Early pharmacological interventions for prevention of post-traumatic stress disorder (PTSD) in individuals experiencing acute traumatic stress symptoms

Background: Acute traumatic stress symptoms may develop in people who have been exposed to a traumatic event. Although they are usually self-limiting in time, some people develop post-traumatic stress disorder (PTSD), a severe and debilitating condition. Pharmacological interventions have been proposed for acute symptoms to act as an indicated prevention measure for PTSD development. As many individuals will spontaneously remit, these interventions should balance efficacy and tolerability. Objectives: To assess the efficacy and acceptability of early pharmacological interventions for prevention of PTSD in adults experiencing acute traumatic stress symptoms. Search methods: We searched the Cochrane Common Mental Disorders Controlled Trial Register (CCMDCTR), CENTRAL, MEDLINE, Embase and two other databases. We checked the reference lists of all included studies and relevant systematic reviews. The search was last updated on 23 January 2023. Selection criteria: We included randomised controlled trials on adults exposed to any kind of traumatic event and presenting acute traumatic stress symptoms, without restriction on their severity. 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. Using a random-effects model, we analysed dichotomous data as risk ratios (RR) and calculated the 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). Our primary outcomes were PTSD severity and dropouts due to adverse events. Secondary outcomes included PTSD rate, functional disability and quality of life. Main results: We included eight studies that considered four interventions (escitalopram, hydrocortisone, intranasal oxytocin, temazepam) and involved a total of 779 participants. The largest trial contributed 353 participants and the next largest, 120 and 118 participants respectively. The trials enrolled participants admitted to trauma centres or emergency departments. The risk of bias in the included studies was generally low except for attrition rate, which we rated as high-risk. We could meta-analyse data for two comparisons: escitalopram versus placebo (but limited to secondary outcomes) and hydrocortisone versus placebo. One study compared escitalopram to placebo at our primary time point of three months after the traumatic event. There was inconclusive evidence of any difference in terms of PTSD severity (mean difference (MD) on the Clinician-Administered PTSD Scale (CAPS, score range 0 to 136) -11.35, 95% confidence interval (CI) -24.56 to 1.86; 1 study, 23 participants; very low-certainty evidence), dropouts due to adverse events (no participant left the study early due to adverse events; 1 study, 31 participants; very low-certainty evidence) and PTSD rates (RR 0.59, 95% CI 0.03 to 13.08; NNTB 37, 95% CI NNTB 15 to NNTH 1; 1 study, 23 participants; very low-certainty evidence). The study did not assess functional disability or quality of life. Three studies compared hydrocortisone to placebo at our primary time point of three months after the traumatic event. We found inconclusive evidence on whether hydrocortisone was more effective in reducing the severity of PTSD symptoms compared to placebo (MD on CAPS -7.53, 95% CI -25.20 to 10.13; I2 = 85%; 3 studies, 136 participants; very low-certainty evidence) and whether it reduced the risk of developing PTSD (RR 0.47, 95% CI 0.09 to 2.38; NNTB 14, 95% CI NNTB 8 to NNTH 5; I2 = 36%; 3 studies, 136 participants; very low-certainty evidence). Evidence on the risk of dropping out due to adverse events is inconclusive (RR 3.19, 95% CI 0.13 to 75.43; 2 studies, 182 participants; low-certainty evidence) and it is unclear whether hydrocortisone might improve quality of life (MD on the SF-36 (score range 0 to 136, higher is better) 19.70, 95% CI -1.10 to 40.50; 1 study, 43 participants; very low-certainty evidence). No study assessed functional disability. Authors' conclusions: This review provides uncertain evidence regarding the use of escitalopram, hydrocortisone, intranasal oxytocin and temazepam for people with acute stress symptoms. It is therefore unclear whether these pharmacological interventions exert a positive or negative effect in this population. It is important to note that acute traumatic stress symptoms are often limited in time, and that the lack of data prevents the careful assessment of expected benefits against side effects that is therefore required. To yield stronger conclusions regarding both positive and negative outcomes, larger sample sizes are required. A common operational framework of criteria for inclusion and baseline assessment might help in better understanding who, if anyone, benefits from an intervention. As symptom severity alone does not provide the full picture of the impact of exposure to trauma, assessment of quality of life and functional impairment would provide a more comprehensive picture of the effects of the interventions. The assessment and reporting of side effects may facilitate a more comprehensive understanding of tolerability.