seven Agreements and disagreements with other studies or
of the included RCTs possessed a high risk of bias related to at reviews
least one aspect of study design, with weaknesses most commonly
The conclusions of the review are only partially consistent
observed with respect to allocation concealment and differential
with those arrived at by other systematic reviews on the
attrition in the medication and control groups. In addition, the
effects of pharmacological interventions to prevent PTSD (Bisson
effects of medication may have been confounded in a number of
2010; Sones 2011). For instance, Bisson 2010 determined that
studies of patients in emergency care, trauma centre and surgery
evidence for the effectiveness of hydrocortisone and various
settings who were receiving other medications concurrently with
other medications was inconclusive, with cognitive behavioural
the intervention to prevent PTSD (Schelling 2001; Weis 2006).
techniques identified as the most beneficial intervention to prevent

Informed decisions.
PTSD. Similar conclusions were reached in a review conducted there is not sufficient evidence at this stage to endorse any
by Forneris 2013. Sones 2011, on the other hand, suggested that medication for the prevention of PTSD.
several pharmacological interventions for PTSD prevention might
be of benefit, including propranolol, morphine, glucocorticoids and Implications for research
SSRIs, based on a review of RCTs and open-label studies. These
This review highlights the need for additional randomised
studies differed from the current review in that they included
controlled trials (RCTs) to evaluate the effectiveness of medications
data from preventative studies containing patients diagnosed
to prevent PTSD, including those agents assessed in this
with PTSD. The finding of minimal effect of the benzodiazepine
review (hydrocortisone, propranolol, escitalopram, gabapentin
temazepam in reducing the onset of PTSD following trauma
and temazepam). Methodological limitations of the studies
exposure is consistent with an earlier study (Gelpin 1996), in which
included in this review, and formalised using the GRADE approach,
the sequential administration of clonazepam (mean 2.7 mg/day) or
include small sample size, no description of methods to conceal
alprazolam (mean 2.5 mg/day) to emergency department trauma-
medication allocation adequately and differences in attrition rate
exposed patients, on average within a week after trauma exposure,
observed between comparison groups. Where possible, these
failed to reduce PTSD symptoms, as assessed using the Mississippi
limitations should be addressed in future studies.
Rating Scale for Combat-Related PTSD-civilian version.
RCTs of medication to prevent PTSD are challenging on many
Other Cochrane reviews on interventions to prevent PTSD have
fronts, including the unique ethical considerations involved in
been conducted, with a focus on single-session psychological
medicating individuals prior to presentation with a trauma-
debriefing interventions (Rose 2002), multiple-session early
associated psychiatric diagnosis, as well as difficulties in recruiting
psychological interventions (Roberts 2010), and psychosocial
participants from this patient population. By pooling participants
interventions (De Silva 2009; Peñalba 2009). This review represents
across multiple centres, future studies would ensure sufficient
an extension of this body of work, with a specific focus
power to investigate the effect of a number of factors that may
on pharmacological interventions for the prevention of PTSD
affect treatment response, including the optimal clinical window
development.
after trauma exposure for the initiation of treatment, dosage and
duration of treatment, and the moderating effect of clinical (e.g.
AUTHORS' CONCLUSIONS
trauma type) and demographic factors (e.g. age, gender, ethnicity)
Implications for practice in predicting response to medication.
The only agent for which there was preliminary evidence of efficacy ACKNOWLEDGEMENTS
in the prevention of post-traumatic stress disorder (PTSD) following
trauma exposure was hydrocortisone. Absence of evidence for the We would like to thank Drs. Schelling, Mellman, Delahanty, Shalev,
efficacy of propranolol, escitalopram, gabapentin and temazepam Hoge and Cohen (on behalf of Zohar 2011a) for responding to
in preventing PTSD or reducing symptom severity argues against requests for additional data for the update of the review. We are
their routine use for this indication. This is particularly the case also grateful to Dr. Nandi Siegfield and Dr. Tamara Kredo for their
given the low quality of the evidence for propranolol, resulting continuous support.
partly from methodological shortcomings that were also apparent
CRG Funding Acknowledgement:
in single trials of gabapentin and temazepam. Although the
The National Institute for Health Research (NIHR) is the largest
limited data on treatment-emergent side effects suggest that all
single funder of the Cochrane Depression, Anxiety and Neurosis
of the medications assessed were well tolerated by patients,
Group.
this should be balanced against the additional complications in
administering these medications in emergency department and Disclaimer:
trauma clinic settings (including possible interactions with other The views and opinions expressed therein are those of the authors
medications being administered to treat the trauma). Based on and do not necessarily reflect those of the NIHR, NHS or the
these considerations, and pending further research, we believe Department of Health.

Informed decisions.
REFERENCES
References to studies included in this review Shalev AY, Ankri Y, Israeli-Shalev Y, Peleg T, Adessky R,
Freedman S. Prevention of posttraumatic stress disorder
Delahanty 2012 {published data only}
by early treatment: results from the Jerusalem Trauma
* Delahanty DL, Gabert-Quillen C, Ostrowski SA, Nugent NR, Outreach And Prevention study. Archives of General Psychiatry
Fischer B, Morris A, et al. The efficacy of initial hydrocortisone 2012;69(2):166-76.
administration at preventing posttraumatic distress in
adult trauma patients: a randomized trial. CNS Spectrums Shalev AY, Ankri YL, Peleg T, Israeli-Shalev Y, Freedman S.
2013;18:103-11. Barriers to receiving early care for PTSD: results from the
Jerusalem trauma outreach and prevention study. Psychiatric
Delahanty DL, Ostrowski S, Nugent N, Gabert C, Fallon W. Services 2011;62:765–73.
Hydrocortisone as a secondary intervention to prevent
subsequent PTSD symptoms [conference abstract]. Stein 2007 {published data only}
Psychosomatic Medicine [abstracts from the 69th Annual Meeting Stein MB, Kerridge C, Dimsdale JE, Hoyt DB. Pharmacotherapy
of the American Psychosomatic Society; 2011 Mar 9-12; San to prevent PTSD: results from a randomised controlled proof-of-
Antonio, TX United States] 2011;73(3):A107. concept trial in physically injured patients. Journal of Traumatic
Stress 2007;20(6):923-32.
Hoge 2012 {published data only}
Hoge EA, Worthington JJ, Nagurney JT, Chang Y, Kay EB, Weis 2006 {published data only}
Feterowski CM, et al. Effect of acute posttrauma propranolol on Weis F, Kilger E, Roozendaal B, De Quervain D-F, Lamm P,
PTSD outcome and physiological responses during script-driven Schmidt M, et al. Stress doses of hydrocortisone reduce chronic
imagery. CNS Neuroscience and Therapeutics 2012;18(1):21-7. stress symptoms and improve health-related quality of life in
high-risk patients after cardiac surgery: a randomized study.
Mellman 2002 {published data only}
Cardiopulmonary Support and Physiology 2006;131:277-82.
* Mellman TA, Bustamante V, Daniella D, Fins AI. Hypnotic
medication in the aftermath of trauma. Journal of Clinical Zohar 2011a {published data only}
Psychiatry 2002;63(12):1183-4. Zohar J, Yahalom H, Kozlovsky N, Cwikel-Hamzany S,
Matar MA, Kaplan Z, et al. High dose hydrocortisone
Mellman TA, Byers PM, Augenstein JS. Pilot evaluation of
immediately after trauma may alter the trajectory of PTSD:
hypnotic medication during acute traumatic stress response.
interplay between clinical and animal studies. European
Journal of Traumatic Stress 1998;11(3):563-9.
Neuropsychopharmacology 2011;21:796–809.
Pitman 2002 {published data only}
Pitman RK, Sanders KM, Zusman RM, Healy AR, Cheema F, References to studies excluded from this review
Lasko NB, et al. Pilot study of secondary prevention of
posttraumatic stress disorder with propranolol. Biological Davidson 2000 {published data only}
Psychiatry 2002;51:189-92. Davidson J, Londborg P, Pearlstein T, Rothbaum B, Brady K,
Farfel G. Sertraline and posttraumatic stress disorder: results
Schelling 2001 {published data only} of 24 weeks of open-label sertraline followed by a 28-week
* Schelling G, Briegal J, Roozendaal B, Stoll C, Rothenhausler H- discontinuation study. European Neuropsychopharmacology
B, Kapfhammer HP. The effect of stress doses of hydrocortisone 2000;10(Suppl 3):S349.
during septic shock on post traumatic stress disorder in
survivors. Biological Psychiatry 2001;50:978-85. Gelpin 1996 {published data only}
Gelpin E, Bonne O, Peri T, Brandes D, Shalev AY. Treatment of
Schelling G, Stoll C, Kapfhammer HP, Rothenhäusler HB, recent trauma survivors with benzodiazepines: a prospective
Krauseneck T, Durst K, et al. The effect of stress doses of study. Journal of Clinical Psychiatry 1996;57(9):390-4.
hydrocortisone during septic shock on posttraumatic stress
disorder and health-related quality of life in survivors. Critical Martenyi 2002 {published data only}
Care Medicine 1999;27(12):2678-83. Martenyi F, Brown EB, Zhang H, Koke SC, Prakash A. Fluoxetine
v. placebo in prevention of relapse in post-traumatic stress
Schelling G, Stoll C, Wichmann A, Haller M, Schuffel W, Briegel J.
disorder. British Journal of Psychiatry 2002;181:315-20.
The effect of hydrocortisone (HC) during septic shock on
incidence and intensity of post-traumatic stress disorder (PTSD) Martenyi 2006 {published data only}
in long term survivors. Critical Care Medicine 1998;26(1):131A.
Martenyi F, Brown EB, Zhang H, Prakash A, Koke SC. Fluoxetine
Shalev 2012 {published data only} versus placebo in posttraumatic stress disorder. Journal of
Clinical Psychiatry 2002;63(3):199-206.
Galatzer-Levy IR, Ankri Y, Freedman S, Israeli-Shalev Y,
Roitman P, Gilad M, et al. Early PTSD symptom trajectories: Martenyi F, Soldatenkova V. Fluoxetine in the acute treatment
persistence, recovery, and response to treatment: results from and relapse prevention of combat-related post-traumatic stress
the Jerusalem trauma outreach and prevention study (J-TOPS). disorder: analysis of the veteran group of a placebo-controlled
PloS One 2013;8(8):e70084.

Informed decisions.
randomized clinical trial. European Neuropsychopharmacology Zohar J. Randomized placebo-controlled trial of hydrocortisone
2006;16(5):340-9. in PTSD prophylaxis. http://projectreporter.nih.gov; Project
Number: 4R01MH086570-03 (accessed 12 March 2014).
Schelling 2004 {published data only}
Schelling G, Kilger E, Roozendaal B, de Quervain DJ-F, Briegel J,
Dagge A, et al. Stress doses of hydrocortisone, traumatic Additional references
memories, and symptoms of posttraumatic stress disorder in APA 1994
patients after cardiac surgery: a randomized study. Society of
American Psychiatric Association. Diagnostic and Statistical
Biological Psychiatry 2004;55:627–33.
Manual of Mental Disorders. 4th Edition. Washington, DC:
Vaiva 2003 {published data only} American Psychiatric Association, 1994.
Vaiva G, Ducrocq F, Jezequel K, Averland B, Lestavel P, Brunet A, Beck 1961
et al. Immediate treatment with propranolol decreases
Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An
posttraumatic stress disorder two months after trauma. Society
inventory for measuring depression. Archives of General
of Biological Psychiatry 2003;54:947-9.
Psychiatry 1961;4:561-71.
Besnard 2012
References to studies awaiting assessment
Besnard A, Caboche J, Laroche S. Reconsolidation of memory: a
Azad 2007 {unpublished data only} decade of debate. Progress in Neurobiology 2012;99(1):61-80.
* Azad S, Shelling G. Influence of Hydrocortisone on
Immunologic Markers and Health Care Related Quality of Life Bisson 2010
in Patients After Cardiac Surgery. http://clinicaltrials.gov/ct2/ Bisson J. Post-traumatic stress disorder. Clinical Evidence
show/NCT00490828 2007 (accessed 12 March 2014). 2010;2:1-62.
Hauer D, Weis F, Campolongo P, Schopp M, Beiras-Fernandez A, Blake 1995

Strewe C, et al. Glucocorticoid-endocannabinoid interaction Blake DD, Weathers FW, Nagy LM, Kaloupek DG, Gusman FD,
in cardiac surgical patients: relationship to early cognitive Charney DS, et al. The development of a clinician-administered
dysfunction and late depression. Reviews in the Neurosciences PTSD scale. Journal of Traumatic Stress 1995;8(1):75-90.
2012;23(5-6):681-90.
Bremner 2004
Marx 2006 {unpublished data only}
Bremner JD, Vermetten E. Neuroanatomical changes associated
Marx CE. Secondary Prevention With Paroxetine vs. Placebo with pharmacotherapy in posttraumatic stress disorder. Annals
in Subthreshold Posttraumatic Stress Disorder (PTSD). http:// of the New York Academy of Science 2004;1032:154-7.
clinicaltrials.gov/ct2/show/NCT00560612 2007 (accessed 12
March 2014). Brewin 2000
Simon 2005 {unpublished data only} Brewin CR, Andrews B, Valentine JD. Meta-analysis of
risk factors for posttraumatic stress disorder in trauma-
* Simon NM. SSRI Administration to Reduce Acute Stress exposed adults. Journal of Consulting and Clinical Psychology
Disorder Symptoms and Prevent Depression and PTSD in 2000;68(5):748-66.
Physical Trauma Victims. http://clinicaltrials.gov/ct2/show/
NCT00114374 2005 (accessed 12 March 2014). Brunet 2008
Brunet A, Orr SP, Tremblay J, Robertson K, Nader K, Pitman RK.
Effect of post-retrieval propranolol on psychophysiologic
References to ongoing studies
responding during subsequent script-driven traumatic imagery
Zohar 2009 {unpublished data only} in post-traumatic stress disorder. Journal of Psychiatric Research
Zohar J. PTSD Prevention Using Escitalopram. http:// 2008;42:503–6.
Brunet 2011
March 2014).
Brunet A, Poundja J, Tremblay J, Bui E, Thomas E, Orr SP, et
Zohar 2010 {unpublished data only} al. Trauma reactivation under the influence of propranolol
Zohar J. The Efficacy of a Single Dose of Intranasal Oxytocin in decreases posttraumatic stress symptoms and disorder: 3
the Prevention of Post Traumatic Stress Disorder (PTSD). http:// open-label trials. Journal of Clinical Psychopharmacology
clinicaltrials.gov/ct2/show/NCT01039766 2009, issue accessed 2011;31:547-50.
12 March 2014.
Bryant 2003
Zohar 2011b {published data only} Bryant RA. Early predictors of posttraumatic stress disorder.
Zohar J. Efficacy of Single Dose IV Hydrocortisone in Post Biological Psychiatry 2003;53:789-95.
Traumatic Stress Disorder (PTSD) Prevention. http://
March 2014).

Informed decisions.
de Jong 2001 members from Iraq and Afghanistan. Military Medicine

de Jong JTVM, Komproe IH, Van Ommeren M, Masri MEI, 2007;172(4):359-63.
Araya M, Khaled N, et al. Lifetime events and posttraumatic
Forneris 2013
stress disorder in 4 postconflict settings. American Medical
Association 2001;286:555-62. Forneris CA, Gartlehner G, Brownley KA, Gaynes BN, Sonis J,
Coker-Schwimmer E, et al. Interventions to prevent post-
de Quervain 2009 traumatic stress disorder: a systematic review. American
de Quervain DJF, Aerni A, Schelling G, Roozendaal B. Journal of Preventive Medicine 2013;44(6):635–50.
Glucocorticoids and the regulation of memory in health and
Gillies 2012
disease. Frontiers in Neuroendocrinology 2009;30:358-70.
Gillies D, Taylor F, Gray C, O'Brien L, D'Abrew N.
De Silva 2009 Psychological therapies for the treatment of post-traumatic
De Silva M, MacLachlan M, Devane D, Desmond D, Gallagher P, stress disorder in children and adolescents. Cochrane
Schnyder U, et al. Psychosocial interventions for the Database of Systematic Reviews 2012, Issue 12. [DOI:
prevention of disability following traumatic physical injury. 10.1002/14651858.CD006726.pub2]
Cochrane Database of Systematic Reviews 2009, Issue 4. [DOI:
Guy 1976
10.1002/14651858.CD006422.pub3]
Guy W. ECDEU Assessment Manual for Psychopharmacology.
Dechartres 2011 Washington, DC: US National Institutes of Health, 1976.
Dechartres A, Boutron I, Trinquart L, Charles P, Ravaud P. Single-
Hamilton 1959
center trials show larger treatment effects than multicenter
trials: evidence from a meta-epidemiologic study. Annals of Hamilton M. The assessment of anxiety states by rating. British
Internal Medicine 2011;155:39-51. Journal of Medical Psychology 1959;32:50-5.
Deeks 2001 Hamilton 1960

Deeks JJ, Altman DG. Effect measures for meta-analysis of trials Hamilton M. A rating scale for depression. Journal of Neurology,
with binary outcomes. In: Egger M, Davey Smith G, Altman DG Neurosurgery and Psychiatry 1960;23:56-62.
editor(s). Systematic Reviews in Health Care: Meta-analysis in
Hebert 1996
Context. 2nd Edition. London (UK): BMJ Publication Group,
2001. Hebert MA, Potegal M, Moore T, Evenson AR, Meyerhoff JL.
Diazepam enhances conditioned defeat in hamsters
Deeks 2002 (Mesocricetus auratus). Pharmacology, Biochemistry and
Deeks JJ. Issues in the selection of a summary statistic for meta- Behavior 1996;55(3):405-13.
analysis of clinical trials with binary outcomes. Statistics in
Heinzelmann 2013
Medicine 2002;21(11):1575-600.
Heinzelmann M, Gill J. Epigenetic mechanisms shape the
Deeks 2011 biological response to trauma and risk for PTSD: a critical
Deeks JJ, Higgins JPT, Altman DG (editors). Chapter 9: Analysing review. Nursing Research and Practice 2013;2013:417010.
data and undertaking meta-analyses. In: Higgins JPT, Green
Higgins 2003
S (editors). Cochrane Handbook for Systematic Reviews
of Interventions. Version 5.1.0 [updated March 2011]. The Higgins JT, Thompson SG, Deeks JJ, Altman DG. Measuring
Cochrane Collaboration, 2011. inconsistency in meta-analyses. BMJ 2003;327(6):557-60.
Del Re 2013 [Computer program] Higgins 2011a

Del Re, AC. compute.es: Compute Effect Sizes. R package Higgins JPT, Green S (editors). Cochrane Handbook for
version 0.2-2. http://cran.r-project.org/web/packages/ Systematic Reviews of Interventions Version 5.1.0 [updated
compute.es, 2013. March 2011]. The Cochrane Collaboration, 2011. Available from
www.cochrane-handbook.org.
Egger 1997
Higgins 2011b
Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis
detected by a simple, graphical test. BMJ 1997;315:629-34. Higgins JPT, Deeks JJ, Altman DG. Chapter 16: Special topics in
statistics. In: Higgins JPT, Green S (editors). Cochrane Handbook
Elbourne 2002 for Systematic Reviews of Interventions. Version 5.1.0 [updated
Elbourne ER, Altman DG, Higgins JPT, Curtin F, Worthington HV, March 2011]. The Cochrane Collaboration, 2011.
Vail A. Meta-analyses involving cross-over trials: methodological
Ipser 2011
issues. International Journal of Epidemiology 2002;31:140-9.
Ipser JC, Stein DJ. Evidence-based pharmacotherapy of post-
Erbes 2007 traumatic stress disorder (PTSD). International Journal of
Erbes C, Westermeyer J, Engdahl B, Johnsen E. Post-traumatic Neuropsychopharmacology 2011;15(6):825-40. [DOI: 10.1017/
stress disorder and service utilization in a sample of service S1461145711001209]

Informed decisions.
Kessler 1995 Nickerson 2013

Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Nickerson A, Aderka IM, Bryant RA, Hofmann SG. The role of
Posttraumatic stress disorder in the National Comorbidity attribution of trauma responsibility in posttraumatic stress
Survey. Archives of General Psychiatry 1995;52(12):1048-60. disorder following motor vehicle accidents. Depression and
Anxiety 2013;30(5):483-8.
Kessler 2005
Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Norris 2007
Walters EE. Lifetime prevalence and age-of-onset distributions Norris F, Sloane LB. The epidemiology of trauma and PTSD. In:
of DSM-IV disorders in the National Comorbidity Survey Friedman MJ, Keane TM, Resick PA editor(s). Handbook of PTSD:
Replication. Archives of General Psychiatry 2005;62(2):593-602. Science and Practice. New York, NY: Guilford Press, 2007:78-98.
Krystal 2009 Ozer 2003

Krystal JH, Neumeister A. Noradrenergic and serotonergic Ozer EJ, Best SR, Lipsey TL, Weiss DS. Predictors of
mechanisms in the neurobiology of posttraumatic stress posttraumatic stress disorder and symptoms in adults: a meta-
disorder and resilience. Brain Research 2009;1293:13-23. analysis. Psychological Bulletin 2003;129(1):52-73.
Lumley 2000 Peñalba 2009

Lumley LA, Charles RF, Charles RC, Hebert MA, Morton DM, Peñalba V, McGuire H, Leite JR. Psychosocial interventions
Meyerhoff JL. Effects of social defeat and of diazepam on for prevention of psychological disorders in law enforcement
behavior in a resident-intruder test in male DBA/2 mice. officers. Cochrane Database of Systematic Reviews 2008, Issue 3.
Pharmacology, Biochemistry and Behavior 2000;67(3):433-47. [DOI: 10.1002/14651858.CD005601.pub2]
Lundbeck 2003 Pitman 1989

Lundbeck Institute. Psychotropics. http:// Pitman RK. Post-traumatic stress disorder, hormones, and
www.psychotropics.dk/ 2003. memory. Biological Psychiatry 1989;26(3):221-3.
Massad 2006 Pitman 2005

Massad PM, Hulsey TL. Causal attributions in posttraumatic Pitman RK, Delahanty DL. Conceptually driven pharmacologic
stress disorder: implications for clinical research and practice. approaches to acute trauma. CNS Spectrums 2005;10:99-106.
Psychotherapy (Chic) 2006;43(2):201-15.
Robert 1999
Mayou 2000 Robert R, Blakeney PE, Villarreal C, Rosenberg L, Meyer WJ 3rd.
Mayou RA, Ehlers A, Hobbs M. Psychological debriefing for road Imipramine treatment in pediatric burn patients with symptoms
traffic accident victims. Three-year follow-up of a randomised of acute stress disorder: a pilot study. Journal of the American
controlled trial. British Journal of Psychiatry 2000;176:589-93. Academy of Child & Adolescent Psychiatry 1999;38(7):873-82.
McCleery 2004 Robert 2008

McCleery JM, Harvey AG. Integration of psychological and Robert R, Tcheung WJ, Rosenberg L, Rosenberg M, Mitchell C,
biological approaches to trauma memory: implications for Villarreal C, et al. Treating thermally injured children suffering
pharmacological prevention of PTSD. Journal of Traumatic symptoms of acute stress with imipramine and fluoxetine: a
Stress 2004;17(6):485-96. randomized, double-blind study. Burns 2008;34(7):919-28.
Meewisse 2007 Roberts 2010

Meewisse ML, Reitsma JB, de Vries GJ, Gersons BP, Olff M. Roberts NP, Kitchiner NJ, Kenardy J, Bisson JI. Multiple session
Cortisol and post-traumatic stress disorder in adults: systematic early psychological interventions for the prevention of post-
review and meta-analysis. British Journal of Psychiatry traumatic stress disorder. Cochrane Database of Systematic
2007;191:387-92. Reviews 2010, Issue 3. [DOI: 10.1002/14651858.CD006869.pub2]
Mueser 2008 Rose 2002

Mueser KT, Rosenberg SD, Xie H, Jankowski MK, Bolton EE, Rose SC, Bisson J, Churchill R, Wessely S. Psychological
Lu W, et al. A randomized controlled trial of cognitive- debriefing for preventing post traumatic stress disorder (PTSD).
behavioral treatment for posttraumatic stress disorder in severe Cochrane Database of Systematic Reviews 2002, Issue 2. [DOI:
mental illness. Journal of Consulting and Clinical Psychology 10.1002/14651858.CD000560]
2008;76(2):259-71.
Ruzek 2001
Nicholson 2013 Ruzek J, Watson P. Early intervention to prevent PTSD and
Nicholson EL, Bryant RA, Felmingham KL. Interaction of other trauma-related problems. PTSD Research Quarterly
noradrenaline and cortisol predicts negative intrusive 2001;12(4):1-7.
memories in posttraumatic stress disorder. Neurobiology of
Learning and Memory 2013;112:204-11.

Informed decisions.
Sapolsky 2000 Van Emmerik 2008

Sapolsky RM. Glucocorticoids and hippocampal atrophy in Van Emmerik AA, Kamphuis JH, Emmelkamp PM. Treating
neuropsychiatric disorders. Archives of General Psychiatry acute stress disorder and posttraumatic stress disorder with
2000;57(10):925-35. cognitive behavioral therapy or structured writing therapy: a
randomized controlled trial. Psychotherapy and Psychosomatics
Schelling 1999 2008;77(2):93-100.
Schelling G, Stoll C, Kapfhammer HP, Rothenhausler HB,
Krauseneck T, Durst K, et al. The effect of stress doses of van Zuiden 2013
hydrocortisone during septic shock on posttraumatic stress van Zuiden M, Kavelaars A, Geuze E, Olff M, Heijnen CJ.
disorder and health-related quality of life in survivors. Critical Predicting PTSD: pre-existing vulnerabilities in glucocorticoid-
Care Medicine 1999;27(12):2678-83. signaling and implications for preventive interventions. Brain,
Behavior, and Immunity 2013;30:12-21.
Schnurr 2009
Schnurr PP, Lunney CA, Bovin MJ, Marx BP. Posttraumatic stress Verbeke 2000
disorder and quality of life: extension of findings to veterans Verbeke M, Molenberghs G. Linear Mixed Models for
of the wars in Iraq and Afghanistan. Clinical Psychology Review Longitudinal Data. New York, NY: Springer, 2000.
2009;29:727-35.
Ware 1992
Shalev 2006 Ware JE, Sherbourne CD. The MOS 36-Item Short-Form Health
Shalev A, Freedman S, Adessky R, Watson P. Early interventions Survey (SF-36): I. Conceptual framework and item selection.
for PTSD: what works, and for whom?. 22nd Annual Meeting, Medical Care 1992;30:473-81.
International Society for Traumatic Stress Studies, November
4-7, Hollywood, CA. 2006. Weathers 2001
Weathers FW, Keane TM, Davidson JR. Clinician-administered
Sheehan 1996 PTSD scale: a review of the first ten years of research. Depression
Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of and Anxiety 2001;13(3):132-56.
disability. International Clinical Psychopharmacology 1996;11
Suppl 3:89-95. Weisaeth 1989
Weisaeth L. Torture of a Norwegian ship's crew. The torture,
Solomon 1997 stress reactions and psychiatric after-effects. Acta Psychiatrica
Solomon SD, Davidson JR. Trauma: prevalence, impairment, Scandinavica. Supplementum 1989;355:63-72.
service use, and cost. Journal of Clinical Psychiatry 1997;58
Suppl 5:1-11. WHO 1997
World Health Organization. Composite International Diagnostic
Sones 2011 Interview (CIDI) 2.1. Geneva, Switzerland: World Health
Sones HM, Thorp SR, Raskind M. Prevention of posttraumatic Organization, 1997.
stress disorder. Psychiatric Clinics of North America 2011;34:79–
94. Yehuda 1990
Yehuda R, Southwick SM, Nussbaum G, Wahby V, Giller EL Jr,
Spitzer 1996 Mason JW. Low urinary cortisol excretion in patients with
Spitzer R, Williams J, Gibbons M. Instructional Manual for the posttraumatic stress disorder. Journal of Nervous and Mental
Structured Clinical Interview for DSM-IV. New York, NY: New York Disease 1990;178(6):366-9.
State Psychiatric Institute, 1996.
Yehuda 2006
Sterne 2011 Yehuda R. Advances in understanding neuroendocrine
Sterne JAC, Egger M, Moher D (editors). Chapter 10: Addressing alterations in PTSD and their therapeutic implications. Annals of
reporting biases. In: Higgins JPT, Green S editor(s). Cochrane the New York Academy of Sciences 2006;1071:137-66.
Handbook for Systematic Reviews of Interventions. The
Cochrane Collaboration, 2011. Yehuda 2008
Yehuda R, Bierer LM. Transgenerational transmission of cortisol
Thompson 1994 and PTSD risk. Progress in Brain Research 2008;167:121-35.
Thompson SG. Why sources of heterogeneity in meta-analysis
should be investigated. BMJ 1994;309(6965):1351-5.
* Indicates the major publication for the study
Turpin 2005
Turpin G, Downs M, Mason S. Effectiveness of providing self-
help information following acute traumatic injury: randomised
controlled trial. British Journal of Psychiatry 2005;187:76-82.

Informed decisions.
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Delahanty 2012
Methods Design: randomised, double-blind, placebo-controlled pilot study
Duration of intervention: 16 days (including 6-day taper off)
Follow-up: 1 and 3 months
Placebo run-in: no
Participants Sample size: 64 participants were randomised to hydrocortisone and placebo
Mean age: 30.6 (10.7)
Gender: 42 males and 22 females were included in the study
Ethnicity: 14% African-American and 2% Native American
Type of trauma: motor vehicle accidents, falls, assault, and pedestrian and/or car accidents
Diagnostic measure: DSM-IV
Inclusion criteria: participants consisted of 64 injury victims, who met criterion A for exposure to a trau-
matic event, ranging in age from 18 to 56 who were admitted as trauma inpatients at a Midwestern Lev-
el-1 trauma unit. Participants were required to have a minimum score of 27 on the Peritraumatic Disso-
ciative Experiences Questionnaire - Self Report
Exclusion criteria: Quote: "Glasgow Coma Scale (GCS) score of less than 14; exposure to a traumatic
event that occurred more than 12 hours before initial medication dose could be given or inability to ini-
tiate first medication dose within 12 hours of event; allergy to cortisol or medical/medicinal contraindi-
cations to cortisol administration; pregnant or breast-feeding; exposure to a trauma of a potentially on-
going nature (e.g. domestic violence); presence of injuries requiring delayed operative procedures; pa-
tient reported corticosteroid use in the previous 6 months; and/or patient had injuries that required
treatment with steroids"
Drop-outs: 21 (12/31 in the medication group and 9/33 in the placebo group)
Number of participants with MDD: data not provided
Interventions Pharmacological intervention: Quote: "Following consent, the nurse administered the first oral dose
[20mg Hydrocortisone (Cortef®, Pharmacia) or placebo capsules] within twelve hours of hospital ad-
mission. Participants continued to take either the 20mg hydrocortisone or placebo capsules every
twelve hours (bid) for 10 days, followed by a 6-day taper period to avoid any potential adrenal suppres-
sion. The medication regimen was tapered by halving the dose every two days"
Outcomes Primary outcomes: Clinician-Administered PTSD Scale (CAPS), 36-Item Short-Form Health Survey
(SF-36) and the Center for Epidemiological Studies – Depression Scale (CES-D)
Secondary outcomes: not specified
Notes Industry-funded: yes. Funding for this study was provided by the National Institute of Mental Health
(R34 MH73014) and the Ohio Board of Regents
Medication provided by industry: no
Any of the authors work for industry: no
Risk of bias

Informed decisions.
Delahanty 2012 (Continued)
Bias Authors' judgement Support for judgement
Random sequence genera- Low risk Participants were randomised to either hydrocortisone or placebo. The inves-
tion (selection bias) tigators indicated in response to a request for additional information that "a
random number table was used to generate the randomization sequence" (11
December 2013)
Allocation concealment Low risk The investigators indicated in response to a request for additional information
(selection bias) that "the group into which a participant was allocated was concealed from the
study investigators via identical pills/blister packs. They were prepared by the
hospital's pharmacist who was a co-author - he maintained the blind so that,
in case of adverse reaction, the blind could be broken quickly - he had no con-
tact with any of the participants" (11 December 2013)
Blinding of participants Low risk Blinding procedures were not specified, but the study was described as dou-
and personnel (perfor- ble-blinded. Quote: "Following eligibility determination, participants were
mance bias) consented in-hospital and randomly assigned, in double-blind fashion, to ei-
All outcomes ther a 10-day course (plus a 6-day taper period) of hydrocortisone or placebo"
Blinding of outcome as- Low risk The investigators indicated in response to a request for additional information
sessment (detection bias) that "individuals who assessed the study outcomes were blinded to the group
All outcomes to which participants had been assigned"
Incomplete outcome data Low risk The most common reason for loss to follow-up in both the hydrocortisone and
(attrition bias) placebo group was inability to contact the participants at follow-up (11/12
All outcomes drops on hydrocortisone and 9/9 on placebo). Quote: "There were no differ-
ences between drop-outs and participants who were retained through the pro-
tocol on any study variable. There was no differential drop out between the
hydrocortisone and placebo groups"
Selective reporting (re- Unclear risk The study protocol was not available
porting bias)
Other bias Unclear risk No other source of bias was identified for this study
Hoge 2012
Duration of intervention: an initial dose was given at the emergency department, followed by a 19-day
treatment course at home
Placebo run-in: no
Participants Sample size: 43 participants were randomised to propranolol and placebo
Mean age: 33.5 (10.2)
Gender: 18 males and 23 females were included in the study
Ethnicity: data not provided
Type of trauma: emergency department

Informed decisions.
Hoge 2012 (Continued)

Inclusion criteria: Quote: "Participant candidates had to experience an event that met the DSM-IV PTSD
A.1 (stressor) and A.2 (response) criteria." "The initial eligibility criterion of an ED admission heart rate
of 80 BPM or greater was done away with, and the requirement that the traumatic event occur no ear-
lier than 4 h prior to first dose of study medication was extended to from 4 to 12 hours, due to recruit-
ment difficulties"
Exclusion criteria: Quote: "These included physical injury that would complicate participation, hospi-
tal stay longer than overnight (the great majority of participants were discharged from the ED the same
day), head injury with loss of consciousness, a medical condition that contraindicated the administra-
tion of propranolol (e.g., asthma), use of medications with potentially dangerous interactions with pro-
pranolol, previous adverse reaction to a β-blocker, blood alcohol concentration above 0.02% or pres-
ence of substances of abuse on saliva testing, pregnancy, traumatic event reflecting ongoing victimiza-
tion, contraindicating psychiatric condition such as psychotic, bipolar, major depressive, or posttrau-
matic stress disorder from another event, suicidality or homicidality, unwillingness or inability to come
to Boston for the research visits, or treating physician did not concur with enrollment in the study"
Drop-outs: 9 of 43 (20.9%). Group-specific drop-out rates were not provided
Number of participants with MDD: 3/20 (15%) on placebo and 3/21 (14.3%) on propranolol
Interventions Pharmacological intervention: Quote: "Following screening, each participant was randomized to re-
ceive an initial oral dose of either 40 mg short-acting propranolol or placebo. One hour after this first
dose, if systolic blood pressure had not fallen by 10 mmHg or more, or to below 100 mmHg, an ad-
ditional oral dose of 60 mg long-acting propranolol or placebo was given; all participants received
both doses. Participants continued taking long-acting propranolol (or placebo) at home over a 19-day
course, starting with 120 mg every morning and evening for 10 days, and then tapering to 120 mg in the
morning and 60 mg in the evening for 3 days, then 60 mg in the morning and 60 mg the evening for 3
days, then 60 mg in the morning only ×3 days, after which the study medication was discontinued"
Outcomes Primary outcomes: Physiological Reactivity, Peritraumatic Emotional Distress Inventory, Clinician Ad-
ministered PTSD Scale (CAPS)
Notes Industry-funded: no
Risk of bias
Random sequence genera- Unclear risk Information about generation of the randomisation sequence was not provid-
tion (selection bias) ed. Quote: "Following screening, each participant was randomized to receive
an initial oral dose of either 40 mg short-acting propranolol or placebo"
Allocation concealment Low risk Lead author confirmed that "the research pharmacy makes up the active drug
(selection bias) and placebo to look the same" (E. Hoge; personal correspondence: 26 Novem-
ber 2013)
Blinding of participants Low risk No description of blinding is provided in the study report, though the protocol
and personnel (perfor- for this study (NCT00158262) describes this study as "Double Blind (Subject,
mance bias) Investigator)". Lead author confirmed that "subjects, the psychologist who did
All outcomes the SCID, and the study nurses who had contact with patients, were all blinded
to treatment allocation through the use of blinded medication" (E. Hoge; per-
sonal correspondence: 26 November 2013)
Blinding of outcome as- Low risk No description of outcome assessment blinding is provided in the study re-
sessment (detection bias) port. Lead author confirmed that "subjects, the psychologist who did the SCID,
Informed decisions.
Hoge 2012 (Continued)

All outcomes and the study nurses who had contact with patients, were all blinded to treat-
ment allocation through the use of blinded medication" (E. Hoge; personal
correspondence: 26 November 2013)
Incomplete outcome data Unclear risk Proportion and characteristics of participants who dropped out by group is
(attrition bias) not described. Nevertheless, the total proportion of drop-outs (20.9%) is rela-
All outcomes tively low, suggesting that drop-out rates may not have biased the outcomes
Selective reporting (re- Unclear risk The outcomes are not described in the study protocol available on ClinicalTri-
porting bias) als.gov (NCT00158262)
Mellman 2002
Methods Design: randomised, placebo-controlled trial
Duration of intervention: 7 days
Follow-up: the final assessment for the trial was 6 weeks after the initial assessment
Placebo run-in: no
Participants Sample size: 22 participants were randomised to temazepam and placebo
Mean age: 36.1 (11.4)
Gender: 14 men and 8 females
Ethnicity: 18 Hispanic, 2 white and 2 black participants
Type of trauma: motor vehicle accidents, industrial accidents and impersonal assaults
Inclusion criteria: participants were recruited from a much larger pool of injured patients on the basis
of having recall of the incident and endorsing at least moderate impairment of sleep initiation or main-
tenance and meeting full criteria for at least 2 PTSD symptoms clusters (DSM-IV) during a structured in-
terview assessment, and the ability and willingness to provide written informed consent
Exclusion criteria: intoxication at the time of the incident, brain injury and pre-existing active psychi-
atric disorders
Drop-outs: 0
Number of participants with MDD: 0
Interventions Pharmacological intervention: Quote: "Subjects were randomly assigned to placebo taken at bedtime
for seven nights or 30mg of temazepam at bedtime for five nights followed by 15mg for two nights"
Outcomes Primary outcomes: CAPS and sleep diary measure
Notes Industry-funded: yes. Supported by grant MH54006 from the National Institute of Mental Health,
Bethesda

Informed decisions.
Mellman 2002 (Continued)
Risk of bias
Random sequence genera- Low risk Predetermined randomisation schedule

tion (selection bias)
Allocation concealment Low risk Medication schedule was known only to the research pharmacist (TA Mellman;
(selection bias) personal correspondence: 09 September 2011)
Blinding of participants Low risk Medication was placed in identical capsules (TA Mellman; personal correspon-
and personnel (perfor- dence: 09 September 2011)
mance bias)
All outcomes
Blinding of outcome as- High risk No information was provided on the blinding of outcome assessment
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk There were no drop-outs reported during this study
(attrition bias)
All outcomes
Selective reporting (re- Unclear risk The study protocol was not available for this study
porting bias)
Other bias High risk Study was terminated at 6 weeks after initial assessment, or in 50% of cases
when non-study medications were indicated. Quote: "The final assessment for
the trial was 6 weeks after the initial assessment or, in one half of cases, just
prior to initiating nonstudy medication, which was initiated on the basis of the
clinical judgment of the investigators when insomnia and/or other PTSD-relat-
ed symptoms that were distressing to the subject did not diminish during or
shortly after the trial (intent-to-treat analysis)"
Pitman 2002
Methods Design: randomised, double-blind, pilot study
Duration of intervention: 19 days (including a 9-day taper-off period)
Placebo run-in: no
Mean age: 34.3 (11)
Gender: 20 males and 21 females
Ethnicity: not specified
Type of trauma: motor vehicle accidents
Inclusion criteria: patients were included if: Quote: "(a) had just experienced a traumatic event that
met the DSM-IV PTSD A.1 (stressor) and A.2 (response) criteria; (b) had a heart rate (HR) of 80 beats per

Informed decisions.
Pitman 2002 (Continued)

minute (BPM) or greater at the time of ED presentation; (c) were without serious physical injury, systolic
blood pressure under 100 mm Hg, substance intoxication, pregnancy or lifetime history of congestive
heart failure, heart block or bronchial asthma; (d) upon mental status examination were found compe-
tent to understand the purpose of the study and the nature of the procedures; and (e) gave written in-
formed consent after the procedures had been fully explained"
Exclusion criteria: serious physical injury, systolic blood pressure over 100 mm Hg, substance intoxica-
tion, pregnancy or lifetime history of congestive heart failure, heart block or bronchial asthma
Drop-outs: 7/18 on propranolol and 8/23 on placebo at the 3-month assessment
Number of participants with MDD: 0
Interventions Pharmacological intervention: patients were randomised to begin, within 6 hours of the event, a 10-day
course of double-blind propanolol versus placebo 40 mg 4 times daily
Outcomes Primary outcome: Clinician-Administered PTSD Scale (CAPS)
Notes Industry-funded: yes. Supported by US Public Health Service Grant #MH58671
Risk of bias
Random sequence genera- Unclear risk Participants were randomly assigned to treatment and comparison. However,
tion (selection bias) the procedure was not specified
Allocation concealment High risk The study did not report on how the intervention was concealed
(selection bias)
Blinding of participants Low risk The study was described as "double-blind", though no information was provid-
and personnel (perfor- ed on which parties were blinded and how blinding was achieved
mance bias)
All outcomes
Blinding of outcome as- Unclear risk The study was described as "double-blind", though no information was provid-
sessment (detection bias) ed on which parties were blinded and how blinding was achieved
All outcomes
Incomplete outcome data Unclear risk Equivalent numbers of drop-outs were reported at the 3-month assessment
(attrition bias) for the propranolol and placebo groups. No information was provided on the
All outcomes reasons for study withdrawal, and whether they differed by group, however
Selective reporting (re- Unclear risk The study protocol was not available for this trial
porting bias)
Schelling 2001
Methods Design: prospective, randomised, double-blind study

Informed decisions.
Schelling 2001 (Continued)

Duration of intervention: hydrocortisone was administered for a median of 18 days (range: 14 to 35
days)
Follow-up: median assessment for PTSD at 31 months (range: 21 to 49 months)
Placebo run-in: no
Mean range: 52 (23 to 76)
Type of trauma: septic shock
Diagnostic measure: SCID-IV
Inclusion criteria: Quote: "Patients who had fulfilled the criteria for hyperdynamic septic shock as pro-
posed by the American college of chest physicians/society of critical care medicine"
Exclusion criteria: psychiatric diseases (including alcohol and drug abuse) and those who could not
complete a questionnaire in German language
Drop-outs: 50% (20/40) of the randomised sample (11/20 in the hydrocortisone and 9/20 in the placebo
group)
Number of participants with MDD: 0 (participants were excluded for "pre-existing psychiatry disease")
Interventions Pharmacological intervention: Quote: "Patients were prospectively and randomly assigned to receive
either placebo or hydrocortisone with a loading dose of 100mg given intravenously over 30 minutes,
followed by a continuous infusion of 1.8mg/kg/hour. This dose was kept constant for six days. When
septic shock was reversed the dose of hydrocortisone was reduced to .08mg for an additional six days
and then tapered in steps of 24mg per day."
Outcomes Primary outcomes: Structured Clinical Interview for DSM-IV (SCID-IV), Post-Traumatic Stress Syndrome
10-Questions Inventory (PTSS-10Q-I) (German version) and the traumatic memory questionnaire
Notes Industry-funded: yes. Supported by grants from Hoffman-La Roche, Grenzach-Wyhlen and the Eli-Lilly
International Foundation, Bad Homburg, in Germany
Medication provided by industry: unclear
Risk of bias
Random sequence genera- Low risk Quote: "In this study, patients were prospectively randomised to receive ei-
tion (selection bias) ther stress doses of hydrocortisone or placebo (saline). Patients were as-
signed to random permuted blocks (G. Schelling; personal correspondence:
15/09/2011)"
Allocation concealment Low risk Quote:"Fifty-milliliter syringes containing 100 mg of hydrocorti-

(selection bias) sone-21-hemisuccinate (Upjohn, Heppenheim, Germany) diluted in physiolog-
ic saline solution or placebo were prepared daily and labelled study medica-
tion"

Informed decisions.
Schelling 2001 (Continued)
Blinding of participants Low risk Quote: "The patients were blinded regarding the facts that their interview-
and personnel (perfor- ers were psychiatrists and that the aim of the interviews was the diagnosis of
mance bias) PTSD. They were told that their interviewers were doctors with special train-
All outcomes ing in interviewing techniques and that the object of the interviews was their
memories from intensive care treatment and their current emotional well-be-
ing"
Blinding of outcome as- Low risk Quote: "For the interviews, the psychiatrists were blinded with regard to treat-
sessment (detection bias) ment characteristics (group assignment, principal diagnoses, traumatic dura-
All outcomes tion of treatment, etc.). They were informed only that the patients were long-
term survivors of care"
Incomplete outcome data Unclear risk Exclusions were conducted after randomisation for this study, making it dif-
(attrition bias) ficult to determine whether participants who did not survive to follow-up (5
All outcomes on hydrocortisone and 6 on placebo) would have been excluded. The exclu-
sion/drop-out rates were similar between the groups (11/20 and 9/20 in the hy-
drocortisone and placebo groups, respectively), though no information was
provided regarding differences between those who were assessed and those
who were not
porting bias)
Other bias High risk Funding for study provided by pharmaceutical companies. Additionally, par-
ticipants receiving placebo required higher norepinephrine doses than par-
ticipants on hydrocortisone (though this difference was not statistically sig-
nificant). The authors concede that this may be an alternative explanation of
higher PTSD onset in the placebo group, as previous studies have documented
higher urinary excretion of norepinephrine in PTSD patients
Shalev 2012
Methods Design: prospective, randomised, double-blind study. Assignment to 1 of 4 treatment arms (prolonged
exposure, cognitive therapy, escitalopram or placebo, and waiting list)
Duration of intervention: escitalopram or placebo was administered for 12 weeks
Follow-up: follow-up assessments were conducted at 5 months and 9 months after trauma exposure.
Quote: "The first clinical assessment took place a mean (SD) 19.8 (5.2) days after the traumatic event"
Placebo run-in: no
Participants Sample size: 46 participants were randomised to propranolol or placebo
Mean range: 38.1 (12.1)
Type of trauma: motor vehicle accident, terrorist attack and other
Diagnostic measure: CAPS
Inclusion criteria: Quote: "All survivors of qualifying events who met all criteria for PTSD, including the
DSM-IV A2 criterion (exposure to a traumatic event that was responded to with fear, helplessness, or
horror), but not the 1 month duration criterion Individuals who did not meet criterion A, but only B, C,
and D for PTSD were classified as having partial PTSD, and included as part of a separate analysis"

Informed decisions.
Shalev 2012 (Continued)

Exclusion criteria: Quote: "Current or past psychosis or bipolar disorder, a current substance abuse
problem, other conditions requiring urgent attention (e.g., suicidal ideations or acute grief), or chronic
PTSD or if they started treatment elsewhere"
Drop-outs: 6/23 (26.1%) on escitalopram and 13/23 (56.5%) on placebo completed the 8 sessions of
treatment, with 1 additional participant on placebo not providing data for the 5-month post-trauma as-
sessment
Number of participants with MDD: 18 (78.3%) and 12 (52.2%) in the escitalopram and placebo arms, re-
spectively
Interventions Pharmacological intervention: Quote: "An initial dose of 1 tablet (10 mg) daily was increased to 2
tablets after 2 weeks of treatment. Trained psychiatrists provided 4 weekly sessions (weeks 1-4) fol-
lowed by 4 biweekly sessions (weeks 6-12). At the end of our study, 8 participants with PTSD who re-
ceived placebo were invited to receive PE"
Outcomes Primary outcome: Clinician-Administered PTSD Scale (CAPS)
Secondary outcomes: PTSD Symptom Scale – Self-Report Version (PSS-SR), Clinician-Administered

PTSD Scale (CAPS, structured interview) and Beck Depression Inventory (BDI)
Notes Industry-funded: yes. Funding was provided by Lundbeck Pharmaceuticals Ltd. (Denmark)
Risk of bias
Random sequence genera- Low risk An equipoise-stratified randomisation procedure was employed, though no
tion (selection bias) information is provided on how this randomisation sequence was generated.
Quote: "The equipoise-stratified randomization is a method for randomly al-
locating participants to interventions in treatment studies that include more
than 2 arms ... It allows potential participants to decline treatment options
that they do not desire and to be randomly assigned to the remaining arms. By
making that choice, each participant assigns himself or herself to a "stratum"
which consists of all the options that he or she finds equally acceptable"
Allocation concealment Low risk Quote: "Concealed tablets of either 10 mg of escitalopram or placebo were
(selection bias) prepared and coded by Lundbeck Pharmaceuticals (Copenhagen, Denmark)
and were supplied to clinicians by a research associate"
Blinding of participants Low risk Both participants and those administering the medication were blinded.
and personnel (perfor- Quote: "Trained psychiatrists provided 4 weekly sessions (weeks 1-4) followed
mance bias) by 4 biweekly sessions (weeks 6-12). The concealment was broken and added
All outcomes to the study's data file at the end of the study". Quote: "To separate the phar-
macological effect of an SSRI from that of receiving medication and psychiatric
care, this blinded group [SSRIs versus placebo comparison] includes both the
active agent and placebo"
Blinding of outcome as- Low risk 5-month (CA-2) and 9-month (CA-3) assessments were blinded. Quote: "Be-
sessment (detection bias) cause those who conducted the CA-2 and CA-3 were blinded to treatment at-
All outcomes tendance and adherence, the resulting comparisons include completers, par-
tial completers, and noncompleters and thereby represent the total yield of
participants randomly assigned to an intervention"
Incomplete outcome data High risk A greater proportion of participants dropped out from the placebo (14/23;
(attrition bias) 60.9%) than the escitalopram (6/23; 26%) arms at the 5-month assessment.

Informed decisions.
Shalev 2012 (Continued)

All outcomes These participants were not contacted to obtain information on their reasons
for withdrawing from treatment" (AY Shalev; personal correspondence: 5 De-
cember 2013)
Selective reporting (re- Unclear risk The protocol for this study was not available
porting bias)
Other bias Low risk Funding for study provided by industry. Additionally, in the equipoise-strati-
fied randomisation scheme employed, participants could indicate 2 of the 4
treatment arms they did not want to be assigned to. A large proportion of el-
igible participants (42.6%) refused treatment with escitalopram or placebo.
Since industry funding and self exclusion from the medication arms would be
expected to bias the study finding towards an effect for medication, we have
interpreted the absence of such an effect as an indication that bias did not oc-
cur
Stein 2007
Methods Design: proof-of-concept-study; double-blind, randomised, placebo-controlled trial
Duration of intervention: 14 days (including the up-titration, treatment and taper phases)
Follow-up: 1, 4 and 8 months
Placebo run-in: no
Participants Sample size: 48 participants were randomised to propranolol, gabapentin and placebo
Mean age: 29.4 (10.10)
Ethnicity: Quote: "The sample was ethnically diverse: 40% Hispanic, 35% White non-Hispanic, 10%
African American, 10% Asian, and 4% Native American"
Type of trauma: Quote: "The most common type of injury was a motor vehicle collision followed by
falls, burns, pedestrian versus automobile, assault, and other (e.g. surfing)"
Diagnostic measure: specified structured or semi structured measurement
Inclusion criteria: Quote: "Potential participants were men and women ages 18-65 who were admitted
to the University of California San Diego (UCSD) Level 1 Surgical Trauma Centre during the 39-month
period from October 2001 through December 2004. Admission to this service reflected a severe physical
injury requiring specialized, emergent trauma care"
Exclusion criteria: Quote: "The most common reasons for exclusion were (a) living outside the region
such that home monitoring could not be arranged, (b) too medically unstable to participate, (c) did not
speak English, or (d) too old or too young"
Drop-outs: 5/17 for propranolol, 4/14 for gabapentin and 1/17 on placebo, as inferred from number of
people assessed for PTSD at the 4-month follow-up assessment
Number of participants with MDD: data not provided
Interventions Pharmacological intervention: 14 days of propranolol, gabapentin or placebo, administered within 48

hours of injury to patients admitted to a surgical trauma centre. Propranolol was started at 20 mg for
3 times daily and up-titrated over 2 days to 40 mg. Gabapentin was started at 300 mg and up-titrated
over 2 days to 400 mg

Informed decisions.
Stein 2007 (Continued)
Outcomes Primary outcomes: the Acute Stress Disorder Scale (ASDS), the Comprehensive International Diagnostic
Interview (CIDI), the Center for Epidemiologic Studies Depression Scale (CES-D) and the Posttraumatic
Stress Disorder Checklist–Civilian Version (PCL-C)
Notes Industry-funded: yes. Supported by NIMH grants MH62037 (R21) and MH64122 (K24) to MBS
Risk of bias
Random sequence genera- Low risk Participants were randomised to receive propranolol, gabapentin or placebo.
tion (selection bias) Quote: "A randomised schedule was set up and maintained by the UCSB Re-
search Pharmacy"
Allocation concealment Low risk Quote: "When a subject was enrolled, the study nurse notified one of the at-
(selection bias) tending physicians on the Trauma Service, who authorized the Research Phar-
macy to provide the medication supplies (according to the randomization
schedule) to the subject"
Blinding of participants Low risk All study medications were supplied in identical capsules. Quote: "All study
and personnel (perfor- medications were supplied in identical capsules to avoid breaking the blind
mance bias) study"
All outcomes
Blinding of outcome as- Low risk Quote: "The study nurse, who was blinded to treatment allocation, conducted
sessment (detection bias) assessments"
All outcomes
Incomplete outcome data High risk A higher proportion of drop-outs was observed in the medication groups
(attrition bias) (propanolol: 29.4% and gabapentin: 28.6%) versus placebo (5.9%). Investiga-
All outcomes tors employed a GEE modelling approach to try and accommodate missing
data. No data on reasons for study withdrawal were provided, though. Quote:
"And finally, although our rate of follow-up (≈80% at 4 months) was satisfacto-
ry, the possibility of differential drop-out across groups creates a missing data
problem that even the use of GEE analyses may not solve"
porting bias)
Weis 2006
Methods Design: prospective, randomised, double-blind trial
Duration of intervention: 4 days
Follow-up: 6 months
Placebo run-in: no

Informed decisions.
Weis 2006 (Continued)

Mean age: 68.5 (range 63 to 73)
Type of trauma: cardiac surgery
Inclusion criteria: Quote: "The study was performed in high-risk patients undergoing CS with CPB. High
risk was defined as a preoperative left ventricular ejection fraction of less than 35% or an expected du-
ration of CPB of greater than 97 minute"
Exclusion criteria: Quote: "Patients were excluded from the study if they met the following criteria
before surgical intervention: pregnancy, emergency operation, hepatic dysfunction (bilirubin 3 mg/
dL), renal dysfunction (plasma creatinine 2 mg/dL), a positive serologic test result for HIV, manifest in-
sulin-dependent diabetes mellitus, an extracardial septic focus, chronic or acute inflammatory disease,
and inability to provide informed consent. In addition, patients who required glucocorticoids other
than hydrocortisone were excluded"
Drop-outs: 5/19 in the medication group and 3/17 in the placebo group. 2 of these participants were not
technically drop-outs, but were not included in the analysis due to missing data
Number of participants with MDD: not assessed
Interventions Pharmacological intervention: Quote: "Hydrocortisone administration started with a loading dose (100
mg over 10 minutes administered intravenously) before induction of anesthesia, followed by a continu-
ous infusion of 10mg/h for 24 hours (postoperative day [POD] 1), which was reduced to 5mg/h on POD
2 and then tapered to 3 X 20 mg administered intravenously on POD 3 and 3 X 10 mg administered in-
travenously on POD 4"
Outcomes Primary outcomes: the Short Form (36) Health Survey (SF-36) and Posttraumatic Symptom Scale
(PTSS-10). Evaluation of traumatic memories: all patients were asked to complete a structured and val-
idated questionnaire, evaluating different categories of traumatic memory from ICU therapy
Notes Industry-funded: unclear
Risk of bias
Random sequence genera- Low risk Quote: "The patients were randomly assigned to one of two treatment groups
tion (selection bias) with the use of a computer-generated randomisation list"
Allocation concealment Low risk Quote: "The vials were prepared by a study nurse who was not involved in the
(selection bias) care of patients participating in the trial"
Blinding of participants Low risk The study was described as "double-blind", though no information was pro-
and personnel (perfor- vided on which parties were blinded and how blinding was achieved. Quote:
mance bias) "One group of patients received stress doses of hydrocortisone (Pharmacia &
All outcomes Upjohn, Erlangen, Germany; the hydrocortisone group) and patients from the
other group (the placebo group) received normal saline in identical vials in a
double-blind fashion"

Informed decisions.
Weis 2006 (Continued)
Blinding of outcome as- Unclear risk The study was described as "double-blind", though no information was pro-
sessment (detection bias) vided on which parties were blinded and how blinding was achieved. Quote:
All outcomes "One group of patients received stress doses of hydrocortisone (Pharmacia &
Upjohn, Erlangen, Germany; the hydrocortisone group) and patients from the
other group (the placebo group) received normal saline in identical vials in a
double-blind fashion"
Incomplete outcome data Low risk Similar proportions of patients withdrew from the hydrocortisone (5/19;
(attrition bias) 26.3%) and placebo (3/17; 17.6%) groups. Between-group comparisons on pa-
All outcomes tient and treatment characteristics for the fully randomised sample as well
as the sample excluding drop-outs were virtually identical, suggesting that
outcomes for the drop-outs would have been similar to those retained in the
study. Quote: "There were no significant differences with regard to patient or
treatment characteristics between included or excluded patients"
porting bias)
Other bias High risk Participants receiving hydrocortisone required significantly lower norepineph-
rine doses (to "counteract vasodilatory hypotension") than participants on
placebo. As noted for the similar finding in Schelling 2001, this might provide
an alternative explanation of higher PTSD onset in the placebo group, as pre-
vious studies have documented higher urinary excretion of norepinephrine in
PTSD patients
Zohar 2011a
Duration of intervention: single dose 1.5 to 5 hours after the traumatic event
Follow-up: 2 weeks, 1 month and 3 months after the trauma
Placebo run-in: no
Mean age: 35.16 (14)
Type of trauma: traffic accidents, work accidents and snake bites
Inclusion criteria: Quote: "Seventy consecutive patients who were exposed to a traumatic event, expe-
rienced either acute stress reaction or sub-threshold acute stress reaction, and met the DSM-IV PTSD
A.1 (stressor) and A.2 (response) criteria (fulfilling criteria A, 2 of the symptoms in criteria B, 3 out of 4 of
criteria C, D, E, and F, and meeting criterion H of the ASD criteria set out in DSM-IV) were recruited from
the emergency department at the Chaim Sheba Medical Center"
Exclusion criteria: Quote: "Exclusion criteria included serious physical injury (a score of 3 or above on
the Abbreviated Injury Scale), brain trauma, substance abuse disorders, cardiac pacemaker implant, a
history of epilepsy, neurosurgery, chronic medical conditions of any sort. Medication specific exclusion
criteria included hypersensitivity to hydrocortisone, pregnancy, or treatment for asthma"
Drop-outs: 6/15 (40%) on hydrocortisone and 2/10 (20%) on placebo

Informed decisions.
Zohar 2011a (Continued)

Number of participants with MDD: MDD was not assessed
Interventions Pharmacological intervention: Quote: "Hydrocortisone or placebo was given between 1.5 and 5.5 hours
following the traumatic event. Patients received hydrocortisone intravenously in a single bolus at a
dose ranging from 100 to 140mg based on body weight: 100 mg for weights of 60–69kg, 120 mg for
weights of 70–89kg, and 140mg for weights of 90–99kg"
Outcomes Primary outcomes: Clinician-Administered PTSD Scale (CAPS), visual analogue scales for anxiety (VAS-
A) and depression (VAS-D)
Notes Industry-funded: no
Risk of bias
Random sequence genera- Low risk Quote: "The participants were randomised by a predetermined program, and
tion (selection bias) entered in a double blind, placebo-controlled design"
Allocation concealment Low risk Quote from Dr. Hagit (11 December 2013): "Hydrocortisone or placebo was giv-
(selection bias) en intravenously and has been prepared by another physician. IV bags were
numbered and were the same for both treatments"
Blinding of participants Low risk Although described as double-blinded, the procedure employed was not spec-
and personnel (perfor- ified. Quote: "The participants were randomised by a predetermined program,
mance bias) and entered in a double blind, placebo-controlled design"
All outcomes
Blinding of outcome as- Low risk Assessment was blinded. Quote: "Ratings of ASD and PTSD symptoms, anxiety,
sessment (detection bias) and depression were carried out at 4 time points — before the intervention, at
All outcomes 2 weeks, 1 month and 3 months after the trauma — by an expert investigator
who was blind to the treatment condition"
Incomplete outcome data High risk A larger proportion of participants were excluded from the hydrocortisone
(attrition bias) (6/15; 40%) than the placebo groups (2/10; 20%). No information was provided
All outcomes regarding the reasons for treatment withdrawal
porting bias)
BPM: beats per minute

CAPS: Clinician-Administered PTSD Scale
CPB: cardiopulmonary bypass
CS: cardiac surgery
DSM-IV: Diagnostic and Statistical Manual IV
ED: emergency department
GEE: generalised estimating equation
ICU: intensive care unit
MDD: major depressive disorder
NIMH: National Institute of Mental Health
PTSD: post-traumatic stress disorder

Informed decisions.
SCID-IV: Structured Clinical Interview for DSM-IV

SD: standard deviation
SSRI: selective serotonin reuptake inhibitor
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Davidson 2000 Relapse prevention study; participants were already diagnosed with PTSD
Gelpin 1996 Non-randomised trial and no placebo control group
Martenyi 2002 Relapse prevention study; participants were already diagnosed with PTSD
Martenyi 2006 Relapse prevention study; participants were already diagnosed with PTSD
Schelling 2004 No comparison group
Vaiva 2003 Participants were not randomised to treatment
Characteristics of studies awaiting assessment [ordered by study ID]
Azad 2007
Methods Prospective, interventional, randomised, double-blind, placebo-controlled study
Participants 92 high-risk patients after cardiac surgery
Interventions Hydrocortisone in stress doses versus placebo
Outcomes Primary outcomes: immunologic markers, health care-related quality of life, PTSD
Secondary outcomes: early clinical outcome parameters
Notes Primary outcomes were assessed at 1.5 years. Secondary outcomes were assessed at 1 year
Marx 2006
Methods Randomised, parallel-group, double-blind, controlled study
Participants 12 veterans, 18 to 55 years of age
Interventions Paroxetine 10 mg to 40 mg (flexible dosing) versus placebo x 12 weeks
Outcomes Primary outcome: improvement in PTSD symptoms as determined by the Clinician Administered
PTSD Scale (CAPS)
Secondary outcomes: short PTSD Rating Interview, Connor Davidson Resilience Scale, Hospital
Anxiety and Depression Scale, Clinical Global Impressions of Severity and of Improvement Scales,
Symptom Checklist 90 and the Sheehan Disability Scale (SDS)
Notes Primary outcome assessed at baseline and at 12 weeks. All secondary outcomes assessed at 12
weeks of intervention

Informed decisions.
Simon 2005
Methods Double-blind, flexible-dose, placebo-controlled study
Participants 60 study participants meeting criteria for the A1, A2 and at least 1 additional ASD criterion (i.e., B, C
and or D criteria), as determined by the Acute Stress Disorder Interview upon initial evaluation
Interventions Escitalopram (10 to 40 mg/day) versus placebo x 12 weeks
Outcomes Primary outcome: symptoms of post-traumatic stress disorder, symptoms of acute stress disorder
Secondary outcome: Clinical Global Improvement
Notes —
ASD: acute stress disorder

Characteristics of ongoing studies [ordered by study ID]
Zohar 2009
Trial name or title PTSD prevention using escitalopram
Methods Allocation: randomised

Intervention model: parallel assignment
Masking: double-blind (subject, investigator)
Primary purpose: prevention
Participants Ages eligible for study:18 years to 65 years
Genders eligible for study: both
Accepts healthy volunteers: no
Interventions Pharmacological intervention: 10 to 20 mg/day of escitalopram versus 1/2 capsules of placebo
Outcomes Primary outcome: CAPS
Secondary outcomes: no information provided
Starting date June 2005
Contact information Contact: Joseph Zohar, MD: jzohar@post.tau.ac.il
Notes Assessment of primary outcome at 1-year follow-up
Zohar 2010
Trial name or title The efficacy of a single dose of intranasal oxytocin in the prevention of post traumatic stress disor-
der (PTSD)
Methods Study type: interventional
Allocation: randomised

Informed decisions.
Zohar 2010 (Continued)

Endpoint classification: efficacy study
Masking: double-blind (subject, caregiver, investigator, outcomes assessor)
Participants Ages eligible for study: 18 67 years
Genders eligible for study: both
Inclusion criteria: (1) Persons over the age of 18, who have been exposed to an event meeting the
DSM-IV "A.1" criterion for trauma exposure, expressing marked anxiety, and/or emotional distress
and/or dissociation, as assessed by the visual analogue scales; (2) the traumatic event occurred up
to 6 hours prior to the arrival to the emergency room; (3) the person can and is willing to provide
written, informed consent to participate in the study
Interventions Pharmacological intervention: oxytocin and placebo - saline nasal spray
Outcomes Primary outcome: the primary outcome measure is DSM-IV diagnosis of PTSD at the end of the trial
Secondary outcome: the secondary outcome measure is the severity of PTSD as expressed by the
Clinician Administered PTSD Scale (CAPS), at the end of the trial
Starting date February 2010
Contact information Contact: Joseph Zohar, MD: jzohar@post.tau.ac.il
Contact: Shlomit Cwikel-Hamzany, MD: shlomitch@gmail.com
Notes —
Zohar 2011b
Trial name or title Randomized placebo-controlled trial of hydrocortisone in PTSD prophylaxis
Methods Study type: interventional
Allocation: randomised
Endpoint classification: efficacy study
Masking: double-blind (subject, caregiver, investigator, outcomes assessor)
Participants Ages eligible for study: no information provided
Genders eligible for study: no information provided
Inclusion criteria: no information provided
Interventions Pharmacological intervention: single injection of 90 to 140 mg (proportioned to body weight) of hy-
drocortisone
Outcomes Primary outcome measures: no information provided

Informed decisions.
Zohar 2011b (Continued)

Secondary outcome measures: no information provided
Starting date August 2011
Contact information Contact: Joseph Zohar, MD; jzohar@post.tau.ac.il
Program Officer: Farris K. Tuma; ftuma@mail.nih.gov
Notes —
CAPS: Clinician-Administered PTSD Scale

DSM-IV: Diagnostic and Statistical Manual IV
DATA AND ANALYSES
Comparison 1. Propranolol versus placebo
Outcome or subgroup title No. of No. of Statistical method Effect size

studies partici-
pants
1 Treatment efficacy 3 118 Risk Ratio (IV, Random, 95% CI) 0.62 [0.24, 1.59]
2 Sensitivity analysis - observed cases 3 97 Risk Ratio (M-H, Random, 95% CI) 0.73 [0.29, 1.84]
Analysis 1.1. Comparison 1 Propranolol versus placebo, Outcome 1 Treatment efficacy.

Study or subgroup Propranolol Placebo Risk Ratio Weight Risk Ratio
n/N n/N IV, Random, 95% CI IV, Random, 95% CI
Hoge 2012 2/22 4/21 34.73% 0.48[0.1,2.34]
Pitman 2002 1/18 2/23 16.28% 0.64[0.06,6.5]
Stein 2007 3/17 4/17 48.99% 0.75[0.2,2.86]
Total (95% CI) 57 61 100% 0.62[0.24,1.59]

Total events: 6 (Propranolol), 10 (Placebo)
Heterogeneity: Tau2=0; Chi2=0.18, df=2(P=0.91); I2=0%
Test for overall effect: Z=0.99(P=0.32)
Favours propranolol 0.01 0.1 1 10 100 Favours placebo
Analysis 1.2. Comparison 1 Propranolol versus placebo, Outcome 2 Sensitivity analysis - observed cases.
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
Hoge 2012 2/22 4/21 33.43% 0.48[0.1,2.34]
Pitman 2002 1/11 2/15 16.36% 0.68[0.07,6.61]
Stein 2007 3/12 4/16 50.2% 1[0.27,3.66]
Favours propanolol 0.01 0.1 1 10 100 Favours placebo

Informed decisions.

Total (95% CI) 45 52 100% 0.73[0.29,1.84]

Total events: 6 (Propranolol), 10 (Placebo)
Favours propanolol 0.01 0.1 1 10 100 Favours placebo
Comparison 2. Hydrocortisone versus placebo
Outcome or subgroup title No. of No. of Statistical method Effect size

studies partici-
pants
1 Treatment efficacy 4 165 Risk Ratio (IV, Random, 95% CI) 0.17 [0.05, 0.56]
2 Sensitivity analysis - observed cases 4 108 Risk Ratio (M-H, Random, 95% CI) 0.20 [0.06, 0.64]
Analysis 2.1. Comparison 2 Hydrocortisone versus placebo, Outcome 1 Treatment efficacy.

Study or subgroup Hydrocortisone Placebo Risk Ratio Weight Risk Ratio
n/N n/N IV, Random, 95% CI IV, Random, 95% CI
Delahanty 2012 0/31 3/33 16.67% 0.15[0.01,2.82]
Schelling 2001 1/20 7/20 35.57% 0.14[0.02,1.06]
Weis 2006 1/19 3/17 30.36% 0.3[0.03,2.6]
Zohar 2011a 0/15 3/10 17.4% 0.1[0.01,1.72]
Total (95% CI) 85 80 100% 0.17[0.05,0.56]

Total events: 2 (Hydrocortisone), 16 (Placebo)
Test for overall effect: Z=2.92(P=0)
Favours hydrocortisone 0.001 0.1 1 10 1000 Favours placebo
Analysis 2.2. Comparison 2 Hydrocortisone versus placebo, Outcome 2 Sensitivity analysis - observed cases.
Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio
Delahanty 2012 0/19 3/24 16.03% 0.18[0.01,3.26]
Schelling 2001 1/9 7/11 37.42% 0.17[0.03,1.17]
Weis 2006 1/14 3/14 29.57% 0.33[0.04,2.83]
Zohar 2011a 0/9 3/8 16.97% 0.13[0.01,2.16]
Total (95% CI) 51 57 100% 0.2[0.06,0.64]

Total events: 2 (Experimental), 16 (Control)
Favours hydrocortisone 0.01 0.1 1 10 100 Favours placebo

Informed decisions.
APPENDICES
Appendix 1. Search strategy (OVID MEDLINE, EMBASE)

CCDAN's Trials Search Co-ordinator (TSC) ran the following searches on OVID MEDLINE and EMBASE:
(i) OVID MEDLINE (2004 to March 2011)
1. ((serotonin or norepinephrine or noradrenaline or dopamine or neurotransmitter) adj (uptake or reuptake or re-uptake)).mp.

2. (antiadrenergic or anti-adrenergic).mp.
3. (5-hydroxytrypotophan or Acetylcarnitine or Alaproclate or alprazolam or Amersergide or Amiflamine or Amineptine or Amitriptyline or
Amoxapine or anticonvulsant* or Antidepress* or antipsychotic* or anxiolytic* or Aripiprazole).mp.
4. (Befloxatone or Benactyzine or Benzodiazepine* or Brofaromine or Bupropion or Butriptyline).mp.
5. (Carbazepine or Caroxazone or cck-4 or Chlorimipramine or Chlorphenamidine or Chlorpoxiten or Cilosamine or Cimoxatone or
Citalopram or Clomipramine or clonidine or Clorgyline or Clovoxamine or Cyproheptadine or d-Cycloserine).mp.
6. (Deanol or Demexiptiline or Deprenyl or Desipramine or Desvenlafaxine or Dibenzipin or Diclofensine or divalproex or dopamin* or
Dosulepin or Dothiepin or Doxazosin or Doxepin or Duloxetine).mp.
7. (Escitalopram or Etoperidone or Femoxetine or Fenfluramine or flumazenil or Fluotracen or fluoxetine or Fluparoxan or fluphenazine or
Fluvoxamine or Furazolidone or Guanfacine).mp.
8. (haloperidol or Harmaline or Harmine or hydrocortisone or Idazoxan or Imipramine or inositol or Iprindole or Iproniazid or Isocarboxazid
or lamotrigine).mp.
9. (Lithium carbonate or Lithium compounds or Litoxetine or Lofepramine).mp.
10. (MAOI* or Maprotiline or medicat* or Medifoxamine or Melitracen or Metapramine or Metyrapone or Mianserin or Milnacipran or
Minaprine or Mirtazapine or Moclobemide or Monoamine Oxidase Inhibitor*).mp.
11. (Naloxone or Naltrexone or Nefazodone or Nialamide or Nomifensine or noradrenerg* or Norfenfluramine or Nortriptyline or Noxiptiline
or Olanzapine or Opipramol or Oxaflozane or Oxaprotiline or Oxcarbazepine).mp.
12. N-Methyl-3,4-methylenedioxyamphetamine/
13. (Pargyline or Paroxetine or pharmacother* or Phenelzine or Pheniprazine or Piribedil or Pirlindole or Pivagabine or Pizotyline or
Prazosin or Pregabalin or Procaine or Propranolol or Prosulpride or Protriptyline or psychotropic*).mp.
14. (Quetiapine or Quinupramine or Quipazine or Reboxetine or Risperidone or Ritanserin or Rolipram).mp.
15. (Selegiline or seroto* or Sertraline or Setiptiline or SNRI* or SSRI* or Sulpiride).mp.
16. (Teniloxine or Tetrindole or Thiazesim or Thozalinone or Tiagabine or Tianeptine or Toloxatone or Tomoxetine or Topiramate or
Tranylcypromine or Trazodone or tricyclic* or Trimipramine or Tryptophan).mp.
17. (Venlafaxine or Viloxazine or Viqualine or Yohimbine or Zimeldine).mp.
18. exp Stress Disorders, Traumatic/dt
19. or/1-18
20. exp Stress Disorders, Traumatic/
21. ((post-traumatic or post traumatic or posttraumatic) and disorder*).tw.
22. PTSD.tw.
23. or/20-22
24. randomized controlled trial/
25. controlled clinical trial/
26. randomi#ed.ti,ab.
27. randomly.ab.
28. placebo$.tw.
29. trial.ab.
30. drug therapy.fs.
31. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$ or dummy)).mp.
32. (control$ adj3 (trial$ or study or studies$ or group$)).tw.
33. (animals not (humans and animals)).sh.
34. or/24-32
35. 34 not 33
36. 19 and 23 and 35
37. (2004$ or 2005$ or 2006$ or 2007$ or 2008$ or 2009$ or 2010$).ed,yr.
38. 36 and 37
(ii) OVID EMBASE (2004 to February 2010)
1. ((seroton* or norepinephrine or noradrenaline or dopamin* or neurotransmitter) adj (uptake or reuptake or re-uptake)).mp.

Informed decisions.
2. (5-hydroxytrypotophan or acetylcarnitine or alaproclate or alprazolam or amersergide or amiflamine or amineptine or amitriptyline or

amoxapine or anticonvulsant* or antidepress* or antipsychotic* or anxiolytic*).mp.
3. (befloxatone or benactyzine or benzodiazepine* or brofaromine or bupropion or butriptyline).mp.
4. (caroxazone or cck-4 or chlorimipramine or chlorphenamidine or chlorpoxiten or cilosamine or cimoxatone or citalopram or
clomipramine or clonidine or clorgyline or clovoxamine or cyproheptadine or d-cycloserine).mp.
5. (deanol or demexiptiline or deprenyl or desipramine or desvenlafaxine or dibenzipin or diclofensine or divalproex or dopamin* or
dosulepin or dothiepin or doxepin or duloxetine).mp.
6. (escitalopram or etoperidone or femoxetine or fenfluramine or flumazenil or fluotracen or fluoxetine or fluparoxan or fluphenazine or
fluvoxamine or furazolidone).mp.
7. (haloperidol or harmaline or harmine or hydrocortisone or idazoxan or imipramine or inositol or iprindole or iproniazid or isocarboxazid
or lamotrigine).mp.
8. (lithium carbonate or lithium compounds or litoxetine or lofepramine).mp.
9. (maoi* or maprotiline or medicat* or medifoxamine or melitracen or metapramine or metyrapone or mianserin or milnacipran or
minaprine or mirtazapine or moclobemide or monoamine oxidase inhibitor*).mp.
10. (naloxone or naltrexone or nefazodone or nialamide or nomifensine or noradrenerg* or norfenfluramine or nortriptyline or noxiptiline
or olanzapine or opipramol or oxaflozane or oxaprotiline).mp.
11. (pargyline or paroxetine or pharmacother* or phenelzine or pheniprazine or piribedil or pirlindole or pivagabine or pizotyline or prazosin
or procaine or propranolol or prosulpride or protriptyline or psychotropic*).mp.
12. (quetiapine or quinupramine or quipazine or reboxetine or risperidone or ritanserin or rolipram).mp.
13. (selegiline or seroto* or sertraline or setiptiline or snri* or ssri* or sulpiride).mp.
14. (teniloxine or tetrindole or thiazesim or thozalinone or tiagabine or tianeptine or toloxatone or tomoxetine or topiramate or
tranylcypromine or trazodone or tricyclic* or trimipramine or tryptophan).mp.
15. (venlafaxine or viloxazine or viqualine or yohimbine or zimeldine).mp.
16. or/1-15
17. posttraumatic stress disorder/
18. ((post-traumatic or post traumatic or posttraumatic) and disorder*).tw.
19. ptsd.tw.
20. or/17-19
21. major clinical study/
22. randomized controlled trial/
23. randomization/
24. placebo/
25. randomi#ed.ti,ab.
26. placebo$.tw.
27. trial$.ti,ab.
28. randomly.ab.
29. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$ or dummy)).mp.
30. (control$ adj3 (trial$ or study or studies$)).tw.
31. ((animal or nonhuman) not (human and (animal or nonhuman))).de.
32. or/21-30
33. 32 not 31
34. 16 and 20 and 33
35. (2004$ or 2005$ or 2006$ or 2007$ or 2008$ or 2009$ or 2010$).yr,em.
36. 34 and 35
Appendix 2. Additional author searches (PubMed, PsycINFO, EMBASE)

The authors ran additional searches (all years to March 2011) on the following databases, using the following terms:
(iii) PubMed
(randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random allocation [mh] OR
double-blind method [mh] OR single-blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR ("clinical trial" [tw]) OR ((singl*
[tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR ("latin square" [tw]) OR placebos [mh] OR placebo*
[tw] OR random* [tw] OR research design [mh:noexp] OR comparative study [mh] OR evaluation studies [mh] OR follow-up studies [mh]
OR prospective studies [mh] OR cross-over studies [mh] OR control* [tw] OR prospectiv* [tw] OR volunteer* [tw]) NOT (animal [mh] NOT
human [mh]) AND (Stress Disorders, Traumatic [mh] OR "acute stress disorder" [tw] OR ASD [tw] OR "posttraumatic stress disorder" [tw]
OR "post traumatic stress disorder" [tw] OR PTSD [tw]) AND (prevent* [tw] OR prophy* [tw]).
(iv) PsycINFO
PsycINFO was searched using the following search query: ("randomisation" OR "randomization") OR "controlled" AND ("post traumatic
stress disorder" OR "PTSD")
(v) EMBASE

Informed decisions.
EMBASE was searched using the following search strategy: (random* OR "controlled") AND ("post traumatic stress disorder" OR "PTSD")
AND (prevent*)
Appendix 3. Systematic reviews search: PTSD/drug therapy (OVID MEDLINE)

1. (((systematic or structured or evidence or trials).ti. and ((review or overview or look or examination or update$ or summary).ti. or
review.pt.)) or (meta analysis.pt. or meta analysis/ or "0266-4623".is.) or (reviewed systematically or systematically reviewed).tw. or
(1469-493X or 1366-5278 or 1530-440X).is.) not ((animals/ not humans/) or letter.pt.)
2. ("review" or "review academic" or "review tutorial").pt.
3. (medline or medlars or embase or pubmed).tw,sh.
4. (scisearch or psychinfo or psycinfo).tw,sh.
5. (psychlit or psyclit).tw,sh.
6. cinahl.tw,sh.
7. ((hand adj2 search$) or (manual$ adj2 search$)).tw,sh.
8. (electronic database$ or bibliographic database$ or computeri#ed database$ or online database$).tw,sh.
9. (pooling or pooled or mantel haenszel).tw,sh.
10. (retraction of publication or retracted publication).pt.
11. (peto or dersimonian or der simonian or fixed effect).tw,sh.
12. or/3-11
13. 2 and 12
14. meta-analysis.pt.
15. meta-analysis.sh.
16. (meta-analys$ or meta analys$ or metaanalys$).tw,sh.
17. (systematic$ adj5 review$).tw,sh.
18. (systematic$ adj5 overview$).tw,sh.
19. (quantitativ$ adj5 review$).tw,sh.
20. (quantitativ$ adj5 overview$).tw,sh.
21. (quantitativ$ adj5 synthesis$).tw,sh.
22. (methodologic$ adj5 review$).tw,sh.
23. (methodologic$ adj5 overview$).tw,sh.
24. (integrative research review$ or research integration).tw.
25. or/14-24
26. (1 or 13 or 25)
27. stress disorders, traumatic/ or combat disorders/ or stress disorders, post-traumatic/ or stress disorders, traumatic, acute/
28. (PTSD or posttrauma* or post-trauma* or post trauma* or stress disorder* or combat disorder*).tw.
29. or/27-28
30. dt.fs.
31. (26 and 29 and 30)
HISTORY
Protocol first published: Issue 4, 2006
Review first published: Issue 7, 2014
Date Event Description
2 November 2008 Amended Converted to new review format.
CONTRIBUTIONS OF AUTHORS
Jonathan Ipser compiled the background and methods sections of the protocol, and assisted in making changes to the review in response
to editorial feedback. Dan Stein assisted in this process and also served as a co-ordinator for the protocol. Taryn Amos compiled the original
version of the review, including the data analysis section.
DECLARATIONS OF INTEREST
Potential conflicts of interest for individual review authors
Taryn Amos has no known conflict of interest outside of her employment by the MRC Unit on Anxiety and Stress Disorders.

Informed decisions.
Jonathan Ipser has no known conflict of interest.
Dan Stein has received research grants and/or consultancy honoraria from AstraZeneca, Eli-Lilly, GlaxoSmithKline, Lundbeck, Orion, Pfizer,
Pharmacia, Roche, Servier, Solvay, Sumitomo and Wyeth. He has participated in a number of ongoing studies and has presented data from
some of these studies on behalf of the sponsoring companies.
SOURCES OF SUPPORT
Internal sources
• University of Cape Town, Cape Town, South Africa.
• MRC Research Unit on Anxiety and Stress Disorders, Cape Town, South Africa.
External sources
• MRC Research Unit on Anxiety and Stress Disorders, Cape Town, South Africa.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

We removed the third objective stated in the protocol, namely to assess whether depression is a predictor of treatment response in the
prevention of PTSD, from the review, as it taps into risk rather than preventative factors for the onset of PTSD.
The timing of the outcome event was not made explicit in the protocol for the review. It has now been stated in the text that for studies
that assessed outcomes at multiple time points (Delahanty 2012; Hoge 2012; Pitman 2002; Shalev 2012; Stein 2007; Zohar 2011a), we
synthesised data at the first time point that was consistent with chronic PTSD, in which the assessment occurred after at least three months
after the index traumatic event.
The original protocol imposed an age range criterion for eligible studies of 18 to 65 years. We decided to remove the restriction on the
maximum age of the sample, as this allowed us to include data from a number of studies that would otherwise have been excluded
(Schelling 2001; Weis 2006). While medications might be expected to metabolise at a different rate in paediatric samples, there is no
evidence that PTSD is less likely to occur in populations over 65 years of age than in middle age, or that the effects of medication in this
older age group will differ substantially from younger adults.
The original protocol described comparisons between medication and placebo arms, as well as alternative 'standard' medication therapy.
The review was restricted to placebo-controlled studies, as we only found one placebo-controlled RCT that included an active medication
control arm (Stein 2007).
We have moved treatment acceptability from a secondary to a primary outcome for this review. This is in keeping with recommendations
within the Cochrane Handbook for Systematic Reviews of Interventions that primary outcomes of a review should include negative as well as
positive outcomes (Section 4.5) (Higgins 2011a), and in recognition that side effects are particularly salient when considering prophylactic
studies.
Clinical response to treatment was included as a secondary outcome in the original protocol, as assessed using the Clinical Global
Impressions Scale - Improvement Item (Guy 1976) or related scales. In light of the tendency of studies to report reductions in PTSD symptom
severity instead of more general responses to treatment, we have instead replaced this outcome in the review with reductions in PTSD
symptom severity (as assessed using scales such as the CAPS and the PTSS-10).
Heterogeneity of treatment response and symptom severity was not assessed by means of Deeks' stratified test of heterogeneity (Deeks
2001), as planned in the original protocol, nor was this assessed visually from the forest plot of relative risk, given the small number of
studies. We did not conduct planned subgroup analyses to assess the extent to which the primary outcomes were affected by (a) source
of trial funding, (b) whether trials were conducted at a single centre or across multiple centres, or (c) whether depressed individuals were
included in the sample, for the same reason.
We have expanded the list of medication categories under Types of interventions to include beta-blockers, to account for the large number
of studies assessing the efficacy of propranolol in preventing the onset of PTSD.
In the protocol it was stated that treatment efficacy of medication in preventing PTSD would be determined using the number of cases
diagnosed according to DSM criteria. In the review we decided to broaden this outcome to include data from studies assigning a probable
diagnosis of PTSD using the Posttraumatic Stress Symptom 10 Questionnaire Inventory (PTSS-10), as this measure has demonstrated
moderate to high (77%) sensitivity and excellent (97.5%) specificity in diagnosing clinically confirmed cases of PTSD (Weisaeth 1989).
The small number of participants in the included studies in this review means that evidence of outcome data that are not normally
distributed might be particularly problematic. There was no procedure in place in the protocol to address skewed data. We have now added
a description of such a procedure to the data synthesis component of the methods section. In addition, we have indicated that we intend

Informed decisions.
to obtain individual patient data (where possible) for the purpose of normalising the data by means of log transformation techniques in
future updates of the review.
We computed Hedges' g effect size estimate and 95% confidence intervals where study results for the PTSD symptom reduction outcome
were described as part of a narrative review. Although not originally part of the protocol, we added this to the review to aid interpretability,
as per the recommendation provided as part of editorial feedback on a draft version of the review.
We added to the review a sensitivity analysis to detect the influence of using the ITT sample as the denominator in calculating risk ratios
for the primary outcome of PTSD prevention, rather than the observed cases sample that was reported in the study publications, based
on feedback provided by an anonymous reviewer of the manuscript for the review.
INDEX TERMS
Medical Subject Headings (MeSH)

Adrenergic beta-1 Receptor Antagonists [therapeutic use]; Amines [therapeutic use]; Anti-Anxiety Agents [therapeutic use]; Anti-
Inflammatory Agents [therapeutic use]; Antidepressive Agents, Second-Generation [therapeutic use]; Citalopram [therapeutic use];
Cyclohexanecarboxylic Acids [therapeutic use]; Gabapentin; Hydrocortisone [therapeutic use]; Propranolol [therapeutic use];
Randomized Controlled Trials as Topic; Stress Disorders, Post-Traumatic [*prevention & control]; Temazepam [therapeutic use];
gamma-Aminobutyric Acid [therapeutic use]
MeSH check words

Adult; Aged; Humans; Middle Aged; Young Adult


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Pharmacological interventions for preventing post-traumatic stress

Amos T, Stein DJ, Ipser JC

Amos T, Stein DJ, Ipser JC.

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review)

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) i

Pharmacological interventions for preventing post-traumatic stress

Taryn Amos1, Dan J Stein1, Jonathan C Ipser1

Editorial group: Cochrane Common Mental Disorders Group

Data collection and analysis

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) 1

PLAIN LANGUAGE SUMMARY

Medications to prevent post-traumatic stress disorder (PTSD): a review of the evidence

Who may be interested in this review?

- People affected by PTSD and their families.

Why is this review important?

What questions does this review aim to answer?

Which studies were included in the review?

What does the evidence from the review tell us?

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) 2

What should happen next?

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) 3

Treatment efficacy Study population RR 0.62 118 ⊕⊕⊝⊝

200 per 1000 124 per 1000

Cochrane Database of Systematic Reviews

Treatment efficacy Study population RR 0.17 165 ⊕⊕⊕⊝

200 per 1000 34 per 1000

GRADE Working Group grades of evidence

Cochrane Database of Systematic Reviews

BACKGROUND suggest that cognitive behavioural therapy (CBT) is likely to be

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) 6

According to Pitman's translational model of PTSD pathogenesis Types of participants

Why it is important to do this review • Antipsychotics

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) 7

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) 8

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) 9

in response between groups (Elbourne 2002). We obtained the Data synthesis

• 0% to 40%: might not be important; Sensitivity analysis

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) 11

Summary of findings • Moderate quality: further research is likely to have an important

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) 12

Figure 1. Flow diagram.

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) 13

Included studies Interventions

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) 14

Clinician-Administered PTSD Scale (CAPS) (Delahanty 2012; Hoge Ongoing studies

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) 15

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) 16

1.5 Quality of life

1.6 Functional impairment

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) 18

Primary outcomes We observed evidence for the efficacy of hydrocortisone in

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) 19

detect differences on the PTSS-10Q-I after a median of 31 months Sensitivity analyses

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) 20

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) 21

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) 22

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) 23

Hauer D, Weis F, Campolongo P, Schopp M, Beiras-Fernandez A, Blake 1995

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) (Review) 24