The Potential Role of SGLT2 Inhibitors in the Treatment of Depression: Mechanisms and Clinical Prospects.

Major depressive disorder (MDD) is a high-burden psychiatric illness characterized by persistent low mood, diminished interest, and cognitive impairment. Its global prevalence continues to rise, accompanied by a significant risk of suicide. Traditional first-line treatments, such as selective serotonin reuptake inhibitors (SSRIs), are limited by delayed onset, limited response rates, and adverse effects, which has spurred the exploration of novel therapeutic strategies. A growing body of research indicates that the pathogenesis of MDD extends beyond the monoamine hypothesis, also involving neuroinflammation, oxidative stress, hypothalamic-pituitary-adrenal (HPA) axis dysfunction, and cerebral energy metabolism impairment. Notably, there is a well-established bidirectional association between MDD and type 2 diabetes (T2DM), with the prevalence of depression nearly doubling among diabetic patients. The pathological processes shared by both conditions include insulin resistance, oxidative stress caused by chronic hyperglycemia, accumulation of advanced glycation end products (AGEs), persistent low-grade inflammation, and overactivation of the HPA axis. These mechanisms work synergistically to promote neuronal damage and emotional dysregulation. In recent years, sodium-glucose cotransporter 2 inhibitor (SGLT2i) have emerged as a novel therapeutic direction with dual "metabolic-neural" regulatory potential, as they may intervene in multiple key pathways central to the comorbidity of MDD and T2DM by mitigating neuroinflammation and oxidative stress, inhibiting apoptosis, and enhancing synaptic plasticity. Although evidence for their application in the psychiatric field remains in its early stages, current preclinical and observational studies have already demonstrated significant potential. It is important to emphasize that SGLT2i may still cause adverse effects such as sleep disturbances and anxiety, requiring cautious evaluation in psychiatric applications. Additionally, there is still a significant lack of prospective randomized controlled trials with depression improvement as the primary endpoint, and their true antidepressant efficacy and safety await further validation. This review discusses their therapeutic potential and provides a foundation for developing comprehensive treatment strategies for patients with comorbid MDD and T2DM.