What are the side effects of Clozapine?

Clozapine Side Effects: Comprehensive Overview

Clozapine has significant and potentially life-threatening side effects including agranulocytosis, seizures, metabolic abnormalities, and cardiovascular complications that require extensive monitoring protocols. 1

Major Life-Threatening Side Effects

1. Hematological Effects

• Agranulocytosis: Occurs in approximately 1% of patients and is potentially fatal 1
  • Higher risk during first 6 months but persists long-term 2
  • Requires mandatory monitoring protocol:
    • Weekly WBC counts for first 6 months, then biweekly thereafter 1
    • Immediate discontinuation if WBC < 2,000/mm³ or ANC < 1,000/mm³ 1
  • Risk factors: Older age, female sex 3

2. Neurological Effects

• Seizures: Occur in approximately 3% of patients 1
  • Dose-dependent risk that increases with higher doses and rapid titration 1
  • More common with clozapine (5% incidence at high doses) than other antipsychotics (<1%) 1
• Neuroleptic Malignant Syndrome: Characterized by mental status changes, fever, muscle rigidity, and autonomic dysfunction 1

3. Cardiovascular Effects

• Myocarditis and Cardiomyopathy: Rare but potentially fatal 4
• Orthostatic Hypotension: Common (13% incidence) 4
• Tachycardia: Common (17% incidence) 4
• QT Interval Prolongation: Can lead to arrhythmias 4

Common Side Effects

1. Autonomic Effects

• Hypersalivation: Very common (31% incidence) 4
• Constipation: Common (14-16% incidence) and can lead to severe complications 4
• Fever: Occurs in approximately 5-13% of patients 4
• Sweating: Occurs in approximately 6% of patients 4
• Dry mouth: Occurs in approximately 5-6% of patients 4

2. Central Nervous System Effects

• Sedation/Drowsiness: Very common (39% incidence) 4
• Dizziness/Vertigo: Common (19% incidence) 4
• Headache: Occurs in approximately 7-10% of patients 4
• Tremor: Occurs in approximately 6% of patients 4

3. Metabolic Effects

• Weight gain: Common and can be extreme 1, 4
• Hyperglycemia and Diabetes: Requires regular monitoring 4
• Dyslipidemia: Requires regular monitoring 4

Monitoring Requirements

Initial Assessment

• Complete baseline physical examination 5
• Baseline laboratory measurements:
  • Complete blood count with WBC ≥ 3,500/mm³ 1
  • BMI, waist circumference, blood pressure 5
  • Fasting glucose and lipid panel 5
  • ECG (for QT prolongation risk) 5
  • Abnormal Involuntary Movement Scale (AIMS) assessment 5

Ongoing Monitoring

• Blood counts:
  • Weekly for first 6 months
  • Biweekly thereafter
  • Continue for 4 weeks after discontinuation 1
• Metabolic parameters:
  • BMI: Monthly for first 3 months, then quarterly 5
  • Blood pressure, fasting glucose, lipids: After 3 months, then yearly 5
• Neurological assessment: Regular evaluation for extrapyramidal symptoms, tardive dyskinesia 5

Special Considerations

Initiation and Dosing

• Start with low doses (6.25-25 mg/day) and increase gradually 1
• Maximum dose increases of 25-50 mg once or twice weekly 1
• Target blood levels: 200-400 ng/mL (though correlation with efficacy/side effects needs further research) 1

Contraindications

• History of clozapine-induced agranulocytosis or granulocytopenia 1
• Myeloproliferative disorders 1
• Concurrent medications that lower blood cell counts (e.g., carbamazepine) 1

Risk Reduction Strategies

• Avoid rapid dose escalation to reduce seizure risk 1
• Monitor for constipation and treat proactively 4
• Regular cardiovascular assessment 5
• Patient education about symptoms requiring immediate attention 5

Despite these significant side effects, clozapine remains the most effective antipsychotic for treatment-resistant schizophrenia, with benefits that include reduced positive and negative symptoms, reduced risk of suicide, and improved quality of life 6. The risk-benefit assessment should consider the severity of the patient's condition and the potential for improved outcomes with appropriate monitoring.