Synopsis
Confirm genuine treatment-resistant schizophrenia after two adequate sequential antipsychotic trials, offer clozapine without avoidable delay, maintain psychological and social care, and prevent haematological, cardiac, gastrointestinal, metabolic and concentration-related harm through registered phased monitoring.
- Before calling illness treatment resistant, review diagnosis, two sequential adequate antipsychotic trials, actual adherence, dose, duration, substances and physical illness; psychological care should be offered but failure of it is not a clozapine eligibility criterion.
- Offer clozapine when schizophrenia has not responded adequately despite at least two different antipsychotics at adequate doses, including at least one non-clozapine second-generation drug.
- Register the patient, prescriber and dispensing pathway with the relevant UK clozapine monitoring service and obtain the required acceptable blood result before supply.
- Start low and use the June 2026 RCPsych Wim's Protocol physical-monitoring phases alongside the SmPC and local policy: baseline, titration weeks one to four, stabilisation weeks five to eight, early maintenance weeks nine to eighteen, maintenance weeks eighteen to fifty-two and review beyond one year.
- Ask about bowel frequency and symptoms at every contact and prescribe active prevention when risk is present; severe constipation is an emergency, not a minor inconvenience.
- Smoking cessation, serious infection and CYP interactions can raise clozapine concentrations, while starting smoking can lower them and reduce response.
- Measure clozapine concentration when toxicity, poor response, non-adherence, infection, smoking change or important interaction makes exposure uncertain, alongside mandatory blood-count monitoring.
- If optimised clozapine is insufficient, confirm adherence, concentration, duration, diagnosis and psychosocial care before a time-limited monitored augmentation trial.
Key red flags
Fever, sore throat, mouth ulceration or other infection symptoms during clozapine treatment requires an urgent full blood count and monitoring-service advice.
Persistent resting tachycardia, chest pain, dyspnoea, unexplained fatigue or flu-like illness early in titration raises myocarditis and requires prompt cardiac assessment.
No bowel movement with increasing distension, severe abdominal pain, vomiting or reduced bowel sounds suggests ileus or obstruction and can be fatal.
New confusion, profound drowsiness, myoclonus or seizure may reflect high clozapine exposure, rapid titration, interaction, infection or smoking cessation.
A treatment gap longer than the product threshold invalidates the previous titration and creates severe hypotension or collapse risk if the full dose is simply resumed.
Investigation priorities
Verify diagnosis, target symptoms, sequential drugs, doses, duration, adherence, response and tolerability.
Management branches
Schizophrenia symptoms remain disabling after two apparent antipsychotic trials.
- Review diagnosis, dose, duration, actual adherence, adverse effects, substances, interactions, physical illness and psychological treatment access.
- Document whether two sequential adequate trials, including a non-clozapine second-generation medicine, have genuinely failed.
- Offer clozapine with balanced benefit-harm information and practical support, avoiding repeated ineffective switching when eligibility is established.