Usage
Cariprazine is prescribed for the treatment of schizophrenia, bipolar I disorder (manic or mixed episodes and depressive episodes), and as adjunctive therapy to antidepressants for major depressive disorder (MDD) in adults.
It is classified as an atypical antipsychotic.
Cariprazine acts as a partial agonist at dopamine D₂ and D₃ receptors and serotonin 5-HT₁ₐ receptors, and as an antagonist at serotonin 5-HT₂ᵇ receptors. This complex interaction is thought to regulate dopamine and serotonin neurotransmission in key brain areas, improving symptoms of schizophrenia, bipolar disorder, and MDD.
Alternate Names
Cariprazine is also known internationally by its generic name. Brand names include Vraylar® and Reagila®.
How It Works
Pharmacodynamics: Cariprazine’s therapeutic effects are primarily mediated through its partial agonism at dopamine D₂ and D₃ receptors, and serotonin 5-HT₁ₐ receptors, coupled with its antagonism at serotonin 5-HT₂ᵇ receptors. This mechanism helps regulate dopamine and serotonin neurotransmission, which is dysregulated in conditions like schizophrenia and bipolar disorder. The partial agonism allows cariprazine to stabilize dopamine levels, reducing excess dopamine activity associated with psychosis while avoiding excessive dopamine blockade that can lead to side effects.
Pharmacokinetics:
- Absorption: Cariprazine is absorbed orally with peak plasma concentrations reached within 3 to 6 hours. Food does not significantly impact absorption.
- Metabolism: It is extensively metabolized in the liver, primarily by CYP3A4 and to a lesser extent by CYP2D6, into two major active metabolites: desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). These metabolites contribute to the drug’s overall clinical effect.
- Elimination: Cariprazine and its metabolites are eliminated through both renal (urine) and hepatic (bile/feces) pathways. The elimination half-life of cariprazine is approximately 1-3 days, while DDCAR has a longer half-life of 1-3 weeks, leading to a slow decline in plasma levels after discontinuation.
Mode of Action: At the cellular level, cariprazine binds to the aforementioned receptors, modulating dopamine and serotonin activity in specific brain regions. By acting as a partial agonist, it can either enhance or diminish neurotransmitter activity depending on the baseline level, providing a more balanced effect. The antagonism at 5-HT₂ᵇ receptors may contribute to improved mood and reduced impulsivity.
Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Cariprazine’s primary mechanism involves receptor binding at dopamine D₂/D₃ and serotonin 5-HT₁ₐ/5-HT₂ᵇ receptors. It does not directly inhibit enzymes but its metabolism is significantly impacted by CYP3A4 and CYP2D6.
Elimination Pathways: Elimination occurs via both renal and hepatic routes, with metabolism by CYP3A4 and CYP2D6 playing a key role in clearance.
Dosage
Standard Dosage
Adults:
- Schizophrenia: Initial dose is 1.5 mg orally once daily, titrated to 3 mg/day on Day 2 if tolerated. Further adjustments can be made in 1.5-3 mg increments up to a maximum of 6 mg/day, based on clinical response and tolerability.
- Bipolar I Disorder (Manic or Mixed Episodes): Initial dose is 1.5 mg once daily, increased to 3 mg/day on Day 2. Further adjustments in 1.5-3 mg increments up to a maximum of 6 mg/day can be made.
- Bipolar I Disorder (Depressive Episodes): Initial dose is 1.5 mg once daily. May increase to 3 mg/day on Day 15 if needed, with a maximum dose of 3 mg/day.
- MDD (Adjunctive Therapy): Initial dose is 1.5 mg orally once daily, titrated as needed up to a maximum of 6 mg/day.
Children:
The safety and efficacy of cariprazine have not been established in children younger than 18 years. Some studies have explored its use in adolescents with bipolar and psychotic disorders, but more research is needed. Dosage in pediatric populations should be individualized and carefully monitored by a healthcare professional.
Special Cases:
- Elderly Patients: Initiate with a lower dose and titrate cautiously due to increased sensitivity and potential for age-related renal or hepatic impairment. Avoid use in patients with dementia-related psychosis due to increased mortality risk.
- Patients with Renal Impairment: Not recommended in severe renal impairment (CrCl < 30 mL/min). Caution advised in mild to moderate impairment.
- Patients with Hepatic Dysfunction: Not recommended in severe hepatic impairment (Child-Pugh score 10-15). Caution advised in mild to moderate impairment.
- Patients with Comorbid Conditions: Careful monitoring is required in patients with diabetes, cardiovascular disease, seizures, or a history of neuroleptic malignant syndrome (NMS), as cariprazine can exacerbate these conditions.
Clinical Use Cases
Cariprazine is not indicated for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations like status epilepticus or cardiac arrest. It is intended for the long-term management of chronic mental health conditions.
Dosage Adjustments
Dosage adjustments may be necessary based on individual patient factors, including renal/hepatic impairment, metabolic disorders, and concomitant medications.
Side Effects
Common Side Effects:
Akathisia (restlessness), insomnia, extrapyramidal symptoms (EPS) such as tremor, dystonia, and parkinsonism, nausea, vomiting, constipation, dizziness, and headache.
Rare but Serious Side Effects:
Tardive dyskinesia, neuroleptic malignant syndrome (NMS), seizures, severe allergic reactions, and suicidal thoughts or behaviors.
Long-Term Effects:
Potential long-term effects include tardive dyskinesia, metabolic changes (weight gain, dyslipidemia, hyperglycemia), and worsening of pre-existing cardiovascular or cerebrovascular conditions.
Adverse Drug Reactions (ADR):
Clinically significant ADRs include NMS, tardive dyskinesia, severe allergic reactions (anaphylaxis, angioedema), and severe dyskinesias.
Contraindications
Absolute contraindications include known hypersensitivity to cariprazine. Relative contraindications include a history of NMS, tardive dyskinesia, dementia-related psychosis, severe hepatic or renal impairment, and certain cardiovascular conditions.
Drug Interactions
Cariprazine is primarily metabolized by CYP3A4 and CYP2D6, making it susceptible to interactions with drugs that affect these enzymes.
- CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin): Increase cariprazine levels, requiring a dosage reduction.
- CYP3A4 inducers (e.g., rifampin, carbamazepine): Decrease cariprazine levels, potentially reducing efficacy. Coadministration is not recommended.
- Alcohol and CNS depressants: Additive sedative effects.
- Antihypertensives: May enhance hypotensive effects.
Pregnancy and Breastfeeding
Cariprazine is not recommended during pregnancy due to potential fetal harm observed in animal studies. There is limited human data available. Neonates exposed to antipsychotics during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery.
There is no information on the use of cariprazine during breastfeeding. Due to high protein binding, it is unlikely clinically important amounts enter breast milk. However, due to limited data, an alternate drug may be preferred, especially when nursing a newborn or preterm infant.
Drug Profile Summary
- Mechanism of Action: Partial agonist at dopamine D₂/D₃ and serotonin 5-HT₁ₐ receptors; antagonist at 5-HT₂ᵇ receptors.
- Side Effects: Akathisia, insomnia, EPS, nausea, vomiting, constipation, dizziness, tardive dyskinesia, NMS (rare).
- Contraindications: Hypersensitivity to cariprazine, dementia-related psychosis in elderly patients.
- Drug Interactions: CYP3A4 inhibitors and inducers, alcohol, CNS depressants, antihypertensives.
- Pregnancy & Breastfeeding: Not recommended during pregnancy; use caution during breastfeeding.
- Dosage: 1.5-6 mg/day for schizophrenia and bipolar I disorder; 1.5-3 mg/day for bipolar depression.
- Monitoring Parameters: Monitor for EPS, metabolic changes, NMS, and suicidal ideation. Assess clinical response and tolerability for dosage adjustments.
Popular Combinations
Cariprazine is sometimes used in combination with other antidepressants, such as bupropion or selective serotonin reuptake inhibitors (SSRIs), in cases of treatment-resistant depression or when adjunctive therapy is needed for MDD.
Precautions
- General Precautions: Screen for allergies, metabolic disorders, cardiovascular disease, and history of seizures or NMS.
- Specific Populations: As detailed in “Dosage,” specific precautions apply to pregnant women, breastfeeding mothers, children, the elderly, and those with renal or hepatic impairment.
- Lifestyle Considerations: Advise patients to limit alcohol intake, avoid driving if experiencing sedation, and monitor diet and exercise due to potential metabolic side effects.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Cariprazine?
A: The starting dose for most indications is 1.5 mg once daily, with titration up to 6 mg/day depending on the condition and individual patient response. Refer to the “Dosage” section above for specific recommendations for schizophrenia, bipolar I disorder (manic/mixed and depressive episodes), and MDD adjunctive therapy, as well as considerations for elderly patients and those with renal or hepatic impairment.
Q2: How should Cariprazine be administered?
A: Administer orally once daily, with or without food.
Q3: What are the common side effects of Cariprazine?
A: Common side effects include akathisia, insomnia, extrapyramidal symptoms (EPS), nausea, vomiting, constipation, dizziness, and headache.
Q4: What are the serious side effects of Cariprazine?
A: Serious side effects include tardive dyskinesia, neuroleptic malignant syndrome (NMS), seizures, and allergic reactions.
Q5: What are the contraindications for Cariprazine?
A: Contraindications include known hypersensitivity to cariprazine and dementia-related psychosis in elderly patients. Use with caution in patients with severe renal or hepatic impairment.
Q6: Does Cariprazine interact with other medications?
A: Yes, Cariprazine interacts with CYP3A4 inhibitors and inducers. Dosage adjustments may be necessary when co-administered with these drugs. It also interacts with alcohol and other CNS depressants.
Q7: Can Cariprazine be used during pregnancy or breastfeeding?
A: Cariprazine is generally not recommended during pregnancy due to potential fetal risk. It should be used cautiously during breastfeeding; discuss risks and benefits with patients. Limited data are available.
Q8: How long does it take for Cariprazine to work?
A: Cariprazine typically takes several weeks to show noticeable improvement in symptoms. Due to the long half-life of cariprazine and its active metabolites, effects may not be fully apparent for several weeks after starting therapy or making dosage adjustments.
Q9: What should be monitored in patients taking Cariprazine?
A: Monitor for EPS, NMS, metabolic changes (weight, blood glucose, lipids), and suicidal ideation. Regularly assess clinical response and tolerability.
Q10: How should Cariprazine be discontinued?
A: Due to the long half-life, gradual tapering is generally not necessary. However, monitor patients for potential withdrawal symptoms or symptom recurrence. If switching to another antipsychotic, cross-titration may be considered.
