Brexpiprazole Plus Sertraline Shows Significant PTSD Symptom Improvement with Tolerable Safety Profile in Phase III Trial

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Findings from a Phase III trial (NCT04124614) published by JAMA Psychiatry demonstrated that brexpiprazole combined with sertraline significantly improved the symptoms of post-traumatic stress disorder (PTSD) compared with sertraline plus placebo, as per change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). The combination also showed a tolerable safety profile with low discontinuation rates, which bolsters its use as an effective treatment for PTSD, according to the trial investigators.^1-3

“About 6% of the United States population will have PTSD at some point in their lives, but around only half will seek treatment,” lead study author Lori Davis, MD, clinical professor of psychiatry in the Department of Psychiatry and Behavioral Neurobiology, University of Alabama School of Medicine, said in a press release. “The Phase III results are an important and encouraging step forward in the hopes of providing PTSD patients with a new therapeutic option in the future.”¹

The FDA approved brexpiprazole in 2015 as an adjunctive therapy to antidepressants in adults with major depressive disorder and as a treatment for adults with schizophrenia. Subsequent approvals of the drug include the treatment of agitation associated with dementia due to Alzheimer disease by the FDA in 2023 and for agitation associated with dementia due to Alzheimer disease by Health Canada in 2024.¹

“Brexpiprazole is an atypical antipsychotic with broad pharmacological activity across noradrenergic, serotonergic, and dopaminergic neurotransmitter systems implicated in psychiatric disorders, including PTSD,” the study authors wrote in JAMA Psychiatry. “In phase 3 randomized clinical trials, brexpiprazole demonstrated efficacy, safety, and tolerability for the treatment of schizophrenia, the treatment of agitation in Alzheimer dementia, and the adjunctive treatment of major depressive disorder. Given its multimodal mechanism of action and efficacy in other psychiatric disorders, brexpiprazole was investigated in a phase 2 randomized clinical trial in PTSD. The combination of brexpiprazole and sertraline (brexpiprazole + sertraline) demonstrated efficacy, with no identified safety concerns.”²

Trial Design

The randomized, double-blind, active-controlled, parallel-arm trial sought to analyze the efficacy, safety, and tolerability of brexpiprazole plus sertraline in patients with PTSD. Investigators enrolled 416 adult outpatients (mean [SD] age, 37.4 [11.9] years; 310 female [74.5%]) who were randomly assigned to receive either brexpiprazole at a dose of 2-3 mg/day plus sertraline at 150 mg/day or sertraline at 150 mg/day plus placebo. The trial’s primary endpoint was change in CAPS-5 total score from randomization in week one to week 10.

CAPS-5 analyzes PTSD diagnostic status and symptom severity as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). CAPS-5 is comprised of 20 DSM-5 PTSD-symptom items, which are scored from zero, meaning absent, to four, meaning extreme or incapacitating.

Trial Results

After 10 weeks, patients in brexpiprazole plus sertraline cohort showed a statistically significant greater improvement in CAPS-5 total score (mean [SD] at randomization, 38.4 [7.2]; LS mean [SE] change, −19.2 [1.2]; n = 148) compared to the sertraline plus placebo cohort (randomization, 38.7 [7.8]; change, −13.6 [1.2]; n = 134), with LS mean difference, −5.59 (95% CI, −8.79 to −2.38; P < .001). Brexpiprazole also achieved all key secondary and additional efficacy endpoints, according to the investigators.

In terms of safety, treatment-emergent adverse events (AEs) with incidence rates of 5% or more in the brexpiprazole cohort compared to placebo, respectively, included nausea (12.2%, 11.7%), fatigue (6.8%, 4.1%), weight increase (5.9%, 1.5%), and somnolence (5.4%, 2.6%). AEs leading to discontinuation occurred in 3.9% of patients in the brexpiprazole cohort compared to 10.2% in the placebo cohort.

“The clinical trial results demonstrate the potential of brexpiprazole in combination with sertraline as a treatment option for patients with PTSD, a condition that affects millions within the United States,” John Kraus, MD, PhD, executive vice president and chief medical officer, Otsuka Pharmaceutical Development & Commercialization, Inc, said in a press release. “The combination of brexpiprazole and sertraline demonstrated meaningful improvements in PTSD symptoms.”¹

References

1. JAMA Psychiatry Publishes Results of Otsuka and Lundbeck's Phase 3 Trial of Brexpiprazole in Combination with Sertraline in Treatment of Post-Traumatic Stress Disorder (PTSD) in Adults. News release. Lundbeck. December 18, 2024. Accessed January 2, 2025. https://www.lundbeck.com/us/newsroom/2024/jama-psychiatry-publishes-results-otsuka-lundbeck-phase-3-trial-brexpiprazole-combo-sertraline-ptsd

2. Davis LL, Behl S, Lee D, et al. Brexpiprazole and Sertraline Combination Treatment in Posttraumatic Stress Disorder: A Phase 3 Randomized Clinical Trial. JAMA Psychiatry. Published online December 18, 2024. doi:10.1001/jamapsychiatry.2024.3996

3. Brexpiprazole as Combination Therapy With Sertraline in Treatment of Adults With PTSD. ClinicalTrials.gov. Updated July 25, 2024. Accessed January 2, 2025. https://clinicaltrials.gov/study/NCT04124614