Initiating clozapine in treatment-resistant schizophrenia (MEQ)

(i) TRRIP and offer. Treatment-resistant schizophrenia: confirmed schizophrenia-spectrum diagnosis; inadequate response to at least two different antipsychotics at adequate dose and duration with adherence confirmed; exclude pseudo-resistance (substances, under-dosing, non-adherence, organic mimics). Kane established clozapine superiority in TRS; Siskind meta-analyses support meaningful response rates and earlier use. Offer clozapine with full monitoring — not endless non-clozapine polypharmacy. Mention InterSePT if suicide risk is prominent.^[1][2][3][7]

(ii) Pre-start. FBC/ANC, metabolic panel, weight/BMI/waist, ECG, CRP ± troponin per local myocarditis protocol, U&E/LFT, pregnancy test if relevant, smoking history, medication review (avoid carbamazepine; caution fluvoxamine). Confirm registry enrolment and that the team can obtain protocol bloods and act on red results. Shared decision with honest risk–benefit counselling.^[4]

(iii) Titration and first month. Start 12.5 mg; slow stepwise rise over days–weeks toward an individualised adult target often in the 200–450 mg/day range. First-month cardiac vigilance: fever, unexplained tachycardia, chest pain → stop and investigate myocarditis (ECG, CRP, troponin, cardiology). Haematology per local schedule (commonly weekly early). Metabolic and bowel monitoring from day one.^[4]

(iv) Smoking and levels. Cigarette smoking induces CYP1A2 and lowers clozapine levels; smokers often need higher doses; cessation raises levels and toxicity risk — plan level checks and possible dose reduction if he stops smoking. If non-response at adequate dose, check trough level (classic teaching ~0.35 mg/L / 350 ng/mL as a response threshold scaffold) and individualise.^[5]

(v) Constipation/CIGH. Proactive laxative protocol and bowel chart from initiation. Teach red flags: severe constipation, vomiting, distension, no flatus. Escalation: stop clozapine, surgical review — life-threatening hypomotility is documented in large series.^[6]