摘要
[背景]
抑郁症是一种危害人类身心健康的常见精神疾病,随着社会经济的高速发展,生活节奏的加快,人们的精神压力逐渐加大,人类疾病谱发生了很大变化,抑郁症发病率逐年上升,逐渐成为影响人类身心健康的常见病、多发病。目前抑郁症的诊断率、治疗率很低,临床上治疗抑郁症的传统方法为药物治疗,由于抑郁症是一种复杂的身心疾患,药物治疗难以兼顾其多发病因,临床应用有一定的局限性。针刺具有整体多靶点的疗效特点,针刺治疗抑郁症受到越来越多研究者的重视,开展了许多相关的研究,但这些研究尚不能为针刺治疗抑郁症的有效性提供足够的循证医学证据。
基于以上考虑,为了证实针刺治疗抑郁症的确切疗效,我们对近年来治疗抑郁症的方案进行筛选和优化,确立了两种针刺治疗抑郁症的方案,在遵循循证医学原则的基础上,进行多中心、大样本的随机对照试验,期待为针刺治疗抑郁症的有效性提供客观依据,使针刺治疗抑郁症的方案能够在临床上广泛推广。
[目的]
1.确认针刺治疗抑郁症不同方案的有效性；
2.在确认针刺治疗抑郁症有效的基础上,评价不同治疗方案抗抑郁的起效时间、作用特点及作用优势；
3.探讨不同抑郁症治疗方案对患者自我临床结局评价的影响,评价不同方案对抑郁症患者自我健康状态的影响；
4.探讨不同抑郁症治疗方案对中医辩证简表的影响,以期为中医临床研究疗效评价方法提供思路。
[方法]
本临床试验采用适宜评价针灸疗效、凸现针灸治疗优势的多中心、大样本、实用性随机对照试验,临床病例收集工作在北京大学第六医院、包头市第六医院、南京中医药大学第一附属医院、南方医院四个分中心同时进行。
试验以抑郁症患者为研究对象,获得知情同意,按照诊断标准、纳入/排除标准,入组后随机分为三组：电针组、手针组、盐酸帕罗西汀对照组。电针组为电针主穴百会、印堂、基本配穴风府、风池、内关、三阴交；手针组为手针主穴百会、印堂,基本配穴风府、风池、内关、三阴交。6周为一个总疗程,结束治疗4周时随访一次。本研究涉及分中心之一北京大学第六医院的样本和多中心的总样本。
分中心病例来自北京大学第六医院自2008年11月至2010年7月的门诊患者,共随机入组病例88例,其中电针组28例,给予电针结合盐酸帕罗西汀干预,手针组25例,给予手针结合盐酸帕罗西汀干预,药物组35例给予口服盐酸帕罗西汀作为对照组。
总病例由四个临床分中心于2008年6月至2010年12月收集病例组成,共随机入组477例,其中电针组161例,给予电针结合盐酸帕罗西汀干预,手针组162例,给予手针结合盐酸帕罗西汀干预,药物组154例给予口服盐酸帕罗西汀作为对照组。
在治疗第0、1、2、4、6周后,以HAMD量表对患者进行评定来判定三组治疗方案的疗效差异,以SDS量表评价患者抑郁状态的改善情况,在治疗第0、2、4、6周后,以SERS量表评定三组在治疗后各个时段药物副反应的变化情况,在治疗第0、6周时,以CGI量表评定各组整体疗效,以WHOQOL-BREF量表对各组患者总体生活质量进行评定,以MYMOP量表让患者对自我临床结局症状进行评价,以自拟中医辨证简表对患者治疗前后中医症候的变化进行评价。在治疗结束后4周时以HAMD量表评定各组远期疗效。
主要疗效结局指标分析采用意向性治疗分析(ITT分析)和依从方案受试者分析(PPS分析)两种方法。
[结果]
分中心研究结果
1.三组疗效构成比较,ITT和PPS两种分析结果显示,三组组间差异有统计学意义(P<0.05)。电针组和手针组的总有效率均高于药物组,但两组之间无显著性差异(P>0.05)。
2.三组之间缓解率比较,ITT和PPS两种分析结果显示,分中心三组缓解率比较无统计学差异(P>0.05)。
3.三组起效时间比较,ITT和PPS两种分析结果显示,电针组和手针组在治疗1周后起效。药物组治疗2周后起效。
在治疗2、4、6周后,HAMD评分三组组间比较均具有显著性差异(P<0.05)。电针组和手针组相比在治疗后各时间段对抑郁症状的改善程度并没有显著性差异。
说明手针组和电针组治疗1周后能够显著改善患者抑郁症状,药物组治疗2周后明显改善患者抑郁症状,手针组和电针组能够明显缩短起效时间。
4.三组之间HAMD量表各因子评分比较,三组在治疗后1,2,4,6周时HAMD焦虑/躯体化因子、睡眠障碍因子评分组间比较均有显著性差异(P<0.05),电针组和手针组对各时间段的焦虑/躯体化因子、睡眠障碍因子改善程度均优于药物组。
三组在治疗后各时间段对HAMD阻滞因子、认知障碍因子和体重因子的改善程度没有显著性差异(P>0.05)。
电针组和手针组对HAMD焦虑／躯体化因子、体重因子、认知障碍因子、阻滞因子、睡眠障碍因子在治疗后各时间段的改善程度均没有显著性差异(P>0.05)
5.三组SDS评分比较,治疗2周后三组SDS评分与基线相比均有显著性差异。在治疗4周,6周后,电针组和手针组SDS评分显著低于药物组(P<0.05),而电针组和手针组SDS评分在各时间段组间比较均没有显著性差异(P>0.05)。
6.三组CGI量表评分比较,三组在治疗6周后病情严重程度,疗效总评和疗效指数组间比较均有显著性差异(P<0.05),电针组和手针组治疗6周后病情严重程度,疗效总评均显著低于药物组(P<0.05)。电针组、手针组疗效指数明显高于药物组(P<0.05)。
电针组和手针组治疗6周后病情严重程度,疗效总评和疗效指数两组之间比较没有显著性差异(P>0.05)。
7.三组不良事件及药物副反应比较,三组不良事件发生率分别为14.29%,12.0%,17.14%,经统计学检验无显著性差异(P>0.05)。
三组在治疗后2周,4周,6周时副反应量表评分组间比较均有显著性差异(P<0.05),电针组和手针组在治疗后各时间段SERS评分均显著低于药物组,电针组和手针组两组各时间段SERS评分组间比较没有显著性差异(P>0.05)。
8.三组WHOQOL-BREF量表评分比较,治疗6周后三组在总生存质量主观感受、总健康状况主观感受、生理领域、心理领域评分组间比较均有显著性差异(P<0.05),电针组和手针组在以上领域评分均显著高于药物组,但电针组和手针组两组之间上述领域评分比较没有显著性差异。在社会关系领域、环境领域评分方面,治疗结束后三组之间比较并没有显著性差异(P>0.05)。
9.三组基于患者报告的症状量表(MYMOP)评分比较,在治疗6周后,三组在症状1、症状2、活动和总体健康情况评分组间比较均有显著性差异(P<0.05),电针组和手针组在以上领域评分均显著低于药物组,但电针组和手针组两组之间上述领域评分比较没有显著性差异(P>0.05)
10.三组之间中医辨证简表评分比较,三组在治疗6周后,三组主诉综合、兼症综合、八纲辨证评分组间比较均有极显著性差异(P<0.01),电针组和手针组的主诉综合、兼症综合、八纲辨证评分均显著低于药物组,但电针组和手针组两组之间上述领域评分比较没有显著性差异(P>0.05)
11.三组在治疗结束后4周随访时HAMD评分组间比较有显著性差异(P<0.05),电针组和手针组HAMD评分均显著低于药物组,电针组和手针组HAMD评分组间比较没有显著性差异(P>0.05)。
多中心研究结果
1.以HAMD减分率作为疗效评价等级资料,经过ITT和PPS统计分析,三组患者差异存在显著性意义(P<0.05)。
2.以治疗后HAMD≤7作为症状缓解率的比较,经过ITT和PPS两种统计分析,三组患者缓解率比较有显著性差异(P<0.05)。
3.以HAMD评分变化观察三组患者起效时间,两种分析显示,各组在治疗1周后开始起效(P<0.01),三组从治疗第2周开始有组间差异(P<0.01),电针组同手针组明显优于药物组,电针组同手针组无差异(P>0.05)。
4.SDS评分两种分析显示,三组SDS各时间段评分与基线比较存在显著性差异(P<0.01),三组SDS各时间段评分组间比较存在显著性差异(P<0.01)。手针组和电针组抑郁自评分数明显低于药物组,电针组同手针组相比无显著性差异(P>0.05)。
5. SERS评分两种分析显示,三组SERS各时间段评分与基线比较存在显著性差异(P<0.01),三组SERS各时间段评分组间比较存在显著性差异(P<0.01)。手针组和电针组明显低于药物组,电针组同手针组相比无显著性差异(P>0.05)
6.经过ITT和PPS统计分析,三组WHOQOL-BREF量表治疗后评分与基线比较存在显著性差异(P<0.01),三组WHOQOL-BREF量表治疗后评分组间比较无显著性差异(P>0.05)。
7.CGI量表两种分析结果显示：
三组病情严重程度(SI)治疗前后评分有显著性差异(P<0.01),三组病情严重程度变化组间比较具有显著性差异(P<0.05),电针组和手针组病情减轻程度优于药物组；电针组同手针组相比无显著性差异(P>0.05)
三组疗效总评(GI)组间比较具有显著性差异(P<0.01),电针组和手针组疗效总评优于药物组；电针组同手针组相比无显著性差异(P>0.05)。
三组疗效指数(EI)组间比较具有显著性差异(P<0.01),电针组和手针组疗效指数优于药物组；电针组同手针组相比无显著性差异(P>0.05)。
多中心与分中心研究结果比较
多中心、大样本的随机对照试验结果与分中心结果基本一致,但在某些指标上存在一定差异：
1.以HAMD≤7分作为症状完全缓解率的评价,分中心显示三组之间无显著性差异,多中心总样本显示两组针刺组优于药物组,结果有差异；
2.在起效时间上分中心显示药物组从治疗2周开始起效,多中心总样本显示从1周开始起效,但组间评分比较两个样本的结果是一致的；
3.SDS评分分中心显示三组均从2周开始与基线比较有差异,4周后组间比较有差异,多中心总样本显示在治疗后各个时间段组内和组间比较均有显著性差异,显著性差异在时间上均早于分中心；
4. SERS评分显示,分中心和多中心总样本结果完全一致,治疗后各个时间段组内和组间比较均存在显著性差异；
5.三组CGI量表各项评分比较显示,分中心和多中心总样本结果完全一致；
6. WHOQOL-BREF评分总样本只对总生存质量一项作了分析,结果治疗前后评分比较多中心和分中心的结果是一致的,而在治疗后组间比较两样本存在差异,分中心样本显示有差异,多中心总样本显示无差异。
[结论]
1.针刺结合盐酸帕罗西汀治疗抑郁症的疗效优于单纯盐酸帕罗西汀,可以提高治疗抑郁症的缓解率。
2.针刺可以缩短盐酸帕罗西汀治疗抑郁症的起效时间,在改善抑郁症患者的焦虑/躯体化因子、睡眠障碍因子等躯体症状上具有显著优势。
3.针刺结合药物对患者抑郁状态和总体生存质量的改善程度优于单纯药物治疗。
4.针刺结合药物可以明显改善患者对自我症状、活动、健康状态的评价,提高患者在治疗过程中的自我意识。
5.以中医辩证的方式评价针刺治疗抑郁症的疗效获得与其它评价方式一致的结果。
Background
Depression is a common mental disorder which afflicts human beings physically and psychologically. With the rapid development of society and economy, and the acceleration of life paces, great changes have taken place in spectrum of diseases as people burden increasing mental pressure. Mental disorders gradually become a usual disease with its rising incidence recent years. The rate of diagnosis and treatment for depression is very low nowadays; and the conventional method is drug treatment.
Because depression is the complicated mental disease, any single drug can not treat the multiple symptoms. Acupuncture therapy has the role of integrated and multiple targeted for depression, and has been paid great attention by many clinical researchers. Although many studies had been carried out, these studies still could not supply enough effective evidence based medicine for acupuncture treatment.
In order to verify the curative effect of acupuncture treatment for depression, we searched and optimized many depression treatment protocols in recent years, confirm two protocols for treating depression by acupuncture. Based on the principles of evidence based medicine, we carried out a multi-center, large samples, randomized and controlled trial, to supply objective evidences for acupuncture treating depression and to promote the wide clinical application of acupuncture treatment for depression.
Object
1. To confirm the validity of different acupuncture therapeutic proposals for depression.
2. To evaluate the effective time, features and advantages of the three different proposals based on the validity of acupuncture for depression.
3. To discuss the influences different depression treatment protocols to patients' self-assessment of clinic results and health condition.
4. To discuss the influences different protocols to TCM syndrome differentiation brief scales, expecting to offer ideas for curative effect assessment method of TCM clinics studies.
Methods
In order to evaluate the effective of acupuncture for depression, multi-center, large samples, randomized and controlled trial were carried out. Clinical cases were collected from four branch centers (The 6th Hospital of Peking University, The Sixth Hospital of Baotou City, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine and Affiliated Hospital of Southern Medical University) simultaneously.
Clinic patients had been selected into the trial, according to the diagnosis standardization, eliminating standardization, grouping standardization and informed consensus principle, and been divided into three groups(electro-acupuncture group, manual acupuncture group, Paroxetine hydrochloride group) randomly. Electro-acupuncture group was intervened by electro-acupuncture, the main acupunctural acupoints were BAIHUI, YINTANG, the acupoints of differentiation of symptoms were FENGFU, FENGCHI, NEIGUAN, SANYINJIAO. Manual acupuncture group was acupunctured by manual operation, the main acupunctural acupoints were BAIHUI, YINTANG, the acupoints of differentiation of symptoms were FENGFU, NEIGUAN, SANYINJIAO. The clinical period of treatment were 6 weeks. Follow-up study was carried out on the fourth week after the clinical treatment. All the clinical cases in this study were collected from the 6th Hospital of Peking University and multiple center respectively.
From November 2008 to July 2010,88 clinic outpatients have been selected into the trial in 6th hospital of Peking university according to the diagnosis standardization, eliminating standardization, grouping standardization and informed consensus principle. The participants are divided into three groups randomly,28 for electro-acupuncture with Paroxetine hydrochloride,25 for manual acupuncture with Paroxetine hydrochloride and 35 for Paroxetine hydrochloride merely.
Total cases are collected from four clinical centers (the 6th hospital of Peking university, the Sixth Hospital of Baotou City, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine and Affiliated Hospital of Southern Medical University Hospital), from June 2008 to December 2010,477 clinic outpatients have been selected into the trial according to the diagnosis standardization, eliminating standardization, grouping standardization and informed consensus principle. The participants are divided into three groups randomly,161 for electro-acupuncture with Paroxetine hydrochloride,162 for manual acupuncture with Paroxetine hydrochloride and 154 for Paroxetine hydrochloride merely.
HAMD and SDS scales are applied in the assessment of curative effect at the 0,1,2,4,6 weeks, and at the 0,2,4,6 weeks, SERS scale is applied to assess the side effects. At the 0,6 weeks, CGI scale is applied to assess the global curative effect of each group, with WHOQOL-BREF scale for patients'life quality assessment, MYMOP scale for self-assessment of clinic syndromes and a TCM syndrome differentiation brief scale for the TCM syndrome changes.4 weeks after the treatment termination, the participants are reviewed with HAMD.
Main effective outcome measures were analyzed by two methods of Intention To Treat analysis (ITT) and Pendence Proposal Single analysis(PPS).
Results
Results for branch center
1. Curative effect:According to ITT and PPS analysis, statistical meaning are found in differences among the three groups (P<0.05), the total effect rate of both the two acupuncture group are higher than the medicine group, but no significant differences are found between two acupuncture groups(P>0.05).
2. Recovery rate:According to ITT and PPS analysis, no statistical meaning are found in differences among the three groups (P>0.05).
3. Effect time:According to ITT and PPS analysis, significant differences are found between 1 week after treatment HAMD scores and baseline scores in the two acupuncture group. In medicine group, significant differences are found between 2 weeks after treatment HAMD scores and the baseline scores.
2,4,6 weeks after treatment, significant differences are found in HAMD scores among three groups(P<0.05), no significant differences are found in the improvement of depressive symptoms after treatment between the two acupuncture groups.
Depressive Symptoms can be improved 1 week after treatment in the two acupuncture groups; while in medicine group is 2 weeks, which indicates that acupuncture has an early curative effect.
4. HAMD factors scores:Significant differences are found at HAMD anxiety/somatization, sleep disorders factors scores after 1,2,4,6 weeks treatment among the three groups(P<0.05), the improvement of the two factors in two acupuncture groups is better than that of medicine group at each period.
No significant differences are found at the improvement of HAMD retardation, cognition disorder, body weight factors scores at each period among three groups at each period(P>0.05).
No significant differences are found at the improvement of HAMD anxiety/somatization, sleep disorders, retardation, cognition disorder, body weight factors scores at each period between two acupuncture groups at each period (P>0.05)
5. SDS scores:Significant differences are found between 2 weeks after treatment scores and baseline scores in all three groups. Scores in two acupuncture groups are significantly lower than that of medicine group after 4,6 weeks treatment P<0.05), but no significant differences are found between two acupuncture scores at each period (P>0.05)
6. CGI scores:Significant differences are found at disease severity, total assessment of curative effect and curative effect index among all three groups after 6 weeks treatment(P<0.05), disease severity, total assessment of curative effect of the two acupuncture groups are significantly lower than that of the medicine group, while the curative effect index of the two groups is apparently higher than the medicine group.
No significant differences are found at disease severity, total assessment of curative effect and curative effect index between the two acupuncture groups after 6 weeks treatment(P>0.05).
7. Adverse events and side effects:Rates of bad events in the three groups are 14.29%, 12.0%,17.14%, without significant differences(P>0.05).
Significant differences are found at SERS scores among three groups after 2,4,6 weeks treatment(P<0.05). SERS scores of two acupuncture groups are significantly lower than that of medicine group at each period, but no significant differences are found between two acupuncture groups at each period(P>0.05).
8. WHOQOL-BREF scores:Significant differences are found at total subjective feeling of living quality, total subjective feeling of health condition, physical aspect and psychological aspect scores among the three groups after 6 weeks treatment(P<0.05), scores in the two acupuncture groups are significantly higher than that of medicine group, but no significant differences are found between the two acupuncture groups. No significant differences are found at social relationship aspect and environment aspect scores among all three groups after 6 weeks treatment.
9. MYMOP scores:Significant differences are found at symptoml, symptom2, activity and global health condition scores among three groups after 6 weeks treatment(P<0.05), Scores in two acupuncture groups are significantly lower than the medicine group, but no significant differences are found between two acupuncture groups.
10.TCM syndrome differentiation brief scale scores:Pretty significant differences are found at main complaints, combined symptoms and Eight-principles syndrome differentiation scores among three groups after 6 weeks treatment(P<0.01), Scores in two acupuncture groups are significantly lower than the medicine group, but no significant differences are found between two acupuncture groups.
11. follow-up HAMD scores:Significant differences are found among three groups. Scores in two acupuncture groups are significantly lower than the medicine group, but no significant differences are found between two acupuncture groups(P>0.05).
Results for total clinical cases of the four centers
1.According to HAMD scores, after the analysis of ITT and PPS, the three groups had the apparently differences (P<0.05) The electro-acupuncture group and manual acupuncture group was more better than Paroxetine hydrochloride group.
2.When HAMD≤7, after the analysis of ITT and PPS, the full remission for three groups was significantly different (P<0.05) The electro-acupuncture group and manual acupuncture group was more better than Paroxetine hydrochloride group.
3.To evaluate the effective time based on HAMD scores, by using the two analysis methods, each group has the anti-depression effect after 1 week treatment(P<0.01). There exist differences among the three groups after 2 weeks treatment(P<0.01), electro-acupuncture group, manual acupuncture group was more effective than Paroxetine hydrochloride group, electro-acupuncture was no differences with manual acupuncture group (P>0.05)
4. SDS scores were analyzed by the two analysis methods, SDS scores for the three groups was significant different from baseline (P<0.01). There exist significant differences among the three groups(P<0.01). SDS scores for manual acupuncture group and electro-acupuncture group was more lower than Paroxetine hydrochloride group. There were no differences between the two acupuncture groups (P>0.05)
5.SERS scores were analyzed by the two analysis methods, SERS scores for the three groups was significant different from baseline (P<0.01). There exist significant differences among the three groups(P<0.01). SERS scores for manual acupuncture group and electro-acupuncture group was more lower than Paroxetine hydrochloride group. There were no differences between the two acupuncture groups (P>0.05)
6. By analysis of ITT and PPS, WHOQOL-BREF table scores for the three groups was significant different from baseline (P<0.01). There were no differences among the three groups for the scores of WHOQOL-BREF table (P>0.05)
7.CGI table were analyzed by the two methods:
SI scores for the three groups were different from the baseline (P<0.01), SI scores were different for the three groups (P<0.05), SI scores for electro-acupuncture group and manual acupuncture groups was lower than Paroxetine hydrochloride group, SI scores for the two acupuncture groups were no differences (P>0.05)
GI were significant different among the three groups (P<0.01), GI for electro-acupuncture group and manual acupuncture group was better than Paroxetine hydrochloride group, GI for the two acupuncture groups were no differences (P>0.05)
El were significant different among the three groups (P<0.01), El for electro-acupuncture group and manual acupuncture group was better than Paroxetine hydrochloride group, El for the two acupuncture groups were no differences (P>0.05)
Comparison for the results of two classification cases
The results for multiple center, large samples,randomization study was almost the same as the results for branch centers, there still existed some differences for relative indexes:
1.When evaluated the full remission of depression by using HAMD≤7, branch center results showed that there were no differences for the three groups; total clinical cases results showed that the two acupuncture groups were more effective than Paroxetine hydrochloride group.
2.To effective time, branch center results showed that Paroxetine hydrochloride group had effective from the second week, total clinical cases results showed that Paroxetine hydrochloride group had effective from the first week. Scores for the three groups were almost the same for branch center and total clinical cases.
3.To SDS scores, branch center results showed that SDS scores for the three groups were different from their baseline, there were differences for the three groups after 4 weeks treatment. Total clinical cases results showed that there were differences for the three groups during different periods, significant differences was more earlier than branch center.
4.To SERS scores, the branch center results were almost the same as the total clinical cases results, there existed differences among the groups and during different periods.
5.CGI for the three groups were almost the same between branch center results and total clinical cases results
6. To WHOQOL-BREF table scores, total quality of life was almost the same for the branch center and total clinical cases. After treatment, branch center results showed that there were differences among the three groups; total clinical cases results showed that there were no differences among the three groups.
Conclusions
1.The effectiveness of combined acupuncture and Paroxetinehas hydrochloride is superior to the Paroxetinehas hydrochloride treatment, the combined treatment improves the recovery rate of depression.
2.Acupuncture can shorten the effective time of Paroxetinehas hydrochloride and have an advantage of improve the patients'somatic symptoms such as the anxiety/somatization, sleep disorders factors as well.
3.The combined treatment of acupuncture and medicine is superior to the medicine group in improving patients'self-assessment of symptoms of depression and health condition.
4.Acupuncture can improve patients'self-condition, activity and health assessment, and increase the self-awareness of the patients.
5.Assessment for depression curative effect based on TCM syndrome differentiation can be in accordance with other assessment methods.
引文
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