REVIEW OF: Davis LL et al, JAMA ­Psychiatry 2025;82(3):218–227

STUDY TYPE: RCT

On paper, the combination of sertraline with brexpiprazole for PTSD makes sense. Sertraline is already approved for PTSD, and atypical antipsychotics like brexpiprazole modulate dopamine and serotonin, in addition to possibly enhancing the efficacy of selective serotonin reuptake inhibitors. In practice, the evidence for this combo is mixed, with two positive trials and one negative. This ultimately led the FDA to vote against recommending it. Let’s look at the evidence that most favored sertraline with brexpiprazole.

This 12-week, industry-funded, double-blind RCT randomized 416 participants with persistent PTSD symptoms to brexpiprazole (2–3 mg/day) plus sertraline (150 mg/day) or sertraline alone. Three-quarters of participants were naïve to PTSD medications. Notably, the trial excluded those with current or recent major depressive episodes, primary anxiety disorders, and ongoing trauma exposures. The primary outcome was change in PTSD symptoms, measured by the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) from randomization time to week 10. Secondary outcomes included change in Clinical Global Impression—Severity (CGI-S) and Brief Inventory of Psychosocial Functioning (B-IPF) scores.

At week 10, brexpiprazole plus sertraline significantly outperformed placebo plus sertraline in reducing symptoms of PTSD:

CAPS-5 score reduction: -19.2 vs -13.6 (mean difference: -5.59; p < 0.001)

Symptom reduction: Greater improvement in all PTSD symptom clusters (intrusion, avoidance, negative mood, arousal)

Response rates: 68.5% vs 48.2% achieved ≥ 30% symptom reduction

Nausea, fatigue, somnolence, and weight gain were common with brexpiprazole, but the dropout rate due to side effects was 3.9%, vs 10.2% for sertraline alone. 

CARLAT TAKE
For PTSD, start with psychotherapy (the APA’s top recommendation) and/or try sertraline and paroxetine (our only FDA-approved meds). And particularly for patients without comorbidities and who are likely to tolerate its side effects, consider recommending brexpiprazole with sertraline. In this trial, it offered broader and more meaningful improvements, and better discontinuation rates, than sertraline alone. The FDA didn’t approve of this on a population-wide level, but it may still be a reasonable choice for individual ­patients.