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The present study was aimed to discriminate the anti-depression of Xiao-yao-san series prescriptions on forced swimming test (FST) rat model via metabonomic. 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 (the total amount of crude drug), respectively. The saline, venlafaxin and Xiao-yao-san series extracts were orally treated to the rat groups for 2 weeks. The forced swimming test was used to evaluate the action of antidepressant and the plasma was collected simultaneously. Plasma samples were prepared and measured using NMR, and the data were processed with SIMCA-P software. Variable importance in score plot and loading plot were used to screen relative biomarkers. Significant difference was observed in the FST 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 plasma of venlafaxin and Xiao-yao-san groups. The 1H NMR analysis suggested that Xiao-yao-san prescription was of significant anti-depression effect which is better than that of Dan-zhi-xiao-yao-san and Chai-hu-shu-gan-san.