Combination Treatment with Rexulti (Brexpiprazole) and Sertraline for PTSD
Yes, brexpiprazole combined with sertraline is an effective treatment for PTSD, demonstrating statistically significant superiority over sertraline alone in reducing PTSD symptoms. 1, 2
Evidence for Combination Therapy
The combination of brexpiprazole (2-3 mg/day) plus sertraline (150-200 mg/day) showed significantly greater improvement in PTSD symptoms compared to sertraline monotherapy in two large randomized controlled trials. 1, 2
In a 2024 phase 3 trial with 416 participants, brexpiprazole + sertraline reduced CAPS-5 total scores by -19.2 points versus -13.6 points for sertraline + placebo at week 10, with a statistically significant difference of -5.59 points (95% CI: -8.79 to -2.38; P < .001). 2
An earlier 2025 trial with 321 participants demonstrated similar results, with brexpiprazole + sertraline showing -16.4 point reduction versus -11.4 for sertraline alone (difference: -5.08 points; 95% CI: -8.96 to -1.20; P = .011). 1
Critically, brexpiprazole as monotherapy did NOT demonstrate efficacy for PTSD—the benefit only emerged when combined with sertraline. 1
Sertraline as Foundation Therapy
Sertraline is one of only two FDA-approved medications for PTSD (along with paroxetine), making it the appropriate foundation for treatment. 3, 4
Sertraline monotherapy results in 53-85% of patients being classified as treatment responders in controlled trials. 3
Sertraline has a favorable tolerability profile and relatively weak effect on the cytochrome P450 system, reducing drug interaction concerns. 4
Safety and Tolerability Profile
The combination was generally well-tolerated with a safety profile consistent with brexpiprazole in its approved indications. 2
Common adverse events (≥5%) for brexpiprazole + sertraline included: nausea (12.2%), fatigue (6.8%), weight increase (5.9%), and somnolence (5.4%). 2
Discontinuation rates due to adverse events were actually LOWER for the combination (3.9%) compared to sertraline alone (10.2%). 2
In the earlier trial, weight increase (12.5%) and somnolence (10.0%) were the most common side effects. 1
Dosing Recommendations
Use flexible dosing: brexpiprazole 2-3 mg/day combined with sertraline 150-200 mg/day. 1, 2
The 2024 trial used fixed sertraline 150 mg/day with flexible brexpiprazole 2-3 mg/day. 2
The earlier trial allowed more flexibility with sertraline 100-200 mg/day and brexpiprazole 1-3 mg/day. 1
Treatment duration should be at least 10-11 weeks to assess full response, as this was the timeframe used in efficacy trials. 1, 2
Clinical Context and Alternative Approaches
If combination therapy is not feasible or tolerated, consider cognitive-behavioral therapy (CBT) as first-line treatment, which may have lower relapse rates than medication alone. 3
Exposure-based CBT results in 42-65% of patients no longer meeting PTSD criteria. 3
Relapse following CBT discontinuation appears less common than relapse following medication discontinuation (26-52% relapse rate when sertraline is stopped). 3
The combination of SSRI with CBT has demonstrated greater efficacy than either monotherapy in controlled trials. 5
Important Caveats
The combination should be avoided in patients with prolonged QT interval, as both medications can affect cardiac conduction. 6
Monitor for serotonin syndrome when combining any serotonergic agents, though this risk is primarily relevant when combining with other serotonergic drugs beyond this specific combination. 6
For nightmare-specific symptoms of PTSD, aripiprazole (a related atypical antipsychotic) has shown benefit when combined with sertraline in case series, though evidence is limited to 5 veterans. 3