Why Rexulti Combined with Sertraline Helps PTSD Symptoms
Brexpiprazole (Rexulti) combined with sertraline significantly improves PTSD symptoms through a synergistic mechanism where sertraline addresses serotonergic dysregulation while brexpiprazole modulates dopaminergic and noradrenergic pathways, resulting in superior efficacy compared to sertraline alone. 1
Evidence for the Combination
The combination of brexpiprazole and sertraline has demonstrated robust efficacy in two large phase 3 randomized controlled trials:
At week 10, the combination produced a statistically significant 5.59-point greater reduction in CAPS-5 total score compared to sertraline plus placebo (p<0.001), with the combination achieving a mean change of -19.2 points versus -13.6 points for sertraline alone. 1
Importantly, neither brexpiprazole monotherapy nor sertraline monotherapy alone separated from placebo in a full-factorial trial, but the combination was significantly superior to all other arms, demonstrating true synergistic benefit rather than simple additive effects. 2
The combination treatment response rate was 60% compared to 38% for sertraline alone in controlled trials. 3
Mechanistic Rationale
Sertraline's Role
Sertraline addresses the core serotonergic dysregulation in PTSD, with established efficacy as one of only two FDA-approved medications for PTSD. 4, 3
Sertraline demonstrates particular efficacy for anxiety symptoms and psychomotor agitation that commonly accompany PTSD. 5
Brexpiprazole's Augmentation Mechanism
Brexpiprazole is a partial dopamine D2 receptor agonist with additional serotonin 5-HT1A partial agonism and 5-HT2A antagonism, providing complementary neurotransmitter modulation beyond sertraline's serotonergic effects. 5
The atypical antipsychotic class (which includes brexpiprazole and its predecessor aripiprazole) demonstrates alpha-1 and alpha-2 noradrenergic antagonism, which is particularly relevant for PTSD given that elevated CNS noradrenergic activity contributes to arousal symptoms, nightmares, and hypervigilance. 5
Case series with aripiprazole (a related compound) combined with sertraline showed substantial improvement in nightmare frequency and intensity in combat veterans with PTSD, with 4 of 5 participants reporting benefit at doses of 15-30 mg/day. 5
Clinical Implications
Symptom Coverage
The combination addresses residual symptoms that persist with sertraline monotherapy, particularly hypervigilance (47.3% persistence rate) and nightmares (45% persistence rate), which are common treatment-resistant symptoms. 6
All key secondary efficacy endpoints were met in the pivotal trial, indicating broad symptom improvement across PTSD symptom clusters. 1
Safety Profile
The combination was well-tolerated with only 3.9% discontinuation due to adverse events (compared to 10.2% for sertraline plus placebo), and treatment-emergent adverse events ≥5% included nausea (12.2%), fatigue (6.8%), weight increase (5.9%), and somnolence (5.4%). 1
Monitor for QT prolongation when combining these agents, as both can affect cardiac conduction, though this risk is manageable with appropriate screening. 7
Serotonin syndrome risk is primarily relevant when combining with additional serotonergic agents beyond this specific combination. 7
Important Caveats
This combination has FDA applications pending but is not yet approved, and current PTSD treatment guidelines recommend trauma-focused psychotherapies (prolonged exposure, cognitive processing therapy, EMDR) as first-line treatments, not pharmacotherapy or combination pharmacotherapy. 4
The combination of an SSRI with cognitive-behavioral therapy demonstrates greater efficacy than either monotherapy in controlled trials, suggesting that optimal treatment may involve adding evidence-based psychotherapy rather than or in addition to medication augmentation. 7
Trauma-focused treatments can be safely and effectively used even in patients with severe comorbidities including substance abuse, borderline personality disorder, and psychotic disorders, without evidence of iatrogenic effects. 5