Different Influences of Classical Antipsychotics and Clozapine on Glucose-Insulin Homeostasis in Patients With Schizophrenia or Related Psychoses

Background: The aim of this study was to investigate the influence of classical antipsychotics and the atypical antipsychotic agent clozapine on glucoseinsulin homeostasis to explain possible mechanisms behind weight gain associated with antipsychotic treatment.

Method: Twenty-eight patients on therapy with classical antipsychotics and 13 patients treated with clozapine (all meeting DSM-III-R criteria for schizophrenia or related psychoses) were studied. Fasting blood samples for glucose and insulin, as well as for 2 markers of the glucose-insulin homeostasis, i.e., the growth hormone (GH)-dependent insulin-like growth factor I (IGF-I) and the insulin-dependent insulin-like growth factor binding protein-1, were analyzed. Body mass index (BMI) was calculated and serum concentrations of the different antipsychotic drugs were measured. In addition, the relationship between the endocrine parameters and drug serum concentrations was examined.

Results: The insulin levels were positively correlated to the serum concentration of clozapine, whereas no correlations were found between insulin and the serum concentrations of perphenazine (N = 12) or zuclopenthixol (N = 9). Insulin elevation was seen in the patients receiving clozapine more frequently than in the patients receiving classical antipsychotics. In addition, the median level of IGF-I was significantly lower in the patients receiving clozapine than in the patients receiving classical antipsychotics. No significant difference in BMI was found between the 2 patient groups, and all patients but 1 were normoglycemic.

Conclusion: The correlation between insulin and the clozapine concentration indicates a probable influence of clozapine on insulin secretion. The normal blood glucose levels in the clozapine group support the theory that clozapine induces concentration-dependent insulin resistance with secondary increased insulin secretion. In addition, lower median level of IGF-I in patients receiving clozapine compared with patients receiving classical antipsychotics points to a lower GH secretion in the clozapine group. This impaired GH secretion together with the clozapine-induced insulin resistance might be mechanisms behind weight gain during clozapine therapy.