Introduction
Zyprexa (olanzapine) is an atypical antipsychotic medication primarily used in the management of psychiatric disorders. Developed by Eli Lilly and Company, it received FDA approval in 1996 and has since become a cornerstone in the treatment of schizophrenia and bipolar disorder. As a second-generation antipsychotic, Zyprexa offers a different side effect profile compared to first-generation agents, though it carries its own unique risks that require careful clinical management.
Mechanism of Action
Zyprexa exerts its therapeutic effects through potent antagonism of multiple neurotransmitter receptors. Its primary mechanism involves blocking dopamine D2 receptors in the mesolimbic pathway, which reduces positive symptoms of psychosis. Additionally, it acts as a serotonin 5-HT2A receptor antagonist, which may contribute to its efficacy in treating negative symptoms and reducing extrapyramidal side effects. Zyprexa also exhibits antagonistic activity at muscarinic M1-5, histamine H1, and adrenergic α1 receptors, which accounts for its various side effects including sedation, weight gain, and orthostatic hypotension.
Indications
FDA-approved indications:
- Treatment of schizophrenia in adults and adolescents (age 13-17)
- Acute monotherapy for manic or mixed episodes of bipolar I disorder in adults and adolescents (age 13-17)
- Maintenance treatment of bipolar I disorder
- Combination therapy with lithium or valproate for acute manic or mixed episodes
- Treatment-resistant depression (in combination with fluoxetine)
Off-label uses include:
- Behavioral symptoms of dementia (with caution due to black box warning)
- Treatment of Tourette's syndrome
- Prevention of chemotherapy-induced nausea and vomiting
Dosage and Administration
Standard dosing:- Schizophrenia: Initial dose 5-10 mg once daily, target dose 10-20 mg daily
- Bipolar mania: Initial dose 10-15 mg once daily, may adjust within 5-20 mg daily range
- Olanzapine-fluoxetine combination: Dosage based on individual components
- Oral tablets: Administer once daily without regard to meals
- Orally disintegrating tablets (Zydis): Place on tongue, dissolves rapidly
- Intramuscular formulation: For acute agitation in schizophrenia/bipolar mania (2.5-10 mg)
- Geriatric patients: Consider lower starting doses (2.5-5 mg daily)
- Hepatic impairment: Initial dose 5 mg daily
- Renal impairment: No dosage adjustment typically needed
- CYP450 poor metabolizers: Consider lower starting doses
Pharmacokinetics
Absorption: Well absorbed orally with peak concentrations in 5-8 hours. Bioavailability approximately 60% due to first-pass metabolism. Food does not significantly affect absorption. Distribution: Extensive tissue distribution with volume of distribution ~1000 L. Highly protein bound (93%) to albumin and α1-acid glycoprotein. Metabolism: Primarily hepatic via direct glucuronidation and cytochrome P450-mediated oxidation (primarily CYP1A2, with contributions from CYP2D6 and CYP3A4). Elimination: Terminal elimination half-life of 21-54 hours. Excreted primarily in urine (57%) with 30% eliminated in feces.Contraindications
- Known hypersensitivity to olanzapine or any component of the formulation
- Patients with narrow-angle glaucoma
- Concomitant use with other drugs that significantly prolong QT interval
- History of severe neutropenia or agranulocytosis with previous antipsychotic use
Warnings and Precautions
Black Box Warnings:- Increased mortality in elderly patients with dementia-related psychosis
- Increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults
- Metabolic effects: Weight gain, hyperglycemia, dyslipidemia
- Neuroleptic malignant syndrome
- Tardive dyskinesia
- Orthostatic hypotension and syncope
- Seizures
- Cognitive and motor impairment
- Dysphagia and aspiration risk
- Hyperprolactinemia
- Hepatic impairment monitoring required
Drug Interactions
Clinically significant interactions:- CYP1A2 inhibitors (fluvoxamine, ciprofloxacin): Increase olanzapine concentrations
- CYP1A2 inducers (carbamazepine, smoking): Decrease olanzapine concentrations
- Antihypertensive agents: Enhanced hypotensive effects
- CNS depressants (benzodiazepines, opioids, alcohol): Additive sedation
- Levodopa and dopamine agonists: Decreased efficacy
- Drugs that prolong QT interval: Increased risk of arrhythmias
- Anticholinergic drugs: Enhanced anticholinergic effects
Adverse Effects
Common (≥10%):- Somnolence (26%)
- Weight gain (12-40%)
- Dry mouth (22%)
- Dizziness (11-18%)
- Constipation (9-11%)
- Increased appetite (6-12%)
- Neuroleptic malignant syndrome
- Tardive dyskinesia
- Diabetes mellitus and hyperglycemia
- Orthostatic hypotension
- Seizures
- Neutropenia/agranulocytosis
- Pancreatitis
- QT prolongation
- Weight gain: Average 2.5-5.9 kg in short-term studies
- Hyperglycemia: May occur even without weight gain
- Dyslipidemia: Increased triglycerides and LDL cholesterol
Monitoring Parameters
Baseline:- Complete medical and psychiatric history
- Weight, height, BMI
- Fasting blood glucose and HbA1c
- Lipid profile
- Liver function tests
- Complete blood count with differential
- Blood pressure (sitting and standing)
- ECG if cardiac risk factors present
- Assessment for movement disorders
- Weight and BMI: Monthly for first 3 months, then quarterly
- Fasting glucose: At 3 months, then annually
- Lipid profile: At 3 months, then annually
- Blood pressure: Regularly
- CBC: Periodically, especially with fever or infection signs
- Treatment response and side effects assessment
- TD assessment every 6-12 months
Patient Education
Key points to discuss:- Take medication exactly as prescribed; do not stop abruptly
- Potential for sedation: Avoid driving or operating machinery until effects known
- Rise slowly from sitting/lying position to prevent dizziness
- Report any unusual movements, muscle stiffness, or fever immediately
- Monitor for symptoms of high blood sugar (increased thirst, urination, hunger)
- Regular weight monitoring and healthy lifestyle recommendations
- Avoid alcohol and other CNS depressants
- Inform all healthcare providers about Zyprexa use
- Use effective contraception; discuss pregnancy plans with provider
- Do not breastfeed while taking this medication
- Keep all follow-up appointments for monitoring
References
1. FDA Prescribing Information: Zyprexa (olanzapine). Revised 2022. 2. Stahl SM. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4th ed. Cambridge University Press; 2013. 3. Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161(2 Suppl):1-56. 4. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Bipolar Disorder. 2nd ed. 2010. 5. Citrome L. Olanzapine: a review of its clinical utility in the management of schizophrenia. Expert Opin Pharmacother. 2004;5(12):2555-2565. 6. Bymaster FP, Calligaro DO, Falcone JF, et al. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology. 1996;14(2):87-96. 7. Meyer JM. Metabolic effects of antipsychotic therapy. Int Clin Psychopharmacol. 2018;33(1):1-15. 8. Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry. 1994;151(6):825-835.
This monograph is for educational purposes only and does not replace professional medical advice. Always consult with a qualified healthcare provider for medical guidance.