Objective To investigate clinical efficacy of Jiaotai Wan (JTW, 交泰丸), and selective serotonin reuptake inhibitors (SSRIs) in patients with depression, and to explore their underlying mechanisms. Methods Based on biological sample data from a previous multicenter, randomized, active-controlled parallel clinical trial, a total of 83 depression patients were divided into three groups: JTW group (n = 25), JTW combined with SSRIs group (n = 29), and SSRIs alone group (n = 29). A mixed linear model was used to analyze changes in short-chain fatty acids (SCFAs), neuroinflammatory markers [cyclooxygenase-2 (COX-2), prostaglandin E₂ (PGE₂)] and brain-derived neurotrophic factor (BDNF) before and after treatment in each group. Spearman correlation and structural equation modeling were used to explore the relationships between post-treatment biomarkers and clinical symptoms [Hamilton depression rating scale (HAMD) scores], and potential mediating pathways. Results HAMD scores decreased significantly from baseline in all three groups (P < 0.001), but there was no significant differences between the groups. The JTW group showed a significant increase in butyrate levels (P = 0.002) and maintained higher levels of acetate and propionate. The SSRIs group was associated with increased levels of isovalerate, isobutyrate, and hexanoate. After treatment, the JTW + SSRIs group showed significant increases in isobutyrate, isovalerate, and isohexanoate levels, and a significant decrease in acetate levels. The combined group had significantly higher BDNF levels than the other two groups (P < 0.05). The PGE₂ levels in the combined group were also higher than in the JTW group both at baseline and after treatment (P < 0.05). Correlation analysis showed a strong positive correlation between PGE₂ and BDNF in the combined group after treatment (r = 0.609, P < 0.001). In the SSRIs group, COX-2 was positively correlated with HAMD score (r = 0.451, P = 0.014). In the JTW group, isohexanoate was positively correlated with BDNF (r = 0.445, P = 0.026). Mediation analysis suggested a potential indirect effect in the combined group, where PGE₂ influenced HAMD scores through BDNF (indirect effect = −0.065, P = 0.093). Conclusion JTW alone, SSRIs alone and JTW combined with SSRIs all can effectively alleviate depressive symptoms. However, they showed different patterns in regulating gut SCFAs, neuroinflammation, and neurotrophic factors. JTW combined with SSRIs may modulate branched-chain fatty acid metabolism and promote a positive association between PGE₂ and BDNF, thereby creating a distinct pathway that differs from single therapies. These findings provide preliminary evidence for understanding the differential mechanisms of various antidepressant strategies, suggesting that personalized treatment should consider patients’ specific biological characteristics.

depression  /  Jiaotai Wan  /  selective serotonin reuptake inhibitors  /  short-chain fatty acids  /  neuroinflammation  /  brain-derived neurotrophic factor  /  cyclooxygenase-2  /  prostaglandin E₂  /  differential regulation  /  mediation analysis