What are the side effects of clozapine?

Clozapine Side Effects: Comprehensive Overview

Clozapine is associated with numerous serious and potentially life-threatening side effects, including severe neutropenia, cardiovascular complications, seizures, and metabolic disturbances, requiring strict monitoring protocols and careful management. 1

Major Adverse Effects

Hematologic Effects

• Severe neutropenia/agranulocytosis: Occurs in approximately 1% of patients 2
  • Requires mandatory blood monitoring:
    • Weekly blood cell counts for first 6 months
    • Biweekly thereafter
    • Continue monitoring for 4 weeks after discontinuation 3
  • Management protocol:
    • If WBC <2,000/mm³ or ANC <1,000/mm³: Stop medication immediately, monitor daily
    • If WBC 2,000-3,000/mm³ or ANC 1,000-1,500/mm³: Stop medication, monitor daily until WBC >3,000 and ANC >1,500
    • If WBC 3,000-3,500/mm³: Repeat count with differential, monitor biweekly until WBC >3,500/mm³ 3

Cardiovascular Effects

• Myocarditis and cardiomyopathy: Potentially fatal, highest risk in first month 1, 4
• QT interval prolongation: Increases risk of arrhythmias 2, 1
• Orthostatic hypotension and syncope: Common, especially during initiation 1
• Tachycardia: Reported in 25% of patients 1
• Hypertension: Less common but significant 1

Neurological Effects

• Seizures: Dose-dependent, occurring in approximately 3% of patients 1
• Sedation/drowsiness: Very common (39% of patients) 1
• Dizziness/vertigo: Common (19% of patients) 1
• Minimal extrapyramidal symptoms: Unlike typical antipsychotics 5

Gastrointestinal Effects

• Hypersalivation: Extremely common (31% of patients) 1
• Constipation: Common (14% of patients), can lead to serious complications 1
• Gastrointestinal hypomotility: Can cause severe complications 1
• Nausea and vomiting: Common 1

Metabolic Effects

• Weight gain: Significant concern, requires monitoring 3, 1
• Hyperglycemia and diabetes: Requires regular monitoring 3, 1
• Dyslipidemia: Requires regular monitoring 3, 1

Other Significant Effects

• Fever: Reported in 5% of patients 1
• Anticholinergic effects: Dry mouth, visual disturbances, urinary abnormalities 1
• Cognitive impairment: Interference with cognitive and motor performance 1
• Rebound psychosis: Risk with abrupt discontinuation 1, 6

Monitoring Requirements

Baseline Assessments

• Complete blood count with WBC ≥3,500/mm³
• BMI and waist circumference
• Blood pressure
• Fasting glucose and lipid panel
• ECG
• Abnormal Involuntary Movement Scale (AIMS) assessment 2

Ongoing Monitoring

• Hematologic: As outlined above
• Metabolic parameters:
  • BMI: Monthly for first 3 months, then quarterly
  • Blood pressure, fasting glucose, lipids: After 3 months, then yearly 2
• Cardiovascular: Regular assessment, especially during first month 4

Management of Common Side Effects

• Sedation: Dose adjustment, administration at bedtime
• Hypersalivation: Anticholinergic medications may help
• Constipation: Dietary modifications, increased fluid intake, stool softeners
• Weight gain: Lifestyle modifications, consider metformin or GLP-1 receptor agonists 3
• Seizures: Dose reduction, consider anticonvulsant if necessary 1

Contraindications

• History of clozapine-induced agranulocytosis or granulocytopenia
• Myeloproliferative disorders
• Concurrent medications that lower blood cell counts 2

Clozapine's side effect profile is extensive and requires vigilant monitoring, but its superior efficacy in treatment-resistant schizophrenia often justifies its use when managed appropriately 5, 7.