Sodium-Glucose Cotransporter-2 Inhibitors in Depression

Abstract

Novel treatment strategies that refract existing treatment algorithms for depressive disorders are being sought. Abnormal brain bioenergetic metabolism may represent an alternative, therapeutically targetable neurobiological basis for depression. A growing body of research points to endogenous ketones as candidate neuroprotective metabolites with the potential to enhance brain bioenergetics and improve mood. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally approved for the treatment of diabetes, induce ketogenesis and are associated with mood improvement in population-based studies. In this column, we highlight the rationale for the hypothesis that ketogenesis induced by SGLT2 inhibitors may be an effective treatment for depressive disorders.

A comprehensive meta-analysis on safety outcomes reveals the novel potentials of SGLT2is, especially preventing respiratory diseases

“…Fourth, our metaanalysis identified that SGLT2is were associated with lower incidences of aphasia and mental status changes. Meanwhile, Liebers et al proposed the hypothesis that ketogenesis induced by SGLT2is could be an effective treatment for depressive disorders (37). Fifth, our meta-analysis identified that SGLT2is were associated with a lower incidence of anemia.…”

“…Meanwhile, Liebers et al. proposed the hypothesis that ketogenesis induced by SGLT2is could be an effective treatment for depressive disorders ( 37 ). Fifth, our meta-analysis identified that SGLT2is were associated with a lower incidence of anemia.…”

Sodium‐glucose cotransporter 1/2 inhibition and risk of neurodegenerative disorders: A Mendelian randomization study

“…Recent studies have increasingly highlighted the neuroprotective effects of SGLT2 inhibitors. Population‐based studies suggest that SGLT2 inhibitors are associated with a decreased risk of dementia and depression (Liebers et al., 2023 ; Wu et al., 2023 ). Preclinical experiments have shown that these medications can improve brain energetics (Pawlos et al., 2021 ), and a recent randomized controlled trial demonstrated improved mood outcomes with the selective SGLT2 inhibitor empagliflozin in combination with citalopram (Zandifar et al., 2024 ).…”