Aripiprazole
Aripiprazole
Generic Name
Aripiprazole
Mechanism
- Partial dopamine agonism at D₂/D₃: acts as a functional antagonist in hyperdopaminergic states (schizophrenia, mania) and as an agonist in hypodopaminergic conditions (major depressive disorder, certain negative symptoms).
- Serotonin modulation:
- 5‑HT₁A partial agonist → ameliorates anxiety and negative symptoms.
- 5‑HT₂A antagonist → improves negative symptoms and reduces extrapyramidal side‑effects.
- Neurotransmitter balance: stabilizes dopaminergic tone without inducing dopamine withdrawal.
Pharmacokinetics
| Parameter | Detail |
| Absorption | Oral bioavailability 87 % (fasted) – >80 % (fed); peak ~2–3 h. |
| Metabolism | Hepatic; CYP3A4 (main) and CYP2D6 (minor). Dehydro‑aripiprazole (active) accounts for ~30 % of plasma levels. |
| Half‑Life | 75 h (active metabolite). Allows once‑daily dosing. |
| Distribution | Volume of distribution 2.1 L/kg; 83 % protein bound. Highly lipophilic, crosses the blood–brain barrier. |
| Elimination | Primarily renal (60 %) and fecal (30 %). No dose adjustment needed for mild–moderate hepatic impairment; caution in severe hepatic disease. |
Indications
- Schizophrenia (adult, adolescent ≥13 yr, and pediatric ≥10 yr)
- Bipolar I disorder – acute manic or mixed phase
- Adjunctive therapy for major depressive episode (with SSRI or SNRI)
- Irritability associated with autistic disorder (Pediatrics)
Contraindications
- Known hypersensitivity to aripiprazole, galenic excipients, or other antipsychotics.
- Severe hepatic impairment (Child‑Pugh C).
- QTc prolongation risk: caution with other QT‑prolonging drugs.
- Severe hyponatremia (unlikely but monitor).
- Risk of akathisia: use lower starting doses in geriatric and motor‑impairment patients.
Warnings:
• May precipitate manic switch in depressed patients.
• Possible orthostatic hypotension; watch for post‑prandial hypotension.
• Metabolic effects: weight gain, dyslipidemia, hyperglycemia (though lower than other atypicals).
Dosing
| Formulation | Initial Dose | Titration | Maintenance | Max |
| Oral (tablet, oral solution) | 2–3 mg/d (1 mg TID for children) | Increase 1–2 mg/d after 3–7 days | 10–20 mg/d (≤30 mg/d for elderly) | 30 mg/d |
| Intramuscular (long‑acting) | Aripiprazole lauroxil 300 mg q4 weeks (start with 2nd injection in 8 weeks) | 300–600 mg q4 weeks | 300–600 mg q4 weeks | 600 mg q2 weeks if needed |
| Depot injection (Aripiprazole lauroxil) | 300 mg every 3 weeks (then 600 mg q3 weeks) | – | – | – |
• Administer with food if GI upset.
• Children: start 1 mg TID, titrate 1 mg weekly.
• Elderly: start 2 mg/d, titrate 0.5–1 mg/d.
Adverse Effects
- Akathisia – most frequent agitation/inner restlessness; treat with beta‑blockers or benzodiazepines.
- Somnolence, dizziness – especially first days.
- Weight gain – modest; monitor BMI.
- Metabolic changes – ↑ triglycerides, LDL, fasting glucose.
- Orthostatic hypotension – avoid in hypotensive patients.
- QTc prolongation – rare; baseline ECG in high‑risk patients.
- Extrapyramidal – less than other atypicals; still possible dystonia.
- Severe allergic reactions – rash, angioedema.
- Neuroleptic malignant syndrome – watch for fever, rigidity.
Monitoring
- Baseline & periodic
- ECG (if QT risk or polypharmacy).
- Weight/BMI, fasting glucose, lipid panel (every 3–6 mo).
- Liver function tests (every 3–6 mo).
- Clinical assessment for akathisia / catatonia.
- During initiation – watch for acute mania, suicidality, and early extrapyramidal symptoms.
- Pregnancy & lactation – use only if benefits outweigh risk; not recommended in pregnancy category N.
Clinical Pearls
1. Partial agonist advantage – aripiprazole can reduce the dopamine withdrawal effect that causes tardive dyskinesia; use it in patients with prior antipsychotic‑induced EPS.
2. Depot usefulness – LAI aripiprazole lauroxil is ideal for nonadherent patients; start loading dose with oral aripiprazole 10 mg/d for 2 weeks to avoid withdrawal.
3. Metabolic profile – although safer than olanzapine or clozapine, monitor lipids; high‑dose (≥20 mg/d) increases risk of dyslipidemia.
4. Drug interactions – potent CYP3A4 inhibitors (ketoconazole, ritonavir) ↑ aripiprazole; adjust dose downward. CYP3A4 inducers (rifampin, carbamazepine) ↓ levels; consider higher dose.
5. Pediatric dosing – children under 12 should receive a maximum of 10 mg/d; avoid exceeding 12 mg/d due to side‑effect escalation.
6. Aripiprazole and sedation – less sedating in elderly; still monitor for excessive sleepiness, especially when combined with benzodiazepines.
7. Withdrawal caution – abrupt discontinuation may lead to rebound psychosis; taper over 2–4 weeks and monitor for depressive switch.
*Aripiprazole* remains a cornerstone antipsychotic, combining unique pharmacodynamics with a relatively favorable side‑effect profile when appropriately monitored.