Receptor Occupancy-based Analysis of the Contributions of Various Receptors to Antipsychotics-induced Weight Gain and Diabetes Mellitus

Summary: Objective: Among various adverse reactions of atypical antipsychotics, weight gain and impaired glucose tolerance are clinically significant. The aim of this study is to analyze quantitatively the contributions of various receptors to these antipsychotics-induced adverse reactions based on the receptor occupancy theory. Methods: Two indices of antipsychotics-induced weight gain (the values estimated by a metaanalysis and the observed values in clinical trials) and the morbidity rate of type 2 diabetes mellitus during treatment with antipsychotics were taken from the literature. We calculated the estimated mean receptor occupancies of α₁adrenergic, α₂adrenergic, dopamine D₂, histamine H₁, muscarinic acetylcholine (mACh), serotonin 5-HT_1A, 5-HT_2Aand 5-HT_2Creceptors by antipsychotics by using the pharmacokinetic parameters and receptor dissociation constants, and analyzed the correlation between the occupancies and the extent of adverse reactions as assessed using the aforementioned indices. Results: There were statistically significant correlations between the estimated occupancies of H₁and mACh receptors and antipsychotics-induced weight gain estimated by metaanalysis (r_s= 0.81 and r_s= 0.83, respectively, p<0.01). There were also statistically significant correlations between these receptor occupancies and observed weight gain in clinical trials (r_s= 0.66 in each case, p<0.01). The morbidity rate of type 2 diabetes mellitus was highly correlated with H₁, mACh, and 5-HT_2Creceptor occupancies (r_s= 0.90 in each case, p<0.05). However, H₁receptor occupancy was also highly correlated with mACh receptor occupancy among antipsychotics, so that only one of them may be critically associated with the adverse reactions. Considering that these adverse reactions have not been reported for drugs with mACh receptor antagonistic action, other than antipsychotics, the H₁receptor may contribute predominantly to the antipsychotics-induced weight gain and diabetes mellitus. Discussion/Conclusion: Model analysis based on receptor occupancy indicates that H₁receptor blockade is the primary cause of antipsychotics-induced weight gain and diabetes mellitus.