Olanzapine - Drug Monograph

Introduction

Olanzapine is an atypical (second-generation) antipsychotic medication primarily used in the treatment of schizophrenia and bipolar disorder. First approved by the FDA in 1996, it has become a widely prescribed psychotropic agent due to its efficacy across multiple psychiatric conditions. Olanzapine belongs to the thienobenzodiazepine class and demonstrates a unique receptor binding profile that distinguishes it from first-generation antipsychotics.

Mechanism of Action

Olanzapine exerts its therapeutic effects through antagonism at multiple neurotransmitter receptors. Its primary mechanism involves:

• High affinity for dopamine D2 receptors in the mesolimbic pathway (reducing positive symptoms of psychosis)
• Serotonin 5-HT2A receptor antagonism (contributing to antidepressant effects and reduced extrapyramidal symptoms)
• Additional activity at muscarinic M1-5, histamine H1, and adrenergic α1 receptors

This multimodal receptor profile results in effective antipsychotic action with potentially fewer motor side effects compared to typical antipsychotics, though it carries increased metabolic risk.

Indications

• Treatment of schizophrenia
• Acute and maintenance treatment of bipolar I disorder (monotherapy and adjunct to lithium or valproate)
• Acute agitation associated with schizophrenia and bipolar I mania (IM formulation)

• Treatment-resistant depression (as adjunct therapy)
• Behavioral symptoms in dementia (with caution)
• Prevention of chemotherapy-induced nausea and vomiting

Dosage and Administration

• Initial dose: 5-10 mg once daily
• Target dose: 10-20 mg daily (maximum 20 mg/day)
• May be taken with or without food

• 2.5-10 mg dose, may repeat every 2-4 hours (maximum 30 mg/day)

• Geriatric patients: Initial dose 2.5-5 mg daily
• Hepatic impairment: Consider lower starting dose (2.5-5 mg)
• Renal impairment: No initial dose adjustment required
• Smokers: No significant dosage adjustments needed

Pharmacokinetics

Contraindications

• Known hypersensitivity to olanzapine or any component of the formulation
• Patients with narrow-angle glaucoma
• Concurrent use with other drugs that significantly prolong QT interval
• Severe hepatic impairment (limited data)

Warnings and Precautions

• Increased mortality in elderly patients with dementia-related psychosis
• Not approved for dementia-related psychosis

• Metabolic effects: Weight gain, hyperglycemia, dyslipidemia
• Neuroleptic malignant syndrome (rare but serious)
• Tardive dyskinesia (risk increases with duration and cumulative dose)
• Orthostatic hypotension (especially during initial dose titration)
• Seizures (use with caution in patients with seizure history)
• Hyperprolactinemia (monitor for clinical symptoms)
• Falls (particularly in elderly patients)

Drug Interactions

• CYP1A2 inhibitors (fluvoxamine, ciprofloxacin): Increase olanzapine levels
• CYP1A2 inducers (carbamazepine, smoking): Decrease olanzapine levels
• Antihypertensive agents: Enhanced hypotensive effects
• CNS depressants (benzodiazepines, opioids): Additive sedation
• Drugs that prolong QT interval: Increased risk of cardiac arrhythmias
• Levodopa and dopamine agonists: Reduced efficacy

Adverse Effects

• Somnolence (26%)
• Weight gain (12-40%)
• Dizziness (11-18%)
• Constipation (9-11%)
• Dry mouth (9-22%)

• Diabetes mellitus and hyperglycemia
• Neuroleptic malignant syndrome
• Tardive dyskinesia
• Seizures
• Pancreatitis
• Neutropenia/agranulocytosis
• QT prolongation

Monitoring Parameters

• Weight, height, BMI
• Fasting blood glucose and HbA1c
• Lipid profile
• Blood pressure and heart rate
• CBC with differential
• Liver function tests
• Assessment for movement disorders

• Weight and BMI at 4, 8, and 12 weeks, then quarterly
• Fasting glucose at 12 weeks, then annually
• Lipid profile at 12 weeks, then annually
• Regular assessment for extrapyramidal symptoms
• Blood pressure monitoring, especially during dose titration
• Clinical evaluation for therapeutic response and side effects

Patient Education

• Take medication as prescribed, typically once daily at bedtime
• Report significant weight gain or changes in appetite
• Monitor for signs of hyperglycemia (increased thirst, urination, hunger)
• Avoid alcohol and other CNS depressants
• Rise slowly from sitting/lying position to prevent dizziness
• Do not stop medication abruptly without medical supervision
• Use effective contraception; notify provider if planning pregnancy
• Regular follow-up appointments are essential for monitoring
• Report any muscle stiffness, fever, or involuntary movements immediately

• May impair alertness; use caution when driving or operating machinery
• Maintain healthy diet and regular exercise to mitigate metabolic effects
• Keep all appointments for laboratory monitoring

References

1. FDA Prescribing Information: Zyprexa (olanzapine). Revised 2021. 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 recent literature. Expert Opin Pharmacother. 2019;20(13):1619-1639. 6. Meyer JM. Pharmacotherapy of psychosis and mania. In: Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 13th ed. McGraw-Hill; 2017. 7. Clinical Pharmacokinetics of Atypical Antipsychotics: An Update. Clin Pharmacokinet. 2018;57(12):1493-1528.