Receptor occupancy-based analysis of the contributions of various receptors to antipsychotics-induced weight gain and diabetes mellitus.
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 meta-analysis 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 alpha1 adrenergic, alpha2 adrenergic, dopamine D2, histamine H1, muscarinic acetylcholine (mACh), serotonin 5-HT1A, 5-HT2A and 5-HT2C receptors 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 H1 and mACh receptors and antipsychotics-induced weight gain estimated by meta-analysis (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-HT2C receptor occupancies (r(s) = 0.90 in each case, p < 0.05). However, H1 receptor 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 H1 receptor may contribute predominantly to the antipsychotics-induced weight gain and diabetes mellitus.


CONCLUSIONS
Model analysis based on receptor occupancy indicates that H1 receptor blockade is the primary cause of antipsychotics-induced weight gain and diabetes mellitus.
Matsui-Sakata
Akiko
A
Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Ohtani
Hisakazu
H
Sawada
Yasufumi
Y
D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced* / Q000378:metabolism; D015201:Meta-Analysis as Topic; D016032:Randomized Controlled Trials as Topic; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects / Q000378:metabolism; D011941:Receptors, Adrenergic / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011955:Receptors, Drug / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects*
D014150:Antipsychotic Agents; D044405:Receptor, Serotonin, 5-HT2C; D011941:Receptors, Adrenergic; D017448:Receptors, Dopamine D2; D011955:Receptors, Drug; D011969:Receptors, Histamine H1; D011976:Receptors, Muscarinic