Unraveling antipsychotic induced weight gain in schizophrenia - A proof-of-concept study exploring the impact of the cumulative historical occupancy of different receptors by antipsychotics.

Obesity is a common complication in schizophrenia contributing to increased mortality rates. We present a proof-of-concept study displaying a new method to investigate the impact of antipsychotic drugs (APs) on obesity in terms of their cumulative historical receptor occupancy (CHRO) in 150 selected from 174 patients with schizophrenia. Based on a thorough medication history, we estimated CHRO of serotonin 5-HT2C, histamine H1, dopamine D2 and muscarinic M3 receptors and studied their relationship with different metabolic outcome variables utilizing stepwise regression analysis and structural equation modelling (SEM). Stepwise regression analysis revealed a significant positive relationship of Body Mass Index (BMI) with H1-CHRO, but a negative relationship with M3-CHRO. Moreover, H1-CHRO was associated with increased triglyceride concentration, while 5-HT2C-CHRO was associated with increased waist circumference and blood pressure. SEM, while confirming the diverging effects of H1-/5-HT2C- and M3-CHRO on obesity, suggested that their effect on other metabolic variables was indirect, i.e. mediated by obesity. Our results suggest that the metabolic side effects of antipsychotics can be described by their cumulative historical receptor occupancy with unique contributions of the different receptors. In particular, M3 receptor antagonism seems to exert a protective effect, confirming findings from rodent M3 receptor knock out models. These findings may provide a framework for estimating the metabolic burden of future APs, guiding the development of drugs with more favorable metabolic profiles.