Role of Serotonin Transporter in Antidepressant-Induced Diabetes Mellitus: A Pharmacoepidemiological–Pharmacodynamic Study in VigiBase®

Background The association between antidepressant exposure and type 2 diabetes mellitus is still debated. Moreover, the pharmacological mechanisms remain unknown. Objective The objective of this study was to investigate this putative relationship with the role of antidepressant pharmacological targets using the ‘pharmacoepidemiological–pharmacodynamic’ method. Methods First, we performed case/non-case analyses in VigiBase® (the World Health Organization international database of suspected adverse drug reactions) to examine a signal of increased type 2 diabetes reporting (expressed as the reporting odds ratio and its 95% confidence interval) for antidepressants in general; examine and rank type 2 diabetes signals between the different pharmacological classes of antidepressants and the different antidepressants (58 in total). Second, we performed linear regression analyses to explore the association between the type 2 diabetes signal ranked between antidepressants and their binding affinities for nine targets (serotonin, norepinephrine, dopamine transporters, 5-HT2C serotonin, D2 dopamine, α1, α2 adrenergic, M3 muscarinic and H1 histamine receptors). Results A significant type 2 diabetes signal was found for antidepressants in general, three classes of antidepressants (tricyclic antidepressants, serotonin reuptake inhibitors and “other” antidepressants) and 15 individual antidepressants in particular. Among the antidepressants, three serotonin reuptake inhibitors [escitalopram (adjusted reporting odds ratio 1.15 [1.07–1.25]), paroxetine (1.15 [1.07–1.23]), sertraline (1.23 [1.17–1.31])] and three “other” antidepressants [duloxetine (1.15 [1.07–1.23]), trazodone (1.20 [1.09–1.32]), venlafaxine (1.15 [1.08–1.23])] were the antidepressants most frequently reported with type 2 diabetes. We found a significant correlation between the type 2 diabetes signal and serotonin transporter affinity (slope = 0.14 [0.06–0.23], p = 0.003, R2 = 0.43) but not the other targets. Conclusion The present study suggests a potential role for serotonin transporter in antidepressant-induced type 2 diabetes.