Cariprazine for Depression: Indications, Dosing, and Side Effects
Cariprazine is FDA-approved as adjunctive therapy to antidepressants for major depressive disorder (MDD) in adults, and for treating depressive episodes associated with bipolar I disorder (bipolar depression) in adults, but is NOT approved for unipolar depression monotherapy. 1
FDA-Approved Indications for Depression
- Bipolar I Depression: Cariprazine is approved for treating depressive episodes associated with bipolar I disorder in adults 1
- Adjunctive Treatment for MDD: Cariprazine is approved as add-on therapy to antidepressants for major depressive disorder in adults, not as monotherapy 1
Recommended Dosing
For Bipolar Depression
- Starting dose: 1.5 mg once daily 1
- Recommended dose range: 1.5 mg or 3 mg daily 1
- Maximum dose: 3 mg daily (dosages above 3 mg do not provide additional benefit but increase adverse reactions) 1
- Administration: Once daily with or without food 1
For Adjunctive Treatment of MDD
- Starting dose: 1.5 mg once daily 1
- Recommended dose range: 1.5 mg or 3 mg daily 1
- Maximum dose: 3 mg daily 1
Common Side Effects
Most Common Adverse Reactions (≥5% incidence and at least twice placebo rate)
For Bipolar Depression:
For Adjunctive Treatment of MDD:
- Akathisia 1
- Restlessness 1
- Fatigue 1
- Constipation 1
- Nausea 1
- Insomnia 1
- Increased appetite 1
- Dizziness 1
- Extrapyramidal symptoms 1
Discontinuation Rates
- Discontinuation due to adverse events occurred in 6.7% of patients on cariprazine versus 4.8% on placebo (not statistically significant) 2
Critical Safety Warnings
Boxed Warnings
- Increased mortality in elderly patients with dementia-related psychosis - cariprazine is NOT approved for this population 1
- Suicidal thoughts and behaviors: Antidepressants increase risk in pediatric and young adult patients; close monitoring required for clinical worsening 1
Important Precautions
- Late-occurring adverse reactions: Due to cariprazine's long half-life (2-4 days) and its active metabolite didesmethyl-cariprazine (DDCAR) with a half-life of 1-3 weeks, monitor for adverse reactions for several weeks after starting or changing doses 1, 3
- Persistent side effects: The long-acting metabolite means side effects may persist for weeks after discontinuation 4, 3
- Neuroleptic malignant syndrome: Requires immediate discontinuation and close monitoring 1
- Tardive dyskinesia: Consider discontinuation if this develops 1
- Metabolic changes: Monitor for hyperglycemia/diabetes, dyslipidemia, and weight gain, though cariprazine shows minimal metabolic effects compared to other antipsychotics 1, 5
Efficacy Data
Bipolar Depression
- Response rate (≥50% MADRS reduction): 46.3% for cariprazine (1.5-3 mg) versus 35.9% for placebo (NNT = 10) 2
- Remission rate (MADRS ≤10): 30.2% for cariprazine versus 20.9% for placebo (NNT = 11) 2
Unique Pharmacological Properties
- Cariprazine has 10-fold higher affinity for dopamine D3 receptors than D2 receptors, distinguishing it from other antipsychotics 2, 6
- This D3 preferring profile contributes to efficacy across multiple symptom domains including mood disturbance, anhedonia, and cognitive impairment 3
- Partial agonism at 5-HT1A receptors provides additional antidepressant effects 5, 6
Key Clinical Pitfalls
- Do not use as monotherapy for unipolar depression - it is only approved as adjunctive therapy to antidepressants 1
- Titration not required but dose escalation should be gradual - patients receiving 3.0 mg versus 1.5 mg experience more adverse events and discontinuations 2
- Account for delayed onset and offset - the long half-life of the active metabolite means therapeutic effects and side effects develop slowly and persist after discontinuation 4, 1
- Higher doses (>3 mg for depression) provide no additional benefit but increase dose-related adverse reactions 1