Testimony before the FDA Psychopharmacologic Drugs Advisory Committee (PDAC) regarding a proposed combination of the antipsychotic, brexpiprazole, and the antidepressant, sertraline, for the treatment of post-traumatic stress disorder (PTSD)
By Michael T. Abrams, M.P.H., Ph.D.
(New Drug Application 205422-S012; Federal Register Docket Number: FDA-2025-N-1450)
I’m Dr. Michael Abrams, senior health researcher with the nonprofit, consumer advocacy organization Public Citizen. I have no financial conflicts of interest related to today’s topic.
The Psychopharmacologic Drugs Advisory Committee (PDAC) is considering the approval of the antipsychotic and antidepressant drug combination of brexpiprazole and sertraline (brex/sert) for the treatment of post-traumatic stress disorder (PTSD).[1]
These drugs are approved as individual pharmacotherapies for the treatment of psychotic, depressive, and anxiety disorders. Brexpiprazole was recently approved for the controversial indication of agitation in older adults suffering from dementia despite a boxed warning that such use heightens the patient’s risk of premature death.[2] Sertraline has long been approved as a monotherapy for PTSD, although it typically results in the desired response to treatment only 32-67% of the time.
Notably, the supplemental application for brex/sert seeks approval for this combination as an initial therapy for PTSD, not for use of the antipsychotic as an adjuvant to selective serotonin reuptake inhibitor (SSRI) treatment that fails to sufficiently address PTSD symptoms.
The evidence to support the supplemental application is data from three randomized clinical trials. FDA scientific review of these studies was straightforward — one phase 3 trial was “robustly positive,” and the other phase 3 trial was “clearly and convincingly negative.” To address these conflicting results, the sponsor performed additional analyses of data from an older phase 2 trial.
The two phase 3 trials were similar in participant composition and study design (multi-center, randomized, controlled, double-blinded, two-week placebo run-in phase, adults, 75% female, exclude those stable on sertraline alone or with at least a nine-year history of PTSD). With 321 participants, the first study (00071) observed a 10-week improvement in DSM (Diagnostic Statical Manual) clinician-derived PTSD scores averaging 6 points (95% confidence interval; 2 to 9 points) in persons taking the brex/sert combination compared with placebo/sert. The second study (00072), with 416 participants, did not show a significant benefit for brex/sert treatment.
To salvage the application, the sponsor reached backward in time to a third study (00061), which randomized 516 participants into four treatment groups based on different dose combinations including a placebo regimen (one regimen being a placebo-placebo dose). That study found that after 10 weeks the brex/sert combination performed an average of 5 points (95% confidence interval; 1 to 9 points) better on PTSD scores than placebo and sertraline. This result, however, was only nominally statistically significant and reliant upon post hoc comparisons that were not prespecified, unacceptably biasing the analyses.
Finally, it should be noted that across all nine treatment arms spanning the three clinical trials, participants improved markedly regardless of the drug treatment used. This included a 10-point improvement in a group of subjects who received placebo only, just exceeding the FDA’s criteria for clinically meaningful improvement.
Accordingly, the evidence supporting the use of combination brex/sert as a treatment for PTSD is weak based on two conflicting phase 3 trials and questionable post hoc analyses of data from a phase 2 trial. Moreover, the sponsor acknowledges that the brex/sert combination has the many and sometimes serious adverse effects of each drug individually.
In sum, the evidence presented should be used by this advisory committee and the FDA to reject the combination of brexpiprazole and sertraline as a treatment for PTSD. Superiority over monotherapy, serial therapy, or even placebo therapy has not been established.
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[1] U.S. Food and Drug Administration. Briefing document: NDA 205422 S-012, brexpiprazole, Otsuka Pharmaceutical Company, Ltd. Psychopharmacologic Drugs Advisory Committee Meeting, 07/18/2025. https://www.fda.gov/media/187617/download. Accessed July 16, 2025.
[2] Public Citizen. Letter to the FDA opposing approval of brexpiprazole for the treatment of agitation associated with Alzheimer’s dementia. May 3, 2023. https://www.citizen.org/article/letter-to-the-fda-opposing-approval-of-brexpiprazole-for-the-treatment-of-agitation-associated-with-alzheimers-dementia/. Accessed July 18, 2023.