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Zhuojun Chen
Abstract: In modern society, due to the pressures of work and academics, there is an increasing trend in the incidence of depression. As people pay more and more attention to mental health and the mind-body connection, the current state of Western medical treatment for depression is not ideal. There is an urgent need for natural therapies with safe and comfortable treatments. Since serotonin imbalance is an important factor in depression, this article takes serotonin as the starting point and analyzes the correspondence between the brain-gut axis and the traditional Chinese medicine concept of liver stagnation and spleen deficiency. It proposes a new approach to the treatment of depression, guided by the theory of the brain-gut axis, integrating both Western and Chinese medicine. It also introduces a number of cases and clinical experiences in treating patients with depression, as well as the results of existing research on traditional Chinese medicine methods for the treatment of depression.
The principal symptoms of depression are that patients are trapped in sadness and anxiety, and not being able to derive interest, happiness, or pleasure from daily activities. The mechanism of depression is not fully understood, but it is currently believed that the hormones that bring feelings of pleasure and happiness to the human body include endorphins and serotonin. Although there is still debate within the academic field whether serotonin deficiency is the main factor in the onset of depression, the current antidepressant medications developed based on the theory of serotonins control over human emotions include: Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), Tricyclic Antidepressants (TCAs), Monoamine Oxidase Inhibitors (MAOIs), Tetracyclic Antidepressants (TeCAs), and Noradrenaline and Specific Serotonergic Antidepressants (NaSSAs).［1］
Production and distribution of serotonin
Serotonin, also known as serum tonicity factor or 5-hydroxytryptamine/serotonamine, is a type of monoamine neurotransmitter. It cannot be directly produced in the human body. Instead, humans must ingest tryptophan (which is one of the 22 standard amino acids and an essential amino acid that cannot be synthesized by the body and must be obtained from food). In the digestive tract, tryptophan is converted into 5-hydroxytryptophan by tryptophan hydroxylase, and then into serotonin by 5-hydroxytryptophan decarboxylase in the central nervous neurons and the enterochromaffin cells of the digestive tract of animals, including humans. About 90% of serotonin is primarily distributed in the mucosal enterochromaffin cells and myenteric plexus, and participates in the regulation of intestinal peristalsis in the intestine. Only 2% of the total serotonin is present in the brain, where it is involved in regulating sleep and emotions, contributing to states of ‘excitation’ or ‘inhibition.’ An additional 8-9% is absorbed through the intestinal mucosa into the bloodstream and stored in platelets. When the body is injured, platelets aggregate and release serotonin, causing blood vessels to constrict and aiding in blood coagulation and hemostasis. Serotonin also acts as a growth factor for some cells and plays a role in wound healing. There are various serotonin receptors. It is worth noting that serotonin cannot cross the blood-brain barrier, so the levels of serotonin in the gut and blood do not affect the serotonin levels in the central nervous system, maintaining a stable and independent system.
The relationship between serotonin and the brain-gut axis
The brain-gut axis is a bidirectional communication network between the brain and the gastrointestinal tract. The concept of the brain-gut axis originated from a 2004 study that found a significant connection between the gut microbiota of mice and the hypothalamic-pituitary-adrenal axis. Subsequent research has increasingly discovered the regulatory effect of gut microbiota on the brain, as seen in conditions like autism and Parkinsons disease, where imbalances in gut microbiota are present. Adjusting the gut microbiota can lead to significant improvements in symptoms. Since serotonin is present in both the brain and the gut, it is considered a very important theoretical basis for the brain-gut axis. Recent studies indicate that changes in the gut microbiota might help regulate 5-hydroxytryptamine (serotonin) signaling. Imbalances in serotonin levels and changes in the gut microbiome are thought to contribute to the onset and severity of depression. Research shows that changes in the composition of the gut microbiota (referred to as dysbiosis) can affect brain function and behavior. Specific bacteria within the gut microbiome can produce or regulate neurotransmitters, including serotonin. Therefore, dysbiosis of the gut microbiota may lead to depressive symptoms. Additionally, the gut microbiome influences the integrity of the intestinal barrier, thus affecting the production of immune molecules and the release of inflammatory mediators related to depression.
The Relationship between Serotonin and Stress
In nature, when mammals face stress, the amygdala in the brain gets activated, and cortisol (a glucocorticoid hormone) secretion increases. This process leads to the breakdown of amino acids into glucose to meet the body’s ‘fight or flight’ needs. In other words, amino acids like tyrosine and tryptophan are also broken down into glucose for these needs, leading to a deficiency in the precursors of serotonin and norepinephrine. This deficiency can cause a range of symptoms in individuals under stress, such as low mood, loss of interest, and even suicidal tendencies. To counter the dual impact of stress on serotonin and norepinephrine, pharmaceutical companies developed SNRI class antidepressants in 1993, which increase the levels of serotonin and norepinephrine in the body to combat negative emotions. However, in the natural world, the increase in cortisol and the breakdown of amino acids into glucose is a normal physiological response to stress, usually resolving after the ‘fight or flight’situation ends. This is not a pathological reaction, so as long as stress exists, the body will respond to it, and this stress response cannot be stopped as it is a normal physiological state. However, the stress in modern human society is different from the ‘fight or flight’mechanism of primitive societies, often being slow and long-term, and not resolvable through ‘fight or flight,’ leading to prolonged stress responses and resulting in depression and anxiety. Since this is not actually a pathological state, it cannot be cured through medication or the passage of time. Antidepressants can only help maintain a temporary state of happiness, and symptoms may reappear after stopping the medication.［2］
Side Effects of Antidepressant Medication
Since the occurrence of depression may be a normal physiological reaction, it is just because we are in a modern civilized society that it cannot eliminate stress factors. Therefore, it may not be cured by drug treatment at all, so long-term antidepressant drugs are needed for relief. Various side effects may occur due to low mood, such as increased appetite, insomnia, dry mouth, fatigue, decreased sexual function, etc. At present, more and more psychiatrists and patients are noticing this and trying to find treatment methods other than drugs. For example, depression can be treated by adjusting stress or changing lifestyle and diet. Among them, traditional Chinese medicine therapy is very popular because of its low incidence of side effects and remarkable effects.
Common Traditional Chinese Medicine Diagnoses for Depression
The most common syndrome type of depression diagnosed in traditional Chinese medicine (TCM) is liver stagnation syndrome, and the main causes of liver stagnation syndrome are divided into two types: liver stagnation and spleen deficiency and kidney deficiency and liver stagnation. This article mainly analyzes the syndrome types of liver stagnation and spleen deficiency. Literally understood, liver stagnation and spleen deficiency means that the low function of the digestive system will affect a persons emotional deficiency and lead to depression. The syndrome of liver stagnation and spleen deficiency can be better explained from the five-element theory of viscera. In the five-element theory, the liver is wood and the spleen is soil. When trees are planted in narrow or poor soil, it is not conducive to the growth of trees. Therefore, in the treatment of liver stagnation and spleen deficiency, traditional Chinese medicine can transplant trees to wider land and the liver wood is overly suppressed, it is equivalent to transplanting a big tree into a small piece of land. This will cause the tree to over absorb nutrients from the soil and lead to serious soil loss. This is a syndrome of liver stagnation insulting the spleen. The main symptoms are that the patient’s depression affects the digestive system, leading to indigestion, loss of appetite, diarrhea, constipation, weight loss, etc.
The relationship between “Liver stagnation and Spleen deficiency” in traditional Chinese medicine and the “brain-gut axis,” as well as some speculations about their role in serotonin regulation
The brain-gut axis is an axis with two-way influence, that is, intestinal microbiota intestinal function, and the brain interact with each other. The theory of liver stagnation and spleen deficiency in traditional Chinese medicine is very consistent with the brain-gut axis theory of western medicine. It reveals that the digestive system not only absorbs nutrients, but also regulates the human nervous system. Conversely, whether the brain is functioning normally or not also affects the digestive system. whether it can operate normally.［3］At present, there is no research on the relationship between “liver stagnation and spleen deficiency” and serotonin. However, since serotonin deficiency is mainly related to excessive stress, traditional Chinese medicine is very helpful in relieving stress and replenishing physical strength, and can solve the root cause. Problems of excessive cortisol and excessive serotonin consumption: Studies by Xu Hong［4］and Wang Shuping et al.［5］ found that acupuncture has an adjustment effect on adrenocortical hormones.
The function of serotonin is mainly responsible for regulating the body’s sleep, mood, appetite and digestive functions. Therefore, when it comes to traditional Chinese medicine’s approach to regulating serotonin for treating depression, there are four potential directions: improving digestion (strengthening the Spleen), relieving stress (smoothing Liver Qi), enhancing mood (tonifying Heart Qi and Yang), and improving sleep (calming the Shen and settling the mind). For patients with digestive issues, focusing on strengthening the Spleen may be an effective approach. Observing symptom improvement and changes in serotonin levels after some time of treatment could be a promising research direction.
Clinical experiences and insights from our clinic in treating patients with depression
Patient A, an 18 year old female, has been treated in our clinic for anxiety-depression since she was 16 years old. She started with acupuncture treatment once a week, and then changed to acupuncture treatment once every two weeks for half a year, with occasional Chinese medicine treatment (5 times in total) ). The tongue is pale and fat with thorns and teeth marks, the tip to stretch the trees, which are a method of soothing the liver; or fertilize the soil, which is a method of strengthening of the tongue is red, and there are veins under the tongue. The pulse is thin and weak. The main symptoms are premenstrual stress, vomiting, reticence, and difficulty falling asleep. Treatment method: Mainly regulate menstruation, soothe liver qi before menstruation, regulate Chong and Ren after menstruation, and also regulate and replenish the spleen and stomach. So far, the patient’s mood and sleep have been greatly improved, with basically no episodes of vomiting, only occasional nausea, and the tongue color has changed from light to slightly red.
Patient B, a 38-year-old male, has a high pressure job, frequent fatigue, anxiety, and body pain, and loose stools. Observation of the tongue and pulse revealed that the patient had a pale, fat tongue with thin and slippery coating, and a slippery pulse. The patient is advised not to eat raw or cold food, and to add yams, millet porridge, and chestnuts to his diet every day, and receive acupuncture treatment once a week or every two weeks. After three months of treatment, the patient’s anxiety and stress were greatly improved, and the pain he experienced was also reduced.
Patient C, female, 35 years old, is usually busy at work and cannot receive acupuncture treatment. Before menstruation, she often experiences uncontrollable depression and sadness, as well as fatigue and muscle aches throughout the body. After 3 years of traditional Chinese medicine, emphasizing nourishing the spleen and kidneys, as well as soothing the liver and relieving depression, the feeling of depression and fatigue have improved significantly.
References
［1］Wikipedia: Serotonin, 09 October 2023, Wikimedia Foundation, Inc. Available at:
https://en.wikipedia.org/wiki/ HYPERLINK “https://en.wikipedia.org/wiki/serotonin”HYPERLINK “https://en.wikipedia.org/wiki/ HYPERLINK ”“https://en .wikipedia.org/wiki/serotonin”serotoninHYPERLINK“https://en.wikipedia.org/wiki/serotonin” HYPERLINK “https://en.wikipedia.org/wiki/serotonin”serotonin
［2］ YouTube Channel: Joseph Psychological Counseling Room, dismantling: Why is serotonin insufficient? (Chinese subtitles) Why does the brain have secretory disorders? Is depression and anxiety an “abnormal” result of the “normal” functioning of the brain? Available at: https://www.youtube.com/watch?v=4uiVsk1mQWw
［3］ Xuebin Sun, Jiaxu Chen, Meifang Song, Chenxi Peng, Yueyun Liu, Research progress on the correlation between liver stagnation and spleen deficiency syndrome and brain-gut peptide, World Science and Technology: Modernization of Traditional Chinese Medicine 2018, 11(5): 1969-1973
［4］ Hong Xu, Zhongren Sun, Liping Li, et al., Acupuncture treatment of depression and its impact on patients hypothalamic-pituitary-adrenal axis ［J］, Chinese Acupuncture 2004, 24(2): 78-80
［5］ Shuling Wang, Lin Li, Xuelian Jiang, etc., Effects of Najia method acupuncture on serum cortisol content in AA rats ［J］, Chinese Medical Journal, 2009.27(1): 170-172
Author information:
Zhuoyun Chen, Second Clinical School of Guangzhou University of Traditional Chinese Medicine
肝鬱脾虛證候下對血清素與腦腸軸理論在治療憂鬱症的對應解釋
陳卓筠
摘要：在現代社會，由於工作以及學業的壓力，憂鬱症呈現越來越高發的趨勢，在人們日益注重精神健康以及身心關係的同時，憂鬱症的西醫治療現狀並不理想。尋求副作用低，治療過程舒適的自然療法是患者的迫切需求。 由於血清素失調是影響憂鬱症的重要因素，故本文以血清素為切入點，分析了腦腸軸以及中醫肝鬱脾虛證的對應關係，提出在抑鬱證治療上以腦腸軸為指導理論進行 中西醫結合的新思路，並介紹了本人在治療憂鬱症患者中的一些案例與心得，以及已有的一些關於中醫療法對憂鬱症的研究的治療成果。
憂鬱症的主要症狀是患者困於悲傷、焦慮的情緒中，在日常的活動中無法獲得興趣和幸福感、愉悅感。憂鬱症產生的原理目前尚未完全清楚，但是目前認為能夠為人體帶來愉悅、幸福的感受的激素主要有內啡肽以及血清素。儘管血清素缺乏是否是憂鬱症產生的主要因素目前學術範圍內尚有爭論，但目前抗憂鬱西藥中針對血清素對人的情緒的控製作用理論而研製的主要有：選擇性5-羥色胺再攝取 抑制劑（SSRI）、5-羥色胺和去甲腎上腺素再攝取抑制劑 （SNRI、三環抗憂鬱劑（TCA、單胺氧化酶抑制劑（MAOI）、四環抗憂鬱劑（TeCA）、去 甲腎上腺素和特異性5-羥色胺能抗憂鬱劑（NaSSA）。［1］
血清素的生成與分佈
血清素， 又稱血清張力素，或5-羥色胺、血清胺，是單胺神經傳導物質的一種， 它不能在人體內直接產生, 人必須要透過外界攝取色胺酸（色胺酸是22個標準胺基酸之一，是屬於人體無法合成的必需胺基酸，須從食物中汲取)，在消化道內經由色氨酸羥化酶轉化為5-羥色氨酸，再經5-羥色氨酸脫羧酵素在中樞神經元及動物（含人類） 消化道之腸嗜鉻細胞合成5-羥色胺。90%的血清素主要分佈於黏膜腸嗜鉻細胞和肌間神經叢，在腸道參與腸蠕動的調節；在大腦中含量僅為總量的2%，參與睡眠及情緒的調節，使人呈現“興奮”或“抑制”的狀態。 而還有8%-9%經由腸黏膜吸收後進入血液而分佈在血小板內，當人體受傷時，血小板凝結成塊並釋放血清素，令血管收縮並有助於促進血液凝固和止血。血清素也是某些細胞的生長因子，在傷口癒合中發揮作用。 有各種血清素受體。值得一提的是， 血清素無法進入血腦屏障，所以腸道、血液內血清素含量與中樞神經系統內的血清素含量是穩定的、互不影響的系統。
血清素與腦腸軸的關係
腦腸軸是大腦和胃腸道之間的雙向通訊網路。腦腸軸的理論提出，系始於2004年一項研究發現小鼠腸道菌叢和下丘腦-去甲腎上腺素軸有明顯的關聯，後來越來越多的研究發現腸道菌叢對大腦 的調節作用，如自閉症、巴金森都存在腸道菌叢失調，調節腸道菌叢後，症狀可明顯改善。 由於血清素在大腦以及腸道中共同存在，可視為腦腸軸的一個非常重要的理論基礎。 近來多項研究結果表明，腸道菌叢的改變可能有助於5-羥色胺訊號傳導的調節。 血清素水平失調和腸道微生物群的改變已被認為是憂鬱症發作和嚴重程度的促成因素。 研究表明，腸道微生物群組成的改變（稱為菌群失調）會影響大腦功能和行為，腸道微生物組內的特定細菌會產生或調節神經傳導物質，包括血清素。 因此腸道菌叢失調可能導致憂鬱症狀。 此外，腸道微生物群會影響腸道屏障的完整性，從而影響免疫分子的產生以及與憂鬱症相關的發炎介質的釋放。
血清素與壓力的關係
在自然界，當哺乳動物面對壓力時，大腦中的杏仁核會被激活，皮質醇（即糖皮質激素）分泌會增加，會促使氨基酸分解成葡萄糖以供應軀體的“Flight or Fight(逃亡或戰鬥 )” 需求，換言之酪胺道內經由色氨酸羥化酶轉化為5-羥色氨酸，再經酸以及色胺酸也會被分解成葡萄糖以供應軀體的「Flight or Fight」 需求，並導致血清素以及去甲腎上腺素的原料不足，因而導致承受壓力者產生血清素 、去甲腎上腺素缺乏而發生的一系列症狀，如情緒低落，失去興趣，甚至自殺傾向等等。 針對1993年藥物公司研發了SNRI抗憂鬱藥，可以提高血清素以及去甲腎上腺素在人體的含量，以達到抵抗負面情緒的效果。但是，自然界中，壓力導致皮質醇升高並分解氨基酸成為葡萄糖是軀體的一種正常反應，通常在逃亡或戰鬥後壓力因素便會消除，這不是一種病理反應，所以只要存在壓力，軀體便會應激，並且無法停止這一應激反應，因為這是正常的生理狀態。然而，現代人類社會的壓力與原始社會的“逃亡或戰鬥”機制並不相同，多數情況下是緩慢、長期的壓力，並且無法透過“Fight or Flight”改變處境， 故而會引起機體長期的應激 反應而出現憂鬱、焦慮的狀態。 並且，因為其實際上不是病理狀態，故無法透過服用藥物或渡過病程時間而治癒。 抗憂鬱藥物只能幫助患者 維持一時的心境快樂狀態，停藥後症狀就會重新出現。［2］
抗憂鬱藥物的副作用
由於憂鬱症的產生可能是正常的生理反應，只是由於我們處於現代文明社會所以導了其無法消除壓力因素，所以可能根本不能靠藥物治療達到治癒的效果，故而需要長期服用抗憂鬱藥物緩解低落情緒而產生各種副作用，如食慾亢進，失眠，口乾，疲勞，性功能減退等等。目前越來越多的精神科醫師以及病患注意到這一點，努力尋求藥物以外的治療方式。例如可以調整壓力或透過改變生活方式、改變飲食來治療憂鬱症。其中，中醫傳統療法因副作用小，效果顯著而備受歡迎。
憂鬱症的常見中醫診斷
憂鬱症在中醫診斷上最常見的證型是肝鬱證，而造成肝鬱證的主要原因又分為肝鬱脾虛和腎虛肝鬱兩種類型。本文主要分析肝鬱脾虛證型。從字面上理解，肝鬱脾虛就是消化系統功能低下會影響人的情虛，導致憂鬱情緒的產生。從臟腑的五行理論能更好地解釋肝鬱脾虛證型，在五行理論中，肝為木，脾為土，當將樹木栽種在狹窄或貧瘠的土壤裡，就不利於樹木的生長。所以中醫對於肝鬱脾虛的治療上可以將樹木移植到更寬闊的土地裡，使樹木得到舒展，此為疏肝的方法；又或者為土壤施肥，此為健脾的方法。而從肝壓力對血清素以及去甲腎上腺素的雙重影響，鬱理論上可以反之推論，情緒也對 消化系統有著很大的影響。當人承受的壓力過大，導致肝木過度壓抑，便相當於將大樹移植到 很小的土地中，因此會導致樹木過度吸取土壤的營養而導致土壤流失嚴重。此為肝鬱侮脾臟的證型。主要表現為病人因為情緒低落而影響消化系統，導致消化不良，食慾減退，或腹瀉，或便秘，或體重下降等等。
肝鬱脾虛與腦腸軸的關係及血清素調節作用的一些猜想
腦腸軸是一條具有雙向影響作用的軸線，即腸道菌叢、腸道功能、大腦三者有相互影響。中醫肝鬱脾虛的理論和西醫的腦腸軸理論十分貼合，揭示了消化系統不僅存在吸收營養的功能，而且對人的神經系統存在調節作用，反之大腦的運作正常與否也影響消化系統 是否能夠正常運作。［3］目前，尚未有關於肝鬱脾虛和血清素關係的研究， 但由於血清素缺乏 主要與壓力過多有關，中醫療法對舒緩壓力，補充體力有極大的幫助作用，可以從根源上解決 皮質醇過高、血清素消耗過多的問題：徐虹［4］及王淑萍等［5］研究發現，針刺對腎上腺皮質激素有調整作用。血清素的功能主要是負責調節人體的睡眠、情緒、食慾和消化功能，而且故對於中醫調節血清素治療憂鬱症的方向也可分為四個方向：改善消化——健脾；舒緩壓力——疏 肝；改善情緒——補心氣、補陽；改善睡眠——安神定志。其中，針對消化不良的患者，重複使用健脾的方法， 觀察治療一段時間後症狀是否有好轉，血清素含量是否出現提升，可能是很好的研究方向。本診所在治療憂鬱症患者的臨床體會與心得
患者A,女，18歲，患者自16歲起在本診所治療焦慮-憂鬱症，開始時每週一次針灸治療，持續半年後改每兩週一次針灸治療，間中配合中藥治療（共5次 ）。 舌淡胖有芒刺及齒印，舌尖紅，舌下有靜脈，脈細弱。 主要症狀是經前情緒緊張嘔吐，沉默寡言，難以入睡。治療方法：以調理月經為主，經前疏洩肝氣，經後補衝任，兼調補脾胃。至今患者心境、睡眠 有很大改善，嘔吐情況基本無發作，僅偶爾會有噁心感，舌象由淡轉稍紅。
患者B,男，38歲，平時工作壓力較大，常疲勞、焦慮及周身疼痛，大便溏。 觀察舌脈發現患者舌淡胖苔薄滑，脈滑。 囑患者勿食生冷，每天吃山藥、小米粥、栗子，每週或每兩 週針灸治療 一次。 經治療三個月後，患者焦慮、壓力感覺有很大改善，周圍疼痛也減少發作。
患者C,女，35歲，平時工作較忙，無法針灸治療。經前常有無法控制的情緒低落及悲傷感，此外有疲勞，周身肌肉酸痛感。至今中藥治療已有3年，以補脾腎為主，疏肝解鬱為輔。情緒低落感及疲勞感明顯改善。
參考文獻
［1］Wikipedia: 血清素， 09 October 2023，Wikimedia Foundation, Inc. Available at:
https://zh.wikipedia.org/wiki/ HYPERLINK “https://zh.wikipedia.org/wiki/血清素” HYPERLINK “https://zh.wikipedia.org/wiki/ HYPERLINK ”“https://zh.wikipedia.org/wiki/血清素”血清素 HYPERLINK“https://zh.wikipedia.org/wiki/血清素” HYPERLINK “https://zh.wikipedia.org/wiki/血清素”血清素
［2］YouTube Channel：Joseph心理咨询室，拆解：血清素為何會不足？（中文字幕）大腦為何會分泌失調？抑鬱焦慮症是大腦「正常」運作下的「異常」結果？Available at: https://www.youtube.com/watch?v=4uiVsk1mQWw
［3］孙雪彬，陈家旭，宋美芳，彭晨习，刘玥芸，肝郁脾虚证与脑-肠肽相关性的研究进展， 世界科学技术：中医药现代化2018,11(5)：1969-1973
［4］徐虹，孙忠人，李丽萍等， 针刺治疗抑郁症及其对患者下丘脑-垂体-肾上腺轴的影响 ［J］，中国针灸2004，24（2）：78-80
［5］王淑玲，李琳，姜学连等，纳甲法针刺对AA大鼠血清皮质醇含量的影响［J］,中华医药学学刊，2009.27(1)：170-172
作者簡介:
陳卓筠,廣州中醫藥大學第二臨床醫學院
