What does Vraylar (cariprazine) do?

What Vraylar (Cariprazine) Does

Vraylar (cariprazine) is an atypical antipsychotic medication that treats schizophrenia, manic or mixed episodes of bipolar I disorder, bipolar depression, and serves as adjunctive therapy for major depressive disorder in adults. 1

Mechanism of Action

Cariprazine works through a unique pharmacological profile that distinguishes it from other antipsychotics:

• Dopamine receptor activity: Cariprazine acts as a partial agonist at both dopamine D2 and D3 receptors, with preferential binding to D3 receptors over D2 receptors. 2, 3, 4 This D3-preferring activity differentiates it from most other antipsychotics and may contribute to its efficacy against negative symptoms of schizophrenia. 5

• Serotonin receptor activity: The drug functions as a partial agonist at serotonin 5-HT1A receptors and as an antagonist at 5-HT2A and 5-HT2B receptors. 3, 4, 6

• Receptor occupancy: At therapeutic doses ≥1.5 mg/day, cariprazine achieves 69-75% D2/D3 receptor occupancy, which is sufficient for antipsychotic efficacy. 4

FDA-Approved Indications

Cariprazine is approved for four specific conditions in adults: 1

• Schizophrenia: Treatment of both positive symptoms (hallucinations, delusions) and negative symptoms (apathy, social withdrawal)
• Bipolar I disorder - manic/mixed episodes: Acute treatment of elevated or irritable mood with increased activity
• Bipolar I disorder - depressive episodes: Treatment of depressive symptoms in patients with bipolar disorder
• Major depressive disorder: As add-on therapy to antidepressants when initial treatment is insufficient

Clinical Efficacy Profile

For schizophrenia, cariprazine demonstrates superior efficacy compared to placebo across multiple trials:

• Pooled responder rates show 31% response with cariprazine 1.5-6 mg/day versus 21% with placebo, yielding a number needed to treat (NNT) of 10. 3
• In relapse prevention studies, significantly fewer patients relapsed on cariprazine (24.8%) compared to placebo (47.5%), with an NNT of 5. 3
• Cariprazine shows particular promise for negative symptoms, which represent an unmet need with most antipsychotics. 5

For bipolar disorder, three positive trials demonstrated efficacy in acute manic/mixed episodes, though specific response rates were not detailed in the provided evidence. 3

Dosing and Pharmacokinetics

• Recommended dose range: 1.5-6 mg once daily for schizophrenia, with 1.5 mg/day as a potentially therapeutic starting dose. 3
• Metabolism: Primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6. 3, 4, 6
• Active metabolites: Cariprazine produces two clinically significant metabolites—desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR)—with DDCAR having a substantially longer half-life and higher systemic exposure than the parent drug. 3, 4, 6
• Time to steady state: In pediatric studies, steady state was reached within 1-2 weeks for cariprazine and DCAR, and within 4-5 weeks for DDCAR. 7

Safety and Tolerability Profile

Common adverse events (incidence ≥5% and at least twice placebo rate): 3, 4

• Extrapyramidal symptoms (EPS): NNH of 15 for 1.5-3 mg/day and NNH of 10 for 4.5-6 mg/day versus placebo
• Akathisia: NNH of 20 for 1.5-3 mg/day and NNH of 12 for 4.5-6 mg/day versus placebo
• Other common effects include insomnia, sedation, nausea, dizziness, and constipation 4

Metabolic effects: 3

• Weight gain appears minimal: approximately 8% of patients on cariprazine 1.5-6 mg/day gained ≥7% body weight versus 5% on placebo (NNH of 34)
• No clinically meaningful alterations in metabolic variables, prolactin levels, or ECG QT interval

In pediatric populations (ages 10-17), the most frequent treatment-related adverse events included sedation, parkinsonism, tremor, dystonia, and blurred vision, though pharmacokinetic parameters were consistent with adults. 7

Clinical Positioning

Cariprazine represents a therapeutic option that may address specific unmet needs:

• Its D3-preferring profile may offer advantages for negative symptoms of schizophrenia, which remain poorly treated by most antipsychotics. 5
• The favorable metabolic profile makes it suitable for patients at risk for weight gain or metabolic syndrome. 3
• Critical caveat: The risk of extrapyramidal symptoms, particularly at higher doses, requires careful monitoring and dose titration, especially in young males who are at highest risk for acute dystonia. 8, 7