Mechanism of traditional Chinese medicine in the treatment of psoriasis with depression: A review

ZHANG Ning, YANG Su-qing, YUAN Rui✉

1. Heilongjiang University of Chinese Medicine, Harbin 150040, China

2. The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin 150040, China

Keywords:

ABSTRACT Psoriasis is a kind of immune-mediated, chronic, inflammatory skin disease, which is often associated with different degrees of psychological disorders.Specifically, there is a significant correlation between psoriasis and depression, and they show the relationships of reciprocal causation and mutual promotion.Psoriasis with depression is more harmful than simple psoriasis, and its prognosis is worse, which brings a huge burden to the family and society and is worthy of clinical attention.Based on the pathogenic factors of western medicine and pathogenesis of traditional Chinese medicine in psoriasis with depression, the paper summarized and elaborated the research progress on the mechanism of traditional Chinese medicine in the treatment of psoriasis with depression, in order to provide new ideas for clinical treatment.

Psoriasis is a common chronic and inflammatory disease characterized by squamous papules or erythema.Depression is a kind of mental disorder which seriously affects the quality of life of patients and mainly characterized by emotional and cognitive disorders.Its main core symptoms include persistent depression,loss of interest, decreased consciousness activity, and even the idea ofsuicide.At present, the incidence of both psoriasis and depression is universal,and a lot of evidence manifes that psoriasis and depression has a vicious circle.Psoriasis will lead to depression, and depression will aggravate psoriasis[1].With the change of medical concept and the promotion of bio-psycho-social comprehensive model, psoriasis has been classified as a typical physical and mental disease.More and more clinicians pay attention to the phenomenon of psoriasiswith depression, and actively take a series of effective measures to improve the disease status.Therefore, evaluating and paying close attention to the psychological changes of patients with psoriasis and actively adjusting the depression of patients with psoriasis as soon as possible can shorten the course of thedisease and achieve better treatment expectations.

The pathogenesis of psoriasis with depression has not been fully elucidated,but the research focuses on susceptibility genes, immune mediation, damage ofmonoamine neurotransmitters, dysfunction of brain-derivedneurotrophic factor (brain-derivedneurotrophicfactor,BDNF), hypothalamus-pituitary-adrenal cortex (hypothalamicpituitary-adrenal, HPA) axis disorderand so on.On the basis of this, biological agents and antidepressants can be used to treat patients with psoriasis with depression, but there are many defects,such as high cost, limited drug choice, many adverse reactions,high recurrence rate and the like.Combined with the complex pathogenesis of the coexistence of psoriasis and depression,andbased on the holistic view of traditional Chinese medicine and the theory of syndrome differentiation, this paper systematically expounds the general situationof the research on the multitarget, multi-pathway, multi-component and overallregulation with traditional Chinese medicine compound prescription and characteristic therapy, in order to provide a reliable basis for the study of the relationship between psoriasis and depression and clinical treatment.

1.Pathogenesis of psoriasis with depression

1.1 genetic susceptibility

Genetic factors may be one of the co-existing mechanisms of psoriasis and depression[5-6].Psoriasis is a genetic disease controlled by multiple genes, butimmunity, infection, emotion and other factors may trigger the expression of genetic susceptibility genes[2].The related evidence suggests that the occurrence of depression may also be related to the geneticmechanism[7].Modern studies have confirmed that TNF α-inducedprotein3-interactingprotein1 (TNIP1)is a recently discovered negative regulator ofnuclear factor κB (NFκB) signaling pathway,which plays a role in regulating immunity and participating in cytokine signal transduction[8].Negative emotions such as anxiety and depression increase the expression of NF- κB in patients and promote inflammatory reaction.TNIP1 gene is closely related to genetic susceptibility to psoriasis, and studies have shown that genotype AG and A allele frequencies of TNIP1 gene polymorphicsite rs17728338 are related to the severity of psoriasis vulgaris with depression, soit is speculated that there may be an interactive effect between TNIP1 gene rs17728338 locus and depression, which may have an effect on psoriasis susceptibility[9-10].

1.2 immune disorders

The accumulation of immunoreactive cells in immune disorders leadsto therelease of a large number of inflammatory cytokines,which not only aggravates the severity of psoriatic lesions, but also leads to immuneactivation, inflammatory process, local brain structural changes and neuroendocrine disorders[11-13].At the same time, various inflammatory mediators stimulated by inflammatory response induce immunoreactive cell differentiation, keratinocyte proliferation, neurotransmitter metabolic disorder, central inflammatory response and HPA axis activation[14-16].Immune cells and inflammatory factors promote each other to increase the incidence of psoriasis comorbid depression.Abnormal immune functionmay be the potential mechanism of psoriasis and depression.Clinical evidence shows that patients with psoriatic depression have significantly increased levels of immunecells and pro-inflammatory factors in serum, and there are common factors prone to infection.Blocking immune cell differentiation and anti-inflammatory therapy can significantly reduce depression-like symptoms[17-18].The use of antidepressants can also reduce the level of inflammatory factors,regulate immune function and restore body balance[19-20].

1.3 Nervous system disorders

Patients with depression often show disordersof the central nervous system,such as increased neuropeptide serum substance P (SP),nerve growth factor (NGF), decreased monoamine neurotransmitters and brain-derived neurotrophic factor (BDNF) dysfunction.In addition, excessive activation of the HPA axis underpsychological stress leads to the release of various stress mediators, which not only produces negative feedback regulation on the nervous system and further aggravates the depression of patients, but also aggravates a series of symptomsand signs produced by psoriasis, and even induces the functional imbalance of the central HPA axis again.Thus the situation forms a vicious circle and increases the difficulty oftreatment[4].

1.4 In other aspects

Intestinal flora plays an important role in maintaining the normal physiological state of the human body.Once a flora disorder occurs, it canact on the brain and skin through blood circulation,immune, endocrine and nerve systems[21].There is a close two-way relationship between them, thus forming the intestinal-brain-skin axis.In addition, vitamin D3 and melatonin deficiency are associated with the pathogenesis of psoriasis with depression.The decrease of vitamin D3 content is not conducive tothe growth and differentiation of keratinocytes, leading to immune imbalance, directly acting on the brain structure that controls emotion, and affecting the pathogenesis of psoriasis and depression[22-24].Although the main function of melatonin is to regulate sleep, studies have found that melatonin can regulate the immune system and affect the level of inflammatory factors, and may play an important role in immune and nervous system diseases[25].

To sum up, the co-disease mechanisms of psoriasis with depression mainlyfocus on genetic susceptibility, elevated levels of inflammatory factors, immunedysfunction, HPA axis dysfunction, nervous system changes and so on.These mechanisms are highly overlapping and have reciprocal causation, which become the potential basis for the occurrence of psoriasis and depression.Therefore, exploring the codisease mechanism of psoriasis and depression and the action ways of traditional Chinese medicine are helpful to open up a new way for the diagnosis and treatment ofpsoriasis and depression.

2.The understanding of psoriasis complicated with depression in traditional Chinese medicine

Psoriasis is called “Baibi”, and depression belongs to the category of “depression syndrome” in traditional Chinese medicine.The occurrenceof depressivecomorbidity of psoriasis is related to the five viscera, especially with the liver[26].Emotional disorder, qi stagnation and dereliction of duty are the basic pathogenesis of psoriatic co-depression.The long course of disease leads to the loss of healthy movement of spleen, deficiency of qi and blood,deficiency of liver and kidney and so on.Moderndoctors are based on the principle of “the same treatment of different diseases”, that is, in view of the common pathogenesis of the two diseases and the main factors in the development of the disease,and the treatment of psoriasis with depression mainly includes treatment based on blood differentiation and treatment from the viscera as an effective supplement.And it has certain reference significance to pay attention to the influenceofpathological factors such as dampness, phlegm and blood stasis on the disease.There is no unified conclusion on the syndrome type of psoriasis comorbiddepression, but a clinical study shows that yin deficiency and internal heat is the most common syndrome type, followed by liver depression and qi stagnation and wind-heat syndrome[27].In addition,through in-depth discussion of the etiology and pathogenesis, doctors obtained the key syndrome types of hyperactivity of heart fire, loss of nourishment of mind,accumulation of lung heat, liver depression and spleen deficiency,liver and kidney deficiency.Most of the patients were accompanied by symptoms and signs such as depression, worry, fullness of ribs,insomnia and dreaminess[28].Based on the syndrome distribution characteristics of the two co-diseases and the core pathogenesis of psoriasis, it is considered that the treatment of local skin lesions based on blood differentiation and whole viscera syndrome differentiation is one of the indispensable treatmentideas for psoriasis comorbidities.

The co-disease phenomenon of Baibi and depression syndrome has acomplex pathogenesis, and they show the relationships of reciprocal causationand mutual promotion.The condition of patients with psoriasis is repeatedand lingering, and the long-term treatment makes that the patients’ compliance is poor, the quality of life is greatly reduced, and the depression of the patients is increasingly severe.At the same time, depression will lead to the imbalance of immune homeostasis and aggravate the skin lesion.It is significant to grasp the common etiology and pathogenesis of the two and treat different diseases at the same time in clinical trail.

3.Experimental study on multi-target intervention of traditional Chinese medicine compound prescription on pathogenesis

3.1 traditional Chinese medicine compound prescription regulates immune inflammatory response

TCM Blood-cooling and soothing the liver significantly can reduce the level of serum neuropeptide Y (neuropeptideY,NPY) and the production ofcytokines, suppresse local inflammation and immune reaction of skin,and relieve the disease effectively[29].Based on the function of Longdan Xiegan decoction in clearing liver and purging fire, recent studies haveconfirmed that Long Dan Xie Gan decoction can reduce the expression ofinflammatory factors in peripheral blood of psoriasis patients with blood-heat syndrome by regulating NF- κB, IL-6R/STAT3 signal transduction and p38MAPK/Th17 signal pathway.And p38MAPK/Th17 signal pathwayand inflammatory cytokines are related to psychological immature defensemechanism factors.Thus it can effectively reduce the skin lesions of patients with psoriasis and regulate depressionlike behavior[30-31].Clinical studies have shown that Zhuhuang granule NO.Ⅱ can reduce the psoriasis area and severity index(PASI) score of patients with psoriasis complicated with depression,alleviate the state of depression and improve the quality of life.In addition, its effects of clearing heat and detoxification, replenishing qi and nourishing yin, soothing the liver and relieving depression are in line with the TCM etiology and pathogenesis of psoriasis depression.The results of mechanism analysis also showed that the compoundcan regulate the levels of CD3, CD4, CD8 and CD4/CD8 ratio and reduc the level of soluble interleukin-2 recepter (sIL-2R).They can significantly improve the lesions, symptoms and depression of patients with psoriasis[32].Yueju Wan can also regulate AKT-mTOR pathway, inhibit inflammation and oxidative stress, and play a role in the treatment of psoriasis and depression by reducing the contents of inflammatory factors suchas IL-1 β and IL-10 in hippocampus and peripheral serum of chronic unpredictable mild stress (CUMS) mice[33].Chaihu Longgu Muli Decoction can significantly reduce the contents of serum IL-1 β, IL-6 and TNFαin depressed mice, maintain immune balance, and achieve positive regulation of psoriatic depression comorbidity[34].The study on the mechanism of Jiaotai Pill shows that it can improve the depressionlike behavior and hippocampal neuronal damage by increasing the contents of anti-inflammatory cytokines IL-4 and IL-10 in serum and hippocampus and reducing the levels of proinflammatory cytokines IL-1 β, IL-6 and TNF- α.These cytokines are also involved in the occurrence and progression of psoriasis[35].

3.2 traditional Chinese medicine compound prescription regulating nervous system disorder

Xiaoyao pills can improve the sugar preference rate of psoriatic depressionmodel mice, increase the independent exploration activities of mice in the openfield experiment, and alleviate the flagging mental state of mice.In addition, the contents of 5-hydroxytryptamine (5-HT), adrenaline (Ad) and norepinephrine(NE) in the prefrontal cortex, hippocampusand hypothalamus of mice were significantly increased, while the content of glutamate (glutamate,GLU) decreased, and the symptoms of psoriasis-like mice were improved, which was significantlysuperior to methotrexategroup[36].Zhuhuang granule NO.Ⅱ can reduce the serumcorticosterone (COR) of restraint immobilization model mice, inhibit the degranulation of mast cells in stressed mice and then reduce the inflammatory reaction, local inflammatory cell infiltration and depression-like behavior in mice[37].Xiegan Liangxue jiedu decoction can promote the secretion of neurotransmitters BDNF and 5-HT in the body, provide neurotrophic support, enhance neuronal function, and actively interfere with patients’ negative emotions, so as to effectively improve patients’ skin lesions.Both of them can form a virtuous circle of positive feedback and have a good synergistic effect to accelerate the improvement or recovery of psoriasis[38].Shugan Jieyu capsule can improve skin lesions and reduce depression, which is mainly related to regulating the level of monoamines in serum of patients[39].The mechanism of traditional Chinese medicinecompound prescription in the treatment of psoriasis with depression summarizedabove is shown in Table 1.Clinical trials of traditional Chinese medicine on the pathogenesisof other psoriasis with depression are still vacant and need to be further improved, which is also a research direction worthy of attention in the future, in order to open up a new way for traditional Chinese medicine in the treatment of psoriasis.

Tab 1 Experimental study of traditional Chinese medicine compound prescription for pathogenesis in the treatment of psoriasis with depression

3.3 Clinical study of traditional Chinese medicine compound prescription in thetreatment of psoriasis with depression

After the treatment of psoriatic depression patients with Yangxue jiedu decoction,patient health questionnaire-9 (PHQ-9) score was lower than before, an the symptomssuch as fullness or pain on both sides, insomnia and dreaminesswere significantly improved.According to the prescription of cooling blood andsuppressing yang,if the patients with insomnia and depression, add Suanzaorenand Yujin, it can reduce the score of Hamilton Depression scale(HAMD), effectively intervene the state of depression and benefit the rehabilitation of skin lesions[40].Modified DangGui decoction is also one of the effective prescriptions for the treatment of psoriasis complicated with depression, not only reducing the area of skin lesions and restoring patients’ skin functional barrier, but also helping sleep, sedation, relieving psychological pressure and reducing the recurrence of psoriasis[41].The clinical markedly effective rate of Tianqi Qingyin decoction which comes from Sini San and Qingying decoction was 83.78%, whichwas significantly higher than that of compound aminopeptide tablets (69.23%), and the toxicity and side effects were small, the psoriatic disability index(PDI) score of patients decreased significantly, and the quality of life was improved[42].Based on the same anti-psoriasis treatment,the antidepressant effect of Chaihu Xiaoyin decoction is better than the Xiaoyin granule, and the effect is obvious in improving the score of self-rating depression scale, and the PASI score of patients is reduced, which can effectively alleviate the condition of skin lesions[43].Professor Yang Suqing established WuGongBaidu Yin based on the theory of “poison evil”.Clinical observation showed that this compound had a positive effect on the psychological state of psoriasis patients with wind-heat syndrome.After taking decoction,the scores of depression and shame self-rating scale were further reduced, and the scores of quality of life and psychological elasticity were on the rise[44].Anshen soothing decoction is also effective in the treatment of psoriasis complicated with depression, which can reduce the symptoms of psoriasis, regulate the bad mood and controlthe development of the disease[45].

4.Intervention study of characteristic therapy of traditional Chinese medicine

Based on the theory of “five sounds and five internal organs”,five elements music therapy has a good effect in improving bad mood, guiding spirit and nourishing qi, reconciling qi and blood and improving sleep quality.It can effectively reduce the levels of serum IL-2 and COR in patients with psoriasis of liver depression and blood stasis, alleviate the hyperactivity of HPA axis, restore the homeostasis of neuroendocrine network and regulate immunoinflammatory reaction.To achieve positive regulation of psoriasis depression syndrome[46].Traditional Chinese medicine believes that people have seven emotions.If seven emotions are too extreme, it will cause viscera dysfunction and stagnant movement of qi and blood.Qi disorder is easy to lead to the occurrence of disease, so in the treatment of emotional factors on the disease.The emotional therapy of traditional Chinese medicine is based on the theory of seven emotions, and the routine therapy of “persuasion”,“transference” and “emotional victory” are selected to dredge the psychology of the patients, the HAMD score is significantly decreased, the depression mood is significantly improved, the serum levels of NPY, COR and IL-2 in the patients are lower than those in the controlgroup, and the neuro-endocrine-immune network gradually returns to balance.Thus, the treatment of psoriasis has achieved satisfactory results[47].Acupuncture therapy of traditional Chinese medicine is widely used in the field of dermatology,especially in patients with vulgaris and plaque psoriasis.With simple operation and good effect, Quchi, Geshu, Feishu, Sanyinjiao and Xuehai are the main acupoints selected by body acupuncture.Combined with narrow-band ultraviolet therapy in western medicine,the scores of depression scale and inflammation were significantly decreased, the function of skin barrier was enhanced, anddepression and overall state were improved[48].Auricular point therapy is a characteristic non-drug effective therapy for psoriasis in traditional acupuncture in China.Traditional Chinese medicine believes that“twelve meridians are on theear”[49], so auricular point therapy can activate meridians, regulate qi and blood,and balance yin and yang.Thus, it plays a positive role in regulating theimmune system,blood microcirculation and autonomic nerve function of the body.In clinic, it can be combined with the classification and staging syndrome differentiation and treatment of psoriasis to develop a personalized acupoint selectiontreatment plan.On the basis of the routine treatment of oral Chinese patent medicine Yinxieling tablet,the patients were treated with dorsal auricular vein puncture and bloodletting, 2～3 mL each time, combined with auricular point pressing and selecting acupoints of lung, Shenmen, endocrine and subcortical, pressing 3 times a day, each time 1min, binaural alternate treatment, the improvementrate of PASI score was as high as 74.4%.At the same time, the dermatology quality of life scale (DLQI), self-rating depression scale (SDS) and visual analog score (VAS) showed a trend of improvement, and the safety was good[50].Itcan be seen that the combination of the two methods can improve the clinical efficacy of traditional Chinese medicine in the treatment of psoriasis and prevent the recurrence of the disease to a certain extent, which is a lasting and stable treatment.Patients use Baduanjin, the traditional health-preserving method ofqi dredging, to dredge meridians through limb activities and breath, so as topromote the operation of qi and blood, regulate the function of Viscera, and achieve the purpose of improving the condition[51].In addition, with theprocess ofBaduanjin exercise, patients can calm their nerves,relieve qi depression and othersymptoms, cooperate with wet application of traditional Chinese medicine, control the recurrence or aggravation of patients with psoriasis, inhibit the inflammatory reaction of the body, and effectively reduce negative emotions.it is worthclinical promotion[52].

5.Conclusion

Psoriasis and depression are chronic and refractory diseases.Modern medical research has found that the clinical manifestations of mutual cause and effect and mutual crosstalk may be formed between them through the common pathological basis of genetic susceptibility, immune disorders and nervous system dysfunction,thus increasing the difficulty of treatment.Under the guidance of the holistic view of the integration of form and spirit and the principle of syndrome differentiation, traditional Chinese medicine has unique advantages and achieved remarkable results in the treatment of psoriasis depression from multi-target and multi-pathway, which provides more choices for clinical patients.However, at present,there are still the following deficiencies in the treatment of psoriatic depression by traditional Chinese medicine: (1) the number of basic literature is single, there is a lack of sufficient animal experiments,and the researchon the complex mechanism of traditional Chinese medicine is still shallow; (2)the quality of clinical research related to traditional Chinese medicine is uneven.Multi-center, high-quality large sample research is insufficient, and there are some detailed problems, reducing the credibility of the conclusion.(3) Psoriatic depressive comorbidity has not yet reached a unified standard of TCM syndrome type, mostly for various clinical experience, lack of complete co-disease diagnosis and treatment and curative effect evaluation system.Therefore, the mechanism of traditional Chinese medicine in the treatment of psoriasis depression still needs in-depth study, excavate the treasure house of traditional Chinese medicine,and provide a reliable basis for its modern diagnosis and treatment.

AuthorS’ contribution

Zhang Ning: writing papers; Yang Suqing: providing clinical ideas,direction and guidance for papers; Yuan Rui: guiding paper writing and improving it.

All authors declare that there is no conflict of interest.