Sodium-Glucose Cotransporter-2 Inhibitors in Mood Disorders: A Narrative Review of Mechanisms, Evidence, and Challenges

Abstract: Mood disorders, including major depressive disorder and bipolar disorder, are frequently comorbid with metabolic syndrome, contributing to greater illness severity and poorer outcomes. Sodium-glucose cotransporter-2 inhibitors (SGLT-2i), a novel class of anti-diabetic agents, not only improve glycemic control but have also shown potential neuroprotective and cognitive benefits. This narrative review summarizes preclinical and clinical evidence on the application of SGLT-2i in mood disorders, with emphasis on their multifaceted mechanisms, including metabolic modulation, anti-inflammatory and antioxidant effects, mitochondrial protection, autophagy regulation, and enhancement of neurotrophic signaling. But it is also notable that current evidence remains limited and heterogeneous. Most clinical data derive from observational studies in diabetic populations and evidence supporting therapeutic effects in patients with established mood disorders is still preliminary. Other important limitations include the scarcity of disorder-specific randomized controlled trials, uncertainty regarding long-term safety in psychiatric populations, and potential interactions with psychotropic medications. Collectively, SGLT-2i may represent a mechanistically relevant and clinically exploratory approach at the interface of metabolic and psychiatric disorders, though further high-quality studies are required to establish their efficacy and safety in mood disorder populations. Keywords: SGLT-2 inhibitors, major depressive disorder, bipolar disorder, metabolic syndrome, neuroinflammation, neuroplasticity