THE ROLE OF HYPOGLYCEMIC AGENTS IN AMELIORATING COGNITIVE FUNCTIONS AND PSYCHIATRIC SYMPTOMS: FROM THE PSYCHIATRIC PATIENT TO EVIDENCE-BASED AND PHARMACOEPIDEMIOLOGIC APPROACHES FOR SUPPORTING THE CLINICAL PRACTICE

Background: Research highlights a complex link between diabetes-related factors such as insulin resistance, hyperglycemia, and chronic inflammation, all contributing to cognitive decline. Schizophrenia and depression, which often co-occur with type 2 diabetes mellitus, show a bidirectional relationship with diabetes, involving both brain and systemic responses. Antidiabetic drugs such as metformin and drug targeting Glucagon-Like Peptide-1 (GLP-1) are being proposed for psychiatric and cognitive treatments, although their use for non-diabetic purposes remains debated. Methods: The role of antidiabetic drugs in ameliorating psychiatric and cognitive functions was explored across various real-world settings where these drugs are already used for glycemic control. A meta-analysis and meta-regression were conducted to study metformin in schizophrenic patients. Innovative approaches regarding disproportionality analysis of concomitant therapies in pharmacovigilance databases were used to explore all antidiabetic drugs (ATC code: A10) in combination with antidepressants. Survival analysis was performed using Danish healthcare registers to evaluate the potential benefits of GLP-1 analogues (GLP-1a) in older patients. Results: Metformin showed a positive trend without reaching strong statistical significance in ameliorating psychiatric symptoms in a meta-analysis of randomized controlled trials involving schizophrenic patients [SMD (95%CI) = -0.40 (-0.82;0.01), OR (95%CI) = 0.5 (-2.4;3.4)] and reducing the reporting risk of therapy failure in depressive patients [ROR95=1.14, PPR(p)= 1.07 (0.00), EBGM95=0.96 ERAM95=0.89 in FAERS and ROR95=1.48 PPR(p)= 1.34 (0.00) EBGM95=1.22 and ERAM95=0.86 in VigiBase]. GLP-1a and DPP-4 inhibitors (DPP-4i) resulted in better outcomes with a preference for GLP-1a for reducing the risk of major cognitive impairment (dementia) in old diabetic patients [aHR (95% CI) = 1.5 (1.16-2.04), p = 0.003 for DPP-4i compared to GLP1-a (reference group)]. GLP-1a resulted also in a lower reporting rate of therapy failure in depressive patients compared to DPP-4i [ROR95=0.66 vs 0.86 in FAERS and ROR95=0.92 vs 1.06 in VigiBase, respectively]. Conclusions: GLP-1 analogues may offer more substantial clinical benefits. Regarding metformin, there is insufficient evidence of its cognitive benefits. Further research is necessary to confirm these findings and explore their clinical significance.