Side Effects of Clozapine

Life-Threatening Hematologic Effects

Agranulocytosis occurs in approximately 1% of patients and is potentially fatal if not detected early, with youth potentially experiencing even higher rates of this complication 1, 2
Agranulocytosis is usually reversible if the drug is stopped immediately upon detection, and 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, 2, 3, 4
Critical WBC thresholds requiring immediate action include WBC <2,000/mm³ or ANC <1,000/mm³, where clozapine should be stopped immediately, and WBC 2,000-3,000/mm³ or ANC 1,000-1,500/mm³, where clozapine should be stopped immediately and resumed when WBC >3,000 and ANC >1,500 with no infection 1, 3, 4, 5, 6

Seizures occur in approximately 3% of adult patients, with potentially higher rates in youth, and the risk increases in a dose-dependent manner, especially with rapid dosage escalation 1, 2, 7
Clozapine has a 5% incidence of seizures at high dosages, significantly higher than other antipsychotics 8
Extrapyramidal symptoms can occur despite clozapine being an atypical antipsychotic, with case reports in youth 1, 2, 7

Hypersalivation occurs in 31-48% of patients, making it the most common autonomic side effect 1, 2
Fever/hyperthermia occurs in 5-13% of patients 1, 2

Neuroleptic malignant syndrome (NMS) is a potentially lethal syndrome with mental status changes, fever, rigidity, and autonomic dysfunction; mortality has decreased from 76% in the 1960s to <10-15% currently 8

Before initiating clozapine, baseline WBC ≥3,500/mm³, no evidence of myeloproliferative disorder, and no history of agranulocytosis or granulocytopenia on clozapine must be confirmed 1, 2
Avoid concurrent medications that lower blood cell counts (e.g., carbamazepine) 1, 2

Pediatric patients face heightened risks, including higher rates of seizures and agranulocytosis compared to adults, and young males are at particularly high risk for extrapyramidal symptoms including acute dystonia 1, 2, 9