Frequently Asked Questions

Yes. Brexpiprazole plus sertraline produced greater improvement in CAPS-5 total score at Week 10 than sertraline plus placebo, brexpiprazole plus placebo, and placebo plus placebo. The treatment differences were −5.08 points versus sertraline plus placebo (95% CI, −8.96 to −1.20; P=.011), −4.24 versus brexpiprazole plus placebo (95% CI, −8.26 to −0.23; P=.038), and −5.99 versus placebo plus placebo (95% CI, −9.79 to −2.19; P=.0021).

No efficacy signal was seen for brexpiprazole monotherapy in this trial. Brexpiprazole plus placebo did not differ from placebo plus placebo on the primary endpoint at Week 10, with a treatment difference of −1.74 points on CAPS-5 total score (95% CI, −5.70 to 2.22; P=.39).

No. Sertraline plus placebo did not separate from placebo plus placebo on the primary endpoint at Week 10, with a CAPS-5 total score treatment difference of −0.91 points (95% CI, −4.74 to 2.92; P=.64).

Improvement with brexpiprazole plus sertraline began to separate from comparator groups by Week 6. The study reported greater improvement versus brexpiprazole plus placebo and versus placebo plus placebo from Week 6 onward.

At Week 10, brexpiprazole plus sertraline showed greater improvement than sertraline plus placebo in multiple domains. These included the CAPS-5 Intrusion, Avoidance, and Negative cognitions and mood symptom clusters, as well as CGI-S, PCL-5 total score, HADS Anxiety, and HADS Depression.

Most treatment-emergent adverse events were mild or moderate, and no unexpected safety events were identified with brexpiprazole plus sertraline. In the combination group, adverse events with incidence at least 10% were weight increased and somnolence; extrapyramidal symptom-related treatment-emergent adverse events were reported in 13 of 80 participants (16.3%).

Mean body weight increased by +1.4 kg from randomization to last visit in the brexpiprazole plus sertraline group. Weight gain of at least 7% occurred in 4 of 80 participants (5.0%) in that group.

Akathisia was reported as a treatment-emergent adverse event, but objective movement rating scales showed minimal change across groups. The discussion states that akathisia was reported in 6.3% of participants receiving brexpiprazole plus sertraline and 13.3% receiving brexpiprazole plus placebo, while changes in SAS, AIMS, and BARS scores were minimal in all treatment groups.

Suicidality events occurred across groups, including active treatment and placebo. On the C-SSRS, treatment-emergent suicidal ideation at any visit occurred in 4 of 80 participants (5.0%) on brexpiprazole plus sertraline, 6 of 75 (8.0%) on brexpiprazole plus placebo, 9 of 79 (11.4%) on sertraline plus placebo, and 8 of 82 (9.8%) on placebo plus placebo; treatment-emergent suicidal behavior occurred in 1 of 79 participants (1.3%) on sertraline plus placebo and in 0 participants in the other groups. One participant on brexpiprazole plus sertraline survived a suicide attempt and withdrew from the trial.

This was a Phase 2, multicenter, 12-week, randomized, double-blind, placebo- and active-controlled, parallel-arm trial in adults with PTSD. After a 1-week double-blind placebo run-in, participants were randomized 1:1:1:1 to brexpiprazole plus sertraline, brexpiprazole plus placebo, sertraline plus placebo, or placebo plus placebo; brexpiprazole was flexibly dosed at 1–3 mg/day and sertraline at 100–200 mg/day.

The randomized sample included 321 adults with DSM-5 PTSD symptoms present for at least 6 months and CAPS-5 total score at least 33 at screening and baseline. Mean age was 39.2 years, 62.0% were female, 61.4% were White, and the mean time since the index trauma was 6.4 years.

The study excluded several groups that are common in routine practice. Key exclusions included a current DSM-5 major depressive episode, current or recent substance/alcohol use disorder within 120 days of screening, psychotropic-treatment resistance or refractoriness by investigator history, current adequate sertraline treatment, prior brexpiprazole exposure, recent PTSD treatment changes, significant suicide risk, a traumatic event within 3 months of screening, an index trauma before age 16 or more than 15 years before screening, and disability payments or compensation litigation related to PTSD or another psychiatric disorder.

The authors identified several limitations. These included no prespecified adjustment for multiplicity, lack of efficacy in the sertraline plus placebo assay-sensitivity arm, flexible dosing of both brexpiprazole and sertraline, and selection criteria and concomitant-medication restrictions that may limit generalizability. The authors also noted that an established CAPS-5 meaningful within-patient change threshold is needed to help interpret clinical relevance.

The placebo run-in was used to reduce placebo-response bias before randomization. During that 1-week double-blind run-in, the mean CAPS-5 total score changed by −7.7 points (SD 9.3) from baseline to randomization, and subgroup analyses suggested that nonresponse during the placebo run-in was associated with a greater Week 10 treatment difference.