What is the comparative effect size on symptoms of Major Depressive Disorder (MDD) when using Rexulti (brexpiprazole) versus Vraylar (cariprazine) as augmentation therapies?

Comparative Effect Size of Rexulti vs. Vraylar for MDD Augmentation

There is insufficient direct comparative evidence between brexpiprazole (Rexulti) and cariprazine (Vraylar) as augmentation therapies for MDD, making it impossible to definitively state which has a superior effect size on depressive symptoms.

Evidence Overview

The available evidence on these two atypical antipsychotics as augmentation therapies for MDD shows:

Brexpiprazole (Rexulti)

• Demonstrated efficacy as an adjunctive therapy in phase III trials for patients with MDD who had incomplete response to antidepressant treatment 1
• In young adults (18-35 years) with MDD, adjunctive brexpiprazole showed a mean change from baseline in MADRS total score of -18.1 points 2
• Generally well tolerated with most common side effects including headache (21.3%), weight increase (17.0%), and somnolence (17.0%), with low rates of akathisia (6.4%) 2

Cariprazine (Vraylar)

• In a randomized, double-blind, placebo-controlled study, the 2-4.5 mg/d dose showed significantly greater reduction in MADRS total score compared to placebo (LSMD = -2.2; p = .0114) 3
• The 1-2 mg/d dose did not show statistically significant improvement over placebo at week 8 3
• Most common adverse events included akathisia (22.3%), insomnia (13.6%), and nausea (12.8%) 3
• Long-term (26-week) safety study showed 53.3% of patients achieved remission (MADRS ≤10) 4

Treatment Algorithm for MDD Augmentation

1. First-line augmentation options:

   • According to the American College of Physicians guidelines, various augmentation strategies involving pharmacologic agents or cognitive therapy render similar symptom relief 5
   • A high risk-of-bias trial reported higher remission rates for aripiprazole augmentation than bupropion (55.4% vs. 34.0%) 5

2. When considering atypical antipsychotic augmentation:

   • Both brexpiprazole and cariprazine have demonstrated efficacy as augmentation strategies
   • The choice between them should consider:
     • Side effect profiles: Brexpiprazole has lower rates of akathisia (6.4%) compared to cariprazine (22.3%) 2, 3
     • Dosing: Brexpiprazole target dose is 2mg/day 2, while cariprazine effective dose range is 2-4.5mg/day 3

3. For patients who failed a previous atypical antipsychotic:

   • Limited evidence suggests that cariprazine may be effective in patients who failed previous augmentation with other atypical antipsychotics (including brexpiprazole) 6
   • In a small case series, 7 out of 10 patients responded to cariprazine after failing other atypical antipsychotics 6

Key Considerations

• Adverse effects: Both medications have distinct side effect profiles that may influence selection

  • Brexpiprazole: Lower akathisia rates but higher weight gain concerns
  • Cariprazine: Higher akathisia rates (22.3%) but potentially different metabolic profile

• Dosing:

  • Brexpiprazole: 1-3mg/day (target 2mg/day)
  • Cariprazine: 1-4.5mg/day (with 2-4.5mg/day showing better efficacy)

• Treatment resistance:

  • For patients who have failed multiple antidepressants, both medications offer potential benefit
  • The VA/DoD and Delphi consensus guidelines define treatment-resistant depression as failure to respond to at least two adequate antidepressant trials 7

Pitfalls and Caveats

• Direct head-to-head comparisons between these two medications are lacking
• Most studies have methodological limitations including short duration and potential bias
• The American College of Physicians notes that many trials had methodological shortcomings that reduced confidence in the results 5
• Long-term comparative efficacy and safety data are limited
• Individual patient factors (comorbidities, prior medication response, side effect sensitivity) may significantly influence medication selection

While both medications show efficacy as augmentation strategies for MDD, the lack of direct comparative studies prevents a definitive statement about which has a superior effect size on depressive symptoms.