Olanzapine

Generic Name: Olanzapine
Brand Names: Zyprexa (global), Zyprexa Zydis (orally disintegrating tablet), Symbyax (combined with fluoxetine), Zalasta, Olzapin

Drug Class: Second-Generation Antipsychotic (Atypical Antipsychotic)

Formulations Available:
– Oral tablet: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg
– Orally disintegrating tablet (Zydis): 5 mg, 10 mg, 15 mg, 20 mg
– Intramuscular injection (short-acting and long-acting depot)
Route of Administration: Oral, intramuscular

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Indications and Clinical Applications

Olanzapine is an atypical antipsychotic with broad psychiatric applications, primarily used in schizophrenia and bipolar disorder.

Approved Therapeutic Uses:

1. Schizophrenia
   – For acute treatment of schizophrenia in adults and adolescents
   – For maintenance treatment to prevent relapse

2. Bipolar Disorder (Type I)
   – Acute manic or mixed episodes (monotherapy or with lithium/valproate)
   – Maintenance therapy (alone or adjunctive)
   – Bipolar depression (as Symbyax, in combination with fluoxetine)

3. Treatment-Resistant Depression
   – In combination with SSRIs (e.g., fluoxetine)

4. Agitation associated with schizophrenia or bipolar mania
   – Short-acting IM injection used acutely in hospital or emergency settings

Off-label Uses:
– Dementia-related behavioral disturbances (caution: black box warning)
– Borderline personality disorder
– Post-traumatic stress disorder (PTSD)
– Chemotherapy-induced nausea and vomiting (CINV, with dexamethasone and 5HT3 antagonists)
– Anorexia nervosa (to promote weight gain and reduce obsessionality)

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Mechanism of Action

Olanzapine acts by antagonizing multiple neurotransmitter receptors in the brain, producing antipsychotic, mood-stabilizing, and sedative effects:

• Dopamine D2 receptor antagonism – improves positive symptoms (e.g., delusions, hallucinations)

• Serotonin 5-HT2A receptor antagonism – reduces extrapyramidal symptoms and improves negative symptoms

• Additional binding to:
  – 5-HT2C, 5-HT3
  – Alpha-1 adrenergic
  – Muscarinic M1–M5
  – Histamine H1 receptors

Pharmacodynamic Effects:

• Reduces psychotic symptoms and manic excitability

• Sedative due to antihistaminic and anticholinergic activity

• High affinity for serotonin and dopamine receptors contributes to balanced efficacy and lower risk of movement disorders compared to typical antipsychotics

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Pharmacokinetics

• Absorption: Well absorbed orally (bioavailability ~60%), not affected by food

• Time to peak (oral): ~5–8 hours

• Protein binding: ~93%

• Metabolism: Hepatic via CYP1A2, CYP2D6, and glucuronidation

• Half-life:
  – Adults: ~30 hours
  – Elderly: ~50 hours

• Excretion: Urine (60%) and feces (30%) as metabolites

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Dosage and Administration

1. Schizophrenia (Adults):
– Initial dose: 5–10 mg once daily
– Maintenance dose: 10–20 mg daily
– Maximum recommended dose: 20 mg/day

2. Bipolar Mania:
– Starting dose: 10–15 mg once daily (monotherapy or with mood stabilizers)
– Adjust in increments of 5 mg at intervals of 24 hours or more

3. Bipolar Maintenance:
– Continued at effective acute dose, typically 5–20 mg daily

4. Bipolar Depression (Symbyax):
– Initial dose (olanzapine/fluoxetine): 6/25 mg once daily
– Adjust based on response

5. Acute Agitation (IM injection):
– 5–10 mg as a single IM injection; max 3 injections per 24 hours
– Not interchangeable with oral dose due to differing kinetics

Special Populations:

• Elderly/frail patients: Start at 2.5–5 mg/day

• Hepatic impairment: Use with caution

• Children/adolescents (13–17 years): Start with 2.5–5 mg/day; titrate cautiously

• Smokers: May require higher dose (CYP1A2 induction)

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Contraindications

• Hypersensitivity to olanzapine or any excipients

• Dementia-related psychosis in elderly – increased risk of death (Boxed Warning)

• Patients with known narrow-angle glaucoma (relative contraindication due to anticholinergic effect)

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Warnings and Precautions

1. Metabolic Changes (Boxed Warning – US FDA)
   – Weight gain, hyperglycemia, and dyslipidemia are frequent and may be severe
   – Risk of new-onset type 2 diabetes

2. Tardive Dyskinesia
   – Involuntary, repetitive movements; may be irreversible
   – More likely with long-term use

3. Neuroleptic Malignant Syndrome (NMS)
   – Rare, life-threatening; presents with hyperthermia, rigidity, altered mental status, elevated CPK

4. Orthostatic Hypotension
   – Common in early treatment or with IM use

5. Sedation and Somnolence
   – Often dose-related; caution in operating machinery

6. Anticholinergic Effects
   – Dry mouth, urinary retention, constipation, blurred vision

7. Seizure Risk
   – Increased in predisposed patients

8. Hepatic Impairment
   – Elevated liver enzymes reported; monitor function periodically

9. Hyperprolactinemia
   – Risk of galactorrhea, amenorrhea, gynecomastia

10. Leukopenia, Neutropenia
    – Monitor CBC in patients with prior blood dyscrasias

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Adverse Effects

Very Common (≥10%):

• Weight gain (often significant)

• Drowsiness/sedation

• Increased appetite

• Orthostatic hypotension

• Constipation

• Dizziness

• Elevated prolactin levels

• Elevated triglycerides and cholesterol

• Hyperglycemia

Common (1–10%):

• Dry mouth

• Akathisia (inner restlessness)

• Extrapyramidal symptoms (less than haloperidol or risperidone)

• Increased liver enzymes

• Insomnia

• Weakness

• Blurred vision

• Edema

Serious/Rare:

• Neuroleptic malignant syndrome

• Seizures

• Tardive dyskinesia

• Hyperosmolar hyperglycemic state

• Severe weight gain (>20% of baseline body weight)

• Suicidal ideation (especially in adolescents or during early treatment)

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Drug Interactions

1. CNS Depressants (benzodiazepines, opioids, alcohol):
   – Additive sedation, respiratory depression

2. Carbamazepine:
   – Induces CYP1A2; reduces olanzapine levels

3. Fluvoxamine:
   – Inhibits CYP1A2; increases olanzapine plasma levels

4. Antihypertensives:
   – May enhance hypotensive effect

5. Anticholinergic Drugs:
   – Additive risk of constipation, urinary retention, cognitive dysfunction

6. Smoking (tobacco):
   – Induces CYP1A2; may reduce drug efficacy; dose adjustment may be required

7. QT Prolonging Drugs:
   – Use cautiously with other agents that prolong QT

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Monitoring Parameters

• Weight and BMI: Baseline, monthly for 3 months, then quarterly

• Fasting blood glucose: Baseline, at 3 months, then annually

• Lipid profile: Baseline, 3 months, then yearly

• Blood pressure and heart rate: Especially with IM injection

• Prolactin levels: If symptoms suggestive

• Liver function tests: Periodically

• CBC: If history of blood dyscrasias

• Extrapyramidal symptoms and movement disorders

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Patient Counseling Information

• Take once daily, preferably in the evening due to sedation

• May be taken with or without food

• Report excessive weight gain, unusual thirst, increased urination

• Avoid alcohol or other CNS depressants

• May cause drowsiness—avoid driving until response is known

• Report persistent restlessness or abnormal movements

• Monitor blood sugar, especially in diabetics

• Use contraception during treatment and discuss pregnancy with provider

• Never discontinue abruptly without medical advice

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Storage and Handling

• Store tablets at room temperature (20–25°C)

• Protect from moisture and light

• Keep orally disintegrating tablets in blister until use

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Comparative Profile with Other Atypical Antipsychotics

Drug	Sedation	Weight Gain	EPS Risk	Prolactin ↑	QT Prolongation
Olanzapine	High	High	Low	Moderate	Minimal
Risperidone	Moderate	Moderate	Higher	High	Moderate
Quetiapine	High	Moderate	Low	Low	Minimal
Aripiprazole	Low	Low	Moderate	Low	Minimal
Clozapine	Very High	Very High	Low	Low	Moderate
Ziprasidone	Low	Low	Moderate	Low	High

Regulatory Status

• Prescription-only (Rx)

• Approved by FDA, EMA, MHRA, TGA, Health Canada

• Included in national mental health formularies

• Considered essential for treatment-resistant psychiatric conditions