Combination Therapy with Brexpiprazole and Sertraline for PTSD
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Reviewed by Dat Tien Nguyen, B.A, ScM.
Translated by Nhi Phuong Quynh Le, B.A |
Posted on March 28th, 2025
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Selective serotonin reuptake inhibitors (SSRIs) such as sertraline and paroxetine are the only US FDA-approved treatments for post-traumatic stress disorder (PTSD). However, these medications are effective in only about half of patients and tend to be inconsistent in managing intrusion and arousal symptoms. This has sparked increased interest in alternative treatments. Funded by Otsuka Pharmaceutical, a study was conducted to evaluate the off-label potential of Brexpiprazole for managing PTSD.
The phase 3 clinical trial enrolled 1,327 participants with an average age of approximately 37, all diagnosed with post-traumatic stress disorder according to DSM-5 criteria. Baseline assessments using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) revealed an average total score of about 38, with the following approximate breakdown by symptom cluster: intrusion (9), avoidance (4.5), negative cognitions and mood (14.5), and arousal and reactivity (10). Additionally, around 25% of participants were receiving medication and approximately 32% were undergoing psychotherapy.
The patients were randomly assigned to receive either a placebo or oral brexpiprazole at a daily dose of 2–3 mg, while all participants concurrently received sertraline at a dose of 150 mg per day. Sertraline, a standard treatment for PTSD, works by inhibiting the reuptake of serotonin by preganglionic neurons, thereby increasing the availability of serotonin in the synapse and enhancing both its duration and magnitude of action. This mechanism helps to correct the disrupted neurotransmitter balance seen in PTSD patients, who typically experience a serotonin deficiency. In contrast, brexpiprazole, which is currently used as an antipsychotic for treating schizophrenia, acts as an agonist by directly activating serotonin receptors, rather than merely increasing serotonin levels. Additionally, brexpiprazole also exerts effects on dopamine and norepinephrine receptors.
After 11 weeks of treatment, researchers found that combining brexpiprazole with sertraline was more effective than using sertraline alone in reducing PTSD severity, as indicated by an average 19.2% decrease in the total CAPS-5 score. This improvement was evident across all symptom clusters. Nausea and fatigue were the most frequently reported adverse effects, occurring in about 12% and 5% of patients, respectively; however, the combination therapy led to fewer treatment discontinuations due to side effects. The researchers emphasized the need for future studies with longer treatment and follow-up durations to better understand the long-term effects and sustainability of this therapeutic approach.
The phase 3 clinical trial enrolled 1,327 participants with an average age of approximately 37, all diagnosed with post-traumatic stress disorder according to DSM-5 criteria. Baseline assessments using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) revealed an average total score of about 38, with the following approximate breakdown by symptom cluster: intrusion (9), avoidance (4.5), negative cognitions and mood (14.5), and arousal and reactivity (10). Additionally, around 25% of participants were receiving medication and approximately 32% were undergoing psychotherapy.
The patients were randomly assigned to receive either a placebo or oral brexpiprazole at a daily dose of 2–3 mg, while all participants concurrently received sertraline at a dose of 150 mg per day. Sertraline, a standard treatment for PTSD, works by inhibiting the reuptake of serotonin by preganglionic neurons, thereby increasing the availability of serotonin in the synapse and enhancing both its duration and magnitude of action. This mechanism helps to correct the disrupted neurotransmitter balance seen in PTSD patients, who typically experience a serotonin deficiency. In contrast, brexpiprazole, which is currently used as an antipsychotic for treating schizophrenia, acts as an agonist by directly activating serotonin receptors, rather than merely increasing serotonin levels. Additionally, brexpiprazole also exerts effects on dopamine and norepinephrine receptors.
After 11 weeks of treatment, researchers found that combining brexpiprazole with sertraline was more effective than using sertraline alone in reducing PTSD severity, as indicated by an average 19.2% decrease in the total CAPS-5 score. This improvement was evident across all symptom clusters. Nausea and fatigue were the most frequently reported adverse effects, occurring in about 12% and 5% of patients, respectively; however, the combination therapy led to fewer treatment discontinuations due to side effects. The researchers emphasized the need for future studies with longer treatment and follow-up durations to better understand the long-term effects and sustainability of this therapeutic approach.