摘要
[背景]
抑郁症是由各种原因引起的一种常见的情感性精神障碍,主要临床表现为：显著而持久的情绪低落,兴趣减低,思维迟缓,悲观无望,缺乏主动,自责自罪,食欲不振,睡眠障碍,多疑多虑,常伴有全身多系统的与客观检查不相符的多种多样的躯体不适,严重者可有自杀的念头和行为。中医古代文献中虽然没有抑郁症之病名,但对其认识有着悠久的历史,与中医文献中的多种病名,如“郁证”、“百合病”等类似。
抑郁症是一种常见的精神疾病,人群中16%的人在一生的某个时期会受其影响。中国的抑郁症发病率大约为5.3%,患者人数大约为6900万,随着现代生活节奏的加快,其发病呈蔓延之势。世界卫生组织(world health organization,WHO)一项研究表明,抑郁症已成为世界第4大疾患,预计到2020年,可能成为仅次于冠心病的第2大疾病,给个人、家庭和社会带来巨大的损失。
目前,现代医学多用舍曲林等西药来治疗抑郁症,但西药治疗周期长、价格较昂贵且毒副作用大,极大地影响了患者依从性及临床疗效。临床研究发现大约一半以上的抑郁症患者都伴有一定程度的焦虑,而抗抑郁西药治疗伴焦虑的抑郁症有更多的急性不良事件。而且,国外学者研究表明,抗抑郁西药对重度抑郁症有明显的治疗效果,但没有证据显示它们对大多数轻中度抑郁症有明显的治疗效果。
中药防治抑郁症已经有两千多年的历史,加味逍遥散等中药防治各种抑郁症临床疗效可靠,与西药疗效大致相当,价格便宜,毒副作用较小,但缺少科研设计严谨的的临床研究,严重地妨碍了向国内外推广应用中医优势防治抑郁症的独特优势。
抑郁症依靠症状进行诊断,诊断标准源自于一系列持续一段时间显著损害人体机能的的症状,这些症状经常和焦虑所引起的症状相重叠,中医诊断也依赖于患者的个人症状进行诊断。中医根据症候进行治疗,所以,根据不同的症候,应用不同的中药。加味逍遥胶囊(药物组成：柴胡、当归、白芍、白术(麸炒)、茯苓、甘草、牡丹皮、栀子及薄荷)具有疏肝清热、健脾养血之功效。在我国,加味逍遥胶囊常常用于治疗抑郁症气郁化火证患者,它治疗抑郁症有以下3个优点：1)加味逍遥胶囊源自于加味逍遥散,加味逍遥散在我国已应用了千百年,因此它对病人是安全有效的；2)加味逍遥胶囊源自于天然药物,更容易被患者接受；3)加味逍遥胶囊价格相对便宜,与常用抗抑郁西药相比,它给患者和社会带来的经济负担更低。
随机、双盲、阳性对照试验是测试治疗有效性的金标准,然而,据我们所知,直到现在,还没有关于加味逍遥胶囊治疗抑郁症的严格临床设计研究。气郁化火证是抑郁症患者的常见证型之一。因此,在前期研究的基础上,我们设计了一项关于轻中度抑郁症气郁化火证患者的多中心、随机、双盲、双模拟、阳性对照的临床研究,以研究加味逍遥胶囊治疗轻中度抑郁症气郁化火证患者的有效性和安全性,证实加味逍遥胶囊是值得推广的一种中医药治疗抑郁症的方法,为抑郁症的中医药治疗提供循证医学证据。
[目的]
研究加味逍遥胶囊治疗轻中度抑郁症气郁化火证患者的疗效和安全性；探索中医药治疗轻中度抑郁症气郁化火证患者相对抗抑郁西药的优势。
[方法]
1.研究设计：多中心、随机、双盲、双模拟、阳性对照临床试验。
2.研究对象：2011年10月～2013年3月在北京中医药大学东方医院、中国中医科学院广安门医院及首都医科大学附属北京安定医院等三家医院门诊就诊入组的轻中度抑郁症气郁化火证患者127例,按入组时间顺序随机分至中药组和西药组,其中中药组65例,西药组62例。
3.治疗方法：中药治疗组予以加味逍遥胶囊+舍曲林安慰剂；西药治疗组则予以舍曲林+加味逍遥胶囊安慰剂,疗程8w。
4.观察指标及观察时点：一般人口学资料在治疗前调查(OW)；汉密尔顿抑郁量表(Hamilton depressive scale,HAMD)和中医症候观察表在OW、2W、4W、8W各评估1次；疗效评定在治疗后2W、4W、8W各观察1次；治疗后第2w、4w、8w分别填写副反应量表(Treatment emergent symptom scale,TESS);血尿常规、肝肾功和心电图在Ow和8W结束时各检测1次；记录两组治疗后不良事件。
[结果]
1.基线资料
本研究实际纳入病例127例,其中中药组65例,西药组62例,男32例(25.20%),女95例(74.80%),两组性别、身高、体重、收缩压、舒张压和心率等人口学资料、HAMD抑郁量表各因子、中医症状及舌脉等基线资料比较,经秩和检验(Z检验),两组均无显著统计学差异(P>0.05),具有可比性。
2.HAMD抑郁量表总分及疗效评定比较
经配对t检验,中药组、西药组各访视时点HAMD抑郁量表评分与基线比较,均有显著统计学差异(P<0.05),两组均有良好治疗效果。
经Z检验或成组样本t检验,中药组、西药组HAMD量表差值组间比较,各访视点均无显著统计学差异(P>0.05)。
第8w,中药组临床治愈0例(0.00%),显效18例(30.00%),有效33例(55.00%),无效9例(15.00%),愈显率(临床治愈率+显效率)为30.00%,总有效率85.00%；西药组临床治愈2例(3.85%),显效13例(25.00%),有效33例(63.46%),无效4例(7.69%),愈显率为28.85%,总有效率为92.31%。
不同访视时点两组HAMD量表疗效评定,经Z检验,均无显著性差异(P>0.05)。
3.HAMD抑郁量表各因子比较
3.1治疗后第8w,中药组与西药组躯体性焦虑症状比较,经Z检验,有显著统计学差异(P<0.05),中药组明显优于西药组。
3.2治疗后第8w,中药组与西药组胃肠道症状比较,经Z检验,有显著统计学差异(P<0.05),中药组明显优于西药组。
3．3治疗后第4w、8w,中药组与西药组偏执症状比较,经Z检验,均有显著统计学差异(P<0.05),中药组明显优于西药组。开始治疗2w后,中药组偏执症状即得以明显减轻,第4w时大多数患者偏执症状消失,之后无明显反复；而西药组在开始治疗2w时偏执症状虽明显减轻,但之后偏执症状又逐渐加重。
3.4治疗后第2w、4w、8w,中药组与西药组强迫症状比较,经Z检验,均有显著统计学差异(P<0.05),中药组明显优于西药组；开始治疗2w后,中药组强迫症状即得以减轻,第4w时大多数患者强迫症状消失,之后无明显反复；而西药组在开始治疗2w后不仅强迫症状未减轻,大多数患者还有一明显加重过程。
3.5治疗后,中药组与西药组患者HAMD抑郁量表各症状均能逐渐减轻。两组其它HAMD抑郁量表症状在治疗各时点比较,经Z检验,均无显著统计学差异(P>O.05)。
4.中医症候观察表症候总分及各症候比较
治疗后,中药组与西药组中医症候均能逐渐减轻；治疗后第2w、4w、8w,经配对t检验,中药组、西药组中医症候总分各访视时点与基线比较,均有显著统计学差异(P<0.05),两组均有良好治疗效果；经Z检验,或成组样本t检验,中药组、西药组中医症候总分差值组间比较,各访视点中医症候均无显著统计学差异(P>0.05);中药组与西药组患者各中医症候在治疗各时点比较,经Z检验,均无显著统计学差异(P>0.05)。
5.治疗安全性
治疗前和治疗8W结束时,两组患者血尿常规、肝肾功和心电图均未见明显异常；两组均无合并用药；治疗后第2w,中药组副反应及其引起的痛苦均明显低于西药组,经Z检验,有统计学差异(P<0.05),副反应严重者停药后症状消失；治疗后4w和8w,两组仅有少数患者有轻度不良反应,均能自行缓解。治疗过程中两组均无其它不良事件及严重不良事件的发生。
6.脱落与剔除病例
在治疗过程中,中药组病例脱落5例,西药组病例脱落10例,西药组脱落高于中药组；脱落率为11.81%,低于15%。两组所有入选病例均符合研究需求,无剔除病例。
[结论]
1.对于治疗轻中度抑郁症气郁化火证患者,加味逍遥胶囊与西药舍曲林相比,两者均有良好的治疗效果。
2.对于治疗轻中度抑郁症气郁化火证患者,加味逍遥胶囊与舍曲林均能明显改善患者中医症候。
3.与舍曲林相比,加味逍遥胶囊在改善轻中度症抑郁气郁化火证患者躯体性焦虑、胃肠道症状、偏执及强迫症状方面有明显优势。
4.在治疗轻中度抑郁症气郁化火证患者时,与舍曲林相比,加味逍遥胶囊副反应小,治疗安全性好,患者依从性较好。
5.加味逍遥胶囊治疗抑郁症伴焦虑症状相对抗抑郁西药舍曲林有一定优势。
[创新性]
1.首次在国内采用多中心临床研究来验证加味逍遥胶囊治疗轻中度抑郁症气郁化火证的有效性和安全性,探索一种治疗抑郁症的新方法。
2.首次在国内采用随机、双盲、双模拟、阳性对照的临床研究来检验加味逍遥胶囊治疗轻中度抑郁症气郁化火证的临床疗效。
3.首次按照药品临床试验管理规范(Good Clinical Practice,GCP)的要求进行顶层设计,用合理统计学方法对加味逍遥胶囊治疗轻中度抑郁症气郁化火证进行严格的临床评价。
[Background]
Depression is a common affective disorder which caused by various reasons. The main clinical manifestations are as follows:a significant and lasting low mood, reducing interest,retardation of thinking, pessimism and hopeless, lack of initiative, remorse since sin, loss of appetite, sleep disturbances, suspicious and worry too much,and it often accompanied by a variety of body discomforts of multiple system which are not consistent with the objective examination, severe cases may have suicidal thoughts and behavior. In the Chinese ancient literature,there is no record of the name of depression disease, but the understanding has a long history and a variety of related terms are found such as "depression syndrome","lily disease" and so on.
Depression is a common mental disease,16%of people will be influenced by it at some point in their life. The incidence rate of depression is about5.3%in china, approximately69million. Depression is associated with a trend of spread along with the accelerating rhythm of modern life. It was reported that depression was ranked as the fourth leading cause of burden among all diseases according to a research of WHO.It should be the disease Second only to coronary heart disease by2020, Currently, depression is treated by modern medicine with western medicine such as Sertraline, but western medicine treatment cycle is long, the price is expensive along with large side-effects,so it greatly influences the patient's compliance and clinical curative effect.It was reported that more than half of the patients with depression are associated with a certain degree of anxiety according to some clinical researches, however, it should bring more acute adverse events when depression with anxiety was treated by western medicine. Furthermore,the foreign scholars also got a conclusion that antidepressant medicine could have a substantial effect on more severe depressions, but there was no evidence showed that they can produce specific pharmacological benefit for the majority of patients with mild to moderate depressions.
Traditional Chinese Medicine (TCM) has long history of prevention and treatment of depression up to two thousand years.TCM,such as JiaWeiXiaoYao (JWXY) power,etc,can bring a reliable clinical curative effect compared with west medicine,and the price is much cheaper following with less side-effects. Because of lack of rigorous clinical research, it seriously prevented the unique advantage of TCM for its popularization and application at home and abroad.
Depression diagnosis is symptom-based diagnostic, the diagnosis criteria is based on the a series of symptoms that significantly impair the function of human body for a long period,which often overlap with other conditions such as anxiety disorders. TCM diagnosis is also based on individual symptom of patients. TCM treatment is based on symptoms differentiation, so according to different type of symptoms different herbs are used. JWXY capsule can smooth the liver and clear heat, strength spleen and nourish blood. It is an effective Chinese medicine commonly used on depression with syndrome of qi stagnation transforming into fire in China.3advantages of JWXY capsule for depression disease are as below:1. JWXY capsule is orient from the formula JWXY powder, which has been used for hundreds and thousands years in our country, so it is relatively safe and effective for people.2. JWXY capsule is originated from natural vegetation, and it is more easily accepted by patients.3. JWXY capsule is relatively cheap, which cause much lower economic load for patients and society than conventional antidepressant.
The randomized, double-blind, positive controlled trial is the gold standard for testing treatment efficacy, but till now as we know there were few strict designed studies of JWXY capsule in treating depression. Syndrome of qi stagnation transforming into fire is one of common syndromes of depressive patients. So on the basis of previous research, we carried out a multicenter, randomized, double-blind, double-dummy, positive controlled study among mild to moderate depressive patients with syndrome of qi stagnation transforming into fire, in order to study the effectiveness and safety of JWXY capsule in treating mild to moderate depressive patients with syndrome of qi stagnation transforming into fire,to confirm JWXY capsule worthy of extending as a kind of TCM in treating depression,and to provide evidence-based medical evidence of TCM in the treatment of depression.
[Objective]
1. To study the effectiveness and safety of JWXY capsule in treating mild to moderate depressive patients with syndrome of qi stagnation transforming into fire.
2. To explore the superiority of TCM in the treatment of mild to moderate depressive patients with syndrome of qi stagnation transforming into fire compared to antidepressant western medicine.
[Methods]
1. Research design
Multicenter, randomized, double-blind, double-dummy and positive controlled clinical study was carried out.
2. Research object
Between October2011to March2013,127mild to moderate depression outpatients with syndrome of qi stagnation transforming into fire were recruited, which from3hospitals in Beijing:Guanganmen hospital of china academy of Chinese medical sciences, Dongfang hospital of Beijing university of Chinese medicine and Anding hospital of capital medical university. The patients were randomly divided into Chinese medicine group and western medicine group according to the time sequence,65in Chinese medicine group and62in western medicine group.
3. Therapeutic method
Chinese medicine group:JWXY capsule and Sertraline placebo, Western medicine group:Sertraline and JWXY capsule placebo. Either of them got different treatment for8weeks.
4. Observation data and observation point
Demographic data were surveyed before the treatment. Hamilton Depressive Scale (HAMD) and TCM symptoms assessed the effects on depression at the0,2nd,4th and8thweek. Curative effect evaluated at the2nd,4th and8th week. Treatment Emergent Symptom Scale (TESS) were filled in the2nd,4th,8thweek. Blood and urine regular,liver and renal function and electrocardiogram were test at0week and8th week. Adverse events were recorded.
[Results]
1. The Baseline Data
A total of127cases with65in Chinese medicine group and62in western medicine group were actually recruited in our study, which including32males (25.20%) and95females (74.80%).There were no significant statistical differences (P>0.05) between the two groups in the demographic data as gender, height, weight, systolic blood pressure, diastolic blood pressure,heart rate and the baseline data as HAMD depression scale entry, TCM symptoms by Z test.
2. Comparison of HAMD depression scale total score and curative effect evaluation
By paired t test, there were statistically significant differences (P<0.05) of HAMD scale total score at each observing point compared with the baseline of the Chinese medicine group and western medicine group,indicating that both groups have good therapeutic effect.
By Rank sum test or group sample t test, there were no statistically significant difference (P>0.05) of HAMD scale comparison between Chinese medicine group and western medicine group on each observing point. There were no significant differences (P>0.05) of HAMD scale curative effect evaluation between the two groups at each observing point.
3. Comparison of HAMD depression scale factors
3.1At8th week, the Somatic anxiety symptoms of the two groups were compared by Z test, there was a significant difference (P<0.05) between the two groups,Chinese medicine group was superior to western medicine group.
3.2At8th week,there was a significant difference (P<0.05) between the Gastro-intestinal symptoms of the two groups by Z test, Chinese medicine group was superior to western medicine group.
3.3At4th and8th week, there was a significant difference (P<0.05) between the Paranoid symptoms of the two groups by Z test,Chinese medicine group was superior to western medicine group.The paranoid symptoms of Chinese medicine group were relieved at2nd week, and disappeared at4th week among most patients without repeating later.Although the paranoid symptoms of Western medicine group relieved at2nd week, they gradually increased after that time.
3.4At2nd,4th, and8th week, there was a significant difference (P<0.05) between the obsessive-compulsive symptoms of the two groups by Z test,Chinese medicine group was superior to western medicine group.The obsessive-compulsive symptoms of Chinese medicine group were relieved at2nd week, and disappeared at4th week among most patients without repeating later. The obsessive-compulsive symptoms of Western medicine group not only didn't relieved at2nd week, but also got an increasing period.
3.5After treatment, every symptom of HAMD scale could be relieved gradually among the patients of both Chinese medicine group and Western medicine group. Other symptoms of HAMD depression scale at each observing point were compared by Z test, and there was no significant difference (P>0.05)between the two groups.
4. Comparison of TCM scale total score and symptoms
By paired t test, there were statistically significant differences (P<0.05) of TCM scale total score at each observing point compared with the baseline of the Chinese medicine group and western medicine group,indicating that both groups have good therapeutic effect.
By Rank sum test or group sample t test, there was no statistically significant difference (P>0.05) of TCM scale comparison between Chinese medicine group and western medicine group on each observing point.
After treatment, every TCM symptom of Chinese medicine group and Western medicine group was all reduced; At2nd,4th and8th week, there was no significant difference (P>0.05) between the symptoms of two groups compared by Z test.
5. Therapeutic safety
Before treatment and8th week later,there was no significant abnormity of blood and urine regular,liver and renal function and electrocardiogram among all patients of two groups. Two groups were no drug combination. At2nd, adverse reactions and pains caused by traditional Chinese medicine group were significantly lower than the Western medicine group,there was a significant difference (P<0.05) between the adverse reactions of two groups compared by Z test, and the severe symptom of adverse reactions disappeared after drug withdrawal. At4th and8th week, only a few patients of two groups had mild adverse reactions, they all could alleviate by themselves, and there was no significant difference (P>0.05) between the adverse reactions of two groups compared by Z test. There were no other adverse events and serious adverse events of two groups in the course of treatment.
6. Falling off and eliminating cases
In the therapeutic process,5cases felled off in Chinese medicine group and10cases in western medicine group, higher rate felled off Western medicine group than that in Chinese medicine group. The expulsion rate was11.81%,and it was inferior to15%. All the cases of two groups were in line with the research needs,and there were no eliminated cases.
[Conclusions]
l.For treating mild to moderate depression with syndrome of qi stagnation transforming into fire, JWXY capsule has similar good therapeutic effect to western medicine sertraline.
2.For treating mild to moderate depression with syndrome of qi stagnation transforming into fire, both JWXY capsule and sertraline can significantly improve patients with symptoms of TCM.
3.Compared with sertraline, JWXY capsule has obvious advantages of improving some symptoms of mild to moderate depressive patients with syndrome of qi stagnation transforming into fire,such as somatic anxiety, gastrointestinal symptoms, paranoia and forced symptoms.
4.1n the course of treating mild to moderate depressive patients with syndrome of qi stagnation transforming into fire,JWXY capsule has smaller side-effects compared with sertraline,both the safety and patient compliance are good.
5.JWXY capsule has certain advantages of treating depression accompany with symptom of anxiety by contrast sertraline.
[Innovations]
1.Multicenter clinical study was firstly used to test the effectiveness and safety of JWXY capsule in treating mild to moderate depression with syndrome of qi stagnation transforming into fire,and to explore a new method for treatment of depression.
2.Randomized, double-blind, double-dummy and positive controlled clinical study was firstly to test the clinical curative effect of JWXY capsule in treating mild to moderate depression with syndrome of qi stagnation transforming into fire.
3.The top-level design based on the GCP requirements and reasonable statistical methods were firstly used for strict clinical trial evaluation of JWXY capsule in the treatment of mild to moderate depression with syndrome of qi stagnation transforming into fire.
引文
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