Abstract: OBJECTIVE To identify potential anti-depressant lead compounds and biomarkers， through observing the behavioral and serum metabolome changes induced by chronic stress in rats. METHODS Twenty-four rats were randomly divided into three groups including normal， model and treatment groups. Six-week of chronic unpredictable mild stress (CUMS) of rats were chosen as chronic depressed model. Weight change， sucrose water preference and opening test were used as indicators of depression assessment. Synephrine (Syn 20 mg/kg) was gavaged once a day in late two weeks. After two weeks of intervention， the serum of rats was collected， and GC-MS/MS were used to detect the changes of endogenous metabolites in rat serum and the drug therapy， to discover potent anti-depressant lead compound， biomarker and relative pathway. RESULTS Synephrine alleviated depression-like behavior and changed 14 metabolites including ethanolamine phosphate， benzoic acid， cholesterol and glutamic acid in CUMS rat serum. Nine targeted metabolic pathways involving synephrine， such as glutamine and glutamate metabolism， valine and isoleucine biosynthesis， were discovered. CONCLUSION Synephrine may be against depression-like behavior mainly via regulating mechanism and biosynthesis from glutamate， valine and isoleucine.