What is Vraylar (Cariprazine)?
Vraylar (cariprazine) is a third-generation atypical antipsychotic medication that acts as a partial agonist at dopamine D3 and D2 receptors with a preference for D3 receptors, and is FDA-approved for the treatment of schizophrenia, bipolar I disorder (manic or mixed episodes), bipolar depression, and as an adjunctive treatment for major depressive disorder. 1
Mechanism of Action
Vraylar works through a unique mechanism compared to other antipsychotics:
- Acts as a partial agonist at dopamine D3 and D2 receptors with approximately 10-fold higher affinity for D3 receptors 2
- Functions as a partial agonist at serotonin 5-HT1A receptors
- Acts as an antagonist at serotonin 5-HT2B and 5-HT2A receptors 1
- Has minimal affinity for histamine H1 receptors and negligible affinity for muscarinic receptors, which contributes to its favorable side effect profile 1
Pharmacokinetics
Vraylar has distinctive pharmacokinetic properties:
- Administered once daily with or without food
- Metabolized primarily through CYP3A4 and to a lesser extent CYP2D6 2
- Forms two major active metabolites:
- Desmethylcariprazine (DCAR) - reaches steady state in 1-2 weeks
- Didesmethylcariprazine (DDCAR) - has a very long half-life of 1-3 weeks and becomes the predominant circulating compound at steady state 1
- Full steady state may take 4-8 weeks to achieve due to the long half-life of DDCAR 1
FDA-Approved Indications
Vraylar is approved for:
- Schizophrenia (1.5-6 mg/day)
- Bipolar I disorder (manic or mixed episodes) (3-6 mg/day)
- Bipolar depression (1.5-3 mg/day)
- Adjunctive treatment of major depressive disorder 1, 3
Clinical Efficacy
Vraylar has demonstrated efficacy in multiple psychiatric conditions:
- For schizophrenia: Pooled response rates of 31% vs 21% for placebo (NNT=10) 2
- For bipolar depression: Response rates of 46.3% vs 35.9% for placebo (NNT=10) 4
- May be particularly effective for negative symptoms of schizophrenia due to its D3 receptor preference 5
- In relapse prevention for schizophrenia, significantly fewer patients relapsed with cariprazine compared to placebo (24.8% vs 47.5%, NNT=5) 2
Common Side Effects
The most common adverse effects include:
- Extrapyramidal symptoms (NNH 15 for 1.5-3 mg/day vs placebo; NNH 10 for 4.5-6 mg/day vs placebo)
- Akathisia (NNH 20 for 1.5-3 mg/day vs placebo; NNH 12 for 4.5-6 mg/day vs placebo) 2
- Nausea
- Restlessness 4
Important Safety Considerations
- Boxed warning: Increased mortality in elderly patients with dementia-related psychosis and increased risk of suicidal thoughts and behaviors in pediatric patients and young adults 1
- Minimal impact on metabolic parameters compared to some other atypical antipsychotics
- Limited weight gain (NNH 34 for ≥7% weight gain) 2
- No clinically significant QTc prolongation at therapeutic doses 1
- Not recommended in severe hepatic or renal impairment 1
Dosing Considerations
- Starting dose varies by indication (typically 1.5 mg/day)
- Dose adjustments should be made gradually due to the long half-life of the active metabolite
- Dose reduction needed with CYP3A4 inhibitors 1
- No dose adjustment required based on age, sex, or race 1
Vraylar represents an important treatment option for several serious psychiatric conditions, with potential advantages in treating negative symptoms of schizophrenia and a relatively favorable metabolic profile compared to some other atypical antipsychotics.