Metformin as a potential antidepressant: Mechanisms and therapeutic insights in depression.

Depression is one of the most disabling psychiatric disorders, whose pathophysiology has not been fully understood. Increasing numbers of preclinical studies have highlighted that metformin, as the first-line hypoglycaemic agent, has a potential pleiotropic effect on depression. Moreover, there is emerging evidence that metformin shows antidepressant activity and improves depressive symptoms in rodent models of depression. However, the exact role and underlying mechanism of metformin in depression remain unclear and still need to be investigated. Recent studies suggest that metformin not only improves neuronal damage and structural plasticity in the hippocampus but also enhances the antidepressant effect of antidepressants. Therefore, in this review, we summarize the existing evidence for the use of metformin as a psychopharmaceutical and elaborate on the underlying mechanisms of metformin in mitigating the onset and progression of depression, as well as the associated biochemical signaling pathways and targets involved in the pathogenesis of depression. After reviewing several studies, we conclude that metformin helps reduce depressive symptoms by targeting multiple pathways, including the regulation of neurotransmitters, enhanced neurogenesis, anti-inflammatory effects, and changes in gut microbiota. We aim to gain a deeper understanding of the mechanism of action of metformin and provide new insights into its clinical value in the prevention and therapy of depression.