Are there evidence‑based studies supporting the use of brexpiprazole (Rexulti) as an adjunct to antidepressant therapy in veterans?

Evidence for Brexpiprazole (Rexulti) as Adjunctive Antidepressant Therapy in Veterans

Yes, there is robust evidence supporting brexpiprazole (Rexulti) as adjunctive therapy with antidepressants in veterans, though the evidence base is primarily from general adult populations rather than veteran-specific studies.

FDA-Approved Indication and Evidence Base

Brexpiprazole is FDA-approved for adjunctive treatment of major depressive disorder (MDD) in adults who have inadequate response to antidepressant therapy 1. The approval was based on two pivotal 6-week, placebo-controlled trials demonstrating efficacy when added to ongoing antidepressant treatment 1.

Key Efficacy Data

In pooled analyses of adult patients with MDD and inadequate antidepressant response, adjunctive brexpiprazole 2-3 mg/day showed statistically significant improvement compared to antidepressant plus placebo:

• Montgomery-Åsberg Depression Rating Scale (MADRS) improvement: -2.15 points greater than placebo (p<0.0001) 2
• Effect size (Cohen's d): 0.33-0.41 depending on baseline response 3, 4
• Response rates (≥50% MADRS reduction): 57% higher with brexpiprazole versus placebo 5
• Remission rates: 55% higher with brexpiprazole versus placebo 5

The treatment effect was consistent across patients with minimal response (>0% to <25% improvement) and partial response (≥25% to <50% improvement) to prior antidepressants 4.

Veteran-Specific Context

While the FDA trials did not specifically target veterans, the 2024 VA/DoD Clinical Practice Guideline for PTSD and ASD provides relevant context 6. The guideline recommends paroxetine, sertraline, or venlafaxine as first-line pharmacotherapy for PTSD, with manualized psychotherapies preferred over pharmacotherapy 6. Notably, the guideline does not specifically address brexpiprazole for PTSD or depression in veterans.

However, brexpiprazole has been studied in PTSD populations. A 2026 meta-analysis found that brexpiprazole augmentation of SSRIs in PTSD patients significantly improved CAPS-5 scores (mean difference -3.77 points, p=0.01) 7. This is relevant since many veterans have comorbid depression and PTSD.

Safety Profile in Clinical Trials

Common adverse events (≥5% incidence) with adjunctive brexpiprazole 2-3 mg/day in MDD trials 1:

• Akathisia: 9% (versus 3% with placebo) - dose-related and the most concerning side effect
• Weight gain: 7% (versus 2% with placebo)
• Headache: 7% (versus 6% with placebo)
• Somnolence: 5% (versus 0.5% with placebo)

Discontinuation due to adverse events occurred in only 3% of brexpiprazole-treated patients versus 1% with placebo 1. In real-world data, 66.7% of patients continued treatment, with akathisia and sedation being the primary reasons for discontinuation 8.

Clinical Application Algorithm

For veterans with MDD and inadequate antidepressant response:

1. Ensure adequate trial of current antidepressant (8+ weeks at therapeutic dose)

2. Consider evidence-based psychotherapy first (per VA/DoD guidelines prioritizing trauma-focused therapies) 6

3. If augmentation needed, initiate brexpiprazole:

   • Start 0.5 mg daily for Week 1
   • Increase to 1 mg daily Week 2
   • Target dose 2 mg daily from Week 3 onward (optimal efficacy/tolerability balance) 1
   • Maximum 3 mg daily if needed, though 2 mg shows best risk-benefit ratio 3

4. Monitor closely for:

   • Akathisia (most common reason for discontinuation) - consider dose reduction or beta-blocker if occurs
   • Weight gain (average 1.47 kg increase) 7
   • Sedation (particularly in elderly or those on multiple CNS medications)

5. Assess response at 4-6 weeks - expect gradual improvement with maximal effect by Week 6 1

Important Caveats

The evidence for brexpiprazole in veterans specifically is limited. Most trials enrolled general adult outpatients with MDD, not veteran populations. Veterans often have more complex presentations with comorbid PTSD, traumatic brain injury, and substance use disorders that may affect treatment response.

Brexpiprazole was studied in PTSD populations (including some veterans) for PTSD symptoms, not depression 7. The 2018 American Academy of Sleep Medicine position paper mentions aripiprazole (a related compound) showed benefit for PTSD-related nightmares in five veterans, but brexpiprazole was not specifically studied 9.

The 2024 VA/DoD PTSD guideline does not recommend atypical antipsychotics as first-line augmentation for PTSD or depression 6. The guideline emphasizes psychotherapy over pharmacotherapy and recommends against benzodiazepines and cannabis 6.

Weight gain and metabolic effects require monitoring, particularly in veterans who may already have metabolic syndrome or cardiovascular risk factors from service-related conditions 1.