What are the effects of Cariprazine (atypical antipsychotic) in treating schizophrenia and bipolar disorder?

Cariprazine for Schizophrenia and Bipolar Disorder

Cariprazine is an effective atypical antipsychotic for treating schizophrenia, bipolar mania, bipolar depression, and as adjunctive therapy for major depressive disorder, with a unique dopamine D3-preferring receptor partial agonist mechanism that distinguishes it from other antipsychotics. 1

Indications and Efficacy

• Cariprazine is FDA-approved for the treatment of schizophrenia in adults, acute treatment of manic or mixed episodes associated with bipolar I disorder, treatment of depressive episodes associated with bipolar I disorder, and as adjunctive therapy to antidepressants for major depressive disorder 1
• In multiple clinical trials, cariprazine demonstrated superiority over placebo for schizophrenia at doses ranging from 1.5-6 mg/day, with significant improvements in Positive and Negative Syndrome Scale (PANSS) total scores 2
• For bipolar mania, cariprazine significantly reduced Young Mania Rating Scale (YMRS) scores versus placebo, with 48% of patients meeting response criteria compared to 25% on placebo 3
• In bipolar depression, cariprazine (1.5-3 mg/day) showed response rates of 46.3% versus 35.9% for placebo (NNT 10) and remission rates of 30.2% versus 20.9% (NNT 11) 4

Dosing Recommendations

• For schizophrenia: Starting dose 1.5 mg daily, with recommended dose range of 1.5-6 mg daily 1
• For bipolar mania: Starting dose 1.5 mg daily, with recommended dose range of 3-6 mg daily 1
• For bipolar depression: Starting dose 1.5 mg daily, with recommended dose of 1.5-3 mg daily 1
• For adjunctive therapy in MDD: Starting dose 1.5 mg daily, with recommended dose of 1.5-3 mg daily 1
• Maximum recommended daily dosage for schizophrenia and bipolar mania is 6 mg; dosages above this do not confer significant benefit but increase risk of adverse effects 1

Mechanism of Action

• Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist, with approximately 10-fold higher affinity for D3 receptors than D2 receptors, distinguishing it from other antipsychotics like aripiprazole 2, 5
• At doses ≥1.5 mg/day, cariprazine achieves 69-75% D2/D3 receptor occupancy 5
• This unique receptor profile may contribute to its efficacy for both positive and negative symptoms in schizophrenia and its antidepressant effects in bipolar depression 6, 5

Safety and Tolerability

• Most common adverse events (≥5% and at least twice placebo rate) include 1:

  • For schizophrenia: extrapyramidal symptoms and akathisia
  • For bipolar mania: extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness
  • For bipolar depression: nausea, akathisia, restlessness, and extrapyramidal symptoms

• In long-term treatment (48 weeks), the most common adverse events were akathisia, insomnia, weight increase, and headache 7

• Unlike many other antipsychotics, cariprazine does not appear to adversely impact metabolic parameters, prolactin levels, or QT interval in short-term trials 2

• Mean changes in total cholesterol (-5.3 mg/dL), LDL (-3.5 mg/dL), and HDL (-0.8 mg/dL) were observed in long-term studies 7

• Mean weight change in long-term treatment was 1.58 kg, with 27% of patients experiencing ≥7% weight gain and 11% experiencing ≥7% weight loss 7

Pharmacokinetics and Special Considerations

• Cariprazine has a half-life of 2-5 days, but produces two clinically relevant metabolites: desmethyl-cariprazine and didesmethyl-cariprazine 5
• Didesmethyl-cariprazine has a longer half-life (1-3 weeks) than the parent compound and at steady state becomes the predominant circulating moiety 5, 4
• Due to this long half-life, late-occurring adverse reactions may appear several weeks after starting treatment or changing doses 1
• Cariprazine is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6 5
• Dose reduction is required when used with strong or moderate CYP3A4 inhibitors; concomitant use with CYP3A4 inducers is not recommended 1

Comparative Advantages and Position in Therapy

• For negative symptoms of schizophrenia, cariprazine may be particularly beneficial due to its D3 receptor selectivity 6
• For treatment-resistant schizophrenia, clozapine remains the gold standard after failed trials of two different antipsychotics (at least one being an atypical) 6, 8
• Cariprazine is one of only four agents approved for bipolar depression in the US, with a favorable benefit-to-harm ratio (likelihood of response or remission substantially greater than likelihood of discontinuation due to adverse events) 4
• For patients with predominant negative symptoms in schizophrenia, cariprazine or aripiprazole may be preferred options 6

Monitoring Recommendations

• Regular monitoring for extrapyramidal symptoms and akathisia is essential, as these are among the most common adverse events 1, 7
• Monitor metabolic parameters (weight, glucose, lipids) regularly, though changes appear less pronounced than with some other atypical antipsychotics 2, 7
• Due to cariprazine's long half-life, monitor for adverse reactions and clinical response for several weeks after starting treatment or changing doses 1
• Be vigilant for potential cardiovascular effects, though mean changes in blood pressure and pulse are generally not considered clinically significant 7