Generic Name

Vraylar (cariprazine)

Mechanism

• Partial agonist at dopamine D2 and D3 receptors (highest affinity for D3), modulating postsynaptic dopamine signaling with a lower propensity for extrapyramidal side‑effects.
• Partial agonist at serotonin 5‑HT1A receptors – contributes to anxiolytic and antidepressant properties.
• Antagonist at serotonin 5‑HT2A receptors, supporting antipsychotic efficacy without significant autonomic side‑effects.

The combined dopamine/serotonin activity underlies Vraylar’s efficacy in psychosis and mood destabilization while favoring a benign metabolic profile.

Pharmacokinetics

• Absorption: ~100 % oral bioavailability. Peak plasma concentrations in 1–2 h.
• Metabolism: Primarily via CYP3A4 and CYP2D6; active metabolites (DCAR) have longer half‑lives.
• Half‑life: ~3 days for the D3-selective active metabolite; 1.4 days for parent drug.
• Distribution: ~73 % plasma protein binding; extensive brain penetration.
• Elimination: Hepatic; 20–25 % renal excretion of unchanged drug.
• Food effect: No clinically meaningful influence; can be taken with or without food.

Indications

• Schizophrenia (adult and pediatric ≥12 yrs) – adjunct therapy or monotherapy.
• Bipolar I disorder – maintenance therapy for manic or mixed episodes (pediatric ≥12 yrs).

Contraindications

• Allergy to cariprazine, any component, or other antipsychotic.
• Severe hepatic impairment (Child–Pugh C).
• QT‑prolongation syndromes: use caution; baseline ECG recommended if QT risk factors present.
• Seizure disorder: not recommended unless closely monitored.

Warnings:
• Extrapyramidal symptoms (EPS) and akathisia may occur, particularly during titration.
• Metabolic effects (weight gain, hyperglycemia, dyslipidemia) – lower risk versus other antipsychotics but still present.
• Neuroleptic malignant syndrome (NMS) – rare; watch for fever, rigidity.

Dosing

• Administer orally with/without food.
• Long‑acting formulation not available.
• Adjust dose cautiously in hepatic impairment or if concomitant CYP3A4 inhibitors/inducers are used.

Adverse Effects

Common (≥10 %):
• Akathisia, restlessness
• Nausea, vomiting
• Sedation (typically mild)
• Weight gain (≈ 4–5 kg over 6 mo)
• Metabolic changes: ↑ fasting glucose, ↑ LDL, ↓ HDL

Serious (≤1 %):
• Neuroleptic malignant syndrome
• Seizure activity
• Severe EPS → tardive dyskinesia
• QT‑interval prolongation (rare)
• Hepatotoxicity (rare)

Monitoring

• Baseline: PANSS / YMRS, BMI, fasting glucose, lipids, liver function tests (ALT, AST, bilirubin), ECG (QTc).
• Follow‑up:
• Weight/BMI q3 mo; metabolic panel q6 mo after 4 weeks.
• Clinical assessment of EPS (AIMS, BARS) q4 w on titration.
• Psychiatric response (PANSS, YMRS) at 4 w, 8 w, then every 3 mo.
• Liver enzymes every 3 mo for first 6 mo or as clinically indicated.

Clinical Pearls

1. Delayed dose adjustments – Due to the ~3‑day half‑life of active metabolites, titration changes take several days to manifest. Avoid rapid up/downtitration to prevent withdrawal EPS or over‑exposure.
2. Negative‐symptom advantage – The high D3 affinity is linked to improved negative and cognitive symptoms in schizophrenia. Useful when those domains are prominent.
3. Metabolic edge – While weight gain can still occur, Vraylar is associated with lower rates of hyperglycemia and dyslipidemia compared with other atypical agents (e.g., olanzapine). Nonetheless, routine metabolic monitoring remains essential.
4. Drug interactions – Concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) can increase plasma cariprazine → caution; consider dose reduction. Inducers (e.g., rifampin, carbamazepine) may decrease efficacy.
5. Akathisia management – Non‑pharmacologic: pacing, music, brief exercise. Pharmacologic: low‑dose benzodiazepines or beta‑blockers; clonazepam is commonly used.
6. Hepatic impairment – In mild to moderate hepatic dysfunction (Child–Pugh A/B), start dose at 0.75 mg QD with cautious uptitration. For severe hepatic disease, Vraylar is contraindicated.

Bottom line: Vraylar offers a valuable antipsychotic profile for patients with schizophrenia and bipolar I who require a drug with favorable EPS and metabolic tolerability. Understanding its unique pharmacokinetics and dosing cadence is key to maximizing benefit while minimizing adverse events.