The Antidepressant Effects of Hypoglycaemic Agents: New Insights from an Analysis of the FDA Adverse Event Reporting System (FAERS) Database

Introduction: Based on recent preclinical and clinical evidence linking together metabolic regulations and psychopathological mechanisms, a potential antidepressant role for glucagon-like peptide 1 (GLP-1) functional agonists (i.e., GLP-1 agonists and dipeptidyl peptidase 4-DPP-4 inhibitors) has been hypothesized [1-4]. Objective: To investigate the antidepressant effects of GLP-1 functional agonists in a huge population scale data from the FDA Adverse Event Reporting System (FAERS) database, in a large period of observation (from 1967 to 2021). Methods: From the primary cohort of patients treated with antidepressants (N = 536,240) (drugs were reported as suspect drugs in the occurrence of any adverse event), we identified cases i.e., depressed patients experiencing therapy failure and non-cases i.e., depressed patients experiencing any other adverse event. We then calculated and compared the ratio of the reporting odds ratios (ROR) as well as the ratio of 5% and 95% CI ROR values for cases versus non-cases in relation to the concurrent exposure to GLP-1 functional agonists (ATC codes: A10BJ and A10BH). Using the ratio of the 5% CI ROR value for non-cases and the 95% ROR CI value for cases is an adaptation of the Interaction Signal Score which represents interaction strength as the ratio of the 5% CI value of the disproportionality score for an event occurring with a pair of interacting drugs and the 95% CI value of the disproportionality score for the same event with the corresponding individual drugs [5]. Results: The results showed that the difference between cases and non-cases with respect to their association with antidiabetic drugs can be considered statistically significant (non-overlapping 90% confidence intervals of ROR values of non-cases compared to cases) for both drug classes. GLP-1 agonists: ROR/ROR = 2,921; ROR05/ ROR95 = 1,961; DPP-4 inhibitors: ROR/ROR = 1,623; ROR05/ ROR95 = 1,628. With regard to the selected antidiabetic agents, drugs mainly involved in the decreased ROR for the occurrence of depression and therapy failure were vildagliptin (ROR/ROR = 9,9662; ROR05/ROR95 = 2,482) and liraglutide (ROR/ROR = 3,099; ROR05/ROR95 = 1,717). It is likely to suppose that these antidiabetic drugs might exert beneficial antidepressant effects to patients with diabetes. Conclusion: This study has provided promising preliminary findings that may contribute to supporting the hypoglycaemic drug repurposing in the field of neuropsychiatric disorders