Jie Gao,Weng-Jie Zhang,Fan Yang*

1School of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China. 2School of Traditional Chinese Medicine, Beijing University of Traditional Chinese Medicine,Beijing,China.

Abstract

Keywords: Depression, Five elements music method, Emotion inter-resistance therapy,Acupuncture treatment, Traditional Chinese medicine

Introduction

Depression is a kind of mental illness in today's society. Clinically, it is mainly characterized by depression, loss of appetite, insomnia,anxiety, cognitive dysfunction. A serious person can appear hallucination, even self-mutilation, and commit suicide. At present,with the acceleration of the pace of life and the increase of life pressure, the incidence of depression has increased significantly, and there is a trend of generalization and younger age. Western medicine mostly uses antidepressant drugs for treatment, but the side effects are obvious and easily repeated. In addition to traditional Chinese medicine (TCM) such as soothing the liver and relieving depression,invigorating spleen and tonifying kidney. There are also non-drug treatments such as emotion, music [1]. In this paper, we sort out the related research on the treatment of depression by TCM therapy to provide a reference for further research.

At present, the etiology and pathogenesis of depression are still unclear, which may involve social, psychological, and many other factors. Western medicine studies on the pathogenesis that depression is mainly caused by pro-inflammatory cytokines, interferon-γ and neopterin, the increase of reactive oxygen species and nitrogen, and damage to oxidative and nitrosative stress, coupled with decreased levels of antioxidants, which may potentially damage mitochondria and mitochondrial DNA, leading to neurodegeneration and reduced neurogenesis [2]. In TCM, depression belongs to the category of depression syndrome, which is divided into broad sense and narrow sense. In a broad sense, depression generally refers to the pathological state of stagnation of Qi, blood, and body fluid in the human body. In a narrow sense, depression refers specifically to a kind of disease syndrome with the stagnation of Qi and dysfunction of viscera as the main pathogenesis [3]. Based on TCM, depression belongs to liver wood, and the liver Qi should be stretched. If the liver Qi is stagnant,the emotions are not stretched, and feel depressed for a long time, it may become depressed. In addition to the liver, depression is also closely related to the heart, spleen, kidney, and other viscera. Liver stagnation for a long time injures the spleen, the spleen loses its function, accumulating dampness and generating phlegm; at the same time, liver stagnation suppresses the spleen and consumes heart Qi[4]. To sum up, the main pathogenesis is that due to emotional internal injury, the Qi machine is not smooth, and then the liver and spleen are lost in catharsis, the essence and blood are deficient, the primordial spirit is out of nourishment, and the Qi, blood and body fluids of the whole body run abnormally, resulting in depression, slow thinking and other main symptoms [1]. Clinically, at first, it was manifested as deficiency syndrome due to the loss of Qi and blood of Zang-fu organs. With the extension of the course of the disease, it becomes a syndrome of deficiency and excess [5]. In terms of treatment, it mainly focuses on tonifying deficiency and dispelling excess, to achieve the therapeutic effect [6]. In this review, we summarize the commonly TCM non-drug therapy and TCM drug therapy in treating depression (Figure 1).

Non-drug treatment of TCM

Emotion inter-resistance therapy

Emotion inter-resistance therapy, derived from theInternal Classic of the Yellow Emperor, is a method of skillfully using the biological restraint relationship of the five elements,using emotion to correct the emotions that are suppressed, to adjust the diseases caused by this bad emotion. Then it forms a psychological therapy in which sorrow overcomes anger, anger overcomes thinking, thinking overcomes fear,fear overcomes joy, and joy overcomes sadness. Li YQ, et al. used emotion inter-resistance therapy to carry out psychological intervention on patients with depression after cerebral infarction. The results showed that TCM emotional nursing could effectively improve the depressive symptoms of patients and was conducive to the rehabilitation of neurological function [7]. Yang L, et al. randomly divided patients with depression into control group and observation group; the control group received routine nursing; the observation group received emotional nursing, acupoint application, and auricular point pressing intervention based on routine treatment; the results showed that emotional nursing could effectively reduce the degree of depression [8]. Fan J, et al. believed that emotion inter-resistance therapy could balance the psychological state and achieve the purpose of treatment through the principle of five elements conquering each other [9].

At present, emotion inter-resistance therapy is the most frequently used TCM non-drug therapy. This therapy guides patients to produce one emotion to relieve another emotion so that the patient's emotions tend to be stable. From the perspective of modern psychotherapy, the principle of emotion inter-resistance therapy to relieve the excess energy of emotional stimulation, change the direction of emotional stimulation, and change the intermediary of emotion - cognition (ABC theory of rational emotional therapy) [10], which is similar to the cognitive behavioral therapy commonly used in the treatment of depression. However, it is necessary to formulate different treatment plans for different patients. The characteristics of individualization and differences are prominent, and the treatment has limitations. At present, further research and discussion are still needed to promote the clinical application of emotion inter-resistance therapy in the treatment of depression.

Emotion leading treatment

Emotion leading treatment refers to a kind of method for medical staff to contact patients with abnormal emotions and psychological concerns such as depression, doubt, anxiety, low self-esteem through non-drug means, which can make the patient's Qi harmonious. There are mainly language enlightenment, emotional guidance therapy,environmental adaptation therapy, and other treatment methods. He ZL, et al. took psychological counseling and mental nursing intervention on patients with depression, which could effectively reduce the mood of depression and anxiety and improve their quality of life [11]. Yao XQ carried out emotional nursing interventions on patients with post-stroke depression, such as empathy counseling. The results showed that emotional nursing interventions effectively improved the mental and psychological state of patients [12]. Liu XY divided patients with postpartum mild depression into the control group and intervention group. The control group received routine nursing and the intervention group received systematic psychological counseling intervention. The results showed that psychological counseling could effectively relieve depression [13].

Emotion leading treatment can make patients with depression feel comfortable improve the bad stress in the process of treatment and reduce the degree of depression. At the same time, it alleviates the patients' anxiety, tension, anxiety, and other adverse emotional reactions, and provides convenience for the further treatment of depression. In addition, as a non-drug therapy, the emotional counseling method is simple and easy to learn. Clinical medical staff can carry out treatment, which is suitable for large-scale promotion.

Five element music therapy

As a traditional Chinese music therapy based on Yin Yang and the five elements theory, five elements of music therapy is a part of TCM. Due to the nature of music, it is divided into five tones (Jiao, Zhi, Gong,Shang, Yu), which connect the five internal organs (liver, heart,spleen, lung, kidney) and the five emotions (anger, joy, anxiety,worry, fear) [14]. By balancing Yin and Yang, regulating Qi and blood circulation in the human body [15], it has the functions of relieving depression and nourishing the liver, calming the heart and mind,regulating Qi and resolving phlegm, strengthening the spleen and nourishing blood, and nourishing kidney Yin [16]. Liao J, et al.randomly divided cancer patients with depression into the control group and treatment group. The treatment group received five elements of music therapy. After the evaluation of their depression, it was found that the degree of depression in the treatment group was significantly reduced [17]. By searching the database, Zhu Y, et al.found that music, yoga,massage, and exercise can alleviate the degree of depression in patients with prenatal depression, of which the therapeutic effect of five-element music is more significant [18]. Mi JG, et al. took five element music therapy to intervene patients with depression and observed the effect on brain wave α. The study found that five element music therapy can increase the frequency and amplitude of α waves related to the degree of depression, and improve the symptoms of depression and anxiety in patients with depression[19]. Chen CJ, et al. divided nursing students with depressions into the control group and music group. The music group received five element music therapy based on maintaining routine life. The results show that Chinese five element music therapy can effectively reduce the depression level of depression students [15]. Zhang HW provided the combination treatment of five elements music and acupuncture for female patients with depression. The results showed that the combined treatment significantly reduced the severity of depression and anxiety, as well as adverse reactions [20]. Lin FK, et al. randomly divided patients with post-stroke depression into the control group and treatment group. Both groups received basic treatment, and the treatment group also received five element music therapy. The results show that five element music therapy can improve the depressive symptoms of patients [21].

Figure 1 Traditional Chinese medicine treatment methods involved in this review

The treatment cycle of depression is long, the treatment effect is unstable and prone to recurrence. At the same time, the price of antidepressants is expensive. Patients often give up treatment because of the economic burden and treatment cycle. The five elements music therapy has no time and place restriction, so it is easier to be accepted by patients, which is beneficial to the treatment of depression.Five-element music therapy mainly relieves depressive symptoms by alleviating anxiety, insomnia, restlessness, and other adverse reactions, and the operation is simple and easy to learn. It can be recommended as one of the most characteristic non-drug therapy to assist the treatment of depression.

Acupuncture therapy

Acupuncture therapy is a TCM treatment method that stimulates acupoints with needles to produce a therapeutic effect [22].Moxibustion is burned on acupoints by herbal moxibustion (Artemisia annua or Artemisia annua) [23], using warm heat to stimulate the treatment of human acupuncture points. Caroline, et al. found that acupuncture and moxibustion treatment can effectively reduce the severity of depression in patients with depression through database retrieval [24]. Tao WW, et al. analyzed 67 randomized controlled trials in the database and found that acupuncture treatment can relieve depression complications such as vomiting, diarrhea, and insomnia [25]. Yang NN, et al. found that acupuncture can alleviate primary depression and reduce the side effects of antidepressants by studying the animal model of patients with depression [26]. Through randomized trials, Zhao BC, et al. found that acupuncture combined with selective serotonin reuptake inhibitors can effectively improve the depressive symptoms of moderate to severe depression, and has advantages in improving anxiety, somatization, and sleep disorders[27]. Zhang K, et al. found that acupuncture combined with antidepressants was more effective than antidepressants alone after a meta-analysis by searching and screening databases [28]. Liu J, et al.randomly divided patients with depression into control group and observation group. The observation group was treated with acupuncture and the control group was treated with sham acupuncture. The results showed that acupuncture was effective and safe in the treatment of depression [29]. Ormsby SM, et al. treated pregnant women with depression with routine treatment plus acupuncture. The results showed that acupuncture was feasible and effective in improving mental health [30]. Wang Y, et al. treated patients with mild to moderate depression with acupuncture ghost point combined with fluoxetine. The results showed that acupuncture combined with drug treatment can significantly improve the clinical treatment effect [31].

At present, acupuncture as a characteristic therapy of TCM has been recognized by the International Health Organization, and acupuncture is effective in the treatment of depression complications such as pain and insomnia, which can effectively relieve the pain of patients.Acupuncture can treat patients with mild to moderate depression in isolation and relieve symptoms of primary depression. At the same time, acupuncture and moxibustion can also be combined with antidepressant drugs as adjuvant therapy to reduce the side effects of drug treatment, with the advantages of fast onset and long curative effect. However, the therapeutic effect of acupuncture may be related to the experience of the acupuncturist, the choice of acupoints, and other interventions. The efficacy of acupuncture combined with other antidepressant drugs still needs to be verified by more experiments.Moreover, the scale of most clinical trials of acupuncture and moxibustion is small, and the individual differences of patients are significant. Further experimental research is needed on whether it can be popularized on a large scale and the potential harm of acupuncture at the wrong acupoints.

TCM drug therapy

In clinical practice, Chinese herbal medicine has certain advantages and potential compared with western medicine in the treatment of depression. The curative effect of western antidepressant drugs is short, and long-term use produces drug dependence, accompanied by dizziness, nausea, vomiting, and other adverse reactions. TCM emphasizes the holistic view of mind-body integration and Chinese herbal medicine it has certain therapeutic advantages in the prevention and treatment of depression. Modern research showed that the multi-target, multi-mechanism, and multi-way action of Chinese herbal medicine plays an important role in the prevention and treatment of depression [32]. We summarized the frequently used Chinese herbs and formulae in treating patients with depression.

Jin Si Tao (Hypericum monogynum L.)

Jin Si Tao (Hypericum monogynum L.) is a kind of herbal plant in temperate regions, which is used as medicine in the dry aboveground part. It has bitter, astringent, and flat nature. It has the effects of soothing the liver and relieving depression, clearing heat, and dampness, reducing swelling, and relieving pain. It is mainly used to treat depression, obsessive-compulsive disorder, and other diseases.Wu QX, et al reviewed 27 clinical trials and compared the use of Hypericum perforatum and antidepressants, and found that Hypericum perforatum was more effective in patients with mild and moderate depression than antidepressants [33]. Shamabadi A, et al.provided evidence support for the safety and tolerability of Jin Si Tao(Hypericum monogynum L.) in the treatment of mild and moderate depression [34]. Zhao XJ studied the mechanism of Jin Si Tao(Hypericum monogynum L.) by constructing a rat model of postpartum depression. The results showed that hypericin can effectively relieve depression by reversing glucocorticoid metabolism, increasing the expressionofestrogenreceptors,andthenrelieving neuroinflammation, which is as effective as fluoxetine [35]. Warnick SJ, et al. analyzed the clinical data and found that the main antidepressant components in Jin Si Tao (Hypericum monogynum L.)were hypericin, and several flavonoids, which may be involved in antidepressant treatment by inhibiting monoamine oxidase A,monoamine oxidase B, 5-hydroxytryptamine, and controlling the gene regulation of hypothalamus-pituitary-adrenal axis [36]. Liu H, et al.summarized five potential mechanisms of Jin Si Tao (Hypericum monogynum L.) in the treatment of depression, that is, inhibiting the reuptake of amine substances by synaptosomes, inhibiting monoamine oxidase, affecting serotonin receptors, and estrogen-like effect [37].

At present,Jin Si Tao(Hypericum monogynum L.)has been used as a substitute for antidepressants in the treatment of mild and moderate depression for decades. It is known as "natural fluoxetine" because it has the advantages of good tolerance, few and mild side effects, and remarkable therapeutic effects. However, the main antidepressant components and antidepressant mechanism of Jin Si Tao (Hypericum monogynum L.) are still in the research stage. Its therapeutic effect is mostly observed from short-term experiments in patients with mild and moderate depression, but the problems such as the effectiveness of the treatment of severe depression and the safety of long-term medication have not been solved. Therefore, it is necessary to continue to strengthen the research on the extraction and clinical application of antidepressant components.

Chaihu(Bupleurum)- Shaoyao (Paeonia lactiflora)

Chaihu (Bupleurum) and Shaoyao (Paeonia lactiflora) is the basic combination of prescription such as Xiaoyao powder,Sini powder,and Xiao Chaihu decoction. The combination of the two herbal medicine plays the function of nourishing blood and softening the liver, which has the characteristics of dispersing and collecting together,harmonizing Qi and blood, dispersing and softening [38]. Chaihu(Bupleurum) has the effect of relieving surface and reducing fever,soothing liver and relieving depression, and lifting Yang Qi, while Shaoyao (Paeonia lactiflora) has the effect of nourishing blood and collecting Yin, soothing liver and relieving pain, calming liver and suppressing Yang. Li X, et al. systematically elucidated the multi-compound, multi-target, and multi-mechanism of Chaihu(Bupleurum) and Shaoyao (Paeonia lactiflora) combined with antidepressants by constructing network pharmacology and evaluating chronic and unpredictable mild stress rat model [39].Zhou YZ, et al. observed the antidepressants effect of Chaihu (Bupleurum)and Shaoyao (Paeonia lactiflora) on chronic unpredictable mild stress by using behavioral indicators, 1H nuclear magnetic resonance, and ultra-high performance liquid chromatography tandem mass spectrometry metabolomics technology, and found that the drug had significant antidepressant effects [40]. Chen CC, et al. found that Chaihu (Bupleurum) and Shaoyao (Paeonia lactiflora) had antidepressant effects by regulating the metabolism of arginine and proline [41]. Chen YY, et al. established a chronic and unpredictable mild stress rat model as a depression model. The combined antidepressant mechanism of Chaihu (Bupleurum) and Shaoyao(Paeonia lactiflora) was analyzed by proteomics, which may be related to oxidative stress response, neuroplasticity, immune response, and neuroprotection [42]. Ge HY, et al. found in the rat swimming experiment that the main component of Bupleurum antidepressant is saikosaponin, and the high-dose saikosaponin group has the same effect on depression as the fluoxetine group [43]. The effectiveness of Shaoyao (Paeonia lactiflora) extract in animal models of depression showed that the effective component of antidepressant may be paeoniflorin, or it may be the combination of the two [44]. In short,the two herbal medicine can improve the depressive symptoms of rats by reversing the decrease of monoamine neurotransmitters, enhancing the expression of neurotrophic factor, brain-derived neurons, and receptor tyrosine protein kinase in the hippocampus of rats, and achieving antidepressant effect [45].

Chaihu(Bupleurum) and Shaoyao(Paeonia lactiflora) have obvious antidepressant effects, and their respective mechanisms of action and coordination, and compatibility have also been studied. The drug pair can be used as an adjuvant drug to be added to the later stage of depression treatment to prolong the therapeutic effect and reduce the recurrence of the disease. At the same time, the main antidepressant components in Chaihu (Bupleurum) and Shaoyao (Paeonia lactiflora)can be extracted to develop new antidepressant drugs, or the extract can be added to antidepressant drugs to improve drug efficacy and reduce adverse reactions.

Baihe Dihuang decoction

Baihe (Liliumbrowniivar.viridulum), cold in nature and sweet in taste,has the effects of nourishing Yin and moistening the lungs, clearing the heart, and calming the mind. It belongs to Yin-tonifying drugs classified under deficiency-tonifying drugs. Dihuang (Rehmannia glutinosa) is sweet in taste and cold in nature. It has the effects of clearing heat and cooling blood, nourishing Yin, and generating fluid.Baihe Dihuang decoction, recorded by Zhang Zhongjing inJingui Yaolue, has long been used as a tonic to nourish the heart and lungs,clear heat and lower blood, and is used to treat mental instability,absent-mindedness, restlessness, and depression [46].

Zhang H used high performance liquid chromatography to measure the levels of main markers in Baihe Dihuang decoction and found that compared with the depression group, Baihe Dihuang decoction reduced the degree of depression. Moreover, the synapses of GABAergic and glutamatergic and brain-derived neurotrophic factor(BDNF)/TrkB-dependent phosphoinositide 3-kinase (PI3K)/Akt/mammalian rapamycin-1 target protein (mTOR1) may be the main signal pathways of Baihe Dihuang Decoction in the multi-target treatment of depression [47]. Zhang HX found that Baihe Dihuang decoction can improve depressive symptoms by eliminating the defect of inhibitory/excitatory neurotransmitters, restoring the balance of Pro/anti-inflammatory cytokines, and regulating the level of HPA axis hormones [48]. Pan J, et al. established a rat model of Yin deficiency and internal heat type and used multi-dimensional analysis of mRNA differentially expressed genes to confirm the scientificity of the model and the mechanism of Baihe Dihuang decoction in the intervention of yin deficiency and internal heat type depression [49]. Xue J, et al.constructed a rat model of chronic mild unpredictable stress and found that Baihe Dihuang decoction can reduce the activity content of monoamine oxidase, thus reducing the decomposition of monoamine neurotransmitters such as norepinephrine, 5-hydroxytryptamine, and dopamine, to achieve the effect of antidepressant [50]. The antidepressant mechanism of main chemical components in Baihe Dihuang decoction was shown in Figure 2.

Baihe Dihuang decoction has a long history in the treatment of depression, which has obvious effects, fast onset, and good safety. It can be used as a new compound antidepressant in clinical application.However, the key technical problems such as the preparation process of standard decoction, the quantity transmission relationship between medicinal materials, drinks, and standard decoction, the quality control of standard decoction, the quality markers of compound TCM,and the evaluation of the quality and efficacy consistency of compound preparation need to be solved urgently [51].

Conclusion

At present, the research on the treatment of depression with TCM has made some important progress, and the mechanism of some treatment methods has been proved. Multi-level and multi-target TCM therapy has obvious advantages in the treatment of depression, and some herbal medicine can be used as a substitute for antidepressants to make new drugs. However, the research on the treatment of depression by TCM is mostly superficial and lacks large-scale clinical application. In the future, we should pay attention to in-depth research on TCM treatment methods, form a comprehensive,multi-level and systematic TCM treatment plan, promote TCM characteristic therapy, and improve the quality of life of the patient with depression.

Figure 2 Antidepressant mechanism of main chemical components in Baihe Dihuang decoction