【作者】 黄叶飞；

【导师】 符文彬；

【作者基本信息】 广州中医药大学 ， 针灸推拿学， 2012， 博士

【摘要】 目的：1.通过文献的系统评价,分析电针治疗焦虑症的临床疗效和安全性。2.观察电针从“心胆”论治广泛性焦虑症的临床疗效、安全性和对生存质量的影响。3.从MAPK/ERK信号通路探讨电针抗焦虑的潜在机制。方法：1.系统评价：收集电针治疗焦虑症的临床研究随机对照文献,计算机检索CBM (1979～)、CNKI(1979～)、VIP(1989～)和万方数字化期刊群(1998～)、PubMed (1966～)、EMbase (1980～)和Cochrane Library,所有检索时间截至2011年1月,并手工检索广州中医药大学图书馆过刊资料库,而后按照Cochrane Handbook5.0对每个纳入试验进行偏倚风险和质量评估,统计学分析采用RevMan5.0.24软件。2.临床研究：将符合纳入标准的64例受试者随机分为治疗组、对照组。治疗组采用电针治疗,穴位选取内关穴(双),阳陵泉穴(双),针刺得气后加用G-6805Ⅱ型电针治疗仪,选择疏密波,频率10Hz,幅度3V,时间30分钟,治疗每周3次,每次时间间隔>24小时,共治疗6周。对照组采用帕罗西汀(天津中美史克制药有限公司生产)口服剂量20mg/d,1次/日,连续服用6周。两组在治疗前和治疗第2、4、6周末、治疗结束后1月五个时间点分别采用汉密尔顿焦虑他评量表(HAMA).焦虑自评量表(SAS)进行疗效评价,并在治疗前、治疗第6周两个时间点进行生活质量评价量表SF-36(short form36questionnaire)评分,结合记录不良反应进行安全性评估。采用SPSS19.0软件进行描述性分析、卡方检验、t检验和多元方差分析和重复测量资料的方差分析。3.实验研究：体重150+10g成年雌性SD大鼠63只随机分为空白组、模型组、电针组、药物组、PD98059(ERK特异性阻滞剂)组、PD98059+电针组、PD98059+药物组,每组9只。空白组不给予任何处理；模型组共接受21天条件性电击造成焦虑模型；电针组在造模成功后进行电针治疗,选择G-6805Ⅱ型电针仪疏密波,频率2Hz,幅度3V,每日针刺一次,每次15分钟,穴位取大鼠内关、阳陵泉,左右交替进行。药物组在造模成功后,每天灌胃给药(帕罗西汀按照1.8mg/kg给予)一次；PD98059组每天予PD98059(ERK特异性阻滞剂)侧脑室注射；PD98059+电针组在造模成功的大鼠上,每天予PD98059侧脑室注射3小时后电针治疗(方法同电针组)；PD98059+药物组在造模成功的大鼠上,每天PD98059侧脑室注射3小时后予帕罗西汀灌胃,各组干预均持续21天。干预前、干预后7、14、21天,观察大鼠体重、高架十字迷宫行为学变化,实验结束后取大鼠海马组织检测各组磷酸化ERK (Extracellular signal-regulated kinase)免疫荧光表达、Western Blot表达。成果：1.系统评价纳入8个随机对照试验,共769例患者的电针治疗焦虑症的Meta分析得出：两组有效率差异无统计学意义[OR=0.95,95%CI (0.55,1.64)],表明电针与西药治疗焦虑症的有效率两者相当；两组痊愈率差异有统计学意义[OR=1.53,95%CI (1.07,2.20)],表明电针在治疗焦虑症的痊愈率高于西药治疗。两组HAMA评分差异无统计学意义[WMD=-0.61,95%CI (-1.96,1.98)];表明电针与西药治疗焦虑症的HAMA评分两者相当。两组SAS评分差异无统计学意义[WMD=-0.35,95%CI (-1.73,1.03)]；表明电针与西药治疗焦虑症的SAS评分两者相当。Grade证据质量评价为很低(very low),提示本系统评价任何效应估计值都是非常不确定的,在将来需要更多高质量的临床研究来证实。2.临床研究2.1基线比较：两组患者性别、中医证型、年龄、病程和HAMA、SAS、SF-36评分比较,无统计学意义(P=0.802、0.979、0.905、0.895>0.05)表明组间一般资料具有同质性,均衡可比性。2.2疗效比较：治疗第6周结束时,治疗组痊愈4例,显效20例,有效6例,无效2例,总有效率93.10%,对照组痊愈3例,显效19例,有效8例,无效2例,总有效率93.10%,两组的总体疗效经秩和检验,差异无统计学意义(P=0.885>0.05),可认为电针与药物在6周治疗结束时疗效相当。治疗结束1月随访时,治疗组痊愈3例,显效13例,有效6例,无效7例,总有效率78.12%.对照组痊愈3例,显效10例,有效10例,无效9例,总有效率71.87%。两组的总体疗效经秩和检验,差异无统计学意义(P=0.769>0.05),表明治疗结束后一个月随访时,治疗组疗效与对照组比较无差异性,可认为电针与药物在治疗结束后1月总体疗效相当。2.3HAMA和SAS量表积分比较：治疗2周时,两组患者HAMA和SAS量表积分均较治疗前明显减少,组间比较有统计学意义。HAMA量表的两个因子精神性焦虑因子与躯体性焦虑因子中,躯体性焦虑因子评分比较具有统计学意义,差异显著(P<0.05),而精神性焦虑因子评分两组间无明显差异。在治疗4、6周时,两组患者HAMA和SAS量表积分仍呈逐渐下降趋势,精神性焦虑因子和躯体性焦虑因子的下降趋势明显,组间比较不具有统计学意义,两组的有效率及总体疗效经统计学处理,差异无统计学意义(P>0.05)。治疗结束后1月随访,两组患者HAMA和SAS量表积分较疗程结束时有缓慢回升趋势,组间比较电针组的回升幅度小于药物组,差异具有显著性(P<0.01)2.4SF-36生存质量量表比较：电针和药物治疗都可以均可以改善SF-36生存质量量表的生理功能(PF)、躯体疼痛(BP)、总体健康(GH)、活力(VT)、社会功能(SF)、情感职能(RE)、精神健康(MH)维度,两者差异不明显(P=0.090>0.05)。但在电针对生理机能(RP)改善程度上优于药物治疗(P=0.00<0.05)。2.5治疗组(15.6%)的复发率低于对照组(21.8%),且不良反应较对照组少。3.实验研究3.1模型组大鼠体重增加程度低于空白组,电针和药物经21天干预后可使焦虑模型大鼠的体重接近空白组水平,而PD98059+电针和PD98059+药物组经21天干预后对焦虑模型大鼠的体重影响不明显(P>0.05)。另外电针组大鼠在第7天时体重增加高于药物组,第14天和21天与药物组无差异,PD98059+电针和PD98059+药物在第7、14、21天均无显著差异(P>0.05)。3.2电针和药物均可改变模型大鼠的焦虑样行为,使其接近正常,而PD98059+电针和PD98059+药物组经21天干预后对模型大鼠的焦虑样行为影响不明显(P>0.05)。且这两种干预措施之间无差异。3.3免疫荧光和Western blot分析结果都显示：电针和药物能降低焦虑模型海马的磷酸化ERK (p-ERK),两种干预之间无明显差异(P>0.05),其抗焦虑作用能被PD98059所阻断。结论：1.系统评价显示电针组和药物组在有效率、HAMA评分、SAS评分差异两者相当,电针在治疗焦虑症的痊愈率高于西药治疗,电针组不良反应低于药物组,但Grade证据质量评价为很低(very low),仍需要高质量的临床研究提供更可靠的证据。2.电针从“心胆”论治广泛性焦虑症与药物疗法(帕罗西汀)均有效,且总体疗效相当,第2周电针疗法对躯体化症状的程度要大于药物疗法；在治疗结束后,电针疗法的作用较药物疗法持久,能降低复发率。电针从“心胆”论治焦虑症不良反应低于帕罗西汀,可作为药物治疗的补充替代疗法在临床上推广运用。3.电针能显著改善焦虑模型大鼠的体重、行为学、显著下调海马p-ERK的表达,且这一效应能被PD98059(ERK特异性阻滞剂)阻断,与药物组比较无明显差异。提不MAPK/ERK信号转导通路是电针抗焦虑的关键作用途径之一。更多还原

【Abstract】 Objective1. Analysis the clinical efficacy and safety of electric acupuncture on anxiety based on systematic review of literatures.2. Observe the clinical efficacy, safety and effect on quality of life of electric acupuncture on generalized anxiety disorder via diagnosis and treatment from the heart and gallbladder.3. Explore the potential mechanism of electric acupuncture on anxiety from MAPK/ERK signal pathway.Methods1. Systematic reviews:The randomized control literature of clinical studies was collected to treat anxiety disorder by electric acupuncture, CBM (1979～), VIP (1989～), Wanfang digital journal groups (1998～), PubMed (1966～), EMbase (1980～) and Cochrane Library. All the search time was by January2011, the back issues data bank in the library of Guangzhou University of Chinese Medicine was manually searched. The risk and quality of bias were assessed on the experiments adopted according to Cochrane Handbook5.0, and RevMan5.0.24was adopted for the statistical analysis.2. Clinical research:64patients met the inclusion criteria were divided into treatment group and control group. Using electric acupuncture and selected Neiguan (two sides), Yanglingquan (two sides), adopted G-6805Ⅱ type electro-acupuncture instrument following needling response, with density wave at a frequency of lOHz and amplitude of3V, treated3times a week and30min for each time with interval more than24h, a total of6w in treatment in treatment group. Adopt paroxetine (China and the United States (GSK) Pharmaceutical Co., Ltd, Tianjin) oral dose of20mg/d for6w in control group. Evaluate curative effect using HAMA and SAS before treatment, at2w,4w,6w of treatment and at lm after treatment in two groups. Perform described analysis, chi square test, t test, multivariate variance analysis and repeated measuring data with SPSS19.0software.3. Experimental study:63adult female SD rats with weighted of150+10g was randomly divided into blank group, model group, EA group, medicine group, PD98059(ERK specific blocker) group, PD98059combined with EA group and PD98059combined with medicine group, with9rats in each group. Blank group remained untreated. Model group received conditioned electric shock for21days to construct anxiety model. EA group performed EA treatment following modeling. Using G-6805Ⅱ type electric acupuncture apparatus density wave at a frequency of2Hz and amplitude of3V, we acupunctured points of Neiguan and Yanglingquan in rats alternatively for15min at each time, once daily. Medicine group were intragastric administered to medicine once daily after modeling (paroxetine were administered at1.8mg/kg). PD98059group was performed intracerebroventricular injection of PD98059(ERK specific blocker). PD98059combined with EA group was performed intragastric administration of paroxetine following at3h after intracerebroventricular injection of PD98059on successful modeling (as indicated above). PD98059combined with medicine group was performed intragastric administration of paroxetine after3h of intracerebroventricular injection of PD98059. Intervention in each group lasted for21days. Observe rats weight and changes in elevated plus-maze behavior before intervention and at7d,14d and21d after intervention. Detect the phospho-ERK, immunofluorescence expression and Western Blot expression of hippocampus in rats after experiment.Results1.System evaluationInto eight randomized controlled trials, including769patients in the local area of the Meta analysis treat anxiety:two groups of efficient difference was statistically significant (OR=0.95,95%CI (0.55,1.64)], show that in the local area and western medicine therapy anxiety both quite efficient; Two groups of recovery rate is statistically significant differences [OR=1.53,95%CI (1.07,2.20)], shows that the recovery in the local area in treat anxiety rates are higher than western medicine. Two groups of HAMA score difference was statistically significant [WMD=0.61,95%CI (1.96,1.98)]; In the local area and western medicine that treat anxiety of HAMA score both quite. Two groups of SAS score difference was statistically significant [WMD=0.35,95%CI (1.73,1.03)]; In the local area and western medicine that treat anxiety SAS score both quite. Grade evidence for very low quality evaluation (very low), suggests that this system evaluation any effect is very uncertain estimate of, in the future, need more high quality clinical studies to confirm that.2. Clinical research2.1Baseline comparison:two groups of patients, gender, TCM syndrome type, age, duration and HAMA, SAS, SF-36score more, no statistically significant (P=0.802,0.979,0.905,0.895>0.05) show that the general information between groups are homogeneous, balance and comparability.2.2Treatment two weeks, two groups of patients HAMA and SAS scale integration which is significantly less before treatment, group is between statistical significance. HAMA scale two factors mental anxiety factor and the body sex anxiety factors, the body sex anxiety factor score more significant, significant difference (P<0.05), and mental anxiety factor score no obvious difference between the two groups.2.3In the treatment of4,6weeks, two groups of patients HAMA and SAS scale integration is still decline gradually, mental anxiety factor and body sex anxiety factor downward trend of the obvious, compare between groups were not significant, the two groups of efficient and overall effect after statistics processing, the difference was not statistically significant (P>0.05).2.4The treatment ended January follow-up, two groups of patients HAMA and SAS scale integration when it was over, more treatment slow upward trend, the group is back in the local area between group by group less than drugs, with significant difference (P<0.01)2.5In the local area and drug therapy can all can improve SF-36survival quality scale of physiological functions (PF), and physical pain (BP), overall health (GH), energy (VT), social function (SF), emotional functions (RE), mental health (MH) dimension, both no obvious difference (P=0.090>0.05). But in electricity for physiological mechanism (RP) is superior to the improvement of the drug treatment (P=0.00<0.05).2.6The treatment group (15.6%) of the recurrence rate lower than those of the control group (21.8%), and adverse reaction is less than control.3. experimental research3.1The weight gain of rats in model group was lower than blank group. After intervention of electric acupuncture and medicine for21days, the weight in rat model of anxiety was close to blank group, while there was no obvious effect of intervention by PD98059combined with EA and PD98059combined with medicine for21days on weight of rat model of anxiety (P>0.05). Furthermore, the weight gain of rats in EA group was higher than medicine group at7days and there was no significant difference with medicine group at14days and21days, while there was no significant difference in PD98059combined with EA and PD98059combined with medicine at7days,14days and21days (P>0.05).3.2Both EA and medicine could change anxiety-like behavior in rat model of anxiety so that it was close to normal. However, the effect of PD98059combined with EA and PD98059combined with medicine on anxiety-like behavior of model rat was not obvious after21days of intervention (P>0.05). There was no difference between the two kinds of intervention.3.3Both immunofluorescence and Western blot analysis revealed that both EA and medicine could reduce phosphated ERK (p-ERK) of hippocampus in anxiety model, and there was no significant difference between two interventions (P>0.05); their antianxiety effect could be blocked by PD98059.Conelusions1.1. Systematic reviews revealed the differences in effective rate, HAMA scores and SAS scores between EA group and medicine group were equivalent. The cure rate in EA group was higher than medicine group and the adverse effect in EA group was lower than medicine group, but GRADE’s Rating Quality of Evidence was very low which remained to need high-quality clinical research to provide more reliable evidences.2. Both the electric acupuncture treating generalized anxiety disorders on heart and gallbladders and medicinal treatment (paroxetine) were effective and the overall efficacies were equivalent. The degree of electric acupuncture on somatization symptom was larger than medical treatment at2w; while the effect of electro-acupuncture therapy was lasting than medical treatment with reduced recurrence rate after treatment. The electric acupuncture was safety in treating anxiety based on heart and gallbladder and had lower adverse effect than paroxetine, which could be promoted to be applied as complementary and alternative therapies for medical therapy in clinical.3.. Electric acupuncture could significantly improve weight and ethology in rat model of anxiety and down regulate p-ERK expression in hippocampus and the effect could be blocked by PD98059(ERK specific blocker). There was no significant difference compared with medicine group. It suggested that MAPK/ERK signal transduetion pathway was one of critical action ways for anti-anxiety by electric acupuncture.更多还原