key: cord-322034-8wwqxkjl
authors: Ma, Ke; Wang, Xin; Feng, Shiyao; Xushan, Xia; Zhang, Hongxiu; Rahaman, Abdul; Dong, Zhenfei; Lu, Yanting; Li, Xiuyang; Zhou, Xiaoyu; Zhao, Haijun; Wang, Yuan; Wang, Shijun; Baloch, Zulqarnain
title: From the perspective of Traditional Chinese Medicine: treatment of mental disorders in COVID-19 survivors
date: 2020-09-30
journal: Biomed Pharmacother
DOI: 10.1016/j.biopha.2020.110810
sha: 
doc_id: 322034
cord_uid: 8wwqxkjl

PURPOSE: The aim of this study is to explore the possible benefits of traditional Chinese medicine on the pathogenesis of psychological and mental health of COVID-19 survivors. METHODS: A literature search was conducted to confirm the effects of COVID-19 on psychological and mental health of survivors. In addition to this, on the basis of signs and symptoms, TCM were used on treat mental disorder as per suggested clinical and animal experimental data plus relevant records in classical Chinese medicine books written by Zhang Zhongiing during Han Dynasty. A series of treatment plans were prescribed for COVID-19 survivors with psychological and mental disorders. RESULTS: According to previous extensive studies focusing on effects on mental health of survivors, high incidence was observed in severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) survivors. During investigations of mental health of COVID-19 patients and survivors, it is observed that they also had symptoms of mental disorders and immune dysfunction. Furthermore, it was also proposed that depression, anxiety and post-traumatic stress disorder (PTSD) were most common mental disorders requiring special attention after the recovery from COVID-19. The symptoms of COVID-19 were analyzed, and the TCM syndrome of the depression, anxiety and PTSD after recovered from COVID19 was interpreted as internal heat and Yin deficiency. These three mental disorders pertains the category of “Lily disease”, “hysteria” and “deficient dysphoria” in TCM. CONCLUSION: Lily Bulb, Rhizoma Anemarrhena Decoction and Ganmai Dazao Decoction were used to treat depression. Suanzaoren Decoction, Huanglian Ejiao Decoction and Zhizi Chi Decoction were suggested for anxiety. Moreover, Lily Bulb, Rehmannia Decoction and Guilu Erxian Decoction were the formula for PTSD.

Coronavirus Disease 2019 (COVID- 19) , which broke out in Wuhan on December 31, 2019, was an emerging, rapidly developing epidemic and a Public Health Emergency of International Concern (PHEIC) that affected people around the world [1, 2] . According to latest investigations, fever, cough and fatigue are the main symptoms of patients with mild COVID-19 while patients with severe COVID-19 might present with respiratory distress syndrome, shock and sepsis [3] . Both post-traumatic stress disorder (PTSD) and acute stress disorder (ASD) refer to the stress response that occurs after the person suffered a fatal and catastrophic traumatic event that is beyond the individual's capacity [4, 5] . The understanding about COVID-19 has been insufficient yet, and there is no effective treatment plan for it at this stage as vaccines are still testing or trial phases [1] .

Most current practice to address COVID-19, Isolation and addressing symptomatic treatment is the only option at this stage, isolation and treatment measures would lead to a battery of emotional and behavioral reactions. Past evidence suggests that mental disturbance in COVID-19 cases is closely J o u r n a l P r e -p r o o f linked to symptoms coming in survivors after large infectious diseases.

Research proved that severe acute respiratory syndrome (SARS) and

Middle East respiratory syndrome (MERS) survivors had a higher prevalence of PTSD [6, 7] . Besides this, individuals with PTSD often suffered from depression and anxiety as well [8] . The research found that 59 percent of those who fully met the PTSD diagnosis had anxiety disorder and 34.5 % had depression [9] . According to the investigation results of Ju el, nearly 50% of COVID-19 patients in isolation ward suffered from ASD, along with anxiety, depression, insomnia and other mental and psychological symptoms [10] .

Moreover, a clinical survey of 68 patients with COVID-19 showed that the anxiety score was (60.20±2.04), the incidence rate was 70.6% (including 32 cases of mild anxiety, 20 cases of moderate anxiety and 3 cases of severe anxiety), the depression score was (64.03±3.21), and the incidence rate was 73 .5% (including 34 cases of mild depression, 15 cases of moderate depression and 1 case of severe depression) among them [11] . Therefore, patients recovering from COVID-19 are more likely to suffer from PTSD, anxiety and depression.

Unfortunately，there are many limitations to treat mental disorders.

Serotonin reuptake inhibitors (SSRIs) and Norepinephrine reuptake inhibitors (SNRIs) are commonly used as antidepressants drugs for the treatment of PSTD. However, their clinical application was very limited (more or less 50%), and this treatment regime comes with possible side effects such as headache, dizziness and increased muscle tension [12] . Although benzodiazepines had a significant anti-anxiety effects, but because of respiratory inhibition effects of these drugs are not suitable for patients with pulmonary damage related to COVID 19 [10] . On the other sides, TCM therapy has the advantages of multi-pathway and multi-target, and is comparatively safer option. In addition to this, Chinese herbs treat symptoms and deal with causes of disease, and it can remedy the remaining symptoms of COVID-19 at the time of treating J o u r n a l P r e -p r o o f 6 mental disorders.

In this review, we were trying to find the pathogenic factors of mental disorders in COVID-19 survivors from the perspective of both western medicine and traditional Chinese medicine theory, and trying to put forward the corresponding TCM treatment plan ( Figure 1 ).

Based on the researches, all of sudden and life-threatening events, people would experience the corresponding psychological stress reaction and emotions such as anxiety, fear and loneliness. A small number of people could even suffer into mental distress [13] . Studies demonstrated that the prevalence of all kinds of mental illness within 30 months after the outbreak of SARS was 33.3%, and a quarter of the patients had PTSD, while 15.6% underwent depression disorder [14, 15] . Besides this, a four-year follow-up of 233 SARS survivors showed that more than 40% claimed to be suffering from mental illness, and 40.3% reported chronic fatigue problem [16] . In addition to this, many patients and medical workers went through severe emotional stress during the outbreak period of MERS [7] . When the epidemic was controlled, many medical workers and recovered patients would be bothered with anxiety, depression and even PTSD [7] . COVID-19 is a respiratory infection caused by corona virus that similar to SARS and MERS. An investigation on the basic reproduction number of SARS-CoV-2 transmission proved that the R0 (2.8, 3.9) of SARS-CoV-2 was higher than the R0 (2.2, 3.7) of SARS-CoV, but lower than the R0 (2.0, 6.7) of MERS-CoV, indicating that SARS-COV-2 was a medium-high infectious disease [17] .

On January 30, 2020, the world health organization declared the outbreak of COVID-19 in Wuhan, central China as a Public Health Emergency of International Concern (PHEIC) [18] . So far, there is no treatment of covid-19 available and the number of infections continuously increasing. Until Thursday, J o u r n a l P r e -p r o o f May 31, 2020, more than 6.15 million people had been infected [19] , i.e. more than the total number of people infected with SARS and MERS. Therefore, due to the fear of disease, physical discomfort, drug side effects and social isolation, COVID-19 patients might be suffering from loneliness, anger, anxiety, depression, insomnia and PTSD in the period of treatment and isolation [20] .

The investigation suggested that the medical workers infected with COVID19 had varying extent of depression, anxiety and sleep disorders [21] . A recent study on 714 COVID-19 patients confirmed that the prevalence of significant post-traumatic stress symptoms among the recovered patients was 96.2% [22] . Furthermore, studies demonstrated that patients with COVID-19 showed higher level of depression, anxiety, and PTSD than people without COVID-19 [23] .Therefore, the mental health of COVID-19 survivors needed to be noticed.

Wang el. [24] analyzed 138 cases of hospitalized COVID-19 patients, and they observed that the number of neutrophils cell were increased in patients.

That might be related to cytokine storm during the invasion of virus. Recent clinical studies had been done to [25, 26] summarize the clinical characteristics of COVID-19 patients. It's also proposed that compared with healthy people, COVID-19 patients' lymphocyte count was significantly less. Besides this, their inflammatory factors such as interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10) and the tumor necrosis factor alpha (TNF-α) were markedly high. These levels of cytokines were sharper in critically ill patients with pneumonia [26] . Therefore, patients with COVID-19 showed signs of immune dysfunction and elevated levels of inflammatory cytokines.

Meanwhile, several researches had provided obvious evidences which indicates that immune system activation, pro-inflammatory cytokines were concern with psychiatric symptoms [27] . Consequently, patients with J o u r n a l P r e -p r o o f 8 COVID-19 could have a higher propensity to be attacked by mental disorders than normal people. There was evidence to support the cross-correlation between cytokine levels and depression risk in many diseases [28] . Along with this, depression may be related to infectious diseases which had been supported by the conclusion of relevant studies [29] . In addition, a meta-analysis which brought into 54 studies demonstrated that levels of pro-inflammatory cytokines, especially IL-1β, IL-6, and TNF-α, were associated with depressive symptoms [30] . An excessive dose of interleukin-1beta had been affirmed to be associated with neuro-inflammatory degenerative diseases and mental disorders [31] . Shim el. stated that lateral ventricular IL-1β could induce anxiety-like behavior in rats [32] . Moreover, systematic reviews had also found that higher levels of interleukin 6, interleukin 1beta, and TNF-α were interrelated with PTSD [33] . As a result, it is necessary to pay close attention to their mental health during and after the treatment.

Traditional Chinese medicine doctors named highly infectious and easily prevalent disease as "Yi disease", which meant epidemic, and considered its etiology as "Yi Qi" [34] . Thus, in accordance with TCM theory, COVID-19 pertained to the category of "Yi disease" [35] . Referring to the theory of TCM, "Yi Qi" entered the human body from the mouth and nose, while the mouth connected the spleen as well as the whole digestive system, and the nose linked the lung as well as the total respiratory system [36] . While, COVID-19 in the infected patients would first affect the lung and spleen, leading to abnormal function of lung and spleen, and triggering a series of digestive and respiratory symptoms [36] . The above statements were consistent with the clinical reports that patients with COVID-19 had not only respiratory symptoms, but also metabolic disorder symptoms such as diarrhea and vomiting [37] .

The harmonious and consistent unity of body and emotion was the stand J o u r n a l P r e -p r o o f point of TCM. Therefore, the emotions of patient were concerned with the function of Five Organs (heart, liver, spleen, lungs and kidneys) [38] . Seven main emotions in TCM (anger, joy, worry, thinking, sadness, fear, shock) were regulated by the state of function of the Five Organs, meaning that the Five Organs control the generation and change of Seven emotions. When the status of Five Organs changed, the moods changed accordingly [38] . The lung controlled worry and sadness, while the spleen controlled thinking [39] . As a result, once lung and spleen was invaded by "Yi Qi", the moods controlled by them would also be abnormal. Then, the patients would be bothered with sadness, or they could be tired of over thinking. Consequently, there was a tendency that the COVID-19 survivors suffered from psychological disorders.

Additionally, there was a view in the TCM theory that the diseases with sign of fever could cause the loss of Yin fluid in human body [34] . Yin fluid referred to body fluid and blood [40] . During the development of COVID-19, "Yi Qi" could cause internal heat in body resulting in the symptom of fever that consumed yin fluid. As a result, the balance of Yin and Yang was broken and the deficiency of Yin led to the relative excess of Yang. Yin was supposed to be cold while Yang was considered hot. Then the relative excess of Yang could make the internal body hotter than normal, which contributed to the internal heat and Yin deficiency syndrome. anxious and grim [42] .

TCM, which provided a record of "Lily disease" caused by internal heat and Yin deficiency in heart and lung. The main symptoms were willingness to eat, loss of appetite, daily in a bad mental, less words, fatigue but unable to sleep, unable to walk. They concluded that a series of symptoms could appears including psychological abnormalities; paresthesia and eating behavior abnormalities [43] . These symptoms were very similar to those of depression [44] .

Another classic book of TCM Typhoid fever theory recorded an opinion that after fever, internal heat had not been cleaned, which contributed to "deficient dysphoria disease", an internal heat disease due to deficiency of Yin.

The symptoms of "deficient dysphoria " such as insomnia, restlessness were consistent with the clinical manifestations of anxiety [45] .

"Lily disease" can be characterized by wandering mind and confusing the illusion and reality, which was similar to PTSD patients' traumatic memory forced into mind to reproduce the event scene in the form of flashbacks or nightmares, compelling them repeatedly to experience the emotion and feeling of that time. On the basis of concept and clinical manifestations of PTSD, Guo also considered PTSD as a kind of "Lily disease", and proposed PTSD of heart-lung Yin deficiency syndrome type [46] . Therefore, as explained in TCM, Anemarrhenae was cold in TCM theory, and it would turn the efficacy of decoction colder [48] . By adding Anemarrhena asphodeloides Bge., the heat-clearing function of the decoction could be strengthened, making it more suitable for those who were already diagnosed as internal heat and Yin deficiency syndrome with more heat.

Ganmai Dazao Decoction was indicated for "Hysteria disease", whose symptoms were sadness, crying, mood disorders, and abnormal behavior, Decoction combined with Flupentixol and Melitracen Tablets in the treatment of menopausal depression and found that the total clinical effective rate of the combined group was significantly higher than that of the single group [51] .

Furthermore, Lily Bulb and Rehmannia Decoction was able to alleviate the symptoms of depression patients with Yin deficiency and internal heat syndrome remarkably and long-term administration was not harmful [52] . In J o u r n a l P r e -p r o o f addition, the investigation used Lily Bulb and Rehmannia Decoction combined with fluoxetine for 6 weeks, confirmed that it was able to reduce the anxiety somatization factor and sleep factor, and the efficacy was more obvious than single modern depression intervention medicine [53] . Yan el. adopted Ganmai Dazao Decoction combined with Lily Bulb and Rhizoma Anemarrhena Decoction to treat depression. Compared with conventional modern medicine, the decoctions were safer and the incidence of adverse reactions was less [54] . patients with initial severe depression, which mechanism may be related to the regulation of monoamines and amino acid neurotransmitters, the regulation of immune inflammation, and the reduction of the level of inflammatory factors [56] .

In addition to this, some animal experiments had been carried out to explore the antidepressant pharmacological mechanism of above decoctions.

After Lily Bulb and Rehmannia Decoction intervention, the content of monoamine such as neurotransmitters norepinephrine (NE), 5-hydroxytryptamine (5-HT) and dopamine (DA) were greatly increased in the hippocampus of CUMS rats, and the activity of monoamine oxidase was significantly reduced [57] . Bi el. treated depressed rats with Ganmai Dazao Decoction, and the results showed that it could significantly improve the depressed behavioral characteristics of rats, and significantly increase the activity and content of neurotransmitters 5-HT and NE in the brain of rats [58] .

Study confirmed that Ganmai Dazao Decoction could significantly improve the depression-like behavior of CUMS rats by regulating HPA axis elevation and protecting hippocampus injury [59] . The intervention of Lily Bulb and J o u r n a l P r e -p r o o f increase the content of monoamine neurotransmitters in the brain of depression animal model [60] . Besides this, research proposed that Lily Bulb and Rhizoma Anemarrhena Decoction could alleviate the loss of pleasure and despair in depressed rats, and promote the remodeling of neurons. The mechanism behind this was related to inhibiting the hyperfunction of HPA axis and up-regulating the expression of BDNF mRNA in hippocampus of depressed rats [61] . Previous evidence showed that antidepressant mechanism of Lily Bulb and Rhizoma Anemarrhena Decoction was also related to up-regulation of monoamine transmitters in serum and cerebral cortex [62] .

Furthermore, there are some experiments about active compounds of these decoctions. Evidence from Guo el. confirmed that lily saponins, as the main component of Lilii Bulbus, could relieve depression symptoms, whose effect might be related to the increased level of monoamine neurotransmitters in brain and the hyperfunction inhibition of HPA axis [63] . Research suggested that lily saponins treated depression with irritable bowel syndrome by synergistically regulating the content of brain-gut peptide and the function of 5-HT nervous system in blood, stomach and intestine [47] . Further, in the alcohol extract of Rehmannia glutinosa Linosch is one of the main effective components with higher content of it. Study proved that catalpol had more remarkable antidepressant effect by involving monoamine nervous system than other ingredients in Rehmannia glutinosa Linosch [64] . reduced the contents of TNF-α, IL-1β and IL-6 in mouse brain tissue for anti-inflammatory treatment of depression [66] .

Therefore, these three TCM decoctions can be applied to the treatment of depression.

Suanzaoren Decoction，Huang lian E jiao Decoction, Zhizi Chi Decoction, were used for anxiety of internal heat and Yin deficiency syndrome ( Table 2) .

They were recorded in Typhoid fever theory, and were classic decoctions for Meng el. [67] randomly divided 90 patients with generalized anxiety disorder into the observation group and the control group with 45 cases each, the observation group was treated with modified Suanzaoren Decoction, and the positive control group was treated with estazolam, the results proved that the total effective rates of the observation group and the control group were 91.11% and 75.56% respectively, suggesting that modified Suanzaoren Decoction was more appropriate than modern medicine in the treatment of generalized anxiety disorder. Zhang el. [68] analyzed the clinical effect of modified Suanzaoren Decoction on cancer patients who met the CCMD-3 anxiety diagnosis standard, the total effective rate of clinical effect was higher than that of the control group and no adverse reactions were found. It indicating that modified Suanzaoren Decoction can significantly improve the mild and moderate anxiety of cancer patients. It was proved that the ant-anxiety effect of Suanzaoren Decoction might be related to the increase of NO concentration in blood and the decrease of IL-1β, TNF-α in serum [69] .

Zhang el. [70] selected 60 patients with generalized anxiety, and randomly divided them into treatment group (30 cases) treated with Huanglian E jiao and Decoction, and control group (30 cases) that treated with lorazepam. The total effective rate of the treatment group was 93.33% and that of the control group was 73.33% at the fourth week of treatment. And the treatment effect of the decoction was more lasting and the adverse reactions were less than that of lorazepam. Huanglian E jiao Decoction had a better curative effect and fewer adverse reactions than fluvoxamine in the treatment of anxiety that pertained to yin deficiency and fire hyperactivity Syndrome [71] . Liu el. reported 50 cases of anxiety treated with Zhizi Chi Decoction, and the total effective rate was 96% [72] .

In addition, study confirmed that Suanzaoren Decoction combined with Zhizi Chi Decoction was more effective than diazepam in the treatment of anxiety disorder, and the relapse rate after cessation of the medication was lower [73] . Liu el. applied Suanzaoren Decoction combined with Zhizi Chi Decoction to the treatment of 60 cases of anxiety insomnia, and consequently the symptoms of anxiety and insomnia were significantly improved [74] .

Meanwhile, there are some reports about the therapeutic mechanism and effective compounds of the above decoction. Researches considered that the anti-anxiety effects of Suanzaoren Decoction and Huanglian E jiao Decoction were both related to the increase of γ-GABAA level [75, 76] . Besides, Suanzaoren Decoction also decreased the release of NE in hippocampus and inhibited the synthesis of 5-HT [76] . Sanjoinine A isolated from Zizyphi Spinosi Semen had been proved to be concerned the GABA ergic transmission [77] . Decoction [78] . In addition, study confirmed that berberine which was the main component of Coptidis Rhizoma in Huanglian E jiao Decoction could regulate the expression of monoamine neurotransmitters and their metabolites and 5 -HT receptors to resist anxiety [79] . Baicalin and wogonin isolated from Scutellariae Radix both perform anti-anxiety effects mediated by γ-GABAA [80, 81] . Moreover, A research mentioned that geniposides, as the main component of Gardeniae Fructus water extract, was one of the anti-anxiety components of Gardeniae Fructus [82] .

Complementarily, mixed anxiety-depression disorder (MAD) was also a common comorbid psychiatric disorder that frequently-observed with PTSD [83] . Thus, COVID-19 survivors may suffer from MAD. The above three kinds of decoctions have been proved to be effective in treating depression [84] .

In conclusion COVID-19 survivors with anxiety could be treated with the above three decoctions, and patients with insomnia and MAD could also take the decoctions.

Lily Bulb and Rehmannia Decoction and Guilu Erxian Decoction were the decoctions for PTSD of internal heat and Yin deficiency syndrome ( Table 3) .

Most of the researches on the treatment of PTSD with Chinese herbal medicine were done on animal but the less clinical studies were reported.

Research suggested that patients with PTSD of Yin deficiency of heart and lung Syndrome were suitable to be treated with Lily Bulb and Rehmannia Decoction. As they showed lung dryness symptoms such as lung heat cough, which are also a common symptom in the convalescence of COVID-19. It was suggested to add Tuber Raidix Ophiopogonis (ophiopogon japonicas), Liquorice Root Radix Glycyrrhizae (licorice) in the decoction [46] . Meanwhile, if patients had insomnia, they can add Ziziphus spinosa Hu and Radix Pseudostellariae (Heterophylly Falsesatarwort Root) [46] . Furthermore, the investigation confirmed that Lily Bulb and Rehmannia Decoction could up regulate 5-HT level in hippocampus and deal with the symptoms of PTSD [85] .

The results demonstrated that Lily Bulb and Rehmannia Decoction down regulated the expression of glucocorticoid receptor (GR) in hippocampus, up regulated the expression of glucocorticoid receptor (MR), and improve the symptoms of PTSD in rats [86] .

Guilu Erxian Decoction was composed of antler gum, tortoise plate gum, ginseng and wolfberry fruit which nourished Yin. Li el. demonstrated that Guilu Erxian Decoction may play an anti-PTSD role by regulating synaptic plasticity, anti-apoptosis, anti-inflammation and promoting fear memory extinction through network pharmacology [87] . Moreover, researches had confirmed that the therapeutic mechanism of was to regulating the function of the HPA axis, the expression of GR and 5-HT receptors in the hippocampus to improve the emotional and behavioral abnormalities in PTSD rats [88, 89] . Besides this, study confirmed that Lycium barbarum polysaccharide in Guilu Erxian Decoction can reduce the level of cortisol in serum to improve the symptoms of PTSD [90] . Previous evidence showed that ginsenoside Rg2 can regulate the function of HPA axis to treat PTSD [91] .Consequently，PTSD patients could be treated with the two decoctions. All funding source just support in conduct of experiments. We strictly disclosed that all funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. 

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