What are the side effects of clozapine?

Side Effects of Clozapine

Clozapine has two potentially fatal side effects that require mandatory monitoring: agranulocytosis (occurring in approximately 1% of patients) and seizures (occurring in approximately 3% of patients), with youth potentially experiencing even higher rates of both complications. 1

Life-Threatening Hematologic Effects

Agranulocytosis is the most serious concern with clozapine therapy:

• Occurs in approximately 1% of patients and is potentially fatal if not detected early 1
• Usually reversible if the drug is stopped immediately upon detection 1
• Youth may have higher rates than adults 1
• Requires extensive mandatory blood monitoring: weekly WBC counts for the first 6 months, then every 2 weeks thereafter, continuing for 4 weeks after discontinuation 1

Critical WBC thresholds requiring immediate action:

• WBC <2,000/mm³ or ANC <1,000/mm³: Stop clozapine immediately, monitor for infection with daily blood counts, obtain hematology consultation 1
• WBC 2,000-3,000/mm³ or ANC 1,000-1,500/mm³: Stop clozapine immediately, monitor for infection with daily counts; may resume when WBC >3,000 and ANC >1,500 with no infection 1
• WBC 3,000-3,500/mm³: Repeat count and monitor biweekly with differential until WBC >3,500/mm³ 1

Neurological Side Effects

Seizures represent the second major life-threatening concern:

• Occur in approximately 3% of adult patients, with potentially higher rates in youth 1
• Risk increases in a dose-dependent manner, especially with rapid dosage escalation 1
• Clozapine has a 5% incidence of seizures at high dosages, significantly higher than other antipsychotics 1
• Can generally be managed by dose reduction 2, 3

Common neurological effects include:

• Sedation/drowsiness: Most common CNS effect, occurring in 39% of patients 4
• Dizziness/vertigo: Occurs in 19% of patients 4
• Extrapyramidal symptoms: Can occur despite clozapine being an atypical antipsychotic, with case reports in youth 1
• Tardive dyskinesia: May occur as a class effect, though less common than with typical antipsychotics 4

Cardiovascular Effects

Cardiovascular complications are frequent and potentially serious:

• Tachycardia: Occurs in 25% of patients, making it one of the most common side effects 4
• Orthostatic hypotension: Occurs in 9-13% of patients 1, 4
• Myocarditis: Can lead to rapid cardiovascular collapse and death, with mortality estimated up to 24%; 90% of cardiotoxic events occur in the first month post-initiation 5
• Cardiomyopathy and mitral valve incompetence: Recognized serious complications 4
• QT interval prolongation: Can lead to potentially dangerous arrhythmias including torsades de pointes 4

Metabolic and Endocrine Effects

Metabolic syndrome is extremely common:

• Occurs in 50% of patients on clozapine 6
• Weight gain: Occurs in 31% of patients and can be extreme 1, 4
• Hyperglycemia and diabetes mellitus: Significant risk requiring monitoring 4
• Dyslipidemia: Part of the metabolic syndrome constellation 4

Gastrointestinal Effects

Gastrointestinal complications range from common to life-threatening:

• Hypersalivation: Occurs in 31-48% of patients, making it the most common autonomic side effect 1, 4
• Constipation: Occurs in 14-25% of patients 4, 6
• Gastrointestinal hypomotility with severe complications: Can lead to bowel ischemia, a potentially fatal outcome 4, 5
• Nausea and vomiting: Occur in 17% of patients 4

Other Common Side Effects

Additional frequently reported effects include:

• Fever/hyperthermia: Occurs in 5-13% of patients 1, 4
• Elevated liver enzyme levels: Requires monitoring 1
• Sweating: Occurs in 6% of patients 4
• Visual disturbances: Occur in 5% of patients 4
• Urinary abnormalities/incontinence: Occur in 2% of patients 4, 2

Rare but Serious Complications

Life-threatening complications requiring immediate recognition:

• Neuroleptic malignant syndrome (NMS): Potentially lethal syndrome with mental status changes, fever, rigidity, and autonomic dysfunction; mortality has decreased from 76% in the 1960s to <10-15% currently 1, 4
• Pulmonary embolism: Recognized serious complication 4
• Aspiration pneumonia: Can be fatal 5
• Hepatotoxicity: Requires monitoring of liver function 4

Critical Monitoring Requirements

Before initiating clozapine, the following must be confirmed:

• Baseline WBC ≥3,500/mm³ 1
• No evidence of myeloproliferative disorder 1
• No history of agranulocytosis or granulocytopenia on clozapine 1
• Avoid concurrent medications that lower blood cell counts (e.g., carbamazepine) 1

Ongoing surveillance should include:

• Weekly cardiac enzymes (troponins, CK-MB), EKG, and inflammatory markers (CRP, ESR) for the first 4 weeks to detect myocarditis 5
• Regular assessment for tardive dyskinesia every 3-6 months using standardized measures like the Abnormal Involuntary Movement Scale 7

Special Considerations for Youth

Pediatric patients face heightened risks:

• Higher rates of seizures and agranulocytosis compared to adults 1
• Young males at particularly high risk for extrapyramidal symptoms including acute dystonia 7
• May be more susceptible to cardiac effects of medications 1

Impact on Disability

The burden of side effects significantly affects patient outcomes:

• Disability correlates positively with the number of side effects and severity of psychopathology 6
• The number of side effects independently predicts the severity of disability 6
• Common side effects like hypersalivation, fatigue, sedation, and constipation can negatively affect the treatment process 6