BLACK BOX WARNING
- increased mortality in elderly patients with dementia-related psychosis
- suicidal thoughts and behaviors (MDD adjunct use)
cariprazine
Brand: Vraylar
⚠ BBW Beers Criteria Prototype: aripiprazole
Drug Class: second-generation antipsychotic (SGA)
Drug Family: antipsychotic
Subclass: dopamine-serotonin receptor modulator
Organ Systems: cns
Mechanism of Action
Partial agonist at D2 and D3 receptors with particularly high D3 receptor affinity; D3 receptor modulation may specifically target negative symptoms of schizophrenia and depressive symptoms. 5-HT2A antagonism contributes to standard SGA antipsychotic mechanism.
D2 dopamine receptor (partial agonist)D3 receptor (partial agonist, high affinity)5-HT2A receptor (antagonist)5-HT2B receptor5-HT1A receptor (partial agonist)
Indications
- schizophrenia
- bipolar I mania and mixed episodes
- bipolar depression (FDA-approved)
- adjunct for major depressive disorder (FDA-approved 2023)
Contraindications
- concurrent strong CYP3A4 inhibitors or inducers
Adverse Effects
Common
- EPS/akathisia (higher than other SGAs)
- weight gain (moderate)
- somnolence
- nausea
Serious
- NMS
- tardive dyskinesia
- metabolic effects
- suicidal ideation (MDD adjunct use)
Pharmacokinetics (ADME)
| Absorption | oral; food has no significant effect on absorption |
| Distribution | protein binding ~91-97% |
| Metabolism | primarily CYP3A4; two active metabolites (DCAR and DDCAR) with similar pharmacology; very long effective half-life due to active metabolites |
| Excretion | fecal (~21%) and renal (~21%) |
| Half-life | 2-5 days (parent); 1-3 weeks (active metabolites collectively) |
| Onset | days to weeks; full effect may require 3-4 weeks |
| Peak | 3-6 hours |
| Duration | once-daily dosing |
| Protein Binding | 91-97% |
| Vd | not well characterized |
Drug Interactions
| Drug / Agent | Mechanism | Severity |
|---|---|---|
| strong CYP3A4 inhibitors (clarithromycin, ketoconazole) | increase cariprazine exposure; reduce dose by 50% | major |
| strong CYP3A4 inducers (rifampin, carbamazepine) | decrease cariprazine levels | major |
Nursing Considerations
- Cariprazine and its active metabolites have an extremely long effective half-life (weeks); dose changes or discontinuation effects may not be apparent for 2-4 weeks.
- Akathisia is more common with cariprazine than with most SGAs — assess for subjective motor restlessness at every visit; do not confuse with psychotic agitation.
- FDA approved in 2023 for adjunct treatment of MDD; when used for this indication, monitor for suicidal ideation per the antidepressant BBW.
- CYP3A4 inhibitors require dose reduction to 50%; verify all medications and supplement use including CYP3A4-inhibiting substances.
Clinical Pearls
- Cariprazine is one of three SGAs FDA-approved for bipolar depression (along with lurasidone and quetiapine), with its high D3 receptor affinity thought to contribute to antidepressant efficacy via reward circuitry modulation.
- The very long half-life of its active metabolites (effectively weeks) means washout of cariprazine after discontinuation takes far longer than its nominal half-life suggests, with clinical implications for drug interactions and adverse effect resolution.
Safety Profile
Pregnancy use-with-caution
Lactation avoid
Renal Adjustment Not required
Hepatic Adjustment Required
TDM Not required
Guideline Update pending
Concordance Terms
Cross-referenced clinical concepts — click any term to see all content where it appears.