Olanzapine
Olanzapine
Generic Name
Olanzapine
Mechanism
Olanzapine exerts its antipsychotic activity through:
• High‑affinity antagonism at dopamine D₂ (≈30 nM) and serotonin 5‑HT₂A (≈0.45 nM) receptors → ↓ positive psychotic symptoms.
• Weak antagonism at D₁, D₃, and α₁-adrenergic receptors – contributes to efficacy with lower extrapyramidal side‑effects.
• Partial agonism at 5‑HT₁A → antidepressant & anxiolytic properties.
• Antagonism at muscarinic M₁, M₃, and histamine H₁ → sedation, weight gain, anticholinergic effects.
The combined blockade of dopamine and serotonin pathways underlies its efficacy in psychosis, mania, and depressive episodes.
Pharmacokinetics
- Absorption: Oral bioavailability ~70 % (food reduces Cmax by ~36 % but no dose adjustment needed).
- Distribution: Highly protein‑bound (≈96 %); volume of distribution ≈1.2 L/kg.
- Metabolism: Hepatic via CYP1A2, CYP2D6, CYP3A4; minimal renal clearance.
- Half‑life: 22–30 h (free form); 48–56 h (total).
- Steady state: ≈3–4 days.
- Contraindicated with potent CYP1A2 inhibitors (e.g., fluvoxamine) increasing plasma levels >2×.
Indications
- Schizophrenia: acute and maintenance therapy.
- Bipolar I disorder: manic or mixed episodes; maintenance mood‑stabilization.
- Adjunctive treatment of major depressive disorder when atypical antipsychotic benefit is desired (per FDA label).
- Short‑term adjunctive use in severe agitation or acute psychosis.
Contraindications
- Contraindications: hypersensitivity to olanzapine or any component.
- Warnings:
- Cardiovascular: QTc prolongation, orthostatic hypotension; caution in patients with arrhythmias or on QT‑prolonging agents.
- Metabolic: hyperglycemia, dyslipidemia, weight gain; baseline and periodic monitoring needed.
- Neuroleptic malignant syndrome (NMS) – rare but treat promptly.
- Seizure threshold lowered – contraindicated in seizure disorders unless risk‑benefit justified.
Dosing
| Formulation | Initial / Titration | Maintenance | Max Daily | Special Populations |
| Oral tablets | 5 mg bid → 10 mg bid (≥7 days) | 10–20 mg /d, titrate to response | 20 mg /d (max) | ↑ dose in pregnancy class N; avoid in lactation |
| Oral dissolvable film | 5 mg → 10 mg (4–7 days) | 10–20 mg /d | 20 mg /d | Use cautiously in hepatic impairment |
| Oral solution | 5 mg/mL → 10 mg/mL | 10–20 mg /d | 20 mg /d | Preferred in swallowing difficulties |
| Injectable (IV/IM) | 2 mg → 10 mg, weekly | 10–20 mg /d via continuous IV | 20 mg /d | Requires monitoring of metabolic profile |
• Administration: May be taken with or without food.
• Missed dose: Take as soon as remembered; skip if <12 h to next dose.
Adverse Effects
Common (≥10 %)
• Sedation, orthostatic hypotension, dry mouth
• Weight gain (mean 5 kg + 2 kg/yr), BMI ↑
• Constipation, sexual dysfunction
Serious (≤1 %)
• Neuroleptic malignant syndrome (fever, rigidity, autonomic instability)
• Tardive dyskinesia (late onset)
• Severe hypoglycemia or new-onset diabetes
• QTc prolongation (>500 ms)
• Severe hepatic impairment (rare)
Monitoring
- Metabolic: fasting glucose, HbA1c, fasting lipids at baseline, 3 months, then annually.
- Weight: baseline, 2, 4, 6, 12 weeks; subsequently every 3 months.
- Cardiac: baseline ECG; repeat if QTc > 450 ms or if arrhythmia suspected.
- Neuropsychiatric: mood, psychosis scales (e.g., PANSS) every 4–6 weeks.
- Laboratory: CBC, CMP at baseline and as clinically indicated.
Clinical Pearls
- Metabolic risk is dose‑dependent: aim for the lowest effective dose; consider adjunctive metformin if weight >10% of baseline.
- CYP1A2 inhibition (e.g., fluvoxamine) can double oral levels – pause olanzapine or monitor plasma concentration.
- Rapid‑onset agitation: IV formulation may be useful, but rapid monitoring for hypotension is essential.
- Adjunctive antidepressant: combining olanzapine with fluoxetine can increase plasma levels of both drugs; dose adjustments should follow therapeutic drug monitoring.
- Bipolar maintenance: low‑dose olanzapine (5 mg/d) can be effective for mood stabilisation, minimizing metabolic side‑effects.
- Pregnancy considerations: Available data suggest teratogenic potential; use only if benefits outweigh risks, with counseling on contraceptive use.
- Tardive dyskinesia surveillance: Check for involuntary movements at every visit; consider switching to a lower risk agent if progression.
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• *Prepared by: Precise Pharmacology Assistant*