PharmacologyTier 1Medical Sciences concept

Clozapine adverse effects (myocarditis, agranulocytosis)

Core concept

Clozapine is the only agent with proven efficacy in treatment-resistant schizophrenia (failure of 2 antipsychotics); every adverse effect is tolerated for that reason
Two life-threatening, time-defined toxicities

Myocarditis - a hypersensitivity reaction

Eosinophilic (and lymphocytic) myocardial infiltrate on endomyocardial biopsy
Weeks 2-4, almost always within the first 6-8 weeks
Not dose-related in the conventional sense; risk rises with rapid titration

Agranulocytosis - immune/toxic marrow injury

Toxicity	Timing	Monitoring
Myocarditis	Weeks 2-4 (first 6-8 weeks)	Weekly troponin, CRP, and clinical review for 4 weeks; baseline echo
Agranulocytosis	First 18 weeks	FBC weekly x18 weeks, then monthly for life
Seizure	Dose-related, >600 mg/day	Consider valproate cover
Constipation / ileus	Any time	Commonest cause of clozapine death
Myocarditis -> cardiomyopathy	Months-years	Annual echo

Myocarditis red flags: tachycardia out of proportion, fever, flu-like illness, dyspnoea, chest pain in the first 2 months
- Troponin >2x ULN or CRP >100 -> cease clozapine immediately
- Eosinophilia and fever are supportive but not required
Neutropenia thresholds (traffic light): amber ANC 1.0-1.5, red ANC <1.0 or WCC <3.0 -> stop, do not rechallenge
Clozapine is a CYP1A2 substrate - smoking induces CYP1A2
- Stopping smoking (or hospital admission) raises clozapine levels sharply -> toxicity, seizures
- Caffeine, fluvoxamine, ciprofloxacin inhibit -> inc levels
Also: sialorrhoea (paradoxical, muscarinic M4 agonism), sedation, weight gain and metabolic syndrome, orthostatic hypotension, myocarditis-independent tachycardia, severe constipation/ileus, nocturnal enuresis
Extrapyramidal effects and tachyphylaxis are minimal - the reason it is used

Any febrile illness in the first 8 weeks of clozapine needs FBC, troponin, CRP and ECG the same day
Clozapine rechallenge after myocarditis is possible under specialist supervision; after agranulocytosis it is not
Constipation is under-recognised and the leading cause of clozapine-associated death - prophylactic aperients from the outset
Sudden cessation -> cholinergic rebound (agitation, diarrhoea, sweating) and psychotic relapse; if stopped >48 h, retitrate from the start
Clozapine reduces suicide in schizophrenia - the benefit is mortality, not just symptoms

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