OBJECTIVE To discriminate the anti-depression effect of Xiao-yao-san series prescriptions on forced swimming test (FST) rat model with metabolomics.METHODS The forced swimming test rat model was used to evaluate the action of antidepressant and the rat plasma was collected simultaneously.Xiao-yao-san (XY), Dan-zhi-xiao-yao-san (DZ) and Chai-hu-shu-gan-san (CH) formula were extracted with aqueous solution, and the final concentration was 46.3, 48.9 and 7.9 g· kg-1(the total amount of crude drug) , respectively.54 rats were divided into 6 groups randomly.The saline, velafaxin and Xiao-yao-san series extractions were orally treated to the rat groups for 2 weeks.A metabonomics method was used to evaluate the pathogenesis of depression and the mechanism of Xiao-yao-san prescriptions.Plasma samples were prepared and measured using NMR, and the data were processed with Microsoft Excel or analyzed by SIMCA-P software.Variable importance in projection statistics and loading plot were used to screen relative biomarkers.RESULTS Significant difference was observed between the FST group and control group, which was an illustration that the pharmacological model was duplicated successfully.The effect of Xiao-yao-san was similar to that of positive drug venlafaxin, while the effect of Dan-zhi-xiao-yao-san and Chai-hu-shu-gan-san is not as good as Xiao-yao-san.Compared with the control group, significant changes were observed in lactate, thrronine, Glu, choline, glucose in serum of positive and Xiao-yao-san group.CONCLUSION The NMR analysis suggested that Xiao-yao-san prescription was of significant anti-depression effect which is better than the effect of Dan-zhi-xiao-yao-san and Chai-hu-shu-gan-san.The forced swimming test rat model is a mature model to evaluate the pathogenesis of depression and to discriminate the anti-depression effect of Xiao-yao-san series prescriptions.