Metabolic Effects of Clozapine Administration Based on Sex Differences and the Relationships Between Dosage and Prolactin Levels: An Observational Study

Objective: Clozapine is the second-generation antipsychotic that induces the largest metabolic disorders. However, evidence is limited to the liabilities based on sex differences. This study aimed to investigate the effects of clozapine treatment on metabolic and neuroendocrine parameters, and the relationships between prescribed clozapine dosage and prolactin levels that may be associated with plasma clozapine concentrations, in 24 female and 24 male Japanese schizophrenia inpatients switched to clozapine. Methods: Within female andmale subjects, sequential changes in 7 items of metabolic parameters, including anthropometric measurements, fasting serum lipid components and glucose levels, and estimated insulin resistance at 2 months were evaluated and analyzed against clozapine dosages and prolactin levels at 2 months. Results: Triglyceride levels, triglyceride to high-density lipoprotein ratios reflecting insulin resistance and glucose levels increased in female and male subjects. High-density lipoprotein cholesterol levels decreased in female and male subjects. High-density lipoprotein cholesterol levels were negatively correlated with prolactin levels in female subjects, and glucose levels were positively correlated with prolactin levels in male subjects, although clozapine doses showed no such correlations. Conclusions: Clozapine administration developed sex-neutral metabolic disorders in the study subjects. Higher prolactin levels seemed to increase the risk of dyslipidemia and hyperglycemia with sex differences, which suggested that serum prolactin levels other than clozapine doses might be useful to predict sex-specificmetabolic disorders. Further prospective studies, combining measurement of metabolic hormones and plasma concentrations of clozapine and its metabolites, will help to confirm our findings.