Clozapine Toxicity

Clozapine toxicity occurs from overdose, or from rising serum levels at therapeutic doses when metabolism is inhibited. It causes sedation, delirium, hypersalivation, hypotension, tachycardia, seizures and, in large ingestions, coma and cardiorespiratory failure.

Clozapine is used for treatment resistant schizophrenia. Toxicity is likely above 400 mg in adults who are naive, and ingestions above 2 g can be fatal. Levels can rise by 50 to 100% with infection, smoking cessation, fluvoxamine or ciprofloxacin.

Risk factors for harm. Infection or inflammation (reduce CYP1A2 activity), smoking cessation, interacting drugs, hepatic impairment, and low body weight.

Course. Onset within 1 to 4 hours, with sedation lasting 24 to 48 hours after overdose. Enzyme inhibition by infection can cause toxicity over days.

Pathophysiology.

Antagonism of muscarinic, alpha-1, histamine and dopamine receptors causes sedation, hypotension and tachycardia, while lowering the seizure threshold.

Clozapine is metabolised by CYP1A2, so inhibitors and infection raise levels.

• Drowsiness, delirium, slurred speech, ataxia and agitation.
• Hypersalivation (paradoxical), tachycardia, postural hypotension, fever and constipation.
• Seizures, myoclonus, coma and respiratory depression.
• Myocarditis, cardiomyopathy and agranulocytosis may coexist; ileus and aspiration.

Red flags.

• Fever with chest pain, tachycardia or rising troponin (myocarditis).
• Neutrophil count under 1.5 x 10^9/L or sore throat with fever.
• Abdominal distension or absent bowel sounds (ileus).
• Seizures, coma or arrhythmia.

• History of dose, recent changes in smoking, infection and interacting drugs.
• Serum clozapine and norclozapine levels (over 1 mg/L suggests toxicity); full blood count with neutrophils, troponin, C-reactive protein and ECG.
• Electrolytes, glucose, renal and liver function, creatine kinase and venous gas.
• Paracetamol and salicylate levels in overdose.

Differential diagnosis. Neuroleptic malignant syndrome, infection, sepsis, serotonin toxicity, anticholinergic toxicity, other antipsychotic overdose and myocarditis.

• Stop clozapine and arrange urgent specialist advice; restart only under the psychiatric team, since abrupt cessation can cause cholinergic rebound and relapse.
• Activated charcoal 50 g orally once (1 g/kg, maximum 50 g, in children) within 1 hour of a significant ingestion if the airway is protected. Monitor the airway for aspiration. Avoid with reduced consciousness, ileus or gastrointestinal obstruction; no renal or hepatic adjustment; acceptable in pregnancy.
• Airway protection and ventilation for coma; aspiration prevention.
• Hypotension: fluids, then noradrenaline 0.05 micrograms/kg/minute intravenously, titrated to a mean arterial pressure of 65 mmHg or higher. Maximum 1 microgram/kg/minute. Give by central line; monitor blood pressure, extravasation and arrhythmia.
• Seizures: lorazepam 0.1 mg/kg intravenously (maximum 4 mg for each dose) over 2 minutes, repeated once after 5 to 10 minutes if seizures continue. Maximum 8 mg in total. Monitor breathing, oxygen saturation, blood pressure and sedation. Use lower doses in older adults, respiratory disease and hepatic impairment; use only when needed in pregnancy.
• Torsades de pointes: magnesium sulphate 2 g (8 mmol) intravenously over 10 minutes, repeated once if needed. Maximum 4 g in the first hour. Monitor reflexes, respiratory rate and magnesium; reduce dose in renal impairment.
• Hypersalivation: head up position and suction; avoid anticholinergics that worsen ileus.
• Constipation and ileus: stop other anticholinergics; osmotic laxative; surgical review for obstruction.
• Treat infection and review interacting drugs; reduce the clozapine dose by 30 to 50% when infection or smoking cessation is the cause, directed by levels.
• Myocarditis: cardiology review, stop clozapine, echocardiography and supportive care.
• Observe for at least 24 hours after large ingestion, with continuous cardiac monitoring.

Monitoring. Conscious level, ECG, blood pressure, full blood count, troponin, serum levels and bowel function.

Referral and escalation. Poisons information centre and psychiatry; intensive care for coma, seizures or shock; cardiology for myocarditis.

Special groups. Patients who stop smoking or develop infection: reduce dose and check levels. Pregnancy: specialist psychiatric advice.