The objective of the present study was to make comparison between rat models of depression achieved by chronic unpredictable mild stress (CUMS) and reserpine injection from the angle of traditional Chinese medicine syndrome, depict the regularity of syndrome variation of the two models, and preliminarily explain its molecular mechanism. Rat depression models were achieved respectively by CUMS and intraperitoneal reserpine injection. The syndromes of liver stagnation, spleen deficiency and liver stagnation with spleen deficiency were judged by equivalently transforming the related clinical symptoms and into macro-characterization of rats. Elisa was used to measure the content of 5- serotonin (5-HT) in serum and Immunohistochemical method was used to measure the content of 5-HT in the hippocampal tissue CA2 district. The regularity of syndrome variation is: Rats in the CUMS group developed liver stagnation syndrome 2 weeks after stress and liver stagnation with spleen deficiency syndrome 6 weeks after stress, while rats in the reserpine injection group developed spleen deficiency syndrome 2 weeks after injection and liver stagnation with spleen deficiency syndrome 4 weeks after injection. Compared with the normal group, rats in CUMS group and reserpine group both presented persistent decrease in brain tissue 5-HT content (P<0.05) and increase in serum and intestine tissue 5-HT content (P<0.05), while degree of increase or decrease differed in the two groups in different period. The model of depression achieved by CUMS develops from liver stagnation syndrome gradually into Liver stagnation and Spleen deficiency syndrome, whose biological basis is that the onset of central 5-HT system dysfunction is faster than the peripheral 5-HT system for the stress conditions; The model of depression achieved by reserpine injection develops from spleen deficiency syndrome gradually into Liver stagnation and Spleen deficiency syndrome, whose biological basis is that the increase of peripheral 5-HT is faster than the decrease of central 5-HT for the effect of reserpine.