Drug reference

Clozapine

Atypical Antipsychotic · Psychoses and schizophrenia

Atypical AntipsychoticPsychoses and schizophrenia

CDSCO approvedSchedule H

EXCRETION

—

not curated

INTERACTIONS

12 major

SEVERE in our sources

PREGNANCY

Use with caution; limited data

FDA category + note

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Mechanism

Clozapine is a dibenzodiazepine atypical antipsychotic with a unique receptor-binding profile: it has high affinity for serotonin 5-HT2A receptors and dopamine D4 receptors, with relatively weak D2 receptor blockade compared to typical antipsychotics. This preferential 5-HT2A/D4 over D2 antagonism explains its efficacy against both positive and negative symptoms of schizophrenia with minimal extrapyramidal side effects. Clozapine carries a 1-2% risk of agranulocytosis via an immune-mediated mechanism peaking at 2-3 months of therapy, mandating weekly CBC monitoring.

Indications

PsychosesSchizophreniaTreatment-resistant schizophreniaschizophrenia with suicidalitypsychogenic polydipsiapersistent impulsive aggressionresistant maniaManagement of hallucinations and psychosis observed in PDTreatment of paranoia and psychosis in rigid HDNegative symptoms of schizophreniaResistant cases of schizophrenia

Dosing

Adult: Day 1: 12.5 mg 1-2 times daily. Day 2: 25-50 mg. Increase by 25-50 mg daily over 14-21 days to up to 300 mg daily in divided doses. Usual: 200-450 mg daily. Max 900 mg/day. Elderly (≥60): start 12.5 mg OD, slower titration. If restarting after >48h gap: re-titrate from 12.5 mg.
Hepatic adjustment: Avoid in severe hepatic impairment
Geriatric: Start 12.5 mg OD; slower titration over 14-21 days
Max dose: 900 mg/day

Pharmacokinetics

Peak effect

2.5 h

Half-life

12 h (range, 4–66 h) with chronic dosing; 22.5 h (norclozapine)

Bioavailability

60%

Protein binding

>95%

Metabolism

Metabolized by FMO3.

Excretion

<1%

Contraindications

History of agranulocytosis or neutropenia
Bone marrow disorders
Severe cardiac disorders
Paralytic ileus
Uncontrolled epilepsy
Active liver disease
Alcoholic/toxic psychoses
Breastfeeding mothers
carbamazepine (due to rare risk for bone marrow effects)
use in elderly dementia patients (increased mortality risk)
psyllium (due to ileus risk)
anticholinergic agents (for constipation)

Side effects

Common

Weight gainSedationHypersalivationTachycardiaConstipationPostural hypotensionMetabolic syndromeFeverMetabolic effects (e.g., type 2 diabetes, hyperlipidemia)Significant constipationileushypotensionsialorrhea (manage with locally administered agents)

Serious

Agranulocytosis (1-2%; mandatory WBC monitoring)
Myocarditis
Cardiomyopathy
Seizures (dose-related)
Intestinal obstruction (fatal cases reported)
Pulmonary embolism
Diabetic ketoacidosis
Cardiovascular actions (e.g., arrhythmias, stroke)
High risk of metabolic adverse effects (weight gain, dyslipidemia, hyperglycemia)
severe neutropenia (mandatory hematological monitoring, risk ~1% highest in first 6 months)
dose-dependent lowering of seizure threshold (3%–5% prevalence)
myocarditis (1% risk, first 6 weeks)
dilated cardiomyopathy
neuroleptic malignant syndrome
increased mortality in elderly dementia patients
increased rate of death in the elderly
Agranulocytosis

Pregnancy & lactation

Pregnancy

Use with caution; limited data

Lactation

Animal studies indicate possible adverse effects of antipsychotic medicines on the developing nervous system. Chronic treatment with antipsychotic drugs whilst breast-feeding should be avoided unless absolutely necessary.