Early pharmacological interventions for acute traumatic stress symptoms: a network meta‐analysis

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To assess the efficacy and acceptability of early pharmacological interventions in adults experiencing acute traumatic stress symptoms, and to generate clinically useful rankings of pharmacological interventions according to their efficacy and acceptability by performing a network meta‐analysis.

Background

Description of the condition

Acute traumatic stress symptoms are a group of psychological manifestations that can precipitate in individuals exposed to traumatic events. Experiences that entail a threat, actual or perceived, to life or physical integrity are generally recognised as possible traumatic events. According to the description in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM‐5) of acute stress disorder (ASD) and post‐traumatic stress disorder (PTSD), potentially traumatic events "include, but are not limited to, exposure to war as a combatant or civilian, threatened or actual physical assault, threatened or actual sexual violence, being kidnapped, being taken hostage, terrorist attack, torture, incarceration as a prisoner of war, natural or human‐made disasters, and severe motor vehicle accidents" (APA 2013). With some limitations regarding the nature of the traumatic incident, witnessing a trauma, learning that a relative or close friend was exposed to trauma, or being exposed to aversive details about a trauma (as in the course of professional duties) may also constitute a traumatic event. As stated by the DSM‐5, this list is not comprehensive and many different traumatic events have proved capable of precipitating traumatic stress symptoms.

Acute traumatic stress symptoms can be grouped in the following five categories (APA 2013).

• Intrusion symptoms: recurrent unwanted intrusive memories, distressing dreams, dissociative reactions as flashbacks, psychological distress at cues that symbolise or resemble the traumatic event.

• Negative mood: inability to experience positive emotions.

• Dissociative symptoms: altered sense of the reality, inability to remember an important aspect of the traumatic event.

• Avoidance symptoms: efforts to avoid distressing memories, thoughts, or feelings related to the traumatic event, or efforts to avoid external reminders of the traumatic event.

• Arousal symptoms: sleep disturbance, irritability, hypervigilance, problems concentrating, exaggerated startle response.

After the exposure to a possible traumatic event psychological distress is common, but usually self‐limited in time. Some individuals, however, progress towards the development of symptoms along with limitation of functioning (acute traumatic stress symptoms), and can develop ASD in the short term, or PTSD in the long term. Time elapsed from the traumatic event and duration of symptoms are the major differences between these two disorders. Symptoms manifest themselves within two days to one month from the traumatic event for ASD, after one month from the traumatic event for PTSD. (Previously, DSM‐IV‐TR also put a different emphasis on dissociation symptoms: APA 2000; APA 2013). Individuals with ASD might progress to PTSD in the case of symptoms persisting over one month from the traumatic event. It should be noted that while individuals with ASD have a high risk of progressing to PTSD, the majority of individuals with PTSD did not previously meet all of the ASD diagnostic criteria (Bryant 2011). Acute traumatic stress symptoms are therefore relevant for two reasons: because they are distressing in themselves, and because they can be a target for indicated prevention of PTSD, a severe and debilitating disorder.

Factors leading to PTSD development are complex and not fully understood, but it is known that multiple and interconnected systems are involved (Kelmendi 2016; Koch 2014; Lee 2016; Pitman 2012), and that PTSD is a disorder with a specific biological profile, as well as the psychological one (Besnard 2012; Nickerson 2013). Appendix 1 presents a summary of the main evidence related to the biological profile of PTSD.

Description of the intervention

Interventions for acute traumatic stress symptoms can be divided into two main categories, psychosocial and pharmacological: this review will focus on the latter. Psychological and pharmacological interventions can be combined and there are several reviews that have addressed early psychosocial interventions (Bryant 2007; Kearns 2012; Qi 2016; Roberts 2019).

With regard to pharmacological interventions for acute traumatic stress symptoms, randomised controlled trials (RCTs) have investigated drugs belonging to very different classes. This is because researchers have investigated both those interventions employed in PTSD treatment and those regarded as possibly effective on the basis of knowledge about the development and maintenance of traumatic memories and post‐traumatic symptoms. Previous meta‐analyses on PTSD prevention, which included early interventions in people with acute traumatic stress symptoms, reported medications belonging to the following drug classes (Amos 2014; Sijbrandij 2015).

Glucocorticoids are synthetic analogues of cortisol, a hormone involved in immunity and stress response. Glucocorticoids can be administered in several ways including orally, intravenously and intramuscularly. Trials testing steroids for PTSD prevention have used either single‐dose administration or a course of a few days in individuals with severe physical conditions (Delahanty 2013; Schelling 2001; Weis 2006). Hydrocortisone, along with some other steroids, is also included in the World Health Organization (WHO) Model List of Essential Medicines (WHO 2017), and therefore expected to be commonly available in several global contexts. Beta blockers are medications that exert a competitive antagonism towards endogenous catecholamines by binding to the beta adrenergic receptors. Beta blockers' main employment is in cardiology; however some trials have tested propanolol on a three‐week time span for PTSD prevention (Hoge 2012; Pitman 2002; Stein 2007). Propranolol is also included in the WHO Model List of Essential Medicines (WHO 2017). Benzodiazepines are minor tranquillisers that, by binding to the GABA_A receptor, enhance the anxiolytic effects of the neurotransmitter gamma‐aminobutyric acid (GABA). A small trial has investigated a short course of temazepam, but found an increase of PTSD onset rather than a decrease (Mellman 2002). Oxytocin is a pituitary hormone with roles in sociability and stress regulation, as well as its more widely known role in childbirth (Qi 2016). It can also be administered as a medication, and a trial investigated oxytocin administered as a single intranasal dose as early intervention (van Zuiden 2017). Selective serotonin reuptake inhibitors (SSRIs) are drugs mostly employed in depressive and anxious disorders. SSRIs have yielded good results in PTSD treatment, but there is uncertainty whether they are effective in reducing the incidence of PTSD (Shalev 2012). Mood stabilisers/anticonvulsants are a broad group of drug agents with effect in treating/preventing seizures. Some of them are effective in bipolar disorder and have anxiolytic properties. The anticonvulsant gabapentin has been included in trials of PTSD prevention (Stein 2007). Opioids are primarily employed in pain relief, but they have been proposed for PTSD after a large retrospective study on US soldiers with combat injury found an association between morphine administration and lower later PTSD incidence (Holbrook 2010).

How the intervention might work

The above‐mentioned biological features provide several possible targets; different rationales could explain the proposed efficacy of the following drugs.

Glucocorticoids

Glucocorticoids are involved in both hormonal stress response and memory formation. The hypothalamic‐pituitary‐adrenal (HPA) axis has been a longtime focus in the field of PTSD and a role for hydrocortisone in facilitating extinction learning has been hypothesised (Hruska 2014). In a rodent model a negative association has been found between high dose of steroids and prevalence of PTSD‐like behaviour in rats exposed to predator scent stress (Cohen 2008); and coherent results were found in a morphological study (Zohar 2011). There is also epidemiological evidence that lower urinary cortisol levels in the immediate aftermath of the trauma are associated with future PTSD symptoms (Delahanty 2000; McFarlane 1997).

Beta blockers

A role for adrenaline in the formation of traumatic memories has long been postulated (Pitman 1989). It has been argued that a surge in adrenaline concentration in conjunction with the trauma results in a strong emotional memory and fear conditioning that could prime traumatic stress symptoms. Later human studies supported a role for the beta adrenergic system in memory storing and in the enhanced memories associated with emotional arousal (Cahill 1994; Southwick 1999); and for propranolol to limit this process (Reist 2001).

Benzodiazepines

Benzodiazepines are known for reducing arousal and decreasing distress. They have amnesic properties as well, mostly inhibiting memory consolidation by impairing long‐term episodic storage (Barbee 1993). Regardless of this framework, it should be noted that no clinical evidence has succeeded in finding a positive effect for benzodiazepines in the management of traumatic stress symptoms (Howlett 2016).

Opioids

Studies on rodents have found retrograde amnesia properties for morphine. To explain this, it has been hypotisezed that morphine might alter the way the hippocampus (a functional component of the brain with a key role in memory consolidation and fear maintenance) handles recently acquired memories by influencing the intracellular cyclic adenosine monophosphate molecular pathway or by activating NMDA receptors (McNally 2003). Human observational studies do support a protective effect for morphine (Bryant 2009; Mouthaan 2015).

Oxytocin

A beneficial role for oxytocin has been hypothesised on the basis of a dual mechanism. Oxytocin might reduce the activity of amygdala, a brain structure with a major role in fear response behaviour, while at the same time increase the activity of social reward brain areas, resulting in enhancement of social bonding and interpersonal trust, thus protecting social functioning. This dual mechanism could then result in re‐establishing a “sense of safety” which is an important goal of therapy (Olff 2010). Behavioural data on rodents seem to confirm a plausible role for oxytocin (Cohen 2010).

SSRIs

SSRI antidepressants mechanism of action has not been fully clarified yet, but their antidepressant and anxiolytic activity has been associated with the modulation of serotonin receptors across different areas of the brain. SSRIs are among the first line pharmacological treatment for PTSD (Centre for Posttraumatic Mental Health 2013) and might thereby have a putative role in the treatment of early symptoms of acute traumatic stress.

Mood stabilisers/anticonvulsants

In a similar way to SSRIs, these might have a putative role in PTSD prevention in consideration of their employment as adjuvant/second line treatment for anxiety disorders (Van Ameringen 2004). A trial of gabapentin has been reported in previous meta‐analysis (Stein 2007).

Omega‐3 fatty acids compounds

Omega‐3 fatty acids compounds have been proposed in consideration of evidence in rodents that hippocampal neurogenesis has a role in the clearance of artificially induced fear memories, and that omega‐3 fatty acids promote hippocampal neurogenesis (Matsuoka 2011).

Why it is important to do this review

Up to 80% of the adult population in the USA have been exposed to a possible traumatic event (Breslau 2012), and estimates are similar for Europe (de Vries 2009). Acute traumatic stress symptoms can progress to ASD and, more importantly from a prognostic point of view, to PTSD. Despite the abundance of clinical and putative biological risk factors for PTSD and various predictive strategies being tested (Galatzer‐Levy 2014; Karstoft 2015; Kessler 2014), there is currently no effective way to predict who will develop PTSD after a traumatic experience. In addition to the affliction from acute traumatic stress symptoms, PTSD represents a heavy burden for the people affected, those around them, health systems and society. The lifetime prevalence of PTSD is estimated at 6.8% (Kessler 2005), and the 12‐month prevalence at 3.5% (Kessler 2005a), with higher general prevalence rates in displaced populations (Bogic 2015; Turrini 2017), and populations exposed to conflict (Steel 2009). Findings from the National Vietnam Veterans Longitudinal Study showed that, even after decades, a considerable number of male war veterans have PTSD (4.5%, 95% CI 1.7 to 7.3) or subthreshold PTSD symptoms (6.4%, 95% CI 3.0 to 9.7) (Marmar 2015). Moreover, PTSD is associated with poor general health status and unemployment (Zatzick 1997).

The aim of early pharmacological interventions for acute traumatic stress symptoms, along with relief of these symptoms, is to attenuate or prevent PTSD. It is then relevant to assess these interventions in the terms of PTSD symptoms. Investigating these interventions is also relevant because the risk‐to‐benefit ratio needs to be carefully assessed: drugs will entail possible side effects for all those receiving them, while for some people acute traumatic stress symptoms are self‐limiting.

In parallel with this review on early interventions, we are conducting a second review on universal PTSD prevention (Bertolini 2019).

As described above, very different drugs have been proposed but there is a lack of trials directly comparing one drug versus another. It is therefore difficult to make an overall comparison and establish a hierarchy, both in terms of efficacy, tolerability and acceptability. It appears, then, to be important to assess pharmacological interventions aimed at preventing the onset of the condition, applying a methodology that allows indirect comparisons.

Objectives

To assess the efficacy and acceptability of early pharmacological interventions in adults experiencing acute traumatic stress symptoms, and to generate clinically useful rankings of pharmacological interventions according to their efficacy and acceptability by performing a network meta‐analysis.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs) comparing one medication with placebo or one medication with another. We will consider trials for inclusion irrespective of language or publication status. For cross‐over trials, we will consider the data from the first randomised phase only.

Types of participants

Individuals

We will include trials which included participants with all of the following characteristics.

• History of any traumatic event

• Presenting acute traumatic stress symptoms, without restriction on their severity

• Aged 18 and older

We assume that any patient that meets the inclusion criteria is, in principle, equally likely to be randomised to any of the eligible interventions.

Trials not targeting symptomatic patients after exposure to traumatic events will be excluded from this review. These trials will be included in a parallel review on PTSD prevention (Bertolini 2019). This will contribute to minimising risk of intransitivity.

Setting

We will consider trials performed in any type of setting.

Subset data

We will include trials in which only a portion of the sample meets the above criteria, provided that the relevant data can be gained from the study report or by contacting the authors and that the effect of randomisation is not affected by doing so.

Types of interventions

We will consider any pharmacological intervention administered with the intention to treat acute traumatic stress symptoms or to prevent the onset of PTSD or PTSD symptoms within a period of three months from the trauma, as the DSM‐5 regards this timing relevant for symptoms’ evolution into PTSD (APA 2013). We will set no restriction regarding dose, duration or administration route of the intervention, nor on the presence of any co‐medication not related to traumatic stress symptoms. We will not consider trials where the experimental medication was used as an augmentation agent to ongoing psychotherapy (e.g. cognitive enhancers).

Based on our knowledge of the literature, we expect drugs from the following pharmacological groups to be found.

• Glucocorticoids

• Beta‐blockers

• Benzodiazepines

• Opioids

• Other hormones (oxytocin)

• Selective serotonin reuptake inhibitors (SSRIs)

• Mood stabiliser/Anticonvulsants

• Omega‐3 fatty acids compounds

We will include any other pharmacological intervention we might find during the review process and clearly report them. We will consider them eligible for the network meta‐analysis after assessing their comparability with the pre‐specified set of competing interventions. When doing so, we will consider the intervention details, the sample characteristics (see 'Data extraction and management' below) and any other additional feature that might affect comparability. This is to preserve the assumption of 'jointly randomisable' treatments.

Types of comparison

We will include studies using both placebo and any active pharmacological comparison. We will not consider studies comparing pharmacological interventions with only psychosocial interventions (i.e. with no other pharmacological or placebo arm).

We will include the studies that meet the above criteria irrespective of whether they report any of our outcomes of interest.

Types of outcome measures

Primary outcomes

• PTSD severity (continuous): we will use the mean score on the Clinician Administered PTSD Scale (CAPS) (Blake 1995), or the Comprehensive International Diagnostic Interview (CIDI) (WHO 1997), or any other validated rating scale to assess symptoms severity.

• Dropouts due to adverse events (dichotomous): we will consider the number of participants who leave the assigned arm early due to side effects, out of the number of randomised individuals.

Secondary outcomes

• PTSD rate (dichotomous): we will consider PTSD rates as measured by a DSM or International Classification of Diseases (ICD) (WHO 1992) diagnosis made with a clinician‐administered measure.

• Depression severity (continuous): we will consider the severity of depressive symptoms using the score on the Hamilton Depression Rating Scale (Hamilton 1960), or the Beck Depression Inventory (Beck 1961), or any other validated scale.

• Anxiety severity (continuous): we will consider the severity of the anxiety symptoms using the score on the Covi Anxiety Scale (CAS) (Covi 1984), or the Beck Anxiety Inventory (Beck 1988), or the Spielberger State‐Trait Anxiety Inventory (Spielberger 1970), or any other validated scale.

• Functional disability (continuous): we will consider the Sheehan Disability Scale (Sheehan 1996), or any other validated scale.

• Quality of life (continuous): we will use the Medical Outcome Study (MOS) 36‐Item Short‐Form Health Survey (SF‐36) (Ware 1992), or any other validated scale to assess quality of life.

• Dropout for any reason (dichotomous): we will consider the number of participants who leave the assigned arm early for any reason, out of the number of randomised individuals.

Hierarchy of outcome measures

The hierarchy of outcome measure scales will follow the order above. As we expect that clinicians' administered scales will have been more frequently employed, in case of trials employing validated scales different from the ones mentioned above we will, for homogeneity reasons, give priority to clinician‐administered scales over self‐reported ones.

Timing of outcome measures

We will synthesise data at three months' follow‐up (i.e. 3 months after experiencing trauma), operationalised as the time point closest to three months of follow‐up (from 2 to 4 months of follow‐up). In addition, we will include data at study endpoint as a secondary time point.

Search methods for identification of studies

We will use the same search strategy as that used for the Cochrane Review of early pharmacological interventions for preventing post‐traumatic stress disorder (Bertolini 2019).

Specialised register: the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR)

Cochrane Common Mental Disorders (CCMD) maintained a specialised register of randomised controlled trials (RCTs), the CCMDCTR, to June 2016. This register contains over 40,000 reference records (reports of RCTs) for anxiety and depressive disorders, bipolar disorder, eating disorders, self‐harm and other mental disorders within the scope of CCMD. The CCMDCTR is a partially studies‐based register with more than 50% of the reference records tagged to 12,600 individually participant‐, intervention‐, comparison‐ and outcome‐coded (PICO) study records. Reports of trials for inclusion in the register were collated from (weekly) generic searches of MEDLINE (1950‐ ), Embase (1974‐ ) and PsycINFO (1967‐ ), quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL) and review‐specific searches of additional databases. Reports of trials were also sourced from international trial registries, drug companies, handsearching of key journals, conference proceedings and other (non‐Cochrane) systematic reviews and meta‐analyses. Details of CCMD's core search strategies (used to identify RCTs) can be found on CCMD's website, with an example of the MEDLINE search presented in Appendix 2. The register became out of date with the relocation of the group from the University of Bristol to York University in June 2016.

Electronic searches

We will cross‐search the CCMDCTR studies and references register for condition alone, using the following terms.

(PTSD or posttrauma* or post‐trauma* or "post trauma*" or "combat disorder*" or "stress disorder*") (all years to June 2016).

We will screen the search results for any pharmacological intervention (active intervention versus placebo or active intervention versus active intervention trials) for acute traumatic stress symptoms.

Biomedical database search

We will search Ovid MEDLINE, Embase and PsycINFO, Proquest PTSDPubs (formerly Published International Literature On Traumatic Stress (PILOTS)), and the Cochrane Central Register of Controlled Trials (CENTRAL) from 2014 onwards using terms to define the population, together with an RCT filter. This is to complement the search of the CCMDCTR and account for the period when it became out of date. This search has already been conducted by the CCMD editorial base (3 March 2018) (Appendix 3). We will screen the results of this search for all relevant pharmacological RCTs for acute stress symptoms.

International trials registers

We will search for unpublished studies in international trials registers via the World Health Organization's trials portal (ICTRP), and the National Institute of Health's trials website (ClinicalTrials.gov). See Appendix 4 for search strategies on these sources.

We will not apply any publication status or language restrictions.

We will re‐run all searches close to publication if a period of more than 12 months has elapsed since the initial search date.

Searching other resources

We will check the reference list of all included studies and relevant systematic reviews.

Data collection and analysis

Selection of studies

We will import all records obtained via the electronic search into EndNote software, in order to remove all duplicates. Two review authors (FB and LR) will work in duplicate and independently. They will screen all potential papers' titles and abstracts and code them as 'retrieve' or 'not retrieve', obtain the full‐text publication of the records coded as 'retrieve', and assess inclusion and exclusion criteria. They will resolve disagreement by discussion or, if necessary, by involving a third review author (NM). We will record the selection process in sufficient detail to complete a PRISMA flow diagram and 'Characteristics of excluded studies' table (Moher 2009).

Data extraction and management

Two review authors (FB and LR), working independently and in duplicate, will extract data from the included trials. We will use a data extraction sheet developed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions section 7.5 (Higgins 2019). We will collect the following data.

• First author, year of publication, journal, source of funding, notable conflict of interest of authors, total duration of study, number of centres and location.

• Methodological characteristics of the trial: randomisation, blinding, allocation concealment, number of arms, follow‐up time points.

• Sample characteristics: study setting, type of trauma, criteria for enrolling, age, gender, number of participants randomised to each arm, baseline acute traumatic stress symptoms, history of previous trauma.

• Intervention details: time from the traumatic event to treatment, medication employed, period over which it has been administered, dosage range, mean dosage prescribed.

• Outcomes: time points of outcome assessment, instrument used to assess PTSD symptoms, instrument used to assess PTSD rate, instrument used to assess depression symptoms, instrument used to assess anxiety, instrument used to assess functional disability, outcome measure employed by original trial (primary and secondary), data of continuous (means and standard deviation or standard error if standard deviation is not provided) and dichotomous variables of interest, number of total dropouts, number of dropouts due to pharmacological side effect, whether the data reflect an intention‐to‐treat (ITT) model, methods of estimating the outcome for participants who dropped out (last observation carried forward (LOCF) or completer/observed case (OC) approach, or other).

Assessment of risk of bias in included studies

Two review authors (FB and LR) working independently and in duplicate will assess risk of bias for each study according to the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019). We will resolve disagreement by discussion, or if necessary by involving a third review author (NM). We will assess the risk of bias according to the following seven domains.

• Random sequence generation (selection bias)

• Allocation concealment (selection bias)

• Blinding of participants and personnel (performance bias)

• Blinding of outcome assessment (detection bias)

• Incomplete outcome data (attrition bias)

• Selective reporting (reporting bias)

• Other bias

We will assess performance, detection and attrition bias on a 'per outcome' basis rather than per study. We will rate each source of bias as high, low or unclear. We will provide reasons to justify the rating. We will present all data regarding risk of bias both graphically and in the text.

Measures of treatment effect

Dichotomous data

For dichotomous data, we will calculate risk ratio (RR) estimates and their 95% confidence interval (CI). RRs are more easily interpreted than odds ratios (ORs) (Boissel 1999), and as clinicians may risk interpreting ORs as RRs (Deeks 2002), this may lead to an overestimation of the effect. We will calculate the number needed to treat for an additional beneficial outcome (NNTB).

Continuous data

For continuous data, we will calculate the mean differences (MDs) and the 95% CI, where data are measured on the same scale. If the studies employed different scales, we will use standardised mean differences (SMDs). The trials may report the results either as endpoint means or using change in mean values from baseline assessment. We will give preference to endpoint measures, given the nature of the review (prevention) and that endpoint data are easier to interpret from a clinical point of view. Where sufficient data are reported, we will convert change scores into endpoint data using standard formulas reported in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019). We will interpret SMDs according to the following guidelines: 0.2 represents a small effect; 0.5 a moderate effect; and 0.8 a large effect (Cohen 1988).

Unit of analysis issues

Cross‐over trials

We will consider only the first phase from cross‐over trials as the carry‐over effect cannot be excluded on a prevention measure regardless of appropriate washout times.

Cluster‐randomised trials

If we include cluster‐RCTs, but they have not been appropriately adjusted for the correlation between participants within clusters, we will contact trial authors to obtain an estimate of the intra‐cluster correlation (ICC), or impute using estimates from the other included trials or from similar external trials. If imputation of ICCs is required we will conduct sensitivity analyses to examine the impact on estimates.

Multiple treatment groups studies

For the pair‐wise meta‐analysis, we will compare each arm with placebo separately and include each pair‐wise comparison separately. We plan the following means to prevent 'double‐counting', in accordance with the Cochrane Handbook for Systematic Reviews of Interventions, section 16.5.4 (Higgins 2019): in the case of dichotomous variables, we will split the comparison group evenly among the intervention ones; in the case of continuous variables only the total number of participants will be divided up, and mean and SDs will be left unchanged.

For the network meta‐analyses, we will adjust for correlations inherent in multiple‐arm trials using standard methods (e.g. Dias 2013a).

Dose‐ranging studies

If a study has multiple arms with the same medication administered at different doses or administered for a different time length, we will pool these intervention groups into a single one, as recommended by the Cochrane Handbook for Systematic Reviews of Interventions, section 16.5.4 (Higgins 2019).

Dealing with missing data

As a first measure, we will contact study investigators to obtain missing data. Should this not be effective, we will employ the following approaches.

Dichotomous data

Where reported, we will use ITT data analysed on a 'once randomised, always analysed' basis. In case of trials conducting different imputational strategies, we will give preference to data derived from multiple imputation or mixed‐effects models. For studies that did not perform an ITT analysis, we will assume a negative outcome (i.e. onset of PTSD) for individuals lost at follow‐up.

Continuous data

As above, we will use ITT data where reported and favour multiple imputation or mixed‐effects models where different imputational strategies have been used. In the context of prevention, last observation carried forward (LOCF) provides the least conservative option and therefore we will prefer observed case (OC) data. For studies not reporting ITT analyses, we will not impute missing data for continuous outcomes, as this usually requires access to individual participant data.

We will report in the relevant section of the results if the data employed were based on an imputational method; and if so, which one.

Missing statistics

Where possible, we will calculate SDs when only P values, CIs, standard errors, etc. are reported. If this is not possible, we will calculate an arithmetic mean of the SDs of studies using the same scale of the one with missing SD, as in Furukawa 2006.

Assessment of heterogeneity

For pair‐wise meta‐analyses, we will assess heterogeneity by means of:

• visual inspection on the overlap of the CIs for individual studies in the forest plot;

• Chi² test, with a P value set at 0.10 (we presume the number of studies to be small);

• I² statistic: in accordance with the suggestion in the Cochrane Handbook for Systematic Reviews of Interventions section 9.5.2 we will follow a rough guide to interpretation as follows: 0% to 40%: might not be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%: considerable heterogeneity (Higgins 2019). We will also take into account magnitude and direction of effects.

For the network meta‐analyses, we will assume a common between‐study heterogeneity standard deviation and use uniform non‐informative priors (0, 5).

We will assess the transitivity assumption (i.e. that effect modifiers are equally distributed across the comparisons) in several steps. First, we will assess the distribution of potential effect modifiers across treatment comparisons for the following study characteristics: year of publication, study setting, type of trauma, criteria for enrolling, age, gender, history of previous trauma of participants, time from traumatic event to treatment, period over which the treatment has been administered.

Second, we will use standard methods to conduct a global assessment of inconsistency using WinBUGS/OpenBUGS (Dias 2013b; WinBUGS 2000). We will compare the goodness of fit of an inconsistency model with the network meta‐analysis model used in the main analyses which assumes consistency between direct and indirect evidence. We will assess the impact on between‐study SD (i.e. heterogeneity) and goodness‐of‐fit statistics (residual deviance and deviance information criterion (DIC)).

Third, if there is sufficient evidence of potential inconsistency (e.g. improved fit of the inconsistency model of 5 or more on the DIC, substantial reduction in between‐study deviation), then we will fit node‐splitting models (van Valkenhoef 2016), using the Graphical Mixed Treatments Comparisons (GeMTC) package in R (R 2017).

Assessment of reporting biases

If we find 10 or more studies to include per primary outcome, we will

• visually inspect the relative funnel plots, test them for asymmetry and investigate possible reasons for funnel plot asymmetry;

• employ Egger's regression test (Egger 1997).

Data synthesis

Methods for pair‐wise meta‐analysis

We will perform standard pair‐wise meta‐analysis with a random‐effects model for every comparison with at least two studies, using Review Manager 5 (Review Manager 2014). Given the nature of the data, and the likely heterogeneity, we think a random‐effects model makes more plausible assumptions. We will perform the pair‐wise comparison at individual medicine level (e.g. propranolol versus placebo), but if this is not feasible due to the number of studies, we will shift to drug class level (e.g. beta blocking agents versus placebo), using the WHO's ATC/DDD Index 2019 as reference (WHO 2018). We will not perform a pair‐wise meta‐analysis in the case of comparison with less than two contributing trials.

Methods for network meta‐analysis

For primary outcomes, at both time points (3 months from trauma and at study endpoint), we will assess if there are sufficient data to perform a network meta‐analysis. If there are sufficient data, we will perform a network meta‐analysis using Markov Chain Monte Carlo methods. We will fit random‐effects models in a Bayesian framework using WinBUGS/OpenBUGS (WinBUGS 2000), with standard code (Dias 2013a).

We will use the binomial likelihood for dichotomous data and the normal likelihood for continuous data.

Normal non‐informative priors (0, 100) will be used for trials baselines and treatment effects.

We will assess convergence of three chains (using different initial values) based on visual inspection of history, Brooks‒Gelman‒Rubin, and autocorrelation plots. If we judge the chains to have converged, we will discard the preceding iterations, and we will run a further 50,000 iterations. We will base estimates on the latter iterations.

We will report posterior medians with 95% credible intervals for all treatment effects, between‐study standard deviations (to assess heterogeneity), and total residual deviance (to assess goodness of fit).

We will calculate the mean rank and probability of being most effective for each treatment (both with 95% credible intervals).

We plan to perform the network meta‐analysis at individual medicine level, but should this not be feasible we will also consider fitting models at drug class level using the WHO's ATC/DDD Index 2019 as reference or including both individual medicine and drug class levels (WHO 2018).

Subgroup analysis and investigation of heterogeneity

For both pairwise and network meta‐analyses we will perform meta‐regression analyses on primary outcomes only, to avoid the risk of identifying false positive findings through multiple testing. We plan to assess the impact on effectiveness of the following covariates.

• Setting (e.g. Acute & Emergency departments, surgery or Intensive Care survivors), as this could result in a selection of both a specific population and trauma types (e.g.: elderly patients who are severe illness survivors).

• Patients with a diagnosis of ASD and patients not fulfilling ASD criteria, as this is likely associated with different risks of developing PTSD.

Sensitivity analysis

We plan to investigate the impact of excluding studies at high risk of bias, defined by unclear allocation concealment or unblinded outcome assessment or uncertain unblinding of outcome assessment; the impact of using ITT data versus completer outcomes; and the impact of excluding cluster RCTs.

To estimate the influence of small‐study effects on the network meta‐analyses we will examine the association between effect estimates and their variance (small studies tend to have larger variances) for the primary outcomes (Dias 2010). We will assess the magnitude of the bias parameter along with its 95% credible intervals as well as the impact on relative effects estimates and between‐trial standard deviation.

Summary of findings

Pair‐wise meta‐analyses

We will present the results of the meta‐analysis using a 'Summary of findings' table for the pair‐wise comparisons. The 'Summary of findings' table will include the following outcomes.

• PTSD severity

• Dropouts due to adverse events

• PTSD rate

• Functional disability

• Quality of life

We will use the five GRADE 'certainty assessment' domains (study design, risk of bias, inconsistency, indirectness, imprecision) to assess the certainty of the evidence in consideration of the studies that provided data for the specific outcome. We will use the GRADEpro software (GRADEpro GDT 2015), and apply the methods and recommendations from the Cochrane Handbook for Systematic Reviews of Interventions, section 11.5 (Higgins 2019). At least two different review authors will assign grading, and they will resolve disagreement through discussion or if required by consulting a third review author (NM). We will use footnotes to justify the downgrading and upgrading of the evidence. We will note comments to aid the reader, when suitable. We will categorise the certainty of the evidence as high (further research is not likely to change our confidence in the estimate of effect), moderate (further research is likely to have an important impact on the estimate of effect and may change it), low (further research is very likely to have an important impact on the estimate of effect and is likely to change it), or very low (estimate of effect is very uncertain).

If we find that additional information regarding the outcome cannot be incorporated in the meta‐analysis, we will report this in the comments and state whether this information supports or contradicts the meta‐analysis results.

Network meta‐analyses

We will create a ‘Summary of findings' table for the primary outcomes.

We will use the five GRADE domains (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the certainty of the evidence from the network meta‐analysis, using the standard methods (Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011)), but with modifications to reflect specific issues in network meta‐analysis. As proposed by Salanti 2014 and Nikolakopoulou 2020, we will:

• evaluate each piece of direct evidence in the network and classify it at low, moderate or high risk of bias, according to the usual GRADE guidelines;

• consider for each pair‐wise network estimate the contribution of all direct estimates feeding into it, using the contributions matrix;

• illustrate the ‘Risk of bias' assessments according to the contributions of each source of direct evidence to each network meta‐analysis effect estimate. We will display this in a bar chart using green, yellow and red to represent low, moderate and high risk of bias, respectively;

• integrate the ‘Risk of bias' judgements and the respective contributions for each pair‐wise comparison into a single judgement about study limitations and consider whether to downgrade the quality of the evidence. We will assign numerical scores to each risk of bias judgement (e.g. 0 for low, −1 for moderate, and −2 for high risk of bias), and take a weighted average of these using the contribution of each direct estimate to the network estimates from the contributions matrix.

• when judging imprecision we will set an equivalence range of RR 0.75 to 1.25 for dichotmous outcomes and SMD ‐0.2 to 0.2 for continuous outcomes. These are default thresholds suggested in the GRADE handbook (GRADEpro GDT 2015) since we are unaware of a consensus on defining minimally important differences in the field of acute traumatic stress symptoms.

We will use GRADEpro GDT and CINeMA software to generate data for the 'Summary of findings' tables, which will be presented according to Yepes‐Nunez 2019, using placebo as comparator (CINeMA 2007; GRADEpro GDT 2015). We will justify all decisions to downgrade or upgrade the quality of the evidence using footnotes and make comments to aid the reader's understanding of the review, where necessary (Salanti 2014).

History

Protocol first published: Issue 5, 2020

Appendices

Appendix 1. PTSD biological profile

Basic biomedical research has identified distinct biological features in the development and maintenance of traumatic stress symptoms. Most of the evidence is derived from animal models of PTSD.

Studies on genetic contribution to the onset of ASD and PTSD estimate this influence to be at about 30% (True 1993; Stein 2002). Since no single gene can explain the variance in heritability, a polygenic network is suggested (Smoller 2016). The loci identified so far are involved in:

• the dopaminergic and serotoninergic systems;

• hypothalamic‐pituitary‐adrenal (HPA) axis regulation;

• encoding of neurotrophins; and

• the locus coeruleus noradrenergic system (Smoller 2016; Pitman 2012).

There are findings to support an epigenetic contribution as well, mainly on the expression of genes related to immune functions, signal transduction, neuronal signalling and HPA axis activity (Yehuda 2009a; Zieker 2007). As a whole, however, the genetic role in PTSD remains mainly uncharted (Smoller 2016). In individuals affected by PTSD the sympathetic nervous system appears to be up‐regulated (Southwick 1999) and hyper‐reactive (Liberzon 1999a; Southwick 1993), and this can be correlated with the hypervigilance‐hyperarousal‐insomnia symptoms and to the cluster of "re‐experience" symptoms. It has also been proposed that an excessive surge in the adrenal response immediately after the trauma may play a role in the formation of persistent memories associated with the event (Pitman 1989). The serotoninergic system also plays a role in both the modulation of PTSD risk and in its clinical manifestations. Evidence of that has been gathered from the aforementioned genetic studies, and from neuropharmacological studies (Southwick 1997;Murphy 1991): the serotonin pathway is highly likely to be implicated in the processes underlying sleep disturbances, stress modulation, mood, aggressivity, and some of the neuroendocrine aspects (Southwick 1999). Additional evidence of serotoninergic pathway involvement is from receptor imaging studies: 5‐HT transporter binding is reduced in the amygdala (Murrough 2011), and 5‐HT_1B receptors are less concentrated in the amygdala and anterior cingulate cortex (Kelmendi 2016); both of these brain regions are of interest in PTSD as confirmed by morphological studies. Cortisol axis regulation is altered in individuals with PTSD and some findings suggest that an altered HPA axis could already be present before the trauma (Yehuda 2009b). Corticotrophin release hormone (CRH) is a known anxiogenic agent and modulates some of the systemic response to stress including cytokine signalling, immunologic and hormonal functions (Friedman 2000). CRH is generally found to be increased in serum samples of individuals with PTSD, but has yielded mixed results regarding the dynamics of its concentration in cerebrospinal fluid (CSF) (Baker 2005; Geracioti 2008). More evidence is required to determine the role of CRH in the central nervous system during stress. Contrary to what one would expect, cortisol levels are reduced in individuals with PTSD (Yehuda 2002), perhaps reflecting an excessively up‐regulated feedback effect (Yehuda 1995). Of interest, some of the genes knows to be involved in process of resilience have glucocorticoid response elements (Hou 1998). Moreover, cortisol has become a focus in traumatic stress symptoms for its role in memory formation and consolidation (McIntyre 2007). In light of the different findings on this relationship on memory formation in PTSD (Schelling 2004), it can be hypothesised that the relationship follows an 'inverted U' tendency (Sandi 2011; Pitman 2012). The immune system itself may play a role, based on early findings of its activation in PTSD (Newport 2000), supported by later epigenetic studies (Uddin 2010). The GABAergic system is likely to be involved, and has a role in both memory registration and fear memory encoding (Corcoran 2001). A receptor binding study found a global overall reduction in the benzodiazepine receptor (Geuze 2008). PTSD patients versus trauma‐exposed people have also lower GABA levels in mesial temporal lobe and in the parieto‐occipital cortex (Meyerhoff 2014). Cannabinoid receptor 1 is involved in modulation of aversive memories (Kelmendi 2016), and was found more available in individuals with PTSD while its endogenous agonist was found lowered (Neumeister 2013). Recently a growing interest is focusing on oxytocin, which holds pro‐social and anxiolytic effects (Olff 2014). A disruption in the oxytocin system has been proposed in the development of PTSD (Feldman 2014); and intranasal oxytocin administration has proven to be able to reduce amygdala reactivity in response to threat (Koch 2016).

Morphological and functional studies of the CNS in people with PTSD have identified several alterations (Admon 2013; O'Doherty 2015; Pitman 2012). Some of the abnormalities might be predisposing risk factors (in particular amygdala and dorsal anterior cingulate), while others may become evident only after the onset of the disorder, i.e. the structural/functional connectivity between hippocampus and ventro‐medial prefrontal cortex (Admon 2013). Meta‐analyses have confirmed a hippocampal reduction (Karl 2006; Smith 2005; Woon 2011); and a recent meta‐analysis found the reduction to be bigger in the left hippocampus (O'Doherty 2015). On the assumption that diminished volume may underline a diminished function, these findings support the theory that the hippocampus fails to signal a safe environment via contextual cues. It is still a matter of debate whether hippocampal alterations are consequent of PTSD or rather a risk factor (Bremner 2001; Gilbertson 2002). Functional studies have produced mixed results with some reporting less activation (Bremner 2003), others more (Shin 2010). There are findings of prefrontal cortex regions of people affected by PTSD to be reduced in volume in the ventromedial prefrontal cortex (Kasai 2008); and in the dorsal anterior cingulate cortex (Kitayama 2006; O'Doherty 2015). Functional studies found areas in the ventromedial prefrontal cortex to be less active during tasks involving trauma‐related stimuli (Shin 1999). Some reports found similar results for non‐trauma‐related stimuli as well (Gold 2011). Findings on the amygdala report a volume reduction when PTSD patients are compared with healthy non‐trauma‐exposed subjects, but no significant reduction was found when compared with trauma‐exposed non‐PTSD subjects (O'Doherty 2015). Functional studies found amygdala to be more activated in response to trauma‐related stimuli (Liberzon 1999b) than to generic stimuli (Etkin 2007); and while acquiring conditioned fear in PTSD patients compared to control subjects (Bremner 2005). Focus on the amygdala is due to its role in the regulation of traumatic and stressful events, related behaviour and emotions and in fear conditioning and generalisation (O'Doherty 2015).

Appendix 2. CCMDCTR (core MEDLINE search)

Core search strategy used to inform pecialised register: OVID MEDLINE (1946 to June 2016)

A weekly search alert based on condition + RCT filter only

1. [MeSH Headings]:

eating disorders/ or anorexia nervosa/ or binge‐eating disorder/ or bulimia nervosa/ or female athlete triad syndrome/ or pica/ or hyperphagia/ or bulimia/ or self‐injurious behavior/ or self mutilation/ or suicide/ or suicidal ideation/ or suicide, attempted/ or mood disorders/ or affective disorders, psychotic/ or bipolar disorder/ or cyclothymic disorder/ or depressive disorder/ or depression, postpartum/ or depressive disorder, major/ or depressive disorder, treatment‐resistant/ or dysthymic disorder/ or seasonal affective disorder/ or neurotic disorders/ or depression/ or adjustment disorders/ or exp antidepressive agents/ or anxiety disorders/ or agoraphobia/ or neurocirculatory asthenia/ or obsessive‐compulsive disorder/ or obsessive hoarding/ or panic disorder/ or phobic disorders/ or stress disorders, traumatic/ or combat disorders/ or stress disorders, post‐traumatic/ or stress disorders, traumatic, acute/ or anxiety/ or anxiety, castration/ or koro/ or anxiety, separation/ or panic/ or exp anti‐anxiety agents/ or somatoform disorders/ or body dysmorphic disorders/ or conversion disorder/ or hypochondriasis/ or neurasthenia/ or hysteria/ or munchausen syndrome by proxy/ or munchausen syndrome/ or fatigue syndrome, chronic/ or obsessive behavior/ or compulsive behavior/ or behavior, addictive/ or impulse control disorders/ or firesetting behavior/ or gambling/ or trichotillomania/ or stress, psychological/ or burnout, professional/ or sexual dysfunctions, psychological/ or vaginismus/ or Anhedonia/ or Affective Symptoms/ or *Mental Disorders/2.

[Title/ Author Keywords]: (eating disorder* or anorexia nervosa or bulimi* or binge eat* or (self adj (injur* or mutilat*)) or suicide* or suicidal or parasuicid* or mood disorder* or affective disorder* or bipolar i or bipolar ii or (bipolar and (affective or disorder*)) or mania or manic or cyclothymic* or depression or depressive or dysthymi* or neurotic or neurosis or adjustment disorder* or antidepress* or anxiety disorder* or agoraphobia or obsess* or compulsi* or panic or phobi* or ptsd or posttrauma* or post trauma* or combat or somatoform or somati#ation or medical* unexplained or body dysmorphi* or conversion disorder or hypochondria* or neurastheni* or hysteria or munchausen or chronic fatigue* or gambling or trichotillomania or vaginismus or anhedoni* or affective symptoms or mental disorder* or mental health).ti,kf.3.

[RCT filter]: (controlled clinical trial.pt. or randomized controlled trial.pt. or (randomi#ed or randomi#ation).ab,ti. or randomly.ab. or (random* adj3 (administ* or allocat* or assign* or class* or control* or determine* or divide* or distribut* or expose* or fashion or number* or place* or recruit* or subsitut* or treat*)).ab. or placebo*.ab,ti. or drug therapy.fs. or trial.ab,ti. or groups.ab. or (control* adj3 (trial* or study or studies)).ab,ti. or ((singl* or doubl* or tripl* or trebl*) adj3 (blind* or mask* or dummy*)).mp. or clinical trial, phase ii/ or clinical trial, phase iii/ or clinical trial, phase iv/ or randomized controlled trial/ or pragmatic clinical trial/ or (quasi adj (experimental or random*)).ti,ab. or ((waitlist* or wait* list* or treatment as usual or TAU) adj3 (control or group)).ab.)4. (1 and 2 and 3)Records are screened for reports of RCTs within the scope of the Cochrane Common Mental Disorders Group. Secondary reports of RCTs are tagged to the appropriate study record.

Similar weekly search alerts are also conducted on OVID Embase and PsycINFO, using relevant subject headings (controlled vocabularies) and search syntax, appropriate to each resource.

Appendix 3. CCMD Editorial Base search strategy (2014 to 2018)

In March 2018, CCMD's Information Specialist (Chris Cooper) ran a search for all PTSD studies (treatment or prevention, RCTs, condition only) on the main biomedical databases listed below. This was to capture relevent studies for a suite of PTSD reviews registered with CCMD and to account for the period when the CCMDCTR was out of date. This search will be updated for this review so it is within 12 months of the date of publication.

Search results were deduplicated and screened in Covidence, each record was screened by at least two members of the CCMD editorial base staff.

Inclusion criteria were as follows.

• Any RCT for the treatment of PTSD (irrespective of intervention, age group or comorbidity)

• Any RCT which might be seen as a PTSD prevention study

• Any RCT for critical incident stress debriefing (CISD) (simulated crises not included)

• Any RCT for debriefing after psychological trauma or any stress resilience studies

• Any CCT where the treatment allocation is ambiguous

• Corrigendums, errors, retractions or substantial comments relating to the above.

Exclusion criteria were as follows.

• All systematic reviews and meta‐analyses

• Healthy populations

• Simulated crises (e.g. for staff training in accident and emergency)

• RCTs which fall outside the scope of CCMD, e.g. serious mental illness (schizophrenia), borderline personality disorder, alcohol use disorder e.g. brief alcohol intervention in accident and emergency department, smoking cessation, traumatic brain injury, fibromyalgia (unless the comorbidity clearly fell within the scope of the search and was an outcome of the trial).

Databases	Hits
MEDLINE	1742
Embase	3319
CENTRAL	2028
PsycINFO	1449
PILOTS	879
Total	9417
‐duplicates	‐4635
Studies to screen	4782
Date of Search	3/3/18

1. Cochrane Central Register of Controlled Trials (CENTRAL)
Host: Wiley interface
Data Parameters: Cochrane Central Register of Controlled Trials: Issue 2 of 12, February 2018
Date Searched: Monday 3 March 2018
Searched by: Chris Cooper
Hits: 2028
ID Search Hits
#1 MeSH descriptor: [Stress Disorders, Post‐Traumatic] this term only 1492
#2 (PTSD or ((posttrauma* or post‐trauma* or post trauma*) near/3 (stress* or disorder* or psych* or symptom*)) or acute stress disorder* or combat disorder* or war neuros*) 5065
#3 (((acute or traumatic) near/1 stress*) and (expos* or psyc*)) 1525
#4 (traumatised near/1 (victim* or survivor*)) 2
#5 (traumatized near/1 (victim* or survivor*)) 4
#6 (trauma* near/2 (event* or memor* or flashback* or nightmare*)) 553
#7 ((trauma* or posttrauma* or post‐trauma* or victim* or survivor*) and (exposure near/3 (therap* or psychotherap* or training or counsel*))) 417
#8 MeSH descriptor: [Crisis Intervention] this term only 166
#9 (critical incident near/1 (stress or debrief* or de‐brief*)) 24
#10 (debriefing or de‐briefing) 328
#11 (crisis intervention* or CISD) 1003
#12 ((stress or group* or psychological or crisis) near/3 (debrief* or de‐brief*)) 107
#13 (trauma* near/2 (event* or memor* or flashback* or nightmare*)) 553
#14 (EMDR or (eye movement desensitization and reprocessing)) 225
#15 (EMDR or (eye movement desensitisation and reprocessing)) 197
#16 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or
#15 Publication Year from 2014 to 2018 2893
Notes: N/A
File: VO1 CENTRAL n2028.txt

2. Ovid MEDLINE(R) Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present
Host: OVID
Data parameters: 1946‐Current (date limits applied, 2014 onwards)
Date searched: Monday 3 March 2018
Searched by: Chris Cooper
Hits: 1742

#	Searches	Results
1	Stress Disorders, Post‐Traumatic/	27503
2	(PTSD or ((posttrauma* or post‐trauma* or post trauma*) adj3 (stress* or disorder* or psych* or symptom?)) or acute stress disorder* or combat disorder* or war neuros*).ti,ab,kf,kw,id.	31111
3	(((acute or traumatic) adj stress*) and (expos* or psyc*)).ti,ab,kf,kw,id.	10567
4	(traumati#ed adj (victim? or survivor?)).ti,ab,kf,kw,id.	34
5	(trauma* adj2 (event? or memor* or flashback* or nightmare?)).ti,ab,kf,kw,id.	8174
6	((trauma* or posttrauma* or post‐trauma* or victim* or survivor?) and (exposure adj3 (therap* or psychotherap* or training or counsel*))).ti,ab,kf,kw,id,hw.	901
7	Crisis Intervention/	5457
8	(critical incident adj (stress or debrief* or de‐brief*)).ti,ab,kf,kw,id.	223
9	(debriefing or de‐briefing).ti,kf,kw,id.	577
10	(crisis intervention? or CISD).ti,ab,kf,kw,id.	1744
11	((stress or group? or psychological or crisis) adj3 (debrief* or de‐brief*)).ti,ab,kf,kw,id.	406
12	(trauma* adj2 (event? or memor* or flashback* or nightmare?)).ti,kf,kw,id.	1150
13	(EMDR or (eye movement desensiti#ation and reprocessing)).ti,ab,kf,kw,id,sh.	510
14	1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13	52168
15	randomized controlled trial.pt.	454849
16	controlled clinical trial.pt.	92204
17	randomized.ab.	404382
18	placebo.ab.	186843
19	clinical trials as topic.sh.	182777
20	randomly.ab.	285994
21	trial.ti.	178689
22	15 or 16 or 17 or 18 or 19 or 20 or 21	1136215
23	14 and 22	4000
24	(2014* or 2015* or 2016* or 2017* or 2018*).yr,dt,ed,ep.	5444042
25	23 and 24	1742

Notes: N/A
File: VO1 MEDLINE n1742.txt

3. Embase
Host: OVID
Data parameters: 1974 to 2018 March 02 (date limits applied, 2014 onwards)
Date searched: Monday 3 March 2018
Searched by: Chris Cooper
Hits: 3319
Search strategy:

#	Searches	Results
1	posttraumatic stress disorder/	48854
2	"trauma and stressor related disorders"/	34962
3	combat disorders/	26663
4	psychological trauma/	5351
5	stress disorders, post‐traumatic/	16743
6	stress disorders, traumatic, acute/	751
7	(PTSD or ((posttrauma* or post‐trauma* or post trauma*) adj3 (stress* or disorder* or psych* or symptom?)) or acute stress disorder* or combat disorder* or war neuros*).ti,ab,kw.	39945
8	(((acute or traumatic) adj stress*) and (expos* or psyc*)).ti,ab,kw.	15122
9	(traumati#ed adj (victim? or survivor?)).ti,ab,kw.	51
10	(trauma* adj2 (event? or memor* or flashback* or nightmare?)).ti,ab,kw.	10514
11	(EMDR or (eye movement desensiti#ation and reprocessing)).ti,kw.	527
12	((trauma* or posttrauma* or post‐trauma* or victim* or survivor?) and (exposure adj3 (therap* or psychotherap* or training or counsel*))).ti,ab,kw.	1096
13	(critical incident adj (stress or debrief* or de‐brief*)).ti,ab,kw.	275
14	(debriefing or de‐briefing).ti,ab,kw.	4133
15	(crisis intervention? or CISD).ti,ab,kw.	2273
16	((stress or group? or psychological or crisis) adj3 (debrief* or de‐brief*)).ti,ab,kw.	602
17	(trauma* adj2 (event? or memor* or flashback* or nightmare?)).ti,ab,kw.	10514
18	1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17	74063
19	crossover‐procedure/ or double‐blind procedure/ or randomized controlled trial/ or single‐blind procedure/ or (random* or factorial* or crossover* or cross over* or placebo* or (doubl* adj blind*) or (singl* adj blind*) or assign* or allocat* or volunteer*).tw.	1970074
20	18 and 19	7601
21	(2014* or 2015* or 2016* or 2017* or 2018*).yr,dc.	7084132
22	20 and 21	3319

Notes: N/A
File: VO1 Embase n3319.txt

4. PsycINFO
Host: OVID
Data parameters: 1806 to February Week 4 2018 (date limits applied, 2014 onwards)
Date searched: Monday 3 March 2018
Searched by: Chris Cooper
Hits: 1449
Search strategy:

#	Searches	Results
1	posttraumatic stress disorder/ or complex ptsd/ or desnos/ or acute stress disorder/ or combat experience/ or "debriefing (psychological)"/ or emotional trauma/ or post‐traumatic stress/ or exp stress reactions/ or traumatic neurosis/	50806
2	exp disasters/	8186
3	(PTSD or ((posttrauma* or post‐trauma* or post trauma*) adj3 (stress* or disorder* or psych* or symptom?)) or acute stress disorder* or combat disorder* or war neuros*).ti,ab.	38985
4	(((acute or traumatic) adj stress*) and (expos* or psyc*)).ti,ab.	16755
5	(traumati#ed adj (victim? or survivor?)).ti,ab.	68
6	(trauma* adj2 (event? or memor* or flashback* or nightmare?)).ti,ab.	11819
7	(EMDR or (eye movement desensiti#ation and reprocessing)).ti,ab.	1640
8	((trauma* or posttrauma* or post‐trauma* or victim* or survivor?) and (exposure adj3 (therap* or psychotherap* or training or counsel*))).ti,ab.	1086
9	crisis intervention/	3314
10	(critical incident adj (stress or debrief* or de‐brief*)).ti,ab.	443
11	(debriefing or de‐briefing).ti,ab.	2186
12	(crisis intervention? or CISD).ti,ab.	3505
13	((stress or group? or psychological or crisis) adj3 (debrief* or de‐brief*)).ti,ab.	596
14	(trauma* adj2 (event? or memor* or flashback* or nightmare?)).ti,ab.	11819
15	1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14	80813
16	clinical trials.sh.	10820
17	(randomi#ed or randomi#ation or randomi#ing).ti,ab,id.	72509
18	(RCT or at random or (random* adj3 (assign* or allocat* or control* or crossover or cross‐over or design* or divide* or division or number))).ti,ab,id.	82020
19	(control* and (trial or study or group) and (placebo or waitlist* or wait* list* or ((treatment or care) adj2 usual))).ti,ab,id,hw.	25590
20	((single or double or triple or treble) adj2 (blind* or mask* or dummy)).ti,ab,id.	24054
21	trial.ti.	25583
22	placebo.ti,ab,id,hw.	37267
23	treatment outcome.md.	18762
24	treatment effectiveness evaluation.sh.	21858
25	mental health program evaluation.sh.	2028
26	16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25	169119
27	15 and 26	4124
28	(2014* or 2015* or 2016* or 2017* or 2018*).yr,dc,mo.	782907
29	27 and 28	1449

Notes: N/A
File: VO1 PsycINFO n1449.txt

5. PILOTS: Published International Literature On Traumatic Stress
Host: Pro Quest
Data parameters: 1871 to Current (date limits applied, 2014 onwards)
Date searched: Monday 3 March 2018
Searched by: Chris Cooper
Hits: 879
Search strategy

Set#: S1 Searched for: ti((posttrauma* near/4 (stress* or disorder* or psych* or symptom*))) OR ab((posttrauma* near/4 (stress* or disorder* or psych* or symptom*))) Results: 16999*
Set#: S2 Searched for: ti((post‐trauma* near/4 (stress* or disorder* or psych* or symptom*))) OR ab((post‐trauma* near/4 (stress* or disorder* or psych* or symptom*))) Results: 6647°
Set#: S3 Searched for: ti((post trauma* near/4 (stress* or disorder* or psych* or symptom*))) OR ab((post trauma* near/4 (stress* or disorder* or psych* or symptom*))) Results: 7214°
Set#: S4 Searched for: ti((PTSD or acute stress disorder* or combat disorder* or war neuros*) ) OR ab((PTSD or acute stress disorder* or combat disorder* or war neuros*) ) Results: 30435*
Set#: S5 Searched for: ti((((acute or traumatic) near/2 stress*) and (expos* or psyc*)) ) OR ab((((acute or traumatic) near/2 stress*) and (expos* or psyc*)) ) Results: 2341°
Set#: S6 Searched for: ti((traumatised near/2 (victim* or survivor*)) ) OR ab((traumatised near/2 (victim* or survivor*)) ) Results: 84°
Set#: S7 Searched for: ti((trauma* near/3 (event* or memor* or flashback* or nightmare*)) ) OR ab((trauma* near/3 (event* or memor* or flashback* or nightmare*)) ) Results: 6974°
Set#: S8 Searched for: ti(((trauma* or posttrauma* or post‐trauma* or victim* or survivor*) and (exposure near/4 (therap* or psychotherap* or training or counsel*))) ) OR ab(((trauma* or posttrauma* or post‐trauma* or victim* or survivor*) and (exposure near/4 (therap* or psychotherap* or training or counsel*))) ) Results: 787°
Set#: S9 Searched for: ti((critical incident near/2 (stress or debrief* or de‐brief*)) ) OR ab((critical incident near/2 (stress or debrief* or de‐brief*)) ) Results: 385°
Set#: S10 Searched for: ti((debriefing or de‐briefing)) OR ab((debriefing or de‐briefing)) Results: 685°
Set#: S11 Searched for: ti((crisis intervention* or CISD)) OR ab((crisis intervention* or CISD)) Results: 784°
Set#: S12 Searched for: ti(((stress or group* or psychological or crisis) near/4 (debrief* or de‐brief*)) ) OR ab(((stress or group* or psychological or crisis) near/4 (debrief* or de‐brief*)) ) Results: 464°
Set#: S13 Searched for: ti((trauma* near/3 (event* or memor* or flashback* or nightmare*)) ) OR ab((trauma* near/3 (event* or memor* or flashback* or nightmare*)) ) Results: 6974°
Set#: S14 Searched for: ti((EMDR or (eye movement desensitisation and reprocessing))) OR ab((EMDR or (eye movement desensitisation and reprocessing))) Results: 888°
Set#: S15 Searched for: ti((EMDR or (eye movement desensitiZation and reprocessing))) OR ab((EMDR or (eye movement desensitiZation and reprocessing))) Results: 888°
Set#: S16 Searched for: (s1 or s2 or s3 or s4 or s5 or s6 or s7 or s8 or s9 or s10 or s11 or s12 or s13 or s14 or s15) Results: 36840*
Set#: S17 Searched for: MAINSUBJECT.EXACT("Randomized Clinical Trial") Results: 1210°
Set#: S18 Searched for: ab((randomized or randomised or placebo or randomly)) Results: 2931°
Set#: S19 Searched for: ti(trial) Results: 784°
Set#: S20 Searched for: (S17 or S18 or S19) Results: 3226°
Set#: S21 Searched for: S16 and s20 Results: 2654°
Set#: S22 Searched for: (S16 and s20) AND pd(20140101‐20180301) Results: 879°

* Duplicates are removed from your search, but included in your result count.
° Duplicates are removed from your search and from your result count.

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
Notes: N/A
File: VO1 PILOTS n879.txt

Appendix 4. ICTRP and ClinicalTrials.gov search strategies

ClinicalTrials.gov

1. PTSD

2. posttrauma

3. post‐trauma

4. "post trauma"

5. (combat and disorder)

ICTRP: (PTSD or posttrauma* or post‐trauma* or “post trauma*” or (combat and disorder*))

Contributions of authors

FB: lead author of the protocol, wrote the protocol. Developed the selection criteria and the methodology.

LR: contributed to the background and commented on the methodology of the protocol.

GO: contributed to the background and commented on the methodology of the protocol.

NM: contributed to the background of the protocol. Developed the methodology.

JIB: contributed to the background of the protocol. Developed the selection criteria and commented on the methodology of the protocol.

RC: contributed to the background and commented on the methodology of the protocol.

CB: contributed to the background and commented on the methodology of the protocol.

Sources of support

Internal sources

• University of Verona, Italy

  Salary for FB, GO, CB

• University of York, UK

  Hosted FB as a Visiting Fellow

External sources

• National Institute for Health Research (NIHR), UK

  LR, NM and RC work on this review is supported by NIHR Cochrane Infrastructure funding to the Common Mental Disorders Cochrane Review Group.

Declarations of interest

FB: no conflicts of interest

LR: no conflicts of interest

GO: no conflicts of interest

NM: no conflicts of interest

JIB: has been involved in the development of a guided self‐help programme for PTSD, which has been tested in a Phase II randomised controlled trial (RCT) in partnership with the Healthcare Learning Company. JIB is leading an application for grant funding for a Phase III RCT of the programme. Cardiff University and JIB stand to benefit from royalties if the product is commercialised.

RC: leads and has responsibility for Cochrane Common Mental Disorders, which has supported parts of the review process and is largely funded by a grant from the National Institute of Health and Research (NIHR) in the UK.

CB: no conflicts of interest

New