Cariprazine (Vraylar)
SGA • Last reviewed 2025-09-23
General information
Cariprazine (brand name Vraylar) is an atypical second-generation antipsychotic approved for schizophrenia, acute manic or mixed episodes associated with bipolar I disorder (as monotherapy or adjunct to lithium/valproate), bipolar I depression, and as adjunctive therapy to antidepressants for major depressive disorder (MDD). The first FDA approval was granted in 2015 for schizophrenia and bipolar mania; indications for bipolar depression followed in 2019 and adjunctive MDD in 2022. No long-acting injectable formulation is currently available, and the product remains brand-only in the United States with patent protection expected into 2029. Clinical trials and meta-analyses suggest cariprazine provides clinically meaningful benefit for negative symptoms and functional outcomes compared with several other SGAs.
Cariprazine is supplied as 1.5, 3, 4.5, and 6 mg capsules administered once daily without regard to meals. For schizophrenia, the recommended dose range is 1.5–6 mg/day (typical maintenance 3–6 mg/day). For bipolar I mania, titrate from 1.5 mg/day to 3–6 mg/day. Bipolar depression is treated with 1.5–3 mg/day, while adjunctive MDD therapy uses 1.5–3 mg/day. Doses above 6 mg/day have not demonstrated additional benefit and increase adverse effect burden. Routine therapeutic drug monitoring is not established; some experts consider trough concentrations ≥20–30 ng/mL of total cariprazine (parent + metabolites) as minimum exposure, but clinical judgement remains primary.
Cariprazine’s pharmacodynamic profile features high-affinity partial agonism at dopamine D3 receptors (greater than D2) and serotonin 5-HT1A receptors, along with antagonism at serotonin 5-HT2B/5-HT2A and histamine H1 receptors. Preferential D3 engagement is theorized to enhance cognition and negative symptom improvement, while moderate D2 occupancy maintains antipsychotic efficacy with relatively low extrapyramidal symptom (EPS) risk. Histamine and alpha-1 blockade explain common adverse effects such as somnolence, weight gain, and orthostatic hypotension; muscarinic binding is negligible, resulting in limited anticholinergic burden.
Cariprazine undergoes extensive hepatic metabolism via CYP3A4 (primary) and CYP2D6 (secondary) to two equipotent active metabolites: desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). Peak plasma concentrations occur 3–5 hours after dosing and oral bioavailability is ~52%. The parent drug has a terminal half-life of 2–4 days, DCAR 1–2 days, and DDCAR 1–3 weeks; combined active moieties reach ~50% steady state within 1 week and ~90% by 3 weeks. Because DDCAR dominates exposure at steady state, dose changes or discontinuation may take several weeks to translate into full clinical effect. Elimination is primarily fecal, with <5% renal excretion of unchanged drug.
Dosing & administration
Start 1.5 mg once daily; increase to 3 mg/day on Day 2. Further dose increases (1.5–3 mg increments) should occur at intervals ≥3 days due to long metabolite half-lives.
Schizophrenia: maintenance 1.5–6 mg/day (typical 3–6 mg/day). Evaluate response after ≥2 weeks at target dose.
Bipolar I mania: titrate to 3–6 mg/day as monotherapy or adjunct to lithium/valproate.
Bipolar I depression: 1.5 mg/day for at least 14 days; may increase to 3 mg/day based on response and tolerability.
Adjunctive MDD: 1.5 mg/day for 14 days; may increase to 3 mg/day. Safety beyond 3 mg/day for MDD not established.
Dose reduction is required with strong CYP3A4 inhibitors (reduce by 50% or interrupt therapy); coadministration with strong CYP3A4 inducers is contraindicated. No adjustment needed for mild/moderate renal or hepatic impairment; avoid in severe impairment due to lack of data.
If ≥1 dose is missed, resume the regular schedule as soon as remembered; long effective half-life limits plasma fluctuations.
Clinical dosing guide
- Schizophrenia
- Start 1.5 mg → 3 mg Day 2; maintenance 3–6 mg/day (max 6 mg).
- Bipolar I mania
- 1.5 mg Day 1 → 3 mg Day 2; titrate to 3–6 mg/day.
- Bipolar I depression
- 1.5 mg/day (increase to 3 mg/day if needed).
- Adjunctive MDD
- 1.5–3 mg/day (start 1.5 mg/day; evaluate after 14 days).
- Renal/hepatic impairment
- No adjustment for mild/moderate impairment; avoid severe due to limited data.
- Strong CYP3A4 inhibitor
- Reduce dose by 50% or interrupt treatment; avoid strong inducers.
Mechanism of action
Partial agonism with preferential D3 binding is thought to balance dopaminergic signaling across mesolimbic and mesocortical pathways, improving both positive and negative symptoms with low EPS liability.
Partial agonism at 5-HT1A receptors may contribute to anxiolytic and antidepressant effects, while antagonism at 5-HT2B/5-HT2A and H1 receptors influences mood stabilization and adverse-event profile.
Norcariprazine and didesmethyl cariprazine share the parent’s receptor profile, extending receptor occupancy well beyond the dosing interval.
- D3 partial agonist (Ki 0.085 nM) with 10-fold selectivity vs D2 (Ki 0.49 nM).
- Partial agonist at 5-HT1A; antagonist at 5-HT2B/5-HT2A and H1.
- Minimal muscarinic binding (limited anticholinergic effects).
- Alpha-1 adrenergic antagonism accounts for orthostatic hypotension risk.
Metabolism & pharmacokinetics
Cariprazine exhibits linear pharmacokinetics across 1.5–6 mg/day. Oral bioavailability is ~52% with peak concentrations in 3–5 hours and extensive protein binding (>90%).
Total cariprazine exposure (parent + metabolites) is dominated by DDCAR at steady state; body weight and CYP3A4 activity influence trough levels. Steady-state concentrations accumulate ~2–3 fold compared with single-dose exposure.
Elimination occurs primarily via feces; renal excretion of unchanged drug is minimal. Smoking status has negligible impact because CYP1A2 is not involved.
- Time to peak concentration (Tmax)
- 3–5 hours
- Elimination half-life (parent)
- 2–4 days
- Elimination half-life (DDCAR)
- 1–3 weeks
- Steady state attainment
- ≈3 weeks (total active moieties)
Drug interactions
Contraindicated with strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin, St. John’s wort) due to drastic reductions in exposure.
Strong CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir) significantly increase concentrations; reduce the dose by 50% or interrupt therapy.
Moderate CYP3A4 inhibitors (fluconazole, erythromycin) warrant cautious titration and monitoring for extrapyramidal symptoms, akathisia, and somnolence.
Cariprazine is not expected to meaningfully inhibit major CYP isoenzymes but is a substrate of P-glycoprotein; caution with narrow therapeutic index P-gp substrates (e.g., digoxin).
Concomitant CNS depressants (benzodiazepines, opioids, alcohol) may enhance sedation; counsel patients accordingly.
| Mechanism | Agents / factors | Management |
|---|---|---|
| Strong CYP3A4 inhibition | Ketoconazole, itraconazole, clarithromycin, ritonavir | Reduce cariprazine dose by 50% or interrupt therapy; monitor closely. |
| Moderate CYP3A4 inhibition | Erythromycin, fluconazole, diltiazem | Consider dose reduction; monitor for akathisia and sedation. |
| CYP3A4 induction | Rifampin, carbamazepine, phenytoin, St. John’s wort | Contraindicated—risk of subtherapeutic exposure and relapse. |
| CNS depressant coadministration | Benzodiazepines, opioids, alcohol | Warn about additive sedation and psychomotor impairment. |
| P-gp substrate caution | Digoxin, dabigatran | Monitor levels/effects; adjust dosing if necessary. |
Monitoring & safety checks
Weight/BMI and waist circumference
Baseline, 3 months, then annually • Monitor metabolic effects (weight gain modest but present).
Fasting lipids & glucose/A1c
Baseline, 3 months, then annually • Detect dyslipidemia or insulin resistance.
Movement disorder assessment (EPS/akathisia)
Each visit during titration • Akathisia/restlessness are the most frequent dose-limiting adverse effects.
Mood and suicidality review
Every visit • Indicated for mood disorders; monitor for worsening depression or mania.
Pregnancy testing as indicated
Baseline/ongoing when appropriate • Limited human data; weigh maternal benefit and fetal risk.
Educate patients that symptomatic improvement may take several weeks due to long-lived metabolites.
Promptly address akathisia (dose adjustment, beta blocker, or benzodiazepine) to maintain adherence.
Discontinuation guidance
Whenever possible, taper cariprazine over 1–2 weeks to mitigate rebound symptoms. Active metabolites persist for weeks, so recurrence or withdrawal phenomena may be delayed; maintain follow-up for at least one month.
When switching to another antipsychotic, cross-titration can often proceed without a washout due to the gradual decline of total active cariprazine concentrations.
Special populations
Hepatic impairment: no adjustment for mild-to-moderate impairment; use caution in severe impairment (not studied).
Renal impairment: no adjustment for mild-to-moderate impairment (CrCl ≥30 mL/min); avoid use in severe impairment due to limited data.
Pregnancy/Lactation: limited human data; enroll in the National Pregnancy Registry for Atypical Antipsychotics and monitor neonates exposed in the third trimester for EPS or withdrawal.
Geriatrics: start 1.5 mg/day with slower titration; monitor orthostatic hypotension and sedation.
Key adverse effects
Common: akathisia, restlessness, insomnia, nausea, dizziness, somnolence, weight gain.
Metabolic changes (weight, lipids, glucose) are generally modest but monitoring is recommended.
Serious risks: tardive dyskinesia, neuroleptic malignant syndrome, orthostatic hypotension, seizures (rare), gastrointestinal hypomotility, impulse-control problems (rare).
References
- VRAYLAR (cariprazine) Prescribing Information — Allergan USA, Inc. (2024)
- Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017 — Pharmacopsychiatry (2018) DOI: 10.1007/s00213-017-4813-7
- Cariprazine for schizophrenia and bipolar disorder: a review — Neuropsychiatric Disease and Treatment (2019) DOI: 10.2147/NDT.S183565
- Long-term safety and tolerability of cariprazine in bipolar I disorder — Pharmacotherapy (2020) DOI: 10.1002/phar.2461
- Cariprazine in negative symptoms of schizophrenia: randomized trial — American Journal of Psychiatry (2015) DOI: 10.1176/appi.ajp.2015.15020164
Educational use only — verify details in current prescribing information and authoritative clinical guidelines before making prescribing decisions.