Plasma metabolomics and network pharmacology identified glutamate, glutamine, and arginine as biomarkers of depression under Shuganjieyu capsule treatment

Depression is a psychiatric disorder and confers an enormous burden on society. Mild to moderate forms of depression (MMD) are particularly common. Our previous studies showed that the Shuganjieyu (SGJY) capsule might improve depressive and cognitive symptoms in patients with MMD. However, biomarkers evaluating the efficacy of SGJY and the underlying mechanism remains unclear. The aim of the present study was to discover efficacy biomarkers and explore the underlying mechanisms of SGJY as antidepression treatment. Twenty-three patients with MMD were recruited and administered with SGJY for 8 weeks. Results showed that the content of 19 metabolites changed significantly in the plasma of patients with MMD, among which 8 metabolites improved significantly after SGJY treatment. Network pharmacology analysis showed that 19 active compounds, 102 potential targets, and 73 enzymes were related to the mechanistic action of SGJY. Through a comprehensive analysis, we identified four hub enzymes (GLS2, GLS, GLUL, and ADC), three key differential metabolites (glutamine, glutamate, and arginine), and two shared pathways (alanine, aspartate, and glutamate metabolism; and arginine biosynthesis). Receiver operating characteristic curve (ROC) analysis showed that the three metabolites had a high diagnostic ability. The expression of hub enzymes was validated using RT-qPCR in animal models. Overall, glutamate, glutamine, and arginine may be potential biomarkers for evaluating the efficacy of SGJY. The present study provides a new strategy for pharmacodynamic evaluation and mechanistic study of SGJY, and offers new information for clinical practice and treatment research.