Zyprexa
Olanzapine
Generic Name
Olanzapine
Brand Names
*Zyprexa*) is a second‑generation (atypical) antipsychotic widely prescribed for schizophrenia, bipolar disorder, and adjunctive use in major depressive disorder.
Mechanism
- High‑affinity antagonism at dopamine D₂ and 5‑HT₂A/₂C receptors → ↓ psychotic symptoms & mood destabilization.
- Modest blockade of α₁‑adrenergic and H1‑histaminergic receptors → sedative effect, orthostatic hypotension.
- Partial agonist at 5‑HT₁A → mood stabilizing and anxiolytic properties.
> *Key point*: The combined D₂/5‑HT₂A blockade gives antipsychotic efficacy with a *lower* risk of extrapyramidal symptoms compared to typical agents, but results in significant metabolic side effects.
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Pharmacokinetics
| Parameter | Olanzapine |
| Absorption | Oral bioavailability ~35‑40 % (first‑pass). Rapid absorption; peak ∼1–3 h. |
| Distribution | ~90 % protein‑bound (primarily to α₁‑acid glycoprotein). Large volume of distribution (~7–10 L/kg). |
| Metabolism | Hepatic via CYP1A2 and CYP2D6 (major: *N‑demethylation*, *hydroxylation*). Genetic polymorphisms of CYP1A2 can alter exposure. |
| Elimination | Renal (≈30 %) and fecal. Half‑life: 21 h (IV) ~30–40 h (oral). Clearance is dose‑linear up to ~20 mg/day. |
| Drug–Drug Interactions | Inhibitors of CYP1A2 (e.g., fluvoxamine) ↑ olanzapine; inducers (e.g., smoking, rifampin) ↓ levels. Caution with CYP2D6 inhibitors. |
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Indications
- Schizophrenia – monotherapy or relapse prevention.
- Bipolar I or II Disorder – acute mania or depression, maintenance therapy.
- Adjunctive treatment of major depressive disorder (with mood stabilizer or SSRI).
Off‑label: comorbid anxiety disorders; treatment‑resistant ADHD (rare).
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Contraindications
| Category | Key Points |
| Contraindications |
• Hypersensitivity to olanzapine or any component. • QT prolongation (ICD‑9/10), uncontrolled arrhythmias. • Unstable medical conditions: heart failure, severe hepatic or renal impairment. |
| Warnings |
• Metabolic syndrome: weight gain, dyslipidemia, new‑onset or worsening diabetes. • Sedation & orthostatic hypotension: risk of falls, especially in elderly. • Neuroleptic malignant syndrome (NMS): rare but fatal. • Agranulocytosis: extremely rare but reported; monitor CBC if prolonged use. |
| Precautions |
• Use lowest effective dose; avoid rapid dose escalation. • Elderly: higher sensitivity to sedation, hypotension, and extrapyramidal symptoms. • Post‑operative & peri‑operative use: increased risk of hypoglycemia (esp. in insulin‑treated patients). |
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Dosing
| Population | Starting Dose | Titration | Maintenance Dose | Notes |
| Adult Schizophrenia | 5 mg PO QHS (or 2.5 mg PO QHS for sensitive pts) | Increase by 5 mg every 3–5 days | 10–20 mg/day (extended‑release) | Oral tablet or once‑daily oral solution. |
| Adult Bipolar I/II | 10 mg PO QHS (or 5 mg if sensitive) | Titrate up to 15–20 mg/day | 10–20 mg/day | Same notes as above. |
| Pediatric (≥12 yrs) | 2.5 mg PO QHS | 2.5 mg increments | 5–10 mg/day | Monitor weight, vitals. |
| Geriatric | 2.5 mg PO QHS | Slow titration | 5–10 mg/day | Watch falls, orthostatic BP. |
| Extended‑Release | 5–10 mg PO QHS | Titrated by 5 mg every 3‑4 days | 10–20 mg/day | Once-daily dosing improves compliance. |
| IV | 1–2 mg IV over 30 min | 2–4 mg IV infusion (up to 15 mg/day) | 4–10 mg IV/24 h | Convert to oral when stable. |
• Administration: Take with or without food; *avoid* meals high in fat because it can delay absorption.
• Missed dose: Skip if >2 h missed; do not double the next dose.
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Adverse Effects
| Adverse Effect | Frequency | Clinical Relevance | |
| Metabolic: weight gain (mean 4–6 kg), dyslipidemia, hyperglycemia, insulin resistance | Common | → Higher risk of new‑onset diabetes, cardiovascular disease | |
| Sedation & dizziness | Common (up to 40 %) | Fall risk, especially in elderly | |
| Anticholinergic: dry mouth, constipation, blurred vision | Common | OTC relief if necessary | |
| Orthostatic hypotension | Common | Monitor BP; modify concomitant antihypertensives | |
| Prolactin elevation | Moderate | Gynecomastia, galactorrhea, menstrual disturbances | |
| Extrapyramidal symptoms (EPS) | Less common (≈10 %) | Dystonia, akathisia | Use anticholinergic (benztropine) if severe |
| QT prolongation | Rare (mild) | Titrate carefully; baseline ECG if high risk | |
| Weight‑related: increased appetite | Common | Implement dietary counseling | |
| Neuroleptic malignant syndrome (NMS) | Rare (<1 %) | Fever, rigidity, autonomic instability – emergency | |
| Agranulocytosis | Extremely rare | Monitor CBC if needed |
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Monitoring
| Parameter | Frequency | Rationale |
| Weight/BMI | At baseline; every 4–6 weeks first 6 mo; then every 3 mo | Detect rapid weight gain |
| Fasting glucose/hemoglobin A1c | Baseline; 3 mo; then every 6 mo | New‑onset diabetes surveillance |
| Lipid profile | Baseline; 6 mo; then annually | Dyslipidemia risk |
| Blood pressure & orthostatic readings | Baseline; monthly first 3 mo; then every 3 mo | Hypotension monitoring |
| Prolactin | Baseline; 6 mo if symptomatic | Hyperprolactinemia |
| ECG | Baseline if QT risk; otherwise if symptomatic | QT prolongation check |
| Complete Blood Count (CBC) | Baseline; monthly for first 8 wks; then every 6 mo | Agranulocytosis vigilance |
| Liver function tests | Baseline; annually (unless hepatic disease) | Metabolism via CYP1A2/CYP2D6 |
| Cognitive/psychiatric assessment | At baseline; monthly first 2 mo; then quarterly | Monitor efficacy & side effects |
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Clinical Pearls
- Weight Gain is the Achilles’ Heel: Initiate lifestyle counseling at first visit; consider adding metformin or a GLP‑1 agonist if metabolic derangements appear.
- “Once‑Daily” is a Selling Point: The extended‑release formulation improves adherence and reduces day‑to‑day blood‑level variability.
- Elderly Dosing: Start 2.5 mg and titrate slowly; avoid doses >10 mg/day unless necessary.
- Smoking Interaction: Smokers have ↑ olanzapine levels (CYP1A2 induction); consider dose reduction or monitor tolerability.
- Cross‑Taper Safely: When transitioning from haloperidol, use a gradual cross‑taper over 3–5 days to reduce EPS risk.
- Not a First‑Line for Mania in Adolescents: Opt for lithium or valproate first for mood‑stabilizing effect.
- Use with Caution in Diabetics: Olanzapine’s impact on insulin sensitivity can worsen glucose control; baseline HbA1c ≤6.5 % recommended before starting.
- Do Not Rescue With L-Dopa: EPS induced by olanzapine respond better to anticholinergic therapy; avoid dopaminergic agents which may worsen metabolic profile.
- Ask About Over-the‑Counter Supplements: St. John’s wort or high‑dose niacin can compete for CYP1A2/CYP2D6 and modify levels.
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• Bottom Line: Olanzapine is a potent, second‑generation antipsychotic with high therapeutic efficacy for schizophrenia and bipolar disorder but demands vigilant metabolic monitoring and dose tailoring, especially in geriatric and diabetic patients.