clozapine
atypical antipsychotic· Brands: Clozaril, Clopine, Zaponex, Fazaclo, VersaclozPO
Mechanism of action
Clozapine is a dibenzodiazepine atypical antipsychotic. Its therapeutic action is thought to involve antagonism of dopamine D2 and serotonin 5-HT2A receptors, with high occupancy of limbic D2 receptors. It also has affinity for alpha-1 and alpha-2 adrenergic, histamine H1, muscarinic M1, and other receptors, which contributes to its side-effect profile. Its superior efficacy in treatment-resistant schizophrenia may involve additional actions, including modulation of glutamate and GABA systems, and anti-inflammatory effects.
Pharmacokinetics
Clearance is reduced in elderly patients but increased in smokers due to CYP1A2 induction, so smokers need higher doses.
Indications & dosing
Treatment-resistant schizophrenia
Start with 12.5 mg twice daily, then increase slowly; usual therapeutic range 200-450 mg/day. Monitor blood counts.
- adult · PO: 100–225 mg twice daily · Start with 12.5 mg twice daily, then increase slowly; usual therapeutic range 200-450 mg/day. Monitor blood counts.
Reducing suicidal behaviour in schizophrenia or schizoaffective disorder
Same dosage as for treatment-resistant schizophrenia; monitor closely during titration.
- adult · PO: 100–225 mg twice daily · Same dosage as for treatment-resistant schizophrenia; monitor closely during titration.
Drug-induced psychosis in Parkinson's diseaseoff-label
Low-dose therapy; titrate slowly to minimise side effects; monitor blood counts.
- adult · PO: 12.5–75 mg once daily · Low-dose therapy; titrate slowly to minimise side effects; monitor blood counts.
Contraindications & precautions
- History of agranulocytosis or bone marrow disorders · Clozapine can cause agranulocytosis, so a prior episode is an absolute contraindication.
- Severe hepatic impairment · Clozapine is metabolised in the liver; severe impairment increases toxicity risk.
- Hypersensitivity to clozapine or any excipient · Rare but serious; avoid re-exposure.
- Myocarditis · Clozapine can cause myocarditis; also avoid if cardiomyopathy is present.
- Epilepsy or seizure disorder · Clozapine lowers the seizure threshold; use with caution and consider dose adjustment.
- Severe cardiovascular disease · Risk of hypotension and tachycardia; monitor closely.
- Monitor white blood cell count regularly (weekly for first 18 weeks, then every 4 weeks) for agranulocytosis; stop if neutrophil count falls below threshold.
- Monitor for signs of myocarditis (fever, chest pain, fatigue, tachycardia); discontinue if suspected and refer immediately.
- Titrate the dose gradually to reduce risk of seizures, hypotension, and sedation.
- Advise patients to avoid smoking, as smoking induces CYP1A2 and can lower clozapine levels.
- Avoid concomitant use of drugs that suppress bone marrow or cause neutropenia.
- Use with caution in patients with diabetes, obesity, or hyperlipidaemia, as clozapine can worsen these conditions.
Adverse effects
- Agranulocytosisserious
- Myocarditisserious
- Seizuresserious
- Orthostatic hypotension
- Sedation
- Constipation
- Weight gain
- Tachycardia
Interactions
- fluoxetinemajorAvoid co-prescription if feasible. If necessary, use a lower clozapine dose, monitor plasma clozapine concentrations, and watch for signs of toxicity. Consider alternative antidepressants that do not inhibit CYP2D6 or CYP3A4.
Renal & hepatic adjustment
- eGFR 0+: No specific dose adjustment required; use caution in severe renal impairment and monitor for adverse effects.
- Hepatic impairment (mild): Use caution; reduce the initial dose and titrate slowly.
- Hepatic impairment (moderate): Use with caution; reduce the dose and monitor liver function closely.
- Hepatic impairment (severe): Avoid use due to the risk of hepatotoxicity and altered metabolism. (avoid)
Monitoring, pregnancy & toxicity
- White blood cell count and absolute neutrophil count · Weekly for the first 18 weeks, then every 4 weeks
- Blood pressure and pulse · Before initiation, then at each dose escalation
- Blood glucose and lipid profile · Before initiation, then every 3 to 6 months
- Weight · Regularly, at least every 3 months
- Liver function tests · Before initiation, then periodically if there is a risk of hepatic disease
- Pregnancy: Clozapine is not recommended during pregnancy unless the potential benefit outweighs the risk. If used, use the lowest effective dose and monitor for neonatal withdrawal syndrome. Consult a specialist.
- Toxicity: Sedation, coma, and respiratory depression · Supportive care with airway, breathing, and circulation; consider activated charcoal if ingested within 1 hour.
- Toxicity: Tachycardia and hypotension · IV fluids and vasopressors as needed; continuous ECG monitoring for arrhythmias.
- Toxicity: Seizures · Benzodiazepines (e.g., lorazepam) for seizure control.
Clinical notes
Clozapine is indicated for treatment-resistant schizophrenia and for reducing suicidal behaviour in schizophrenia or schizoaffective disorder. It is also used for psychosis in Parkinson's disease when other treatments fail. Because of the risk of agranulocytosis, it requires strict haematological monitoring: patients must have a normal white cell count before starting, and regular blood tests are mandatory (weekly for the first 18 weeks, then every 4 weeks, with continued surveillance). It is also associated with myocardial and other side effects, including severe constipation, metabolic syndrome, and myocarditis. It should be used under specialist supervision and with caution in elderly patients, those with cardiovascular risk, and those receiving other drugs that affect CYP1A2 or CYP3A4. Smoking cessation can increase clozapine levels, and concurrent use of other antipsychotics should be avoided. Abrupt discontinuation can cause rebound psychosis, so gradual withdrawal is recommended.
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BNF; local formulary