Clozapine (Clozaril)

Class

Second-generation (atypical) antipsychotic

Mechanism

Antagonist at dopamine D2 receptors with rapid dissociation; high affinity antagonist activity at dopamine D4 and D3 receptors; also blocks serotonin 5-HT2A/2C, histamine H1, muscarinic, and adrenergic receptors, contributing to its unique efficacy and side effect profile

FDA-Approved Use

Treatment-resistant schizophrenia, reduction of suicidal behavior in schizophrenia or schizoaffective disorder

Off-Label Use

Psychosis in Parkinson’s disease (PD), Lewy body dementia (LBD), severe agitation in neurodevelopmental disorders and neurodegenerative conditions

Formulation

Oral tablets

Titration

12.5–25 mg p.o. daily initially, titrated slowly to reduce risk of hypotension and sedation

Dose Range

150–600 mg/day

Kinetics

Half-life ~12 hours; metabolized primarily via CYP1A2 and CYP3A4; steady state in approximately 1 week

Common AEs

Sedation, sialorrhea (excessive salivation), constipation, orthostatic hypotension, tachycardia, weight gain

Serious/Rare AEs

Agranulocytosis, seizures, myocarditis, cardiomyopathy, bowel obstruction, neuroleptic malignant syndrome (NMS)

Monitoring

Mandatory absolute neutrophil count (ANC) monitoring weekly for 6 months, then every 2 weeks for 6 months, then monthly if stable; also monitor weight, fasting glucose, lipids, blood pressure, and seizure risk

Black Box Warning

Severe neutropenia/agranulocytosis, myocarditis, seizures, orthostatic hypotension, increased mortality in elderly patients with dementia-related psychosis

Considerations

Clozapine is preferred for managing psychosis in Parkinson’s disease and Lewy body dementia due to minimal extrapyramidal symptoms (EPS). It may reduce aggression and self-injurious behavior in individuals with intellectual disability or traumatic brain injury (TBI). Close monitoring of hematologic parameters, seizure risk, and cardiac function is critical, especially in older adults or medically complex patients.