Smoking, plasma concentration, antipsychotic polypharmacy and adverse drug reaction burden in clozapine outpatients

BACKGROUND: Clozapine is the most effective therapy for treatment-resistant schizophrenia, yet adverse drug reactions (ADRs) limit its use. The concurrent ADR burden in outpatients and its relation to psychotropic polypharmacy, tobacco smoking and measured clozapine exposure has not been well characterised. METHOD: We conducted a retrospective, cross-sectional review of medical records for 360 adults receiving maintenance clozapine at a dedicated outpatient clinic. Adverse drug reactions (ADRs) were ascertained using a standardised patient checklist alongside clinical measures. We used multivariate logistic regression to estimate the association between antipsychotic polypharmacy and the presence of ADRs, and negative binomial regression to quantify its association with ADR burden. We conducted a log-linear model to evaluate dose-concentration compensation in tobacco smokers. RESULTS: At the clinic visit, 89.6% had ⩾1 symptomatic ADR. The most prevalent were metabolic syndrome (71.8%), hypersalivation (64.7%) and tachycardia (61.2%). Antipsychotic augmentation (51.4%) was independently associated with ADRs (adjusted odds ratios [aOR] = 3.38, 95% confidence interval [CI] = 1.41-8.06) and a 28% higher ADR count per person (incidence-rate ratio [IRR] = 1.28, 95% CI = 1.11-1.48). Smokers received higher doses yet had lower plasma concentrations, suggesting incomplete dose compensation for CYP1A2 induction and had higher odds of antipsychotic augmentation (odds ratio [OR] = 2.50, 95% CI = 1.53-4.10). CONCLUSION: In maintenance clozapine care, persistent ADRs were common and were more frequent in patients receiving antipsychotic augmentation. Smokers were under-exposed to clozapine and were more likely to receive antipsychotic augmentation. Services should implement structured ADR surveillance and prioritise therapeutic drug monitoring-guided dose optimisation, particularly in smokers, before considering antipsychotic augmentation.