Repurposing glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of depression: A systematic review of preclinical, observational and clinical investigations

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), currently used for metabolic conditions, have demonstrated potential antidepressant effects via neuromodulatory pathways. This systematic review aims to provide evidence on the antidepressant effects of GLP-1 RAs and elucidate their underlying mechanism of action. METHODS: We examined studies that investigated the effect of GLP-1 RAs on depressive symptoms. A comprehensive search was performed, and articles were retrieved from MEDLINE, PubMed, and PsychINFO. Both animal and human studies were included. RESULTS: 18 preclinical studies, 5 observational studies, and 3 clinical studies were included in our systematic review. Among the preclinical studies, 15 out of 18 (83 %) reported significant antidepressant-like effects, associated with enhanced neuroplasticity, reduced neuroinflammation, and neurotransmitter alterations. Observational studies indicated mixed results, with 4 out of 5 studies reporting reductions in depressive symptoms. However, only 1 of the 3 clinical trials showed statistically significant antidepressant effects. DISCUSSION: GLP-1 RAs show promise as treatment for depression through multiple neuromodulatory mechanisms. While there is strong preclinical evidence, observational results are mixed, and clinical findings are still preliminary. There is a need for short and long-term studies to establish whether GLP-1 RAs are capable of treating and/or preventing depressive symptoms and episodes in adults with major depressive disorder (MDD).