A combination of brexpiprazole (Rexulti) and sertraline improved post-traumatic stress disorder (PTSD) symptoms more than sertraline alone, a phase III trial found.
The primary endpoint was the change in the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total score. Improvement in the CAPS-5 total score was significantly better at 10 weeks with the brexpiprazole-sertraline combination versus sertraline plus placebo (mean -19.2 vs -13.6 points, P<0.001), reported Mary Hobart, PhD, of Otsuka Pharmaceutical Development & Commercialization in Princeton, New Jersey, and co-authors.
Although there is no widely agreed threshold for clinically meaningful change in CAPS-5 total score, the -19.2 change in the brexpiprazole group "is above existing estimates of greater than or equal to 12 to 14 points for reliable change (i.e., beyond what may be attributed to measurement error)," the researchers wrote in .
The CAPS-5 total score ranks the severity of 20 PTSD symptoms from 0 (not present) to 80 (most severe). Baseline values for the combination and placebo groups, respectively, were 38.4 and 38.7 points.
A greater proportion of participants receiving brexpiprazole also had a 30% or greater improvement at week 10 as well (68.5% vs 48.2%), "which is a common definition of clinically meaningful change in PTSD trials," Hobart and co-authors added.
Novel therapies are needed for PTSD, noted John Krystal, MD, of Yale School of Medicine in New Haven, Connecticut, who was not involved with the trial. "New PTSD treatments are a high priority," he wrote in an email to ֱ.
"Currently, we have two FDA-approved medication treatments for PTSD, sertraline and paroxetine. They are helpful for many people, but patients are often left with residual symptoms or tolerability issues," Krystal continued.
"New medications that might address the important 'effectiveness gap' in PTSD could help to reduce the remaining distress, disability, and suicide risk associated with PTSD," he said.
Brexpiprazole is an atypical antipsychotic approved as adjunctive therapy to antidepressants for major depressive disorder, as schizophrenia treatment, and for agitation in Alzheimer's disease. Prescribing information includes for increased mortality in elderly people with dementia-related psychosis and for suicidal thoughts and behaviors with antidepressants in younger people.
The evaluated adult outpatients with PTSD randomized to daily oral doses of brexpiprazole (flexibly dosed at 2 mg to 3 mg) plus sertraline, or to sertraline plus placebo. The daily dose of sertraline was 150 mg in both groups. The study was conducted from October 2019 to August 2023.
Patients receiving disability payments or with ongoing litigation were excluded, as were those with ongoing trauma, a current major depressive episode, current or recent anxiety disorder, or those who were being treated with sertraline. Prohibited medications, including psychotropic agents, were washed out during the screening period.
"Of note, almost three-quarters of participants were PTSD-pharmacotherapy naive at baseline, which is not uncommon in PTSD due to various treatment barriers," Hobart and co-authors noted.
Mean age was 37.4 years, 74.5% were women, and 70% were white. On average, about 4 years had passed since the index traumatic event. The most common trauma types included assault, sexual trauma, exposure to sudden death, and vehicle incidents.
In total, 214 participants were randomized to the brexpiprazole group and 202 to the placebo group. Baseline demographics, clinical characteristics, and treatment history were similar between groups.
Trial completion rates were 64% for the brexpiprazole group and 55.9% for the placebo group, with respective discontinuation rates due to adverse events of 3.3% (seven participants) and 10.9% (22 participants).
Overall, 60% in the brexpiprazole group and 58.2% of the placebo group reported any treatment-emergent adverse event (TEAE).
TEAEs with an incidence of 5% or more were nausea (12.2% and 11.7%), fatigue (6.8% and 4.1%), weight increase (5.9% and 1.5%), and somnolence (5.4% and 2.6%) in the brexpiprazole and placebo groups, respectively. No participants reported TEAEs that were related to suicidality.
Brexpiprazole-sertraline also met key secondary and other efficacy endpoints, including scores of clinician-reported global impression of severity and patient-reported psychosocial functioning, anxiety, and depression.
"Results of this trial support starting patients on combination therapy; however, the effect of adding brexpiprazole to existing sertraline therapy was not evaluated," Hobart and colleagues wrote. "This trial cannot be used to advise on duration of treatment, and longer-term efficacy and safety data are needed."
The trial was not powered for subgroup analyses. Excluding patients with a current major depressive episode was both a strength (to show an effect on PTSD) and a limitation (given the high prevalence of comorbid depression in PTSD), the researchers said.
of brexpiprazole-sertraline in PTSD have been conducted, according to Otsuka and its corporate partner Lundbeck. The whether to approve brexpiprazole-sertraline for PTSD by Feb. 8, 2025.
Disclosures
This trial was supported by Otsuka Pharmaceutical Development & Commercialization and H. Lundbeck A/S.
Hobart reported being an employee of Otsuka.
Co-authors disclosed relationships with Otsuka and other companies.
Krystal reported being the co-founder of Freedom Biosciences and receiving royalties from patents that Yale licensed to Johnson & Johnson, Freedom Biosciences, and Biohaven Pharmaceuticals. He served as a consultant to several pharmaceutical and biotechnology companies, including companies developing treatments for PTSD.
Primary Source
JAMA Psychiatry
Davis LL, et al "Brexpiprazole and sertraline combination treatment in posttraumatic stress disorder: A phase 3 randomized clinical trial" JAMA Psychiatry 2024; DOI: 10.1001/jamapsychiatry.2024.3996.