Cariprazine

Indications

• Schizophrenia in adults and in pediatric patients ages 13-17, for acute treatment and for continued maintenance.
• Acute manic or mixed episodes of bipolar I disorder in adults and in pediatric patients ages 10-17.
• Depressive episodes associated with bipolar I disorder in adults, where it is one of a small number of approved options.
• Adjunctive therapy to antidepressants for major depressive disorder in adults with inadequate response to the antidepressant alone.
• Off-label interest centers on predominant negative symptoms of schizophrenia, supported by a positive comparison against risperidone.

Mechanism of action

• Partial agonist at dopamine D3 and D2 receptors with roughly tenfold higher affinity for D3, a profile unique among marketed agents.
• D3 preference is proposed to underlie effects on negative symptoms, anhedonia, and cognition beyond positive symptom control.
• Partial agonism at serotonin 5-HT1A and antagonism at 5-HT2B and 5-HT2A add antidepressant and anxiolytic activity.
• Low histamine H1 and negligible muscarinic affinity keep sedation, weight gain, and anticholinergic effects modest.
• Partial D2 agonism means prolactin does not rise, but it also drives the akathisia and insomnia seen during titration.

Pharmacokinetics

• Absorption is unaffected by food, so the capsule can be taken with or without meals at any consistent time of day.
• Metabolized primarily by CYP3A4 to desmethyl and didesmethyl cariprazine, both active, with didesmethyl the dominant circulating species.
• The didesmethyl metabolite has a half-life of 1-3 weeks, giving an effective total half-life near one week and steady state at about 4 weeks.
• Because of this, dose changes take weeks to express fully and adverse effects can persist for weeks after stopping.
• Not recommended when creatinine clearance is below 30 mL/min or in severe hepatic impairment, where data are absent.

Dosing

• Schizophrenia in adults: start 1.5 mg once daily, may increase to 3 mg on day 2, usual range 1.5-6 mg/day, maximum 6 mg/day.
• Bipolar mania in adults: start 1.5 mg/day, increase to 3 mg on day 2, with an effective range of 3-6 mg/day and a 6 mg/day maximum.
• Bipolar depression and adjunctive major depressive disorder in adults: start 1.5 mg/day, target 1.5 or 3 mg/day, maximum 3 mg/day.
• Pediatric schizophrenia ages 13-17 and bipolar mania ages 10-17 start at 0.5 mg/day, with a maximum of 4.5 mg/day.
• Halve the dose when a strong CYP3A4 inhibitor is added; concomitant strong CYP3A4 inducers are not recommended.
• Taper is rarely necessary given the long metabolite half-life, but reassess several weeks after any change before concluding it failed.

Adverse effects

• Akathisia occurs in roughly 10-20 percent and is dose related, most often appearing within the first two weeks of a dose step.
• Extrapyramidal symptoms including parkinsonism and tremor are more common than with quetiapine but less than with risperidone.
• Insomnia, nausea, restlessness, and constipation are frequent early effects that often settle without a dose change.
• Weight gain is modest at about 1-2 kg, with small effects on lipids and glucose, placing it in the lower metabolic tier.
• Impulse control problems, tardive dyskinesia, neuroleptic malignant syndrome, and rare leukopenia are the serious labeled risks.
• Because active metabolites persist, adverse effects can continue for weeks after the drug is stopped.

Monitoring

• Weight, BMI, blood pressure, fasting glucose or A1c, and lipids at baseline, at 12 weeks, and annually thereafter.
• Screen for akathisia and parkinsonism at every visit during the first month and after every dose increase.
• AIMS at baseline and every 6-12 months, with the reminder that resolution after stopping may be slow given the long metabolites.
• Check renal and hepatic function at baseline, since severe impairment in either makes the drug unsuitable.
• Ask about new gambling, spending, eating, or sexual urges at follow-up, as with other dopamine partial agonists.

Interactions

• Strong CYP3A4 inhibitors including ketoconazole, itraconazole, clarithromycin, and ritonavir require halving the cariprazine dose.
• Strong CYP3A4 inducers such as rifampin and carbamazepine markedly lower exposure, and concomitant use is not recommended.
• Grapefruit juice should be avoided because intestinal CYP3A4 inhibition unpredictably raises exposure.
• Additive sedation with opioids, benzodiazepines, and alcohol; intrinsic QT prolongation is minimal.
• Cariprazine antagonizes dopamine agonists functionally at high dopamine tone, so avoid it in Parkinson disease psychosis.

Special populations

• Third-trimester exposure carries the class risk of neonatal extrapyramidal and withdrawal signs, prolonged by the long-lived metabolites.
• Lactation data are absent, so monitor breastfed infants closely or choose a better-characterized antipsychotic.
• Approved from age 10 for bipolar mania and 13 for schizophrenia, with a lower 4.5 mg/day ceiling than adults.
• In older adults start at the lowest dose and expect slower resolution of akathisia; the dementia mortality warning applies.
• Not recommended when creatinine clearance is below 30 mL/min or in severe hepatic impairment.

Clinical pearls

• Metabolites persist for weeks, so both benefit and akathisia lag every dose change.
• Best evidence in the class for predominant negative symptoms of schizophrenia.
• Bipolar depression and adjunctive MDD both cap at 3 mg/day, not the 6 mg schizophrenia maximum.