Research on adverse drug events. I. Muscarinic M3 receptor binding affinity could predict the risk of antipsychotics to induce type 2 diabetes

Antipsychotics are associated with a wide range of adverse effects, several of which may represent a serious health risk to patients. There is an increased concern about metabolic disturbances associated with antipsychotics, including weight gain, dyslipidemia, hyperglycemia, and type 2 diabetes. However, little is known about the mechanisms underlying antipsychotic-induced metabolic disturbances and, in particular, those related to the induction of abnormal glucose metabolism and diabetes. The present article aimed to identify those receptor(s) that are most likely to be involved with or mediate antipsychotics-induced diabetes. Two independent measures taken from literature to indicate the risk of type 2 diabetes associated with 25 typical and atypical antipsychotic drugs were considered, along with their binding affinities to 21 specific receptors (obtained from the resources of Prous Science Integrity). A range of both exploratory and predictive statistical analyses were applied, including principal component factorial analysis, multivariable linear regression analysis, and discriminant analysis. Binding affinities (pKi) to human neurotransmitter receptors and monoaminergic transporters were used as independent variables (predictors). Measures to determine the risk to induce new-onset type 2 diabetes associated with each antipsychotic, logistic regression odds-ratio (dOR) and a discrete scale-based risk (three levels: 'low,' 'moderate,' 'high'), were used as the dependent variables (criteria). Similarly, parallel analyses were also conducted for other measures (average effective therapeutic dose) or adverse effects (weight gain, extrapyramidal side effects, hyperprolactinemia, anticholinergic, hypotension, and sedation) associated with antipsychotics, where underlying mechanisms have been previously established and, therefore, serve as positive-control references. Affinity for the cholinergic muscarinic M3 receptor subtype was presented as the best predictor for the propensity of antipsychotics to induce type 2 diabetes. This was independently revealed by means of multiple linear regression analysis, using the dOR as criterion (R=0.90, p<0.0001), and discriminant analysis, using the scale-based risk of type 2 diabetes (3 levels) as criterion (Wilks' lambda=0.33, chi2=14.11, p<0.001). To our knowledge, this study provides the first direct evidence to indicate that antipsychotic agents with high binding affinity to the muscarinic M3 receptor are associated with an elevated risk for type 2 diabetes. Rationale of the M3 receptor involvement in this adverse effect is discussed further in relation to M3 receptor mediation of glucose-dependent parasympathetic acetylcholine regulation of insulin secretion by pancreatic beta-cells. This study is the first in a series of investigations that aim to further our understanding of mechanisms underlying adverse drug effects.