Is Vraylar Effective as Adjunctive Treatment for Depression?
Yes, Vraylar (cariprazine) at 1.5 mg/day is an effective and FDA-approved adjunctive treatment for major depressive disorder in patients with inadequate response to antidepressant monotherapy. 1
FDA-Approved Indication and Efficacy
Vraylar is FDA-approved as adjunctive therapy to antidepressants for treating major depressive disorder in adults who have had an inadequate response to 1-3 courses of prior antidepressant therapy. 1
Evidence from Pivotal Trials
The 1.5 mg/day dose demonstrated consistent efficacy:
- In Study 10 (6-week trial, N=751), cariprazine 1.5 mg/day + antidepressant showed statistically significant superiority over placebo + antidepressant, with a placebo-subtracted difference of -2.5 points on the MADRS scale (95% CI: -4.2 to -0.9). 1, 2
- Response rates were significantly higher: 44.0% vs 34.9% for placebo. 2
- Significant improvements were observed as early as week 2 and maintained through week 6. 1, 2
The 3 mg/day dose showed mixed results:
- In Study 10, the 3 mg/day dose did not achieve statistical significance versus placebo. 1, 2
- In Study 11 (8-week trial, N=808), the flexible-dose 2-4.5 mg/day range (mean dose 2.6 mg) was superior to placebo (placebo-subtracted difference: -2.2,95% CI: -3.7 to -0.6). 1, 3
- However, another phase 3 trial found neither 1.5 mg nor 3 mg doses achieved statistical significance on primary outcomes. 4
Recommended Dosing Strategy
Start with 1.5 mg/day as this dose has the most consistent evidence of efficacy. 1, 2
- The 1.5 mg dose demonstrated superiority in multiple trials with better tolerability than higher doses. 1, 2
- Higher doses (3 mg and above) do not consistently show additional benefit and may increase adverse effects, particularly akathisia and insomnia. 1, 5
- The FDA label notes that doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. 1
Safety and Tolerability Profile
Cariprazine is generally well tolerated with a favorable metabolic profile:
Common Adverse Events (≥5% and twice placebo rate):
- Akathisia (15.9-22.3%, dose-dependent) 6, 5
- Nausea (11.6-12.8%) 6, 5
- Insomnia (dose-dependent) 5, 3
- Headache (11.6%) 6
Metabolic Effects:
- Mean weight increase <1 kg, demonstrating a neutral metabolic profile. 5
- Mean changes in clinical laboratory, cardiovascular parameters were generally not clinically relevant. 6
Discontinuation Rates:
- Adverse events led to discontinuation in only 4.3% of patients in pooled phase 3 studies. 5
- Study completion rates were high at 90%. 5
Clinical Context and Guidelines
Current guidelines support augmentation with second-generation antipsychotics for treatment-resistant depression:
- The American College of Physicians suggests that quetiapine or aripiprazole augmentation is effective for treatment-resistant depression. 7
- Vraylar represents an additional evidence-based option in this class, with FDA approval specifically for adjunctive treatment of MDD. 1
- Guidelines recommend confirming adequate antidepressant trial (6-8 weeks at therapeutic dose) before initiating augmentation. 8, 7
Treatment Duration
Continue augmentation therapy for 4-9 months after achieving satisfactory response. 8, 7
- For patients with recurrent depression (≥2 episodes), longer treatment duration may be beneficial. 8, 7
- In long-term studies (26 weeks), 53.3% of patients achieved remission (MADRS ≤10) by week 26. 6
Important Caveats
Monitor for metabolic effects when using second-generation antipsychotics, though cariprazine has a favorable profile. 7, 5
- While cariprazine shows neutral metabolic effects, routine monitoring remains prudent given class effects. 7, 5
- Akathisia is the most common reason for discontinuation and should be proactively assessed and managed. 6, 5
- The evidence base shows some inconsistency across trials, with one negative study, though the preponderance of evidence and FDA approval support efficacy at 1.5 mg/day. 1, 2, 4