Multi-Layered Antidepressant Mechanisms of Gami-Soyosan in a Corticosterone-Induced Mouse Model

This study aimed to evaluate the antidepressant-like effects of Gami-Soyosan (GSS) in a corticosterone-induced mouse model of depression. Behavioral assessments, including the forced swim test and tail suspension test, demonstrated that GSS significantly reduced immobility, indicating improved coping behaviors comparable to those of fluoxetine. Serum analysis revealed that GSS lowered pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α, indicating an attenuation of systemic inflammatory cytokine responses in this model. Metabolomic profiling further showed that GSS modulated amino acid and nitrogen-related pathways, including branched-chain amino acids, arginine, and histidine/β-alanine metabolism, supporting the restoration of metabolic homeostasis under stress. Distinct metabolic signatures were also observed when compared to fluoxetine, indicating that GSS may exert antidepressant-like effects through partially different mechanisms. In addition, <i>in vitro</i> experiments using neuronal cells demonstrated that GSS attenuated oxidative stress by reducing whole-cell ROS generation and enhancing lysosomal activity, highlighting a neuroprotective role. Together, these findings provide multi-layered evidence that GSS acts through behavioral, immune, metabolic, and oxidative pathways, supporting its potential as a complementary therapeutic approach for stress-related depression.