title: Role of serotonin 5-HT2C and histamine H1 receptors in antipsychotic-induced diabetes: A pharmacoepidemiological-pharmacodynamic study in VigiBase.
abstract: 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.
authors.affiliation: Service de Pharmacologie Médicale et Clinique, Faculté de Médecine de Toulouse, Centre Hospitalier Universitaire de Toulouse, France; INSERM UMR 1027, Pharmacoépidémiologie, Evaluation de l׳utilisation et du risque médicamenteux, Université de Toulouse, France; Pharmacopôle Midi-Pyrénées, Centre Midi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie et d׳Informations sur le médicament, Toulouse, France; Inserm CIC 1436 Toulouse, CIC de Toulouse, Toulouse University Hospital, Place du Dr Baylac, 31059 Toulouse Cedex 9, France. Electronic address: francois.montastruc@univ-tlse3.fr.
authors.forename: François
authors.initials: F
authors.lastname: Montastruc
authors.affiliation: Service de Pharmacologie Médicale et Clinique, Faculté de Médecine de Toulouse, Centre Hospitalier Universitaire de Toulouse, France; INSERM UMR 1027, Pharmacoépidémiologie, Evaluation de l׳utilisation et du risque médicamenteux, Université de Toulouse, France; Inserm CIC 1436 Toulouse, CIC de Toulouse, Toulouse University Hospital, Place du Dr Baylac, 31059 Toulouse Cedex 9, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Palmaro
authors.affiliation: Service de Pharmacologie Médicale et Clinique, Faculté de Médecine de Toulouse, Centre Hospitalier Universitaire de Toulouse, France; INSERM UMR 1027, Pharmacoépidémiologie, Evaluation de l׳utilisation et du risque médicamenteux, Université de Toulouse, France; Pharmacopôle Midi-Pyrénées, Centre Midi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie et d׳Informations sur le médicament, Toulouse, France; Inserm CIC 1436 Toulouse, CIC de Toulouse, Toulouse University Hospital, Place du Dr Baylac, 31059 Toulouse Cedex 9, France.
authors.forename: Haleh
authors.initials: H
authors.lastname: Bagheri
authors.affiliation: Service Hospitalo-Universitaire de Psychiatrie et Psychologie Médicale, Faculté de Médecine de Toulouse, Centre Hospitalier Universitaire de Toulouse, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Schmitt
authors.affiliation: Service de Pharmacologie Médicale et Clinique, Faculté de Médecine de Toulouse, Centre Hospitalier Universitaire de Toulouse, France; INSERM UMR 1027, Pharmacoépidémiologie, Evaluation de l׳utilisation et du risque médicamenteux, Université de Toulouse, France; Pharmacopôle Midi-Pyrénées, Centre Midi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie et d׳Informations sur le médicament, Toulouse, France; Inserm CIC 1436 Toulouse, CIC de Toulouse, Toulouse University Hospital, Place du Dr Baylac, 31059 Toulouse Cedex 9, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Montastruc
authors.affiliation: Service de Pharmacologie Médicale et Clinique, Faculté de Médecine de Toulouse, Centre Hospitalier Universitaire de Toulouse, France; INSERM UMR 1027, Pharmacoépidémiologie, Evaluation de l׳utilisation et du risque médicamenteux, Université de Toulouse, France; Inserm CIC 1436 Toulouse, CIC de Toulouse, Toulouse University Hospital, Place du Dr Baylac, 31059 Toulouse Cedex 9, France.
authors.forename: Maryse
authors.initials: M
authors.lastname: Lapeyre-Mestre
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D062313:Databases, Pharmaceutical; D003920:Diabetes Mellitus / Q000139:chemically induced* / Q000453:epidemiology / Q000378:metabolism*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D043587:Receptor, Muscarinic M3 / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D043587:Receptor, Muscarinic M3; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D050637:Receptors, Dopamine D3; D011969:Receptors, Histamine H1; D044282:Receptor, Serotonin, 5-HT1A
keywords: Antipsychotics; Diabetes; Histamine H1; Pharmacoepidemiology; Pharmacovigilance; Serotonin 5-HT2C