Post-traumatic stress disorder (PTSD) is a psychiatric problem mostly developed in those who experienced or witnessed a traumatic incident, a sequence of events, or a set of circumstances. People mostly experience emotional or physical harm, life-threatening, affecting their mental, physical, social, and/or spiritual well-being. Examples include natural disasters, severe accidents, terrorist acts, war or combat exposure, rape or sexual assault, historical trauma, intimate partner violence and harassment.
Approximately 3.6% of the US population has experienced PTSD annually. Around 8% of the US population had been diagnosed with PTSD in their adolescents ages (13-18 years). It was estimated that one in 11 individuals will experience PTSD in their lives and women are twice as likely as men to experience this condition. PSTD potentially influences patients’ quality of life including social and occupational disability, enhanced risk of suicide, etc.
US Food and Drug Administration (FDA) approved sertraline and paroxetine medications classified as selective serotonin reuptake inhibitors (SSRIs) for PTSD condition. However, 42% of patients with PTSD did not respond to these SSRI medications in a large meta-analysis. Moreover, individual clinical trials fail to determine the efficacy of these medications on PTSD symptoms including clusters, especially intrusion and arousal. Therefore, polypharmacy with off-label drugs was recommended for the treatment of a broader range of PSTD symptoms. This evidence highlights the unmet need for new treatment alternatives for PTSD.
This paper focused on the efficacy, safety, and tolerability of brexpiprazole (2 to 3 mg/day) and sertraline (150 mg/day) combining medications for PTSD treatment. Lori L. Davis and co-authors conducted the parallel-design, double-blind, randomized phase 3 clinical trial from October 2019 to August 2023. PSTD patients (18-65 years) with symptoms associated for 6 or more months before screening, up to 20% index trauma (combat), and a total clinician-administered PTSD scale (CAPS-5) score of 33 or more were included in this trial. Placebo is carried out for one week whereas double-blind, randomized, parallel design for 11 weeks followed for 21 days. A total of 86 US sites were included in this clinical trial.
In this multi-center study, a total of 416 patients (74.5% females) were selected for randomization. Out of 64% of patients who underwent treatment with brexpiprazole + sertraline 55.9% of patients underwent treatment with sertraline + placebo. After 10th week, brexpiprazole + sertraline combination showed significant improvement in CAPS-5 total score (mean = 38.4 [standard deviation, SD = 7.2], least squares mean [LS means] = −19.2) than sertraline + placebo (mean = 38.7 [SD = 7.8], LS means = −13.6) with LS mean difference of -5.59; 95% confidence interval (CI) −8.79 to −2.38 and P < 0.001.
A total of 5% or greater adverse events (AE) were reported in brexpiprazole + sertraline compared with sertraline + placebo. AE including nausea (12.2% vs 11.7%), fatigue (6.8% vs 4.1%), weight gain (5.9% vs 1.5%), and drowsiness (5.4% vs 2.6%). Moreover, 3.9% (8/205) patients in brexpiprazole + sertraline have discontinued the treatment due to adverse events whereas 10.2% (20/196) patients in sertraline + placebo.
This randomized clinical trial concluded that brexpiprazole + sertraline combination treatment showed statistically significant improvement in symptoms of PTSD compared to sertraline + placebo. Hence, this combination showed efficient treatment for PTSD. This combination was well tolerated by most of the patients. Its safety profile is associated with that of brexpiprazole in approved indications. “This combination needs further long-term efficacy and safety data,” says, Lori L. Davis, Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham.
Reference: Davis LL, Behl S, Lee D, 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
