Clozapine induces metformin-resistant prediabetes/diabetes that is associated with poor clinical efficacy in patients with early treatment-resistant schizophrenia

Two distinct subtypes of treatment-resistant schizophrenia (TRS) have been recently reported, including early-treatment resistance (E-TR) and late-treatment resistance (L-TR). This study was to assess clozapine-induced metformin-resistant prediabetes/diabetes and its correlation with clinical efficacy in schizophrenia E-TR subtype.This prospective cohort study enrolled 230 patients with schizophrenia E-TR subtype and they were treated with adequate doses of clozapine for 16 weeks, during which patients with prediabetes/diabetes were assigned to receive add-on metformin. The main outcomes and measures included incidence of clozapine-induced prediabetes/diabetes and metformin-resistant prediabetes/diabetes, and the efficacy of clozapine as assessed by the Positive and Negative Syndrome Scale (PANSS) score.Clozapine-induced prediabetes/diabetes occurred in 76.52% of patients (170 prediabetes and 6 diabetes), of which the blood sugar of 43 (24.43%) patients was controlled with metformin. Despite add-on metformin, 47.06% (74/170) of prediabetes patients progressed to diabetes. In total, the incidence of clozapine-induced metformin-resistant prediabetes/diabetes was 75.57% (133/176). On completion of 16-week clozapine treatment, 16.52% (38/230) patients showed clinical improvement with PANSS scores of ≥50% declining. Furthermore, clozapine-induced prediabetes/diabetes was significantly correlated with the poor clinical efficacy of clozapine for schizophrenia E-TR subtype.The incidence of clozapine-induced metformin-resistant prediabetes/diabetes was considerably high in the schizophrenia E-TR subtype. Clozapine-induced metformin-resistant prediabetes/diabetes represents an independent risk factor that adversely affects the clinical efficacy of clozapine for the schizophrenia E-TR subtype. This study provided new evidence for re-evaluating the use of clozapine for TRS, especially E-TR subtype, and the use of metformin for the glycemic control of clozapine-induced prediabetes/diabetes.