Trauma is a very common experience. Not everyone will develop psychiatric reactions to trauma like post-traumatic stress disorder (PTSD), but it certainly can develop in significant numbers of people. It has long been a hope that we might nip PTSD in the bud, i.e. intervene soon after someone has been exposed to trauma to reduce the risk of PTSD developing.
One approach that has been mooted is the universal deployment of some intervention to prevent the emergence of later PTSD. A universal approach has several advantages; it would avoid the cost and disruption of screening, might be associated with less stigma than more targeted approaches, and might even be easier to deliver in a way that ensures equality of access. Brief psychological interventions have been tested, but ultimately shown to be ineffective (NICE, 2018; Rose et al. 2002; Sibrandij et al. 2006).
In their Cochrane review on this issue, Bertolini and colleagues (2022) have completed a systematic review of pharmacological interventions for the universal prevention of PTSD. Could medication help where brief psychological interventions have failed? As the authors point out, many of the medications included in their review are cheap and widely available; could they be a powerful weapon in the fight against the misery of PTSD?
The authors conducted a systematic review that follows the methodology recommended by the Cochrane handbook for systematic reviews (Higgins et al. 2022). Bertolini and colleagues leave no stone unturned in their search strategy, and adhere to the Cochrane standards in all their exacting attention to detail and methodological rigour. The protocol alone is 26 pages long. There’s an eye-watering amount of detail here.
All the searches and quality checks were conducted by two members of the review team. The team paid particular attention to handling data on an intention to treat basis, assessing risk of bias using the Cochrane handbook, and using the GRADE approach (Schünemann et al. 2013) to judge the certainty of the evidence they draw together. The authors note the places where they had to deviate from their original planned analyses, and the deviations are clearly justified.
Bertolini and colleagues identified 13 studies addressing nine different interventions:
- Hydrocortisone (steroid)
- Propranolol (beta-blocker)
- Dexamethasone (glucocorticoid)
- Omega-3 (fatty acid)
- Gabapentin (anticonvulsant)
- Paroxetine (antidepressant)
- PulmoCare (enteral formula)
- Oxepa (enteral formula) (i.e. different tube feed products)
- 5-hydroxytryptophan (a naturally occurring amino acid that is a precursor to the production of serotonin).
All 13 studies were randomised controlled trials (RCT), with the overwhelming majority being placebo controlled. Only hydrocortisone and propranolol were explored in more than one trial (four trials each); the other seven interventions were each covered in one RCT only.
In some regards the included studies were of high quality (i.e. they incorporated features that ensure a low risk of bias), but common weaknesses included attrition and selective reporting. Emergency departments or intensive care units were the most common trial settings. Most trials comprised few participants (eight comprised 60 or fewer; only three comprised more than a hundred participants).
The largest study by some way (>1,000 participants) looked at the administration of dexamethasone, but the main goal of the trial was to prevent adverse events following surgery, not poor psychiatric outcomes. At 1.5 to four years post-surgery there was no effect found for dexamethasone (Kok et al., 2016). One of the hydrocortisone studies was similarly not focused on mental health, but improving physical outcomes after septic shock (Schelling et al. 2001).
There was no evidence that dexamethasone, omega-3 fatty acids, gabapentin or paroxetine were superior to placebo; PulmoCare enteral formula did not differ from Oxepa enteral formula (i.e. different tube feed products); and propranolol did not differ from gabapentin. One trial suggested that 5-hydroxytryptophan was superior to placebo at preventing PTSD in ICU patients (Tincu et al. 2016).
For hydrocortisone and propranolol there was (just) enough data to conduct a meta-analysis. In the case of hydrocortisone, pooling PTSD severity data was not possible. For PTSD rate, two studies could be subjected to meta-analysis (Schelling 2001; Weis 2006) and demonstrated efficacy relative to placebo; this analysis only comprised 48 participants, however. Propranolol RCTs comprised similarly few participants and when pooled did not demonstrate efficacy with respect to PTSD severity or rate. Sub-group analysis suggested that when administering propranolol more than 12 hours post-trauma, the drug was efficacious; however, this was only observed in one study comprising 28 participants.
Data on dropout rates, another outcome of interest to the review authors, was either missing or inconclusive.
Frustratingly there’s just very little evidence to draw on. There was a slither of evidence to suggest that hydrocortisone, propranolol and 5-hydroxytryptophan might be doing something, but the most sensible interpretation of the review’s findings comes from the authors’ plain language summary:
The evidence we found does not support the use of any medicines for the prevention of PTSD in people exposed to a traumatic event, regardless of whether or not they have psychological symptoms.
Strengths and limitations
This is a very thorough, well conducted systematic review, and you would be hard pressed to see how they could have strengthened the review from a methodological perspective. You can even download their data (in RevMan format), so the whole enterprise is completely transparent. The reviewers’ conclusions are robust.
The comprehensiveness of the Cochrane format is impressive, but for this review, with relatively few included trials, the manner of presenting results is unwieldy (e.g. there’s a lot of empty cells in the opening “Summary of findings” tables). A “study characteristics” table outlining the key features of each included study, the like of which you’d find in most peer-reviewed journal formats, would have been helpful and highlighted the large gaps in the extant literature.
In the Discussion section the review authors provide welcome reflections on the feasibility of this type of research, and the barriers to getting trials in this area completed. Embedding research trials in emergency departments is not easy, and potential participants often only want to get home. As hard as basing research in this or any other hospital setting may be, the barriers likely proliferate when other settings are considered; to date no research into preventative pharmacological interventions has considered large-scale traumas (e.g. war, terror attacks, natural disasters) or low- and middle-income countries.
Implications for practice
According to the results of this well-conducted review, there is insufficient evidence to warrant the use of pharmacological interventions for the prevention of PTSD.
Much of the research on this topic was opportunistic (e.g. being tacked on to trials that primarily addressed physical health outcomes). As such, the evidence base is not even close to providing robust support for the use of pharmacological interventions for the prevention of PTSD. Research programmes seem very under-developed and restricted to medical settings, and lack the sort of statistical power that would be required to show an effect. Many people do not develop PTSD, while a significant proportion of adults may recover from acute traumatic stress without any formal intervention (e.g. Galatzer-Levy et al. 2018). As such it may be difficult for pharmacological outcomes to demonstrate an effect, just as with brief psychological interventions delivered to all individuals exposed to trauma.
There are some seeds of hope for a handful of interventions, but extending the study of these drugs to a broader range of settings may be difficult.
Bertolini and colleagues are conducting a parallel review looking at whether early pharmacological interventions might be effective for acute post-traumatic stress; this will be worth looking out for.
Statement of interests
RMS receives payment for training clinicians in the use of trauma-focused cognitive behavioural therapy for PTSD in children and adolescents.
Bertolini F, Robertson L, Bisson JI, Meader N, Churchill R, Ostuzzi G, Stein DJ, Williams T, Barbui C. Early pharmacological interventions for universal prevention of post‐traumatic stress disorder (PTSD). Cochrane Database of Systematic Reviews 2022, Issue 2. Art. No.: CD013443. DOI: 10.1002/14651858.CD013443.pub2. Accessed 23 April 2022.
Galatzer-Levy, I.R., Huang, S.H. and Bonanno, G.A., 2018. Trajectories of resilience and dysfunction following potential trauma: A review and statistical evaluation. Clinical Psychology Review, 63, pp.41-55.
Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane, 2022.
Kok L, Hillegers MH, Veldhuijzen DS, Cornelisse S, Nierich AP, Van der Maaten JM, et al. (2016). The effect of dexamethasone on symptoms of posttraumatic stress disorder and depression after cardiac surgery and intensive care admission: longitudinal follow-up of a randomized controlled trial. Critical Care Medicine, 44(3), 512-20. DOI: 10.1097/CCM.0000000000001419
NICE. (2018). Guidelines for post-traumatic stress disorder. NICE guideline (NG116). Retrieved from
Rose, S.C., Bisson, J., Churchill, R. and Wessely, S., 2002. Psychological debriefing for preventing post traumatic stress disorder (PTSD). Cochrane database of systematic reviews, (2).
Schelling G, Briegel J, Roozendaal B, Stoll C, Rothenhausler HB, Kapfhammer HP (2001). The effect of stress doses of hydrocortisone during septic shock on posttraumatic stress disorder in survivors. Biological Psychiatry 2001;50(12):978-85. [DOI: 10.1016/s0006-3223(01)01270-7]
Schünemann H, Brożek J, Guyatt G, Oxman A, editors. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013.
Sijbrandij, M., Olff, M., Reitsma, J.B., Carlier, I.V. and Gersons, B.P., 2006. Emotional or educational debriefing after psychological trauma: Randomised controlled trial. The British Journal of Psychiatry, 189(2), pp.150-155.
Tincu R, Cobilinschi C, Tomescu D, Ghiorghiu Z, Macovei R. (2016). Can 5-hydroxytriptophan prevent post-traumatic stress disorder in critically ill patients? [abstract]. Critical Care 2016;20(Suppl 2):119.