Early pharmacological interventions for universal prevention of post-traumatic stress disorder (PTSD)

Federico Bertolini, Lindsay Robertson, Jonathan I Bisson, Nicholas Meader, Rachel Churchill, Giovanni Ostuzzi, Dan J Stein, Taryn Williams, Corrado Barbui, Federico Bertolini, Lindsay Robertson, Jonathan I Bisson, Nicholas Meader, Rachel Churchill, Giovanni Ostuzzi, Dan J Stein, Taryn Williams, Corrado Barbui

Abstract

Background: Post-traumatic stress disorder (PTSD) is a severe and debilitating condition. Several pharmacological interventions have been proposed with the aim to prevent or mitigate it. These interventions should balance efficacy and tolerability, given that not all individuals exposed to a traumatic event will develop PTSD. There are different possible approaches to preventing PTSD; universal prevention is aimed at individuals at risk of developing PTSD on the basis of having been exposed to a traumatic event, irrespective of whether they are showing signs of psychological difficulties.

Objectives: To assess the efficacy and acceptability of pharmacological interventions for universal prevention of PTSD in adults exposed to a traumatic event.

Search methods: We searched the Cochrane Common Mental Disorders Controlled Trial Register (CCMDCTR), CENTRAL, MEDLINE, Embase, two other databases and two trials registers (November 2020). We checked the reference lists of all included studies and relevant systematic reviews. The search was last updated on 13 November 2020.

Selection criteria: We included randomised clinical trials on adults exposed to any kind of traumatic event. We considered comparisons of any medication with placebo or with another medication. We excluded trials that investigated medications as an augmentation to psychotherapy.

Data collection and analysis: We used standard Cochrane methodological procedures. In a random-effects model, we analysed dichotomous data as risk ratios (RR) and number needed to treat for an additional beneficial/harmful outcome (NNTB/NNTH). We analysed continuous data as mean differences (MD) or standardised mean differences (SMD).

Main results: We included 13 studies which considered eight interventions (hydrocortisone, propranolol, dexamethasone, omega-3 fatty acids, gabapentin, paroxetine, PulmoCare enteral formula, Oxepa enteral formula and 5-hydroxytryptophan) and involved 2023 participants, with a single trial contributing 1244 participants. Eight studies enrolled participants from emergency departments or trauma centres or similar settings. Participants were exposed to a range of both intentional and unintentional traumatic events. Five studies considered participants in the context of intensive care units with traumatic events consisting of severe physical illness. Our concerns about risk of bias in the included studies were mostly due to high attrition and possible selective reporting. We could meta-analyse data for two comparisons: hydrocortisone versus placebo, but limited to secondary outcomes; and propranolol versus placebo. No study compared hydrocortisone to placebo at the primary endpoint of three months after the traumatic event. The evidence on whether propranolol was more effective in reducing the severity of PTSD symptoms compared to placebo at three months after the traumatic event is inconclusive, because of serious risk of bias amongst the included studies, serious inconsistency amongst the studies' results, and very serious imprecision of the estimate of effect (SMD -0.51, 95% confidence interval (CI) -1.61 to 0.59; I2 = 83%; 3 studies, 86 participants; very low-certainty evidence). No study provided data on dropout rates due to side effects at three months post-traumatic event. The evidence on whether propranolol was more effective than placebo in reducing the probability of experiencing PTSD at three months after the traumatic event is inconclusive, because of serious risk of bias amongst the included studies, and very serious imprecision of the estimate of effect (RR 0.77, 95% CI 0.31 to 1.92; 3 studies, 88 participants; very low-certainty evidence). No study assessed functional disability or quality of life. Only one study compared gabapentin to placebo at the primary endpoint of three months after the traumatic event, with inconclusive evidence in terms of both PTSD severity and probability of experiencing PTSD, because of imprecision of the effect estimate, serious risk of bias and serious imprecision (very low-certainty evidence). We found no data on dropout rates due to side effects, functional disability or quality of life. For the remaining comparisons, the available data are inconclusive or missing in terms of PTSD severity reduction and dropout rates due to adverse events. No study assessed functional disability.

Authors' conclusions: This review provides uncertain evidence only regarding the use of hydrocortisone, propranolol, dexamethasone, omega-3 fatty acids, gabapentin, paroxetine, PulmoCare formula, Oxepa formula, or 5-hydroxytryptophan as universal PTSD prevention strategies. Future research might benefit from larger samples, better reporting of side effects and inclusion of quality of life and functioning measures.

Trial registration: ClinicalTrials.gov NCT00158262 NCT01099501 NCT00671099 NCT02090309 NCT03166501 NCT00674570 NCT01039766 NCT02069366 NCT02505984 NCT03724448 NCT04071600 NCT00146900 NCT00182078 NCT00300313 NCT00855270 NCT02866071 NCT03997864 NCT04274361.

Conflict of interest statement

FB: no conflicts of interest

LR: works as part of the Cochrane Common Mental Disorders Review Group Editorial Base. LR was not involved in the editorial process for this review.

JIB: has been involved in the development of a guided self‐help programme for post‐traumatic stress disorder (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.

NM: is Deputy Co‐ordinating Editor of the Cochrane Common Mental Disorders Review Group. NM was not involved in the editorial process for this review.

RC: is Joint Co‐ordinating Editor of the Cochrane Common Mental Disorders Review Group. RC was not involved in the editorial process for this review. Cochrane Common Mental Disorders, which has supported parts of the review process, is largely funded by a grant from the National Institute for Health Research (NIHR) in the UK.

GO: no conflicts of interest

DS: has received research grants and/or consultancy honoraria from AMBRF, Biocodex, Cipla, Lundbeck, National Responsible Gambling Foundation, Novartis, Servier, and Sun.

TW: no conflicts of interest

CB: no conflicts of interest