Systems Pharmacology-Based Research on the Mechanism of Danzhi Xiaoyao San in the Treatment of Depression

Research Article

Austin Pharmacol Pharm. 2023; 7(1): 1026.

Systems Pharmacology-Based Research on the Mechanism of Danzhi Xiaoyao San in the Treatment of Depression

Jingxiao Zhang1,2; Ziyi Chen1; Fengge Gao2; Yanli Fan2; Xuezhen Huang2; Wei Zhou1-3*

1State Key Laboratory of Respiratory Disease for Allergy at Shenzhen University, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen University, China

2College of Food and Drug, Luoyang Normal University, China

3Department of Respirology & Allergy. Third Affiliated Hospital of Shenzhen University, Shenzhen University, China

*Corresponding author: Wei Zhou State Key Laboratory of Respiratory Disease for Allergy at Shenzhen University, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen University, China. Tel: +0379-68618516 Email: [email protected]

Received: May 09, 2023 Accepted: June 08, 2023 Published: June 15, 2023


Depression is a common and serious mental disorder characterized by persistent feeling of sadness and loss of interest in activities. Despite conventional treatments can improve depression symptoms and prevent a recurrence, complementary and alternative therapies are necessary to be involved because of the detrimental effects of the current therapy. Traditional Chinese Medicine (TCM) formulas are considered to be a potential complementary method with special advantages for treating the multiple pathogenesis of depression in a holistic way. However, the underlying pharmacological mechanism of TCM formula on depression therapy remained elusive. Therefore, in current study, a systems pharmacology approach integrating Absorption, Distribution, Metabolism, and Excretion (ADME) filtering, target fishing, gene enrichment analysis, network pharmacology, and pathway analysis was developed to comprehensively explore the multiple therapeutic mechanisms of Danzhi Xiaoyao San (DZXYS) for the treatment of depression. Finally, 111 active components and 112 potential targets of DZXYS were identified through ADME filtering and target fishing. Gene enrichment analysis found that DZXYS played a significant role in treating depression through the regulation of multiple pathogenesis including neurotransmitter systems imbalance, brain derived neurotrophic factor, hypothalamic-pituitary-adrenal axis dysregulation, inflammation, and immune. Moreover, the compound-target and target-pathway networks were constructed to elucidate the therapeutic mechanism of DZXYS from the system perspective. This study proposes a promising way for facilitating in-depth understanding of the complicated therapeutic mechanism of TCM on depression.

Keywords: Danzhi xiaoyao san; Systems pharmacology; Active compounds; Depression; Mechanisms


Depression is a multifactorial psychiatric disorder, characterized by specific symptoms including listlessness, interest drops, extreme of inferiority, hopelessness or guilt and a reduced ability to enjoy life [1]. According to the report released by World Health Organization (WHO), more than 350 million people worldwide are affected by depression, leading to a tremendous public health burden [2]. Evidence showed that depression is a systemic disease rather than a mental disorder, which always involves different pathophysiology mechanisms including neurotransmitter systems imbalance, decreased Brain Derived Neurotrophic Factor (BDNF), abnormal gene expression, Hypothalamic-Pituitary-Adrenal (HPA) axis dysregulation, impaired inflammatory response and immune regulation.

Antidepressant drugs are commonly used to help alleviate the symptoms of depression and prevent relapse of the illness. The current available clinical antidepressant medications mainly act on monoamine transmitters including serotonin and norepinephrine [3]. However, these drugs often cause detrimental effects, such as lagging, low compliance and failed treatment, which will lead to the intolerant or refractory responses of many patients [4,5]. Therefore, it is urgent to develop antidepressant drugs based on multiple pathogenesis against depression. Traditional Chinese medicine (TCM) as one of the major complementary and alternative medicine therapies featured as multi-components and multiple targets have been shown to possess special advantages for the treatment of complex pathogenesis of depression [6,7].

Danzhi Xiaoyao San (DZXYS), recognized as a classical prescription from Abstract for Chinese Internal Medicine (Nei Ke Zhai Yao) has been widely used to treat depression for many years. This herbal formula is composed of Radix Bupleuri (Chai- Hu), Paeoniae Radix Alba (Bai-Shao), Angelica Sinensis Radix (Dang-Gui), Fu-Ling, Atractylodes macrocephala Koidz. (Bai-Zhu), Licorice (Gan-Cao), Moutan Cortex (Mu-Dan-Pi), and Gardeniae Fructus (Zhi-Zi). A previous clinical study suggested that DZXYS played a significant role in lowering the Hamilton depression scale (HAMD), reducing the scores of anxiety/somatization, reversing cognitive impairment and feeling of despair in depressive patients [8]. Although DZXYS exhibit multiple therapeutic effects for relieving the symptoms of depression, its active compounds, related targets, pathways and underlying pharmacological mechanism remain elusive.

Systems pharmacology has been suggested as a promising approach to shift away from the traditional “one-drug, one-target, one-disease” towards the “multi-component, multi-target” strategy, which will shed light on a comprehensive investigation to systemically dissect the relationship between drugs, targets, pathways and diseases, as well as the potential pharmacological mechanisms of herbal formulae on disease therapy. Growing evidence revealed that systems pharmacology method is capable of uncovering the complicated pharmacological mechanisms of TCM herbs and formulas on the treatment of various diseases. For example, the combinatorial rule and the pharmacological mechanisms of Qing-Luo-Yin and Liu-Wei-Di-Huang Pill for the treatment of rheumatoid arthritis and various diseases were elucidated from a network/systemic perspective [9,10]. In our previous work, systems pharmacology has been successfully used to explore the potential mechanisms of the single herb and herb pairs for various diseases therapy [11,12]. In addition, a series of systems pharmacology frameworks have been developed to disclose the underlying mechanisms of TCM formulas for stroke, asthma and obesity [13-15].

Therefore, in current study, an integrative systems pharmacology strategy, which combines ADME (absorption, distribution, metabolism, and excretion) filtering, target fishing, gene enrichment analysis, network pharmacology and pathway analysis is proposed to reveal the multiple mechanisms of DZXYS in treating depression based on a holistic and systemic way. The detailed work flowchart is shown in Figure 1. The systems pharmacology framework constructed in our study not only sheds light on providing a probe to explore the complex therapeutic mechanism of DZXYS for depression at the system level, but also promotes the modernization and internationalization of TCM formulas.