An Enigma of Brain Gasotransmitters: Hydrogen Sulfide and Depression

Depression is a leading global cause of disability. Emerging evidence highlights glutamatergic dysfunction, particularly impaired NMDA receptor signaling, as a key contributor to its neurobiology. Hydrogen sulfide (H₂S), once regarded solely as toxic, is now recognized for its role in regulating synaptic plasticity, inflammation, and neuronal survival. This review synthesizes recent findings on the antidepressant effects of H₂S. In animal models, H₂S administration improves depression-like behaviors while modulating key pathways such as PI3K/AKT/mTOR, Sirt1, and the cGAS-STING pathway. These benefits extend across models of stress, neuropathic pain, diabetes, and sleep deprivation. Among H₂S donors, sodium hydrosulfide (NaHS) demonstrated the most consistent antidepressant effects in preclinical studies. Clinical studies further show that individuals with major depression exhibit lower plasma H₂S levels, with symptom severity inversely correlated to H₂S concentration. Together, these findings support a multifaceted role for H₂S in mood regulation and highlight its promise as both a therapeutic candidate and a potential biomarker in depressive disorders, though translational studies remain needed.