A recent Phase 3 clinical trial has demonstrated the effectiveness of brexpiprazole in combination with sertraline for the treatment of post-traumatic stress disorder (PTSD) in adults. The findings, published in "JAMA Psychiatry", highlight that this combination significantly reduced overall PTSD symptoms compared to sertraline administered with a placebo, as measured by the change in the total score on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) from week 1 to week 10.
PTSD is a neuropsychiatric disorder characterized by symptoms of intrusion, avoidance, negative alterations in cognition and mood, and hyperarousal. It develops following exposure to traumatic events and can have a significant impact on patients' quality of life.
Currently, the most effective treatments for PTSD primarily include antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), which act by altering the levels of neurotransmitters involved in regulating mood and stress response.
The combination of brexpiprazole and sertraline aims to modulate these symptoms through interaction with the neurotransmitter systems involved in the stress response and recovery from traumatization.
Brexpiprazole, in particular, is an atypical antipsychotic, approved for the treatment of schizophrenia and as an adjunctive therapy for major depressive disorder. It acts as a partial agonist at the serotonergic 5-HT1A and dopaminergic D2 receptors, and as an antagonist at the serotonergic 5-HT2A and alpha-adrenergic receptors.
Sertraline, a selective serotonin reuptake inhibitor (SSRI), is commonly used in the treatment of depression and anxiety disorders.
The association of brexpiprazole and sertraline could therefore provide a dual mechanism of action, acting on both serotonin modulation and dopaminergic activity, proving particularly effective in treating the complex symptoms of PTSD.
The study, conducted at 86 clinical sites in the United States from 2019 to 2023 by a group of researchers led by Lori L. Davis, of the University of Alabama at Birmingham Heersink School of Medicine, included an initial one-week placebo phase, followed by an 11-week double-blind, placebo-controlled period, with a 21-day follow-up.
Overall, 1,327 individuals were evaluated for eligibility, with 416 participants randomized. Completion rates were 64.0% for the brexpiprazole and sertraline group and 55.9% for the sertraline and placebo group.
The safety profile of brexpiprazole in combination with sertraline was found to be consistent with that of the approved indications for brexpiprazole. The percentage of participants who discontinued treatment due to adverse events was 3.9% in the brexpiprazole and sertraline group, compared to 10.2% in the sertraline and placebo group.
Adverse events with an incidence of 5% or more in patients treated with brexpiprazole and sertraline (n=205) compared to those treated with sertraline and placebo (n=196) were nausea (12.2% vs 11.7%), fatigue (6.8% vs 4.1%), weight gain (5.9% vs 1.5%), and somnolence (5.4% vs 2.6%).
Patients treated with brexpiprazole and sertraline showed a significantly greater improvement in the total CAPS-5 score (-19.2) compared to those treated with sertraline and placebo (-13.6), with a least squares (LS) mean difference of -5.59 (95% CI: -8.79 to -2.38; P<0.001).
Both secondary endpoints, the change in the Clinical Global Impression-Severity of Illness (CGI-S) score from week 1 to week 10 and the change in the Brief Inventory of Psychosocial Function (B-IPF) from baseline (day 0) to week 12, were met.
The results of this clinical trial indicate that the combination of brexpiprazole and sertraline led to a significant improvement in PTSD symptoms compared to sertraline alone with placebo, suggesting the potential of brexpiprazole as a new effective treatment for PTSD. The combination was well tolerated by most participants, with a safety profile in line with that of brexpiprazole in approved indications.