The association between receptor binding affinity and metabolic side effect profile of antipsychotics and major cardio- and cerebrovascular events: A case/non-case study using VigiBase

Antipsychotics (APs) have been associated with major adverse cardio- and cerebrovascular events (MACCE), but the underlying mechanisms are unclear. Our aim was to elucidate the association between APs, stratified for receptor affinity and metabolic side effects (MSE), in the reporting of MACCE. A case/non-case study was conducted using data from the WHO global Individual Case Safety Report (ICSR) database, VigiBase, among all reports associated with an AP. Cases were ICSRs of MACCE, while non-cases were all other adverse drug reactions (ADRs). APs were classified by AP group, the degree of receptor affinity for adrenergic, dopaminergic, muscarinic, histaminic, and serotoninergic receptors and by MSE profile. The strength of the association was estimated with logistic regression and expressed as crude and adjusted reporting odds ratios (ROR_adj.) with corresponding 95% confidence intervals (95%CIs). We identified 4987 reports of MACCE and 328,907 reports of other ADRs. Atypical APs (ROR_adj. 2.46; 95%CI 2.20–2.74) were significantly associated with the reporting of MACCE compared to typical ones. APs with high affinity for Adrenergic alfa-1 (ROR_adj. 2.98; 95%CI 1.93–4.59), Histaminic H₁ (ROR_adj. 2.31; 95%CI 1.98–2.68), Muscarinic M₁ (ROR_adj. 1.87; 95%CI 1.74–2.01), and Serotoninergic 5-HT_2A (ROR_adj. 3.19; 95%CI 2.07–4.92) were associated with a higher risk of reporting of MACCE compared to low affinity. APs with higher-risk of MSE were associated with higher risk of reporting of MACCE (ROR_adj. 1.88; 95%CI 1.73–2.05) compared to the lower-risk. APs with high affinity for Adrenergic alfa-1, Histaminic H₁, Muscarinic M₁, and Serotoninergic 5-HT_2A receptors and with high-risk of MSE may explain the occurrence of those events.