Xiaoyaosan- A Famous Herbal Formula With Multiple Antidepressant Bioactive Components

Xiaoyaosan (XYS), also called Free and Easy Wanderer, is a famous Chinese Herbal Formula for depression, with the function of coursing the liver and resolving depression, nourishing the blood and fortifying the spleen. It is from the formulary of the Pharmacy Service for Benifiting the people in Taiping Rea Volume 9 (1107), and comprises eight herbs: Radix Bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, Rhizoma Atractylodis Macrocephalae, Poria, Rhizoma Zingiberis Recens, Herba Menthae, and Radix Glycyrrhizae. The formula is fundamentally comprised of six herbs. Three of the herbs (Radix Bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba) are aimed at improving liver function, three (Rhizoma Atractylodis Macrocephalae, Poria, Radix Glycyrrhizae) are aimed at improving spleen function. Looking at it another way, three of the herbs serve primarily as nourishing tonics (Radix Angelicae Sinensis, Radix Paeoniae Alba, and Radix Glycyrrhizae) and three serve primarily as herbs to disperse stagnation (Radix Bupleuri, Rhizoma Atractylodis Macrocephalae, and Poria). The complete XYS formulation is filled out with two other herbs as adjuncts: Herba Menthae, to aid in the dredging of the liver; and Rhizoma Zingiberis Recens, to aid the function of the spleen. XYS has been used to treat depression for centuries in China.

Currently, the medication used to treat depression are selective serotonin reuptake inhibitors (SSRIs), examples of it are citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline; serotonin and noradrenaline reuptake inhibitors (SNRIs) such as duloxetine, venlafaxine and desvenlafaxine, and other antidepressants including agomelatine, bupropion, mirtazapine and vortioxetine, etc. XYS used alone or combined with antidepressants has been used to treat major depressive disorder (MDD) in China. A systematic review of randomized controlled trials to evaluate the efficacy of XYS in the treatment of MDD has showed that Xiaoyaosan combined with antidepressants was more effective than antidepressants alone, and was superior to antidepressants in terms of the score of Hamilton depression scale (HAMD) (Zhang, 2012). XYS exhibited similar effectiveness as antidepressants with fewer side effects. The combinational use of XYS with antidepressants prolonged remission time and reduced adverse side effects in most of the trials (Jing, 2015). XYS, with obvious antidepressant effect and less side effect, has bring a new hope for the development of better antidepressants.

Scientists have done series of researches on XYS, in order to find which components worked in the formula and their mechanisms of action on MDD. Due to the multiple components of XYS, the antidepressant mechanisms are complicated.  Researches has found 13 antidepressant active ingredients in XYS: saikosaponin A, saikosaponin C, saikosaponin D, ferulic acid, Z-ligustilide, atractylenolide I, atractylenolide II, atractylenolide III, paeoniflorin, albiflorin, liquiritin, glycyrrhizic acid and pachymic acid (Zhou, 2012; Liu, 2013; Gao, 2015). However, the detailed mechanisms for these ingredients are still not clear. Gao, et al. futher predicted 25 targets of main active ingredients of XYS according to reversed pharmacophore matching method (Gao, 2015). These targets include Carbonic anhydrase 2, Glutathione S-transferase P, Thymidylate synthase, Thrombomodulin, Acetylcholinesterase, Dihydrofolate reductase, Cystic fibrosis transmembrane conductance regulator, Glucocorticoid receptor, Amine oxidase [flavin-containing] B, Estrogen receptor Fatty acid-binding protein, intestinal, etc. They are mainly involved in the energy metabolism-immune- signal transmutation relevant biological processes. The finding of these targets provides a scientific basis for deep research of antidepressant mechanism of XYS. Meanwhile, the antidepressant effect of XYS reflects the features of multi-components, multi-targets and multi-pathways, which is a new trend for finding inovative medicine.

Work Cited


GAO Y, GAO L, GAO XX, et al. An exploration in the action targets for antidepressant bioactive components of Xiaoyaosan based on network pharmacology. Acta Pharmaceutica Sinica 2015, 50 (12): 1589?1595 (in Chinese).

Jing LL, Zhu XX, LV ZP, et al. Effect of Xiaoyaosan on major depressive disorder. Chin Med ,2015 (10):18.

Liu JL, Yang L, Cui J, et al.  Preliminary study on serum pharmacochemistry of petroleum ether fraction in ethanol     extract from Xiaoyao Powder based on UPLC-PDA [J].  Chin Tradit Herb Drugs, 2013: 2816?2822.

Zhang Y, Han M, Liu Z, et al. Chinese herbal formula xiao yao san for treatment of depression: a systematic review of randomized controlled trials. Evid Based Complement Alternat Med. 2012:1-13.

Zhou YZ, Ren YL, Ma ZJ, et al.  Identification and quantification of the major volatile constituents in antidepressant active fraction of Xiaoyaosan by gas chromatography-mass spectrometry [J].  J Ethnopharmacol, 2012, 141: 187?192.

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