Fixed-Dose Brexpiprazole and Sertraline Combination Therapy for the Treatment of Posttraumatic Stress Disorder

Purpose: This trial aimed to investigate the efficacy, safety, and tolerability of fixed-dose brexpiprazole in combination with sertraline for posttraumatic stress disorder (PTSD). Methods: This was a phase 3, randomized, parallel-arm trial in adult outpatients with PTSD, across 95 sites in the United States (ClinicalTrials.gov: NCT04174170). After a 1-week placebo run-in, participants entered 11 weeks of randomized (1:1:1) double-blind treatment with brexpiprazole 2 mg/d+sertraline 150 mg/d, brexpiprazole 3 mg/d+sertraline 150 mg/d, or sertraline 150 mg/d+placebo (active control). The primary endpoint was the change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total score from randomization (week 1) to week 10. Safety was also assessed. Findings: The trial (October 2019 to August 2023) screened 1821 participants, and randomized 553 (brexpiprazole 2 mg+sertraline, n=191; brexpiprazole 3 mg+sertraline, n=185; and sertraline+placebo, n=177). All groups showed CAPS-5 total score reductions [LS mean (SE) change at week 10: brexpiprazole 2 mg+sertraline, −16.5 (1.2), n=132; brexpiprazole 3 mg+sertraline, −18.3 (1.2), n=124; and sertraline+placebo, −17.6 (1.2), n=130]. LS mean differences (95% CI) versus sertraline+placebo at week 10: brexpiprazole 2 mg+sertraline, 1.03 (−2.09 to 4.16), P =0.52; brexpiprazole 3 mg+sertraline, −0.71 (−3.88 to 2.46), P =0.66. Treatment-emergent adverse events with incidence ≥5% for either brexpiprazole+sertraline group were headache (brexpiprazole 2 mg+sertraline, 7.0%; brexpiprazole 3 mg+sertraline, 5.6%; and sertraline+placebo, 7.6%), nausea (4.9%; 8.3%; 8.7%), and diarrhea (3.8%; 6.1%; 6.4%). Conclusions: PTSD symptom improvement was similar with fixed-dose brexpiprazole+sertraline and sertraline+placebo; the primary endpoint was not met. This differs from 2 prior trials that showed greater efficacy for brexpiprazole+sertraline versus sertraline+placebo. No new safety signals were observed.