Role of serotonin 5-HT2C and histamine H1 receptors in antipsychotic-induced diabetes: A pharmacoepidemiological-pharmacodynamic study in VigiBase

Pharmacodynamic mechanisms of diabetes induced by antipsychotic drugs remain unclear, while numerous receptors have been suspected to be involved in the genesis of this Adverse Drug Reaction (ADR). We investigated potential relationships between antipsychotics׳ receptor occupancy (serotonin 5-HT1A, 5-HT2A, 5-HT2C, histamine H1, muscarinic M3, adrenergic α1, α2 or dopaminergic D2 D3 occupancies) and reports of diabetes using VigiBase®, the World Health Organization (WHO) global Individual Case Safety Report (ICSR) database. All ADR reports from 15 first and second generation antipsychotic drugs recorded in VigiBase® were extracted. Logistic regression models, completed by disproportionality analysis, were used to determine the associations between antipsychotics׳ receptor occupancy and ICSRs of diabetes on VigiBase®. During the study period, 94,460 ICSRs involved at least one of the 15 antipsychotics of interest. Diabetes was reported in 1799 (1.9%) patients. Clozapine was the most frequently suspected drug (n=953; 53.0%). A significant and positive association was found between histamine H1, muscarinic M3 and serotonin 5-HT2C, 5-HT2A receptor occupancies and reports of diabetes. A multivariable stepwise regression model showed that only serotonin 5-HT2c (AOR=2.13, CI 95% 1.72-2.64) and histamine H1 (AOR=1.91, CI 95% 1.38-2.64) predicted the risk for diabetes mellitus (p<0.001). Using an original pharmacoepidemiology-pharmacodynamic (PE-PD) approach, our study supports that antipsychotic drugs blocking simultaneously histamine H1 and serotonin 5-HT2C receptors are more frequently associated with diabetes reports in VigiBase® than other antipsychotics. These findings should encourage investigation of histamine H1 and serotonin 5-HT2C properties for predicting the risk of glycemic effects in candidate antipsychotics.