Metabolic syndrome in stable long-term antipsychotic monotherapy and polypharmacy among patients with schizophrenia: a real-world comparative study

Background Metabolic syndrome is a major contributor to premature cardiovascular morbidity and mortality among people with schizophrenia. Antipsychotic polypharmacy is common, but its independent metabolic burden remains uncertain. Objective To compare metabolic syndrome in patients receiving stable long-term antipsychotic monotherapy or polypharmacy and to examine high metabolic-risk exposure, chlorpromazine-equivalent dose, and long-acting injectable (LAI) use. Methods This retrospective study included 370 adults with schizophrenia spectrum disorders receiving an unchanged antipsychotic regimen for at least five years at a community mental health center. Patients received monotherapy (n=144) or polypharmacy (n=226). Metabolic syndrome was defined using International Diabetes Federation criteria. Antipsychotic dose was standardized to chlorpromazine equivalents, and multivariable logistic regression was used. Results Metabolic syndrome was present in 143 patients (38.6%) and was numerically more frequent with polypharmacy than monotherapy (41.2% vs. 34.7%, p=0.216). LAI use (67.3% vs. 37.5%, p<0.001) and median chlorpromazine-equivalent dose (1010.0 vs. 454.5 mg/day, p<0.001) were higher with polypharmacy. However, neither LAI use (adjusted OR = 1.220, 95% CI 0.767-1.941, p=0.401) nor chlorpromazine-equivalent dose per 100 mg/day (adjusted OR = 1.003, 95% CI 0.954-1.055, p=0.899) was independently associated with metabolic syndrome. Current smoking remained associated with metabolic syndrome (adjusted OR = 1.996, 95% CI 1.251-3.185, p=0.004). Conclusions In this selected cohort with stable long-term treatment, polypharmacy was associated with greater dose and LAI exposure, but independent associations of treatment modality, current dose, LAI use, or olanzapine/clozapine exposure with metabolic syndrome were not detected. Comprehensive cardiometabolic monitoring and smoking cessation remain priorities.