Challenge and Prospect of Traditional Chinese Medicine

in Depression Treatment
YUAN-WEI ZHANG1*, Yung-Chi Cheng2

1
School of Life Sciences, Guangzhou University, China, 2Department of Pharmacology,
School of Medicine, Yale University, United States
Submitted to Journal:
Frontiers in Neuroscience

Specialty Section:
Neuropharmacology

ISSN:
1662-453X

Article type:
Perspective Article

Received on:

o n al
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04 Jan 2019

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Accepted on:

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18 Feb 2019

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Provisional PDF published on:

P r 18 Feb 2019

Frontiers website link:

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Citation:
Zhang Y and Cheng Y(2019) Challenge and Prospect of Traditional Chinese Medicine in Depression
Treatment. Front. Neurosci. 13:190. doi:10.3389/fnins.2019.00190

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 1 Challenge and Prospect of Traditional Chinese Medicine in Depression
2 Treatment
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4 Running title: TCM and Depression Treatment
5 Keywords: Depression, Depression Treatment, TCM, Antidepressant, Systems Medicine, and TCM formula.
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7 Yuan-Wei Zhang1,2,⁎ and Yung-Chi Cheng2
8 1, School of Life Sciences, Guangzhou University, Guangzhou, China
9 2, Department of Pharmacology, School of Medicine Yale University, New Haven, USA
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11 Correspondence:
12 Dr. Yuan-Wei Zhang
13 yuanwei.zhang@yale.edu
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49 Abstract
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51 Current medications for depression are inadequate and far from ideal. Development of novel antidepressant
52 drugs is a pressing task. The discovery of ketamine and the related agents represents a new era in drug
53 discovery for rapid treatment of depression. Due to potential neurotoxicity, short-lasting efficacy, limitation of
54 single target approach, and a limited role in depression prevention of these agents, additional approaches or
55 drugs that exert synergy and compatibility with the rapid-acting agents are required for a better treatment.
56 Traditional Chinese Medicine (TCM) is a systems medicine and its clinical experience and integrated theory for
57 diagnosis and treatment provides an alternative way for novel drug discovery in depression treatment. In TCM,
58 there are numerous claimed effective antidepressant formulas, but comprehensive research and evidence-based
59 clinical study are required for their acceptance. In this essay, we review current attempts in discovery of new
60 agents, TCM drug formulation, and TCM treatment of depression, and discuss the challenge and opportunity of
61 TCM in the new era of antidepressant discovery. TCM could provide an important resource in discovery of
62 novel agents, assistance of the rapid-acting antidepressants, development of new agents for female patients, and
63 prevention of depression at its early stages. Hence, study of depression with TCM not only provides an
64 opportunity to scientifically evaluate the benefits and risks of TCM, but also accelerates to develop novel
65 antidepressant agents by combining the principle of modern molecular medicine with the ideas of the empirical
66 systems medicine.
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 95 Depression is a chronic, recurrent, potentially life-threatening mental illness that affects approximately15-20%
96 of the globe population (Manji et al., 2001; Charney, 2004) and it is thought to be caused by a complex
97 interplay of genetic vulnerabilities and unfavorable environmental events. However, the specific genes or non-
98 genetic events are poorly defined (Nestler et al., 2000). Many genes or physical and emotional factors might be
99 involved in the etiology of depression. Hence, most experts agree that depression should be viewed as a
100 multigenetic and multifactorial syndrome.
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102 1. Development of new antidepressants
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104 Current monoaminergic systems-based medications for depression are far from ideal. Over the past three
105 decades, although immense efforts have been focused on development of novel treatments towards new
106 potential targets beyond the monoamine hypothesis, however, none of these attempts has succeeded in
107 development of any fundamentally novel medications (Berton and Nestle, 2006).
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109 Recently, the finding that ketamine, a NMDA receptor antagonist, produces rapid improvement in depression
110 has shifted efforts towards novel agents targeting the glutamatergic system (Berman et al., 2000; Zarate et al.,
111 2006). The mechanism of ketamine action has been identified to activate AMPA receptors, subsequently release
112 BDNF and activate mTOR signaling (Zhou et al., 2014; Maeng et al., 2008; Lepack et al., 2015). The work on
113 ketamine has led to investigations of several rapid-acting agents targeting NMDA receptor, which include
114 selective GluN2B antagonists, traxoprodil (Preskorn et al., 2015) and Ro-25-6891 (Li et al., 2011), and a
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NMDA receptor positive allosteric modulator, rapastinel (Burgdorf et al., 2013). Despite of their potential for

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drug abuse and neurotoxicity, these agents have been shown promise as rapid-acting antidepressants and

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119 There are many reasons for the difficulty in searching new antidepressants. First, most of the potential target

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120 proteins are broadly expressed throughout the brain and peripheral tissues, and exert diverse physiological
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effects in different brain regions. It increases our concerns about neurotoxicity of any agent directed against
these targets. Second, depression is a multifactorial and multigenetic syndrome, in which symptoms can vary
from patient to patient. Depression is not a unified syndrome. It is impossible to find a specific gene responsible
for induction or termination of depression in all patients. Third, single target approach has been successful when
applied to well-validated targets in the treatment of monogenic diseases, but is less effective for multifactorial
and multigenic diseases, in which various entities exist with different underlying pathological mechanisms
(Butcher, 2005). Therefore, improved strategies for effective treatment of depressive syndrome should
128 simultaneously target dysregulation of several genes involved in the pathophysiology of depression. Moreover,
129 considering their psychotomimetic, dissociative, and abuse potentials, the rapid-acting agents might be
130 beneficial only for the patients with severe forms of depression, but for most of the patients with mild and
131 moderate forms, the best healing approach should be to find the principal cause that is unique to each individual
132 patient and then to apply an appropriate medical treatment or psychotherapy for correcting the homeostatic
133 imbalances. A systems biology-orientated healing approach to this problem may exist through Traditional
134 Chinese Medicine (TCM).
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136 2. TCM and Depression
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138 TCM is an experience-based medicine that has been developed in China over thousands of years, and it
139 emphasizes on the integrity of human body and physical or emotional effects of external environment on the
140 internal stability. Dynamic homeostasis is its basic principle. In TCM, all illnesses result from homeostatic
141 imbalance, which can be occurred for a variety of social or environmental factors, and treatments aim to restore
142 internal balance. Based on its “systems” point of view, a typical treatment approach in TCM views the body as
143 a whole entity and cures an illness by not only alleviating its symptoms but also restoring the internal balance.
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145 More importantly, in TCM, a combination of multiple drugs is often used to ensure effective actions on various
146 targets (Figure 1). According to TCM, depression is caused by imbalance within organ systems that eventually
147 results in dysregulation of the brain function, and it is viewed as a multifactorial illness with varying
148 pathological mechanisms in different patients. Depression may be caused by stagnation of “Qi” (vital energy),
149 dysregulation of blood circulation, “Re” (inflammation), dampness and phlegm in body. A TCM practitioner
150 typically finds the principal cause of depression that is unique to each patient and adopts an acupuncture or
151 medical treatment. Release of stagnated vital energy is the general therapeutic principle for depression (Feng et
152 al., 2016). It may be supplemented by activating blood circulation, suppressing inflammation, or eliminating
153 phlegm and dampness.
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155 The systems, multi-drug, multi-target approach of TCM fits perfectly with the multifactorial pathophysiology of
156 depression. There are numerous TCM empirical antidepressant formulas, which are widely used for treatment of
157 patients with depression in East Asia today. Clinical researches have demonstrated that these antidepressant
158 formulas are effective (Yeung et al., 2015). On the other hand, although great efforts have been made to
159 scientifically elucidate these formulas, our understanding of their mechanism of action, bioactive constituents,
160 and pharmacology of synergy and compatibility of formulation is still at a rudimentary level. Facing the
161 challenge in the new era of antidepressant discovery, we are wondering what we can learn from the ancient
162 systems medicine in antidepressant discovery and how we can integrate the empirical TCM into mainstream
163 research in neuropharmacology of depression treatment. Here, we discuss future research directions and
164 possible roles of TCM in depression treatment.
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3. Prospect of TCM in depression treatment

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The discovery of ketamine and the related agents represents a new era in drug discovery for rapid treatment of
depression. It does not mean no role of TCM can play in developing novel antidepressants or approaches.
Conversely, we expect that the study of TCM will attract more attention and participation of outstanding
scientists in the near future for several reasons. First, side effects and drug abuse potentials are critical problems
with these glutamate transmission-targeted rapid-acting agents, although some agents have been claimed to
have fewer psychotomimetic side effects than ketamine (Zarate et al., 2006; Preskorn et al., 2008). These side
178 effects limit their chronic use. New agents that can be used on a daily sustained basis are needed. Second, the
179 rapid-acting agents are directed toward glutamate transmission and treatment with these agents increases spine
180 synapse formation. However, the new agent-induced synapses are lost after 1 week (Zarate et al., 2006;
181 Abdallah et al., 2015). It reflects that glutamate transmission is a critical factor but not the principal cause in the
182 pathophysiology of depression. Although these agents can rapidly but temporarily alleviate depressive
183 symptoms, new agents that can sustain the synaptic as well as the therapeutic actions of the rapid-acting agents
184 are needed. Third, it is common that the patients with depression are accompanying with other symptoms, such
185 as chronic fatigue, chronic pain, heartburn, lupus, chronic constipation, and so on. Additional medications as
186 adjuvants directed toward to those symptoms are needed. Fourth, like monoamine-based antidepressants, the
187 rapid-acting agents have a limited value in prevention of depression at its early stages. New approaches or
188 agents that can correct internal imbalance to prevent depressive symptoms at its early stages are needed.
189 What can TCM do in the new era in discovery of new antidepressants? Here, we list several aspects, but not
190 limited to, in which TCM could exert its excellence in development of new antidepressants or approaches.
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192 3.1. Developing new antidepressant agents.
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194 Identification of bioactive ingredients will significantly improve our understanding of the mechanisms of action
195 as well as benefits/risks of a TCM antidepressant formula at a molecular level. This effort will be also critical
196 for developing a TCM antidepressant formula as a novel antidepressant agent. It can be exemplified with the
197 study on ibogaine, a hallucinogenic alkaloid found in Tabernanthe iboga, and Yuanzhi-1, a triterpenoid saponin
198 separated from Polygala tenuifolia. Both herbs are empirically used for treatment of depression. Ibogaine has
199 been shown to be an inhibitor for both serotonin and dopamine transporters but unique among the transporter
200 ligands in which it inhibits noncompetitively and apparently binds to the extracellular surface of a cytoplasmic-
201 facing transporter conformation (Jacob et al., 2007; Bulling et al., 2012). On the other hand, Yuanzhi-1 was
202 reported to inhibit all three monoamine transporters with a high potency in a low nanomolar range (Jin et al.,
203 2014; 2015). The mechanism underlying antidepressant-like effects was thought to be their influence on
204 monoaminergic systems, but lack of selectivity for serotonin or serotonin/norepinephrine reuptake increases our
205 concerns about their additive side effects due to the rewarding effects evoked by elevated synaptic
206 concentrations of dopamine in the brain.
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208 Another example relevant to TCM is scopolamine, which is a natural compound isolated from Solanaceae
209 family of plants that have been used for surgical anesthesia. Scopolamine is a non-selective mAChR antagonist
210 and has been reported to have rapid antidepressant effects within days through blockade of mAChR1 on GABA
211 interneurons (Drevets et al., 2013; Voleti et al., 2013; Wohleb et al., 2016). These studies provide evidence that
212 scopolamine treatment results in a rapid burst of glutamate in the medial prefrontal cortex and increases the
213 number of spine synapses.
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3.2. Adjuvating the rapid-acting antidepressant agents.

Although the rapid-acting agents produce rapid antidepressant responses, the effects last for about 1 week, at
which time patients typically relapse (Duman, 2018). Therefore, additional agents that have synergistic activity
and compatibility with the rapid-acting agents are required for preserving the therapeutic efficacy. In TCM
practice, a patient with depression is usually given a formula in order to relieve the depressive symptoms by
using on a daily sustained basis for weeks. The composite formula is not unified formulation, rather based on
227 symptoms within organ systems, prescribed to fit each individual patient aiming at activation of blood
228 circulation, elimination of phlegm and dampness, correction of digestive and gastrointestinal dysfunction, or
229 improvement of immune function, etc. In this context, TCM could exert its strengths as an adjuvant to the rapid-
230 acting antidepressants through different underlying mechanisms.
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232 Among numerous TCM formulas, we use one prescribed for treatment of gastrointestinal (GI) diseases, “Dai-
233 Kenchu-To” (DKT in Japanese), as an example further to illustrate that TCM could be an ideal adjuvant. It is
234 well known that the bidirectional communication between the GI microbiota and the brain links the CNS with
235 peripheral intestinal functions by means of neural, endocrine, immune, and humoral interactions (Rhee et al.,
236 2009; Diaz Heijtz et al., 2011). Hence, GI tract and microbiota have been suggested to be involved in the
237 pathophysiology and etiology of depression (Schroeder et al., 2007; Arseneault-Breard et al., 2012; Desbonet et
238 al., 2008). Patients with GI tract-induced depression might not show complete remission in about one week with
239 the rapid-acting antidepressant treatment, an additional medication directed toward GI tract is required for a
240 better treatment.
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242 DKT is a three-herb decoction and used for treatment of GI disorders, including postoperative paralytic ileus,
243 ischemic intestinal disorders, irritable bowel syndrome, and Crohn’s disease (Hasebe et al., 2016). It has been
244 reported that DKT treatment prevents bacterial translocation and maintains microbiome diversity in rats with
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245 acute stress (Yoshikawa et al., 2013). Studies also showed that DKT increases intestinal blood flow in rats
246 (Murata et al., 2002) and small intestinal movement in dogs (Jin et al., 2001), and prevents postoperative
247 intestinal obstruction in rats (Tokita et al., 2007). From these studies, it is clear that DKT significantly improves
248 GI tract function and can eliminate the risk of GI tract dysregulation in the pathophysiology of depression.
249 Therefore, DKT should have a synergistic activity with the rapid-acting agents in GI tract-induced depression
250 treatment, but additional researches are needed to assess its synergistic efficiency and compatibility.
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252 3.3. Developing new antidepressant agents for women
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254 Studies reported that females are twice as likely to suffer from depression (Kuehner, 2017) and that
255 antidepressants have differential efficacy in males and females (Mazure and Jones, 2015; Soldin and Mattison,
256 2009). However, our knowledge on the gender-specific pathophysiology of depression is limited and currently
257 no antidepressants specific for women are available in the market. It should be noted that women suffering from
258 depression present additional variables for depression treatment. Studies have revealed that women are more
259 likely to experience depression during times of hormonal flux postpartum and perimenopausal periods (Ahokas
260 et al., 2001; Parker and Brotchie, 2004). Circulating sex hormones and the differences in inflammatory,
261 neurotrophic, and serotonergic responses to unfavorable events between sexes have been suggested to be
262 important factors in the pathophysiology of gender-specific depression (Bangasser and Valentino, 2014;
263 Labonte et al., 2017; Duman, 2017). Therefore, a better understanding of the gender-specific pathophysiology
264 of depression could help reveal novel and gender-specific therapeutic targets or approaches.
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Hsieh, 2011). Preclinical studies indicated that XYS exerts an antidepressant activity in stress-induced animal
models through various underlying mechanisms, including elevation of 5-HT contents in both cerebral cortex
and hippocampus, regulation of HPA axis, improvement of BDNF expression in hippocampus, and reduction of
cytokine levels in serum (Jing et al., 2015). XYS has also been showed immense promise as an antidepressant
agent in postpartum depression treatment in several clinical studies (Yang et al., 2018; Li et al, 2016). However,
its mechanism of action underlying gender-specific depression treatment is poorly understood. Most of the
preclinical studies on XYS have been performed in male rodents, and most of the clinical studies do not provide
278 gender-specific effects of treatment response. Thus, it is necessary to conduct these studies in female animal
279 models and obtain gender-specific clinical data, especially on cardiovascular system, neuroendocrine responses,
280 circulating hormones, and cognitive control circuits, for our understanding of its mechanism of action.
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282 3.4. Preventing depression at its early stages
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284 Clinical and basic studies have significantly improved our understanding of the pathophysiology of depression
285 and numerous pathological factors have been revealed to be involved in the development of depression. Notable
286 factors and systems include brain neurotransmitter systems, the HPA axis and cortisol, the innate immune
287 system and inflammatory cytokines, ovarian steroids, the GI system, adipose tissue and related peptides, the
288 microbiome, vascular endothelial growth factor, and gene polymorphisms (Duman et al., 2016). These systems
289 influence on susceptibility to depression and lead to an increased incidence of depression. Interactions between
290 these systems and CNS, and within these systems constitute an immense network across organ systems in the
291 pathophysiology of depression. Current efforts are focusing on identification of specific interactions between
292 these systems, and a large-scale, integrated network or database including all the interactions in the
293 pathophysiology of depression still remains to be generated. Once we attain such a network, we will be able to
294 elevate our study from the molecular level to the system level that will revolutionize our understanding of

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296 develop new approaches for prevention of depression.
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298 TCM is a systems medicine and it could play a role in prevention of depression. Here, we give an example
299 further to illustrate that TCM could prevent depression at its early stages. Immune dysregulation, specifically of
300 inflammatory processes, is associated with symptoms of depression. In particular, increased levels of circulating
301 pro-inflammatory cytokines and subsequent activation of brain-resident microglia contribute to neurobiological
302 changes underlying depression and then lead to depressive behavioral symptoms (Wohleh et al., 2016). Thus,
303 agents that exert anti-inflammatory activity could be used for prevention of depression before immune
304 dysregulation triggers neurobiological changes in the brain. We have recently investigated anti-inflammatory
305 activity of one major category, “Qing-Re-Yao” (medicines that treat inflammation related syndrome) (Guan et
306 al., 2018). Total 54 herbs in this category were studied by examining their effects on six main mechanisms
307 underlying inflammation. Our results indicated that 93% of the herbs exert anti-inflammatory activity via at
308 least one underlying mechanism and 68% via two or more mechanisms. TCM formulas aiming to alleviate
309 inflammation-induced depressive symptoms generally contain at least one herb in this category. Thus, we ask if
310 “Qing-Re-Yao”-containing antidepressant formulas can be used for preventing inflammation-induced
311 depressive symptoms. Several benefits generally have been acknowledged. First, TCM herbs can be used on a
312 daily basis, like most of off-counter daily supplements in pharmacy stores. Second, most of TCM herbs exert
313 their action via multiple mechanisms simultaneously. Compared to single-target drugs, the multi-target drugs
314 have more potentials to treat an illness with multiple symptoms, such as depression. Third, TCM is a
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In summary, for TCM, both challenge and opportunity are existing in the new era of antidepressant discovery.
The clinical experience and “systems” concept of TCM for diagnosis and treatment could provide an alternative
way for improving our understanding of the pathophysiological mechanism underlying depression and for
discovering novel antidepressant agents or approaches. We expect that translational medicine for complex
human diseases, such as depression, would benefit by the combination of principle of modern molecular
medicine with certain ideas of empirical TCM.

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345 Acknowledgements
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347 YWZ was funded by a research grant (69-18ZX10026) from Guangzhou University. We thank Dr. Ryota
348 Shinohara at Department of Psychiatry, Yale University School of Medicine for critical reading the manuscript
349 and helpful discussion.
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351 Author Contributions Statement
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353 YWZ and YCC wrote the manuscript.
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356 Conflict of Interest Statement
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358 The authors declare that they have no conflict of interest.
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519

520

521

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522 Figure legend
523
524 Figure 1. Composition of a typical TCM formula. In general, there are four classes of drugs in each formula:
525 emperor drugs, minister drugs, messenger drugs, and assistant drugs. One TCM formula contains at least one
526 emperor drug supplemented by minister, assistant, and messenger drugs at varying numbers from zero to
527 multiple, in order to ensure effective actions on various targets simultaneously. The empirical composite
528 formulas have been proven to have greater efficacy and safety than single drugs in clinical practices, possibly
529 due to their synergistic interaction and mutual detoxification (Ung et al, 2007). The composition and dosage
530 depend on signs or symptoms of individual patients and can be modified to fit specific individuals more closely,
531 which is in accordance with the idea of individual therapy in modern medicine. The major risk of TCM is
532 thought to use a combination of several herbs with some uncertain factors, such as toxicity, consistency of
533 bioactive ingredients, drug-drug interaction, and so on. All of these are major challenges to develop TCM, but
534 can be managed by the proper processing to minimize toxic effects, standardization of formulas by quality
535 control to ensure a consistent level of bioactive ingredients and reproducible pharmacological actions, and
536 dosing and avoiding usage at the same time with other drugs, respectively.
537
538
539

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Emperor drug Minister drug

i
acts on the main cause in acts on the main/second

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pathophysiology.

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causes in pathophysiology.

A classic TCM formula

Assistant drug
strengthens the effect of Messenger drug
Emperor drug, reduces the helps actions of other drugs
toxic effects of Emperor and on a particular organ of the
Minister drugs, or provides body.
paradoxical assistance.
 Figure 01.TIF

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