中药复方治疗抑郁症的临床研究
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摘要
[背景]
     近年来,抑郁症的发病率逐年攀升,据预测,到2020年将成为既冠心病之后的第二类疾病负担源。中国的自杀率目前为22.2/10万,和抑郁障碍有关者占自杀的40%~70%。抑郁症的防治工作越来越受到医学界乃至社会各界的重视。目前西医治疗仍有许多不足之处,据研究中药复方具有多途径、多靶点、多层次的治疗优势,在抑郁症方面逐渐显示出一定的疗效和研发前景。但是中药复方的疗效评估及其主治功用也存在着问题,需要运用现代研究方法进行大样本的临床研究来进一步提取复方治疗的靶症状,并且经过大样本研究使复方的功效更具有说服力,更有利复方的推广性使用。甘丙肽(Galanin)最早是1983年从猪的小肠分离提取的一种神经多肽,近年来研究发现Galanin和焦虑、抑郁情绪关系密切,可能参与抑郁症的发病过程,一些研究证明其可以作为治疗抑郁症的种新的靶点,有广阔的发展前景。目前关于甘丙肽和抑郁症的关系的研究多为实验性,临床研究尚少,需要临床研究进行进一步探索甘丙肽与抑郁症之间的关系。
     [目的]
     观察逍遥散、归脾汤、血府逐瘀汤治疗抑郁症的疗效、安全性、依从性,并观察三个经典方剂治疗抑郁症的疗效是否存在差异;提取逍遥散、归脾汤、血府逐瘀汤治疗抑郁症的靶症状;观察抑郁症患者血浆甘丙肽水平与正常对照组是否有差异、在中药治疗前后是否有差异,探索在抑郁症诊断、疗效评价中的价值;探索血浆甘丙肽与抑郁症疾病特征的相关性。
     [方法]
     第一部分:中药复方治疗抑郁症的临床研究。采用ICD-10版抑郁发作的诊断标准确定抑郁的存在,并采用中医证候标准进行辨证分型,对抑郁症患者进行人口学资料、一般发病资料、中医四诊资料的采集及对HAMD、 HAMA、 MADS、 GAF量表的专业评定。治疗方法:根据辨证分型的情况,分别给予肝郁脾虚组、心脾两虚组、气滞血瘀组以逍遥散、归脾汤、血府逐瘀汤复方免煎颗粒常规治疗,疗程12周,分别在基线、用药2周、4周、8周、12周后对各组进行评估,包括中医症状的观察和HAMD等量表评分情况。在基线及用药12周后进行安全性指标的观测以评定药物安全性。疗效评价主要以HAMD减分率作为疗效等级评价指标。
     第二部分:中药复方对抑郁症患者血浆甘丙肽水平的影响。采用ELISA方法检测135例抑郁症患者(轻度57例,中度78例)和50名健康对照血浆甘丙肽浓度,比较三组间血浆甘丙肽水平的差异;并进一步探索肝郁脾虚、心脾两虚、气滞血瘀三个证型的抑郁症患者甘丙肽水平之间是否存在差异;采用HAMD、 MADS、 HAMA评定抑郁症患者的抑郁状态及伴发的焦虑状态,探讨血浆Gal水平与一般情况及疾病特征的相关性,并结合第一部分对135例抑郁症患者采用中药复方辨证施治研究,检测治疗12周后抑郁症患者血浆甘丙肽水平,观察治疗前后Gal水平的变化情况。
     [结果]
     各证型抑郁症患者不同时点的HAMD、 HAMA、 MADS评分有显著性差异(P<0.01),随着随访时间呈逐渐下降趋势,且与时间成线性相关关系(P<0.01),轻、中度两组患者HAMD评分变化趋势有显著性差异(P<0.05)。各证型抑郁症患者不同时点GAF评分比较有显著性差异(P<0.01),且不同时点GAF评分随着时间逐渐升高,与时间成线性相关关系(P<0.01)。各证型抑郁症患者不同时点HAMD各因子评分均有显著性差异(P<0.01),随着随访时间呈逐渐下降趋势,且与时间成线性相关关系(P<0.01)。其中焦虑因子评分随时间变化趋势与证型分组有交互作用(P<0.05),认知障碍因子阻滞因子随时间变化趋势与抑郁程度有交互作用(P<0.05)。经过各量表评分的多重比较,HAMD、 HAMA、 MADS评分从2周开始与基线比较有显著性差异,GAF(功能大体评定量表)从4周开始与基线比较有显著性差异。本研究整个中药治疗过程,不良反应少,出现躯体不适的共有3例,经处理不良反应均消失。服药后出现血常规异常3例,尿常规4例,肝肾功异常8例,心电图异常1例,程度轻微,复查后恢复正常。逍遥散治疗抑郁症靶症状:心理学症状:心神不定、懒言、善处独室、易怒、胆小怕事、反应迟钝、情绪低落、善恐易惊、表情淡漠、心烦不安;躯体症状:两胁胀痛、胃脘胀满、气短、纳差、嗜卧、倦怠、头昏沉、善叹息、双眼干涩、失眠、视物模糊、口舌干燥、面色不华。归脾汤治疗抑郁症靶症状:心理学症状:懒言、反应迟钝、胆小怕事、易怒、心神不定、心烦不安;躯体症状:心悸、嗜卧、气短、倦怠、面色萎黄、善太息、视物模糊、头晕、头昏沉、双眼干涩、失眠、口舌干燥。血府逐瘀汤治疗抑郁症靶症状:心理学症状:心神不定、易怒、懒言、反应迟钝、表情淡漠、心烦不安、情绪低落;躯体症状:两胁胀痛、胃脘胀满、气短、倦怠、失眠、心悸、面色晦暗、口舌干燥、痛经、月经有血块、舌瘀点瘀斑、肢体麻木。轻、中度抑郁患者血浆Gal水平较正常人均显著升高(P<0.01),并随着抑郁程度加重而有升高的趋势。抑郁症患者血浆Gal水平与HAMD积分(R=0.126P=0.036)、HAMA积分(R=0.160P=0.008)、MADS积分(R=0.213P=0.000)均呈明显正相关关系,与HAMD量表7因子中的焦虑因子(R=0.138P=0.027)、阻滞因子(R=0.133P=0.035)有明显正相关关系。抑郁症患者中药复方治疗12周后Gal水平与基线相比明显下降,有显著性差异(P<0.01)。
     [结论]
     1.逍遥散、归脾汤、血府逐瘀汤对抑郁症具有较好的疗效、安全性及依从性,且三个复方的疗效相当,抑郁状态及伴发焦虑状态的改善在2周时起效,整体功能状态的改善在4周时起效,且治疗效果均随治疗时间逐渐提高。
     2.肝郁脾虚证、气滞血瘀症在逍遥散、血府逐瘀汤治疗12周后其核心证候要素仍占主要组成要素,未发生向它证转化。心脾两虚证在归脾汤治疗12周后有向肝郁脾虚转化的趋势。
     3.轻、中度抑郁症患者血浆甘丙肽水平均显著高于正常人,且随着抑郁、焦虑程度的加重而升高,甘丙肽可能不仅参与了抑郁症的发病过程,且与治疗机制也有关联,血浆Gal水平对抑郁症的诊断、疗效评价的具有一定参考价值。
Background:In recent years, the incidence of depression is rising year by year, it is predicted that by2020depression will be the second class source of disease burden in both coronary heart disease.So far China's suicide rate is22.2/10million, and which is related with depressive disorder accounted for40%to70%of suicide[1].The prevention and cure work of depression is given more and more attention by the medical profession and even the community.But there are still many inadequacies in Western medicine treatment,according to the research,Chinese herbal compound has a multi-channel, multi-target, multi-level therapeutic advantage and shows certain curative effect and prospects of research and development in depression gradually.But the curative effect evaluation and attending functions of Chinese herbal compound also exist problems.So we need large sample of clinical studies using the modem research methods to further extract Chinese herbal compound therapeutic target symptoms,and make the effect of compound more persuasive, and be good for better compound used,promote use of the compound.Galanin is a neuropeptide which at first was separated and extracted from pig intestine in1983,in recent years,studies have found that galanin was closely related to anxiety and depression,may be involved in the pathogenesis of depression,some research demonstrated that it can be a new target for treatment of depression,there are broad prospects for development.The study of the relationship of galanin and depression are experimental,clinical research is less, so need for further clinical research to explore the relationship between galanin and depression.
     Objective:To observe the clinical efficacy,safety and compliance of the Xiaoyao powder,Guipi decoction and Xuefuzhuyu decoction in the treatment of depression,and to compare the efficacy differences of three classic prescriptions in treating depression.To extract therapeutic target symptoms of Xiaoyao powder,Guipi decoction and Xuefuzhuyu decoction in treating depression.To explorer the difference of plasma galanin level in patients with depression,and further to explorer the valve of plasma galanin level in depression diagnosis and efficacy evaluation,to explorer plasma galanin correlation with disease characteristics of depression.
     Methods:The first part:the clinical research of Chinese herbal compound treating depression.Using ICD-10(F32),《depressive episode diagnostic criteria》 to determine the existence of depression,and using the criteria for TCM syndrome to differentiate syndromes, to collect demographic data,general incidence data,TCM four diagnostic data and give patients with depression professional assessment of the HAMD,HAMA,MADS,GAF scales. Treatment:according to the classification of syndrome differentiation,respectively give inhibition of the liver-qi with spleen deficiency group,deficiency of both heart and spleen group,and qi stagnation and blood stasis group a regular treatment with Chinese herbal compound granules of the Xiaoyao powder,Guipi decoction and Xuefuzhuyu decoction, treatment for12weeks,to evaluate each group situation at baseline,2weeks,4weeks,8weeks,12weeks respectively,including observation of TCM symptoms and HAMD rating scale and so on.At baseline and after treatment for12weeks to observe safety index to assess drug safety.The effects were assessed mainly by reducing score rate of the Hamilton depression rating scale.
     The second part:the clinical research of influence of Chinese medicine compound on the plasma levels of galanin of patients with depression.Using ELISA method to detect plasma concentration of galanin of135cases of depression patients(57cases of mild depression,78cases of moderate depression) and50cases of healthy control,comparing the difference of plasma levels of galanin in the three groups;and to further explore the difference of galanin plasma levels in the inhibition of liver-qi with spleen deficiency,qi stagnation and blood stasis and deficiency of both heart and spleen those three syndrome types;using HAMD,MADS, HAMA rating scale to evaluate depression and anxiety status of patients with depression to explore the correlations of plasma level of galanin with general situation and disease characteristics,and combined with the first part research of treatment based on syndrome differentiation using traditional Chinese medicine compound in135depression patients, detect plasma level of galanin of depression patients after treatment for12weeks, observe changes of the galanin levels between before and after treatment.
     Results:Different point of HAMD,HAMA,MADS score of different syndrome types depression patients had significant differences (P<0.01),as the follow-up time showed a trend of gradual decline,and had the relation with time linearly (P<0.01),HAMD score trends in both mild and moderate groups had significant difference(P<0.05).Different point of GAF score had significant difference(P<0.01),as the follow-up time showed a trend of gradual rise, and had the relation with time linearly (P<0.01).Different point of each fator score of HAMD of different syndrome types depression patients had significant differences (P<0.01),as the follow-up time showed a trend of gradual decline,and had the relation with time linearly (P<0.01).There is interaction between anxiety factor score trends over time and syndrome group(P<0.05),there cognition obstacle factor, blocking factor with time changing trend and degree of depression have interaction effect(P<0.05).Through the multiple comparison of each rating scale,HAMD,HAMA,MADS score since2weeks had significant differences compared with baseline,GAF(function overall rating scale) since4weeks had significant difference compared with baseline.In this study the whole process of Chinese medicine treatment,there few adverse reactions,body discomfort in3cases,after processing all adverse reactions disappeared.There were3cases of abnormal blood routine,4cases of abnormal routine urine,8cases of abnormal liver and kidney function test,electrocardiogram abnormality in1case after medication,all in slight degree,and returned to normal after review.Therapeutic target symptoms of Xiaoyao powder in the treatment of depression: psychological symptoms:insecurity,no desire to speak,like to be alone, irritability,timid and overcautious,slow response,depression,easy to panic,apathetic facial expressions,upset; somatic symptoms:pain in the hypochondriac regions,stomach fullness feeling,short of breath,anorexia,addicted to lying,languor,giddy head,frequent sighs,dryness of the eyes, insomnia,blurred vision,dry of mouth and tongue,lusterless complexion.Therapeutic target symptoms of Guipi decoction in the treatment of depression:psychological symptoms:no desire to speak,slow response,irritability,insecurity,upset;somatic symptoms:palpitations, addicted to lying,short of breath, languor,sallow complexion,frequent sighs,blurred vision,dizziness,giddy head,dryness of eyes, insomnia,dry of mouth and tongue.Therapeutic target symptoms of Xuefuzhuyu decoction in the treatment of depression:psychological symptoms:insecurity,irritability,no desire to speak,slow response,apathetic facial expressions, upset,depression;somatic symptoms:pain in the hypochondriae regions,stomach fullness feeling,short of breath,languor,insomnia,palpitations,gloomy complexion,dysmenorrhea,blood clots in menstruation,petechiae and ecchymoses of tongue,limb numbness.Plasma galanin level of patients with mild and moderate depression both higher than normal person significantly(P<0.01),and had a tendency to rise with the increase of depression degree.Plasma galanin level of patients had significantly positive correlations with HAMD score (R=0.126,P=0.126), HAM A score(R=0.160,P=0.160),MADS score(R=0.213,P=0.213), and anxiety factor(R=0.138,P=0.138),retardation factor(R=0.133,P=0.133) of HAMD scale7factors.Plasma galanin level of patients significantly decreased by comparing with baseline after treatment for12weeks with TCM compound,there was significant difference(P<0.01).
     Conclusion:The Xiaoyao powder,Guipi decoction and Xuefuzhuyu decoction have good efficacy,security and compliance in treatment for depression,and those have the same effect,improvement of depression state and concomitant anxiety state began to work in2weeks,improvement of the overall function state began to work in4weeks,and the curative efficacy increased with treatment time gradually.The core syndrome elements of the inhibition of liver-qi with spleen deficiency syndrome and qi stagnation and blood stasis syndrome are still the main elements of syndrome elements after treatment for12weeks respectively with the Xiaoyao powder and Xuefuzhuyu decoction,not to transform into the other syndromes.The deficiency of both heart and spleen syndrome have the trend to transform into the inhibition of liver-qi with spleen deficiency syndrome after treatment for12weeks with the Guipi decoction.Plasma levels of galanin in mild and moderate depression patients are significantly higher than normal people,and increase with the deterioration of the degree of depression and anxiety,galanin may not only involve in the process of the onset of depression,and also is associated with treatment mechanism,the plasma level of galanin has a certain reference value of efficacy evaluation and diagnosis of depression
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