针刺四关穴治疗肝郁型抑郁症的临床及cAMP-PKA信号通路研究
|
摘要
目的：
1.通过与针刺非经非穴及安慰针对照,评价针刺四关穴对肝郁型抑郁症的临床疗效。
2.从胞内AC-cAMP-PKA信号通路的影响探讨针刺抗抑郁的作用机制。
方法：
1.临床研究
将符合纳入标准的108例受试者随机分为四关穴组、非经非穴组、安慰针组。
四关穴组：取四关穴(双合谷、双太冲)针刺,先针合谷穴后针太冲穴。常规消毒后,将带有可伸缩针管的泡沫圈垫粘于穴位皮肤上,以0.35×40mm毫针放入针管内,垂直进针,刺破泡沫圈垫并刺入皮下,采取均匀提插手法,以得气为度。针刺完后留针30分钟。期间每隔15分钟行提插手法一次。
非经非穴组：选取①手背面3,4掌骨中点之间,②足背面3跖骨中点外侧,第3,4跖骨之间,两对非经非穴点。针刺操作方法、留针时间同四关穴组。
安慰针组：取穴同四关穴组,操作过程同四关穴组,但是采用安慰针具,即一次性钝头针,将其放入针管内,垂直进针,穿破泡沫圈垫后仅能刺激表皮,不穿透皮肤,拿捏针柄使针随针管伸缩如同提插动作。留针时针尖由泡沫圈垫固定,针体由针管固定,以保持针立于穴位上。调节伸缩针管使针外露部分有如针刺入皮下。
以上治疗均在留针时,配合深呼吸以调气。每周共治疗3次,每次治疗间隔时间>24h,共治疗6周。
分别在治疗前、治疗后2周、治疗后4周及治疗后6周分别采用汉密尔顿抑郁量表(HAMD)、抑郁自评量表(SDS)、中医症状改善量表进行疗效评价,并在治疗结束后2周时采用HAMD量表进行随访,结合严重不良反应记录进行安全性评估,运用卡方检验、秩和检验、方差分析等统计方法进行三组间对照,探讨各组疗效差异。
2.实验研究
体重200-250g的成年SD雄性大鼠56只,随机分为7组：空白组、模型组、电针组(合谷+太冲)、药物组(氟西汀)、电针+盐水组、电针+H89组及氟西汀+H89组,每组8只。空白组不给予任何处理；模型组共接受42天各种不同的应激从而造成长期不可预见性温和刺激模型；电针组在应激21天起造模的同时选取四关穴(合谷、太冲),用G6805Ⅱ型电针治疗仪的疏密波(2-20HZ,强度以大鼠肢体微颤为度)进行治疗。每日针刺一次,每次30分钟,左右交替进行,持续3周。药物组在应激21天起造模的同时,每天灌胃给药(按照1.8mg/kg给予氟西汀)一次,持续3周。电针+盐水组,造模后取穴、电针操作、治疗时间及疗程与电针组一致,但于每日行电针前30min行侧脑室注射生理盐水(NS)；电针+H89组,造模后取穴、电针操作、治疗时间及疗程与电针组一致,但于每日电针前30min行侧脑室注射PKA阻滞剂H89。氟西汀+H89组,同氟西汀组,但在给药前予侧脑室注射H89。分别在实验开始前、实验第14天、21天、42天,观察大鼠Opnfield行为学、糖水消耗量,并在实验结束后对大鼠海马内的AC转化率,cAMP含量及PKA的活性进行检测。
结果：
1.1临床研究
1.1.1基线比较
三组患者在性别、年龄、病程、病情、合并用药及合并镇静催眠药用量方面,经统计分析,均无显著性差异(P>0.05)；三组患者在治疗前HAMD量表、抑郁自评量表(SDS)评分以及抑郁症中医证候量表评分组间比较,差异均无统计学意义(P>0.05),可认为三组基线水平一致,具有可比性。
1.1.2总有效率及显效率
治疗后四关穴组的显效率为44.74%,总有效率为84.21%；非经非穴的显效率为14.71%,总有效率为67.65%；安慰针组的显效率为5.56%,总有效率为38.89%。三组疗效构成比较,组间差异有统计学意义(X2=16.0375,P<0.0167)。
三组总有效率比较,组间差异无统计学意义(P>0.05),四关穴组显著高于安慰针组(P<0.05),但与非经非穴组比较,差异无统计学意义(P>0.05)。安慰针组的显效率与总有效率和非经非穴组相比,均无统计学差异(P>0.05,P>0.05)。
三组显效率比较,四关穴组均极显著高于非经非穴组和安慰针组(X2=4.1649, P<0.0167; X2=9.0925, P=P<0.0167);
1.1.3HAMD抑郁量表各因子评分
三组在治疗后各时段的HAMD的焦虑/躯体化因子、阻滞因子、睡眠障碍5个因子的评分均较治疗前上升,差异均有统计学意义(P<0.05)；四关穴组和非经非穴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安慰针组。四关穴组对各时间段的阻滞因子改善程度均优于非经非穴组和安慰针组。四关穴组在治疗后4,6周时对认知障碍因子改善程度优于安慰针组(P<0.0167),在治疗6周时对体重因子改善程度优于安慰针组(P<0.0167)。
1.1.4抑郁自评量表(SDS)评分
在以抑郁自评量表(SDS)评分为测量指标的评价中,在治疗4周及6周时,四关穴组的疗效均显著优于非经非穴组和安慰针组(P<0.0167,P<0.0167)；而在治疗各时点,非经非穴组优于安慰针组,但差异无统计学意义(P>0.05)。
1.1.5抑郁症中医症候评定量表
在以抑郁症中医证候量表评分为测量指标的评价中,在治疗6周时,四关穴组的疗效均显著优于非经非穴组和安慰针组(P<0.0167,P<0.0167)；在治疗各时点,非经非穴组和安慰针组比较均无显著性差异(P>0.05)。
1.1.6三组随访HAMD评分比较：在治疗结束后2周时,以HAMD量表随访一次。三组组间比较,差异有统计学意义(P<0.05),四关穴组HAMD评分均优于非经非穴组和安慰针组(P<0.05,P<0.05),而后两组HAMD评分组间比较不存在统计学差异(p>0.05)。各组分别与治疗6周时评分相比,均无显著性差异(P>0.05)。
1.2实验研究
1.2.1openfield行为学变化
各组水平及垂直运动的基础值均无明显差异(P>0.05),具有可比性。在接受3周慢性应激后,各组造模大鼠的水平及垂直运动次数均显著下降,与空白组相比有显著性差异(P<0.05)；各造模组大鼠组间比较没有显著性差异(P>0.05)。治疗3周后,模型组大鼠水平及垂直运动显著低于空白组(P<0.05)；电针组、药物组及电针+盐水组的运动次数分别与模型组比较均有显著升高(P<0.05,P<0.05,P<0.05)；电针组与电针+盐水组比较,无显著性差异；电针+H89组水平运动次数显著下降,与模型组比较没有显著性差异(P>0.05)。
1.2.2糖水消耗量变化
应激前各组之间大鼠的糖水消耗量没有显著性差异(P>0.05)；应激第22天后,糖水消耗量造模组大鼠的糖水消耗量显著下降,与空白组比较有显著性差异(P<0.05)；在治疗3周后(应激第42天),电针组、药物组糖水消耗量有所增加,均较应激3周时有显著改善(F=3.215,P=0.0156; F=5.167,P=0.0035);电针组与电针+NS组糖水消耗量之间没有统计学差异(P>0.05)；而电针+H89组糖水消耗量持续下降,与电针组比较,差异有统计学意义(F=4.321,P=0.0021)
1.2.3海马AC转化率,cAMP含量及PKA活性检测
在实验结束时,抑郁症模型大鼠海马组织AC转化率、cAMP含量及PKA活性均显著降低,与空白组比较,差异有统计学意义(P<0.05)。药物和电针均可增加抑郁症模型大鼠海马组织AC转化率、cAMP含量及PKA活性,基本达到空白组水平。
结论：
1.针刺四关穴、非经非穴、安慰针治疗肝郁型抑郁症在减轻抑郁程度上均有一定疗效,但四关穴针刺较其他两组疗效更为显著且持久。
2.针刺四关穴对于抑郁症HAMD量表各因子的改善疗效优于非经非穴位与安慰针具组,随着治疗时间的延长疗效更为显著。
3.针刺四关穴能显著改善抑郁症大鼠的行为学,显著上调海马AC、PKA活性及cAMP含量,PKA阻滞剂H89可阻断针刺抗抑郁的作用,提示AC-cAMP-PKA受体后信号转导通路可能是针刺抗抑郁的重要途径和作用靶点之一。
Objectives
1.From a randomized, single blind and controlled trial, we explore the effectiveness and safety of acupuncture treatment of "Siguan" acupoints on depression of stagnation of liver-Qi type.
2. To explore the mechanism of acupuncture for antidepressive effect on AC-cAMP-PKA postreceptor signal transduction pathway.
Methods
1. Clinical study
108cases were randomized into the following groups:Siguan acupoints group, non-acupoint group and Streitberger needle group groug.
Siguan acupoints group:Siguan points (bilateral Hegu (LI4) and Taichong(LR3)) were selected to received acupuncture. After sterilizing,0.35×40mm acupuncture needles were put through the needle pipe and vertically inserted below to the skin through the foam tray which was stick to the surface of the points. Manipulated the needle until de-qi was felt by the patient. Retained the needle for30min with needle manipulation once per15min.
Non-acupoint group:Two points that correspond to Siguan points were located①on the dorsum of hand and between the middle of the3th and4th metacarpal bone;②on the3th lateral metatarsal bone on dorsum pedis, between the3th and4th metatarsal bone. Needle manipulation and retaining were similar to Siguan points group.
Streitberger needle group:The selected points and the needle insertion procedure were similar as Siguan acupoints group, except that the tip of the needle was blunt and could not puncture into the skin. During the needle retaining, the needle was hold by the foam tray and the needle pipe and adjust the stretching pipe to keep the appearance of the placebo needle look like as inserted into the skin as the verum needle in Siguan points group.
All the patients in the three groups were asked to deep breath to regulating qi during needle retaining and received3sessions weekly with total6weeks of treatment.
The effects were evaluated by the HAMD Scales, the SDS Scales, and the improvement Scales of symptoms of Traditional Chinese Medicine before the treatment and4time points (at the end of2week,4week and6week) during the treatment course. ITT analysis were used for all the data analysis.
2. Animal study
Adult Sprague-Dawley male rats (200-250g) were used in the present experiment. Animals were divided randomly into7groups:the control group, the model group, the electroacupuncture(EA) group and drug group, EA plus normal saline (NS)group, EA plus H89group and Fluo plus H89group;8rats in each group. The chronic mild stress model(CMS) of depression was induced by various kinds of stress for42days. In the model group, rats were exposed to chronic mild unpredictable mild stress for6weeks. In the EA group, rats receive CMS procedure and electroacupuncture stimulation at Siguan points (bilateral Hegu (LI4) and Taichong(LR3)) once every other day for3weeks after CMS exposure. In the drug group, rats receive the same treatment as the CMS group and Fluoxetine treatment everyday for3weeks after CMS. The groups plus H89/NS were conditioned with the same as the EA or Fluoxetine group except for the intracerebroventricular injection of H89between CMS and EA. Changes of open-field behavior, sucrose consumption, AC activity, cAMP level and PKA activity in hippocampus of rats were observed in the study.
Result
1.Clinical study
1.1Baseline
The difference in terms of age, height, weight, disease duration, sex, educational level, occupation, living habits, history of western medicine taking or acupuncture treatment receiving among3groups is no significant (P>0.05); And, the difference of scores of HAMD scale, SDS scale and TCM syndrome rating scale among the three groups of depressed patients on baseline was not statistically significant(P>0.05), baseline level can be considered the same among the three groups and comparability. 1.2Total effective rate and excellence rate
After6weeks of treatment, the total effective rate and the excellence rate of the3groups respectively were84.21%and44.74%in Siguan acupoints group,67.65%and14.71%in non-acupoint group,38.89%and5.56%in the Streitberger needle group. Compare the total effective rate of the3groups, there was a significant difference among the3groups (P<0.0167).
1.3HAMD Scale
The gross effective rate was higher and the HAMD Scale score was better in the Siguan acupoints group than that of the non-acupoint group and sham-acupuncture group (P<.05). The improvement of score of anxiety/somatization factor, body weight factor, cognitive handicap factor, blockage factor and the sleeping disorder factor in Siguan acupoints group was started on the2week during the treatment, and which was lasted to the end of the treatment.
1.4SDS scale
The SDS Score was better in the both acupuncture groups than that in the non-acupoint group and Streitberger needle group (P<0.0167, P<0.0167), however, no significant difference was found between the non-acupoint group and Streitberger needle group.
1.5Improvement Scales of symptoms of Traditional Chinese Medicine
The Improvement Scales of symptoms of TCM Score was better in the both acupuncture groups than that in the non-acupoint group and Streitberger needle group (P<0.0167,P<0.0167), again, no significant difference between the non-acupoint group and Streitberger needle group.
2. Animal study
2.1Changes of openfield behavior
The behavior (horizontal and vertical motion) of the depression rats decreased significantly following stress, and EA treatment as well as EA+NS can effectively improve it, which is better than that of the drug (P<0.05, P<.0.05, P<0.05). Enhanced effects induced by EA were reversed by H89pretreatment.
2.2Changes of sucrose consumption
Sucrose intake in all stress groups decreased significantly in the3rd week and was much less than the control group (P<0.05). However, there was no remarkable difference among all stress groups. EA or Fluoxetine treatment leaded to increase in sucrose intake in the sixth week, however, not indicating significant difference with CMS group. H89pretreatment inhibited obviously increase in sucrose intake induced by EA.
2.3AC activity, cAMP level and PKA activity
Animals exposed to stressors also showed a significant decrease in the ratio of AC transformation after the last week when the experiment ended. In the EA group and Fluxitine group, the ratio of AC transformation increased significantly after EA treatment for3weeks compared to the CMS group. EA and Fluxitine can improved the level of AC transformation ratio in the hippocampus of rats to a level as of normal rats. Changes in cAMP level and PKA activity were similar to AC (P<0.05, P<0.05, P<0.05)
Conclusion
1. Acupuncture treatment of Siguan acupoints was effective and safe in treating depression.
2. Acupuncture treatment of Siguan acupoints regulating liver showed a more obviously curative effect on all factors of depression after treatment when compared to non-acupoint group and Streitberger needle groug.
3. Acupuncture could improve signif ieantly changes of the behavior, sucrose consumption, AC activity, cAMP level and PKA activity in hippocamp of rats, therefore, AC-cAMP-PKA postreceptor signal transduction pathway is an important approach and target of acupuncture in treating depression.
1.通过与针刺非经非穴及安慰针对照,评价针刺四关穴对肝郁型抑郁症的临床疗效。
2.从胞内AC-cAMP-PKA信号通路的影响探讨针刺抗抑郁的作用机制。
方法：
1.临床研究
将符合纳入标准的108例受试者随机分为四关穴组、非经非穴组、安慰针组。
四关穴组：取四关穴(双合谷、双太冲)针刺,先针合谷穴后针太冲穴。常规消毒后,将带有可伸缩针管的泡沫圈垫粘于穴位皮肤上,以0.35×40mm毫针放入针管内,垂直进针,刺破泡沫圈垫并刺入皮下,采取均匀提插手法,以得气为度。针刺完后留针30分钟。期间每隔15分钟行提插手法一次。
非经非穴组：选取①手背面3,4掌骨中点之间,②足背面3跖骨中点外侧,第3,4跖骨之间,两对非经非穴点。针刺操作方法、留针时间同四关穴组。
安慰针组：取穴同四关穴组,操作过程同四关穴组,但是采用安慰针具,即一次性钝头针,将其放入针管内,垂直进针,穿破泡沫圈垫后仅能刺激表皮,不穿透皮肤,拿捏针柄使针随针管伸缩如同提插动作。留针时针尖由泡沫圈垫固定,针体由针管固定,以保持针立于穴位上。调节伸缩针管使针外露部分有如针刺入皮下。
以上治疗均在留针时,配合深呼吸以调气。每周共治疗3次,每次治疗间隔时间>24h,共治疗6周。
分别在治疗前、治疗后2周、治疗后4周及治疗后6周分别采用汉密尔顿抑郁量表(HAMD)、抑郁自评量表(SDS)、中医症状改善量表进行疗效评价,并在治疗结束后2周时采用HAMD量表进行随访,结合严重不良反应记录进行安全性评估,运用卡方检验、秩和检验、方差分析等统计方法进行三组间对照,探讨各组疗效差异。
2.实验研究
体重200-250g的成年SD雄性大鼠56只,随机分为7组：空白组、模型组、电针组(合谷+太冲)、药物组(氟西汀)、电针+盐水组、电针+H89组及氟西汀+H89组,每组8只。空白组不给予任何处理；模型组共接受42天各种不同的应激从而造成长期不可预见性温和刺激模型；电针组在应激21天起造模的同时选取四关穴(合谷、太冲),用G6805Ⅱ型电针治疗仪的疏密波(2-20HZ,强度以大鼠肢体微颤为度)进行治疗。每日针刺一次,每次30分钟,左右交替进行,持续3周。药物组在应激21天起造模的同时,每天灌胃给药(按照1.8mg/kg给予氟西汀)一次,持续3周。电针+盐水组,造模后取穴、电针操作、治疗时间及疗程与电针组一致,但于每日行电针前30min行侧脑室注射生理盐水(NS)；电针+H89组,造模后取穴、电针操作、治疗时间及疗程与电针组一致,但于每日电针前30min行侧脑室注射PKA阻滞剂H89。氟西汀+H89组,同氟西汀组,但在给药前予侧脑室注射H89。分别在实验开始前、实验第14天、21天、42天,观察大鼠Opnfield行为学、糖水消耗量,并在实验结束后对大鼠海马内的AC转化率,cAMP含量及PKA的活性进行检测。
结果：
1.1临床研究
1.1.1基线比较
三组患者在性别、年龄、病程、病情、合并用药及合并镇静催眠药用量方面,经统计分析,均无显著性差异(P>0.05)；三组患者在治疗前HAMD量表、抑郁自评量表(SDS)评分以及抑郁症中医证候量表评分组间比较,差异均无统计学意义(P>0.05),可认为三组基线水平一致,具有可比性。
1.1.2总有效率及显效率
治疗后四关穴组的显效率为44.74%,总有效率为84.21%；非经非穴的显效率为14.71%,总有效率为67.65%；安慰针组的显效率为5.56%,总有效率为38.89%。三组疗效构成比较,组间差异有统计学意义(X2=16.0375,P<0.0167)。
三组总有效率比较,组间差异无统计学意义(P>0.05),四关穴组显著高于安慰针组(P<0.05),但与非经非穴组比较,差异无统计学意义(P>0.05)。安慰针组的显效率与总有效率和非经非穴组相比,均无统计学差异(P>0.05,P>0.05)。
三组显效率比较,四关穴组均极显著高于非经非穴组和安慰针组(X2=4.1649, P<0.0167; X2=9.0925, P=P<0.0167);
1.1.3HAMD抑郁量表各因子评分
三组在治疗后各时段的HAMD的焦虑/躯体化因子、阻滞因子、睡眠障碍5个因子的评分均较治疗前上升,差异均有统计学意义(P<0.05)；四关穴组和非经非穴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安慰针组。四关穴组对各时间段的阻滞因子改善程度均优于非经非穴组和安慰针组。四关穴组在治疗后4,6周时对认知障碍因子改善程度优于安慰针组(P<0.0167),在治疗6周时对体重因子改善程度优于安慰针组(P<0.0167)。
1.1.4抑郁自评量表(SDS)评分
在以抑郁自评量表(SDS)评分为测量指标的评价中,在治疗4周及6周时,四关穴组的疗效均显著优于非经非穴组和安慰针组(P<0.0167,P<0.0167)；而在治疗各时点,非经非穴组优于安慰针组,但差异无统计学意义(P>0.05)。
1.1.5抑郁症中医症候评定量表
在以抑郁症中医证候量表评分为测量指标的评价中,在治疗6周时,四关穴组的疗效均显著优于非经非穴组和安慰针组(P<0.0167,P<0.0167)；在治疗各时点,非经非穴组和安慰针组比较均无显著性差异(P>0.05)。
1.1.6三组随访HAMD评分比较：在治疗结束后2周时,以HAMD量表随访一次。三组组间比较,差异有统计学意义(P<0.05),四关穴组HAMD评分均优于非经非穴组和安慰针组(P<0.05,P<0.05),而后两组HAMD评分组间比较不存在统计学差异(p>0.05)。各组分别与治疗6周时评分相比,均无显著性差异(P>0.05)。
1.2实验研究
1.2.1openfield行为学变化
各组水平及垂直运动的基础值均无明显差异(P>0.05),具有可比性。在接受3周慢性应激后,各组造模大鼠的水平及垂直运动次数均显著下降,与空白组相比有显著性差异(P<0.05)；各造模组大鼠组间比较没有显著性差异(P>0.05)。治疗3周后,模型组大鼠水平及垂直运动显著低于空白组(P<0.05)；电针组、药物组及电针+盐水组的运动次数分别与模型组比较均有显著升高(P<0.05,P<0.05,P<0.05)；电针组与电针+盐水组比较,无显著性差异；电针+H89组水平运动次数显著下降,与模型组比较没有显著性差异(P>0.05)。
1.2.2糖水消耗量变化
应激前各组之间大鼠的糖水消耗量没有显著性差异(P>0.05)；应激第22天后,糖水消耗量造模组大鼠的糖水消耗量显著下降,与空白组比较有显著性差异(P<0.05)；在治疗3周后(应激第42天),电针组、药物组糖水消耗量有所增加,均较应激3周时有显著改善(F=3.215,P=0.0156; F=5.167,P=0.0035);电针组与电针+NS组糖水消耗量之间没有统计学差异(P>0.05)；而电针+H89组糖水消耗量持续下降,与电针组比较,差异有统计学意义(F=4.321,P=0.0021)
1.2.3海马AC转化率,cAMP含量及PKA活性检测
在实验结束时,抑郁症模型大鼠海马组织AC转化率、cAMP含量及PKA活性均显著降低,与空白组比较,差异有统计学意义(P<0.05)。药物和电针均可增加抑郁症模型大鼠海马组织AC转化率、cAMP含量及PKA活性,基本达到空白组水平。
结论：
1.针刺四关穴、非经非穴、安慰针治疗肝郁型抑郁症在减轻抑郁程度上均有一定疗效,但四关穴针刺较其他两组疗效更为显著且持久。
2.针刺四关穴对于抑郁症HAMD量表各因子的改善疗效优于非经非穴位与安慰针具组,随着治疗时间的延长疗效更为显著。
3.针刺四关穴能显著改善抑郁症大鼠的行为学,显著上调海马AC、PKA活性及cAMP含量,PKA阻滞剂H89可阻断针刺抗抑郁的作用,提示AC-cAMP-PKA受体后信号转导通路可能是针刺抗抑郁的重要途径和作用靶点之一。
Objectives
1.From a randomized, single blind and controlled trial, we explore the effectiveness and safety of acupuncture treatment of "Siguan" acupoints on depression of stagnation of liver-Qi type.
2. To explore the mechanism of acupuncture for antidepressive effect on AC-cAMP-PKA postreceptor signal transduction pathway.
Methods
1. Clinical study
108cases were randomized into the following groups:Siguan acupoints group, non-acupoint group and Streitberger needle group groug.
Siguan acupoints group:Siguan points (bilateral Hegu (LI4) and Taichong(LR3)) were selected to received acupuncture. After sterilizing,0.35×40mm acupuncture needles were put through the needle pipe and vertically inserted below to the skin through the foam tray which was stick to the surface of the points. Manipulated the needle until de-qi was felt by the patient. Retained the needle for30min with needle manipulation once per15min.
Non-acupoint group:Two points that correspond to Siguan points were located①on the dorsum of hand and between the middle of the3th and4th metacarpal bone;②on the3th lateral metatarsal bone on dorsum pedis, between the3th and4th metatarsal bone. Needle manipulation and retaining were similar to Siguan points group.
Streitberger needle group:The selected points and the needle insertion procedure were similar as Siguan acupoints group, except that the tip of the needle was blunt and could not puncture into the skin. During the needle retaining, the needle was hold by the foam tray and the needle pipe and adjust the stretching pipe to keep the appearance of the placebo needle look like as inserted into the skin as the verum needle in Siguan points group.
All the patients in the three groups were asked to deep breath to regulating qi during needle retaining and received3sessions weekly with total6weeks of treatment.
The effects were evaluated by the HAMD Scales, the SDS Scales, and the improvement Scales of symptoms of Traditional Chinese Medicine before the treatment and4time points (at the end of2week,4week and6week) during the treatment course. ITT analysis were used for all the data analysis.
2. Animal study
Adult Sprague-Dawley male rats (200-250g) were used in the present experiment. Animals were divided randomly into7groups:the control group, the model group, the electroacupuncture(EA) group and drug group, EA plus normal saline (NS)group, EA plus H89group and Fluo plus H89group;8rats in each group. The chronic mild stress model(CMS) of depression was induced by various kinds of stress for42days. In the model group, rats were exposed to chronic mild unpredictable mild stress for6weeks. In the EA group, rats receive CMS procedure and electroacupuncture stimulation at Siguan points (bilateral Hegu (LI4) and Taichong(LR3)) once every other day for3weeks after CMS exposure. In the drug group, rats receive the same treatment as the CMS group and Fluoxetine treatment everyday for3weeks after CMS. The groups plus H89/NS were conditioned with the same as the EA or Fluoxetine group except for the intracerebroventricular injection of H89between CMS and EA. Changes of open-field behavior, sucrose consumption, AC activity, cAMP level and PKA activity in hippocampus of rats were observed in the study.
Result
1.Clinical study
1.1Baseline
The difference in terms of age, height, weight, disease duration, sex, educational level, occupation, living habits, history of western medicine taking or acupuncture treatment receiving among3groups is no significant (P>0.05); And, the difference of scores of HAMD scale, SDS scale and TCM syndrome rating scale among the three groups of depressed patients on baseline was not statistically significant(P>0.05), baseline level can be considered the same among the three groups and comparability. 1.2Total effective rate and excellence rate
After6weeks of treatment, the total effective rate and the excellence rate of the3groups respectively were84.21%and44.74%in Siguan acupoints group,67.65%and14.71%in non-acupoint group,38.89%and5.56%in the Streitberger needle group. Compare the total effective rate of the3groups, there was a significant difference among the3groups (P<0.0167).
1.3HAMD Scale
The gross effective rate was higher and the HAMD Scale score was better in the Siguan acupoints group than that of the non-acupoint group and sham-acupuncture group (P<.05). The improvement of score of anxiety/somatization factor, body weight factor, cognitive handicap factor, blockage factor and the sleeping disorder factor in Siguan acupoints group was started on the2week during the treatment, and which was lasted to the end of the treatment.
1.4SDS scale
The SDS Score was better in the both acupuncture groups than that in the non-acupoint group and Streitberger needle group (P<0.0167, P<0.0167), however, no significant difference was found between the non-acupoint group and Streitberger needle group.
1.5Improvement Scales of symptoms of Traditional Chinese Medicine
The Improvement Scales of symptoms of TCM Score was better in the both acupuncture groups than that in the non-acupoint group and Streitberger needle group (P<0.0167,P<0.0167), again, no significant difference between the non-acupoint group and Streitberger needle group.
2. Animal study
2.1Changes of openfield behavior
The behavior (horizontal and vertical motion) of the depression rats decreased significantly following stress, and EA treatment as well as EA+NS can effectively improve it, which is better than that of the drug (P<0.05, P<.0.05, P<0.05). Enhanced effects induced by EA were reversed by H89pretreatment.
2.2Changes of sucrose consumption
Sucrose intake in all stress groups decreased significantly in the3rd week and was much less than the control group (P<0.05). However, there was no remarkable difference among all stress groups. EA or Fluoxetine treatment leaded to increase in sucrose intake in the sixth week, however, not indicating significant difference with CMS group. H89pretreatment inhibited obviously increase in sucrose intake induced by EA.
2.3AC activity, cAMP level and PKA activity
Animals exposed to stressors also showed a significant decrease in the ratio of AC transformation after the last week when the experiment ended. In the EA group and Fluxitine group, the ratio of AC transformation increased significantly after EA treatment for3weeks compared to the CMS group. EA and Fluxitine can improved the level of AC transformation ratio in the hippocampus of rats to a level as of normal rats. Changes in cAMP level and PKA activity were similar to AC (P<0.05, P<0.05, P<0.05)
Conclusion
1. Acupuncture treatment of Siguan acupoints was effective and safe in treating depression.
2. Acupuncture treatment of Siguan acupoints regulating liver showed a more obviously curative effect on all factors of depression after treatment when compared to non-acupoint group and Streitberger needle groug.
3. Acupuncture could improve signif ieantly changes of the behavior, sucrose consumption, AC activity, cAMP level and PKA activity in hippocamp of rats, therefore, AC-cAMP-PKA postreceptor signal transduction pathway is an important approach and target of acupuncture in treating depression.
引文
[1]Nemeroff CB. The neurobiology of depression[J]. Scientific American,1998,278:42.
[2]周学东,陈兴宝.抑郁症经济负担研究进展[J].上海医药,2006,27(12)：539-541
[3]周庚生,胡纪明.中西医临床精神病学,中国中医药出版社,1998：316
[4]Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron.2002,34:13-25.
[5]Hampton T. Suicide caution stamped on antidepressants. JAMA.2004,291:2060-2061.
[6]罗和春,Ureil Halbriech,沈渔邮,孟凡强.电针与氟西汀治疗抑郁症疗效的对照研究[J].中华精神科杂志,2003,36：215-219.
[7]吕梅,王玲玲,刘兰英,利达.针药结合治疗抑郁症的临床研究[J].南京中医药大学学报,2004,20：149-151.
[8]俞瑾,李晓艳,曹小定,吴根诚.电针合用抗抑郁药能明显减少小鼠强迫游泳实验中的静止时间[J].针刺研究,2002,27：214-219.
[9]吴绪平,韩肖华,王亚文,刘又香.头穴透刺对急性脑梗塞大鼠脑组织中p-EP与cAMP含量的相关性研究[J].中国中医基础医学杂志,2003,9：47-49.
[10]韩森,.李学武,李晓私,郭顺根.电针对慢性应激抑郁模型大鼠海马BDNF的影响[J].中国中医基础医学杂志,2001,7：55-57.
[11]符文彬.针灸对抑郁症的治疗作用[J].中国临床康复杂志,2002,6：5.
[12]樊莉,符文彬,蒙昌荣.应用汉密顿抑郁量表评估正穴位与非穴位针刺治疗抑郁症的疗效[J].中国临床康复,2005,9：14-16.
[13]符文彬,樊莉,朱晓平等.疏肝调神治疗抑郁症的临床研究[J].针刺研究,2006,31：355-35
[14]中华医学会精神科分会.中国精神障碍分类与诊断标准第三版[M].济南：山东科学技术出版社,2001,87-89
[15]国家中医药管理局发布.中医病证诊断疗效标准[M].南京大学出版社出版,1994,7,第1版;20
[16]张宏耕主编.中西医结合精神病学[M].中国中医药出版社.2005,8,第1版,19
[17]周仲瑛主编.中医内科学[M]..中国中医药出版社.第一版,北京,2003,1,393-395
[18]章洪流,王天芳,郭文,等.抑郁症中医证型的近10年文献分析[J].北京中医药大学学报,2005,28(3)：79-81
[19]赵燕,王天芳,于春光,等.抑郁症中医证候及证候要素分布特点的文献研究[J].中医杂志,2006,47(9)：691-693
[20]周玲,陈文垲,梅晓云,等.抑郁症中医证候的群体分布特点及其相关因素研究[J].中国中西医结合杂志,2006,26(2)：106-109.
[21]胡随瑜,张宏耕,郑林,等.1997例抑郁症患者中医不同证候构成比分析[J].中国医师杂志,2003,5(10)：1312-1313.
[22]张海男,胡随瑜,陈泽奇等.抑郁症常见中医证候类型第一轮专家问卷分析[J].湖南医科大学学报,2002.27(6)：519-521
[23]蔡光生,赵玉庸.中西医结合内科学.中国中医药出版社.2005.916-920
[24]王腾云.丹栀逍遥汤加减治疗抑郁症34例[J].中国中西医结合杂志,2001,21(9)：710-711.
[25]张金茹.小柴胡汤治疗抑郁症40例[J].北京中医,2003,22,(5)：38-39.
[26]朱春山.文拉法辛与消遥丸联合治疗抑郁症的疗效观察.中国中西医结合杂志,2002,22(2)：152
[27]陈建冲.逍遥散加味治疗难治性抑郁症18例.黑龙江中医药,2003,(1)：21-22
[28]杜元濒,李桂平,颜红,等.调神疏肝法治疗郁证的临床研究[J].中国针灸,2005,25(3)：151-154.
[29]张春虹,李金波,王舒,等.在德国运用“醒脑开窍法”治疗郁证的临床观察[J].针刺临床杂志,2002,18(8)：6-7
[30]李静.针刺治疗中风后抑郁症67例[J].上海针灸杂志,2005,24(6)：27.
[31]符文彬,樊莉,朱晓平,等.针刺调肝法治疗抑郁性神经症176例疗效观察[J].新中医,2007,39(12)：42-44.
[32]徐世芬,庄礼兴.电针百会印堂对肝郁型抑郁性神经症的影响.现代中西医结合杂志,2010,19(15)：1835—1838
[33]Andrade L, Caraveo-duaga JJ, Berglund P, et al. The epidemiology of major depressive episodes:results from the International Consortium of Psychiatric Epidemiology(ICPE)Surveys[J]. International Journal of Methods in Psychiatric Research, 2003,12:3-21
[34]Kessler RC. Epidemiology of depression in the Asia pacific region[J]. Australasian Psychiatry,2004,12(suppl):4-10
[35]Kessler RC. Epidemiology of women and depression[J]. Journal of Affective Disorders,2003,74:5-13
[36]严和骏,肖世富,陆余芬,等.综合性医院就诊者的心理障碍[J].上海精神医学,1996,8：65-68
[37]余殿飞,谢铜华.战胜人类第一心理杀手：抑郁症的早期认识和有效防治[M].北京：中国医药科技出版社,2001：28
[38]Udziszewska B, Jaworska-Feil L, kajtaM, et al. Antidepressant Drugs inhibit Glucocorticoid receptor-mediated gene transcription-a possible mechanism[J]. BrJ Pharmaco,2000,130(6):1385-1393
[39]Sweeney JA, Kmiec JA, Kupfer DJ. Neuropsychologic impairments in bipolar and unipolar mood disorders on the CANTAB neurocognitive battery. Biol Psychiatry.2000,48:674-684
[40]Airaksinen E, Larsson M, Lundberg I,Forsell Y. Cognitive functions in depressive disorders:evidence from a population based study. Psyehol Med.2004,34:83-91
[41]Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA.1996,93:3908-3913
[42]Videbech p, Ravnkilde B. Hippocampal volume and depression:a meta-analysis of MRI studies. Am J Psychiatry.2004,161:1957-1966
[43]Cheryl A, Frye, JoAnna W. Effect of prenatal stress and gonadal hormone condition on depressive behaviors of female and male rats[J].Hormones and Behavior,2003,44(4): 319-326.
[44]Owen BM, Eceleston D, Ferrier IN, et al. Raised levels of plasma inierleukin-1 βin major and postviral depression[J]. Acta Psychlatrica Scandinavica,2001,103(3): 226-228.
[45]Levine J, Barak Y, Chengappa KN, et al. Cerebrospinalcytokine levels in Patients with acute depression[J]. NeuroPsychobiology,1999,40(4):171-176.
[46]左玲俊,罗星光.抑郁症的防治[M].上海：复旦大学出版社,2001：90.
[47]唐济生,翟静.吗氯贝胺治疗抑郁症双盲对照研究.中国神经精神疾病杂志,2001,27(1)：69-70.
[48]Breen R, Mc Cormac RJ. A fresh look at management of depression, How to choose and use the newer antidepressant drugs. Postgradmed,2002,112(3):25-40.
[49]陈瑞玲,赵志刚.抗抑郁症类药物的临床应用研究进展.中国临床药理学杂志,2007,23(1)：54-57.
[50]赵志刚,张星虎,张石革.当代神经精神科用药选择[M].北京：人民卫生出版社,2003：45-60.
[51]王巍巍,王春晓,高洪丽.抑郁症药物治疗的研究进展,中国实用医药,2008,3(17)：211-212.
[52]Sanz EJ, De-las-Cuevas C, Kiuru A, Bate A, Edwards R. Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome:a database analysis. Lancet,2005,365:482-487.
[53]Burt T, Lisanby SH, Sackeim HA. Neuropsychiatric applications of transcranial magnetic stimulation:a meta analysis. Int J Neuropsychopharmacol,2002,5:73-103.
[54]Shajahan PM, Glabus MF, Steele JD, et al. Left dorso-lateral repetitive transcranial magnetic stimulation affects cortical excitability and functional connectivity, but does not impair cognition in major depression. ProgNeuropsychopharmacol Biol Psychiatry, 2002,26:945-954.
[55]Dwork AJ, Arango V, Underwood M, et al. Absence of histological lesions in primate models of ECT and magnetic seizure therapy. Am J Psychiatry,2004,161:57.
[56]Kosel M, Friek C, Lisanby SH, Fiseh HU, et al. Magnetic seizure therapy improves mood in refractory major depression. Neuropsychopharmacology,2003,28:2045-2048.
[57]Lisanby SH, Moserip T, Morales 0, et al. Neurophysiological characterization of magnetic seizure therapy(MST) in non-human primates. Suppl Clin Neurophysiol,2003, 56:81-99.
[58]UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders:a systematic review and meta analysis. Lancet,2003,361:799-808. [59]Sackeim HA, Haskett RF, Mulsant BH, et al. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy:a randomized controlled trial. JAMA,2001,285:1299-1307.
[60]White AR, Emst E. A systematic review of randomized controlled trials of acupuncture for neck pain[J]. Rheumatology,1999,38(2):143-147.
[61]刘鸣.系统评价、Meta-分析设计与实施方法[M].人民卫生出版社,北京,2011,68-70.
[62]Higgins JPT, Green S, Eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1. The Cochrane Collaboration 2008.
[63]Allen J, Schnyer RN, HittSK. The efficacy of acupuncture in the treatment of major depression in women[J]. Psychol Sci,1998,9(5):397-401.
[64]Allen J, Schnyer RN, Chambers AS, et al. Acupuncture for depression a randomized controlled trial[J].J Clin Psychiatry,2006,67(11):1665-1673.
[65]樊莉,符文彬,蒙昌荣,等.应用汉密顿抑郁量表评估正穴位与非穴位针治疗抑郁性神经症的疗效[J].中国临床康复,2005,9(28)：14-16.
[66]罗和春,Urei1H,沈渔邨,等.电针与氟西汀治疗抑郁症疗效的对照研究[J].中华精神科杂志,2003,36(4)：215-219.
[67]符文彬,樊莉,朱晓平,等.针刺调肝法治疗抑郁性神经症的临床研究[J].针刺研究,2006,31(6)：355-358.
[68]李颖文.针刺治疗抑郁性神经症的临床研究[D].广州：广州中医药大学学位论文,2005.
[69]Eich H, Agelink MW, Lehman E, Lemmer W, Kliesser E. Acupuncture in patients with minor depression or generalized anxiety disorders-results of a randomized study. Fortschritte Der Neurologie Psychiatrie 2000:68:137-44.
[70]Whiting M, Leavey G, Scammell A, Au S, King M. Using acupuncture to treat depression: a feasibility study. Complementary Therapies in Medicine 2008:16:87-91.
[71]Carmen A, Ronald MG, Chetachi AE, et al. Acupuncture for the treatment of major depressive disorder:A Randomaied controlled trial. J Clin Psychiatry,2011,72 (8): 1129-1135.
[72]Wing-Fai Yeung, BCM, Ka-Fai Chung, et al. Electroacupuncture for Residual Insomnia Associated with Major Depressive Disorder:A Randomized Controlled Trial. Sleep,2011, 34(6):807-900.
[73]Yeung A, Mischoulon D, Alpert J, et al. Acupuncture for major depressive disorder: has its efficacy been disproved[J]. J Clin Psychiatry,2007,68 (10):1617-1618.
[74]Park J, White A, Stevinson C, Ernst E, James M:Validating a new non-penetrating sham acupuncture device:two randomised controlled trials. Acupunct Med 2002, 20(4):168-174.
[75]杨维杰.针灸五输穴应用.世界图书出版公司.1993.
[76]王葳,李坤成,单保慈,等.针刺正常老年人“四关穴”的脑功能MRI研究.中国医学影像技术,2006,22(6)：829-832.
[77]刘永源,陈杰辉.四关穴临床应用概况[J].针灸临床杂志,2003,19(4)：56.
[78]王宁宁,陈俊琦,江晓宇,等.针灸治疗原发性抑郁症取穴规律的文献分析.中医杂志,2011,52(24)：2132-2133.
[79]孙畅,黄东勉,曾令友.针刺治疗抑郁症64例临床观察.中国康复理论与实践.2007,13(12)：1186.
[80]Spiker B. Clinical trials come of age:the development of clinical trial methodology since 1945 has been remarkable. DN&P,1993,6:22.
[81]Park J, White AD, Lee H, et al. Development of a new sham needle. Acupuncture in Medicine,1999,17:110.
[82]张宏伟,唐金陵.针灸临床试验中安慰针的设计与选用. 中国中西医结合杂志.2003,23(4)：247-249.
[83]Marwich C. Acceptance of some acupuncture application. JAMA.1997,278:1725.
[84]刘慧林,张琰,李敬道,等.针灸临床研究安慰对照方法的设计与实践.中国循证医学杂志.2008,8(12)：1133-1135.
[85]Streitberger K.一种用于针刺研究的新安慰法[J].沈嘉怡摘译. 国外医学中医中药分册,2000,22(5)：316.
[86]Kong J, Ma L, Gollub R L, et al. A pilot study of functional magnetic resonance imaging of the brain during manual and electroacupuncture stimulation of acupuncture point (LI-4 Hegu)in normal subjects reveals differential brain activation between methods. J Altern Compl Med,2002,8(4):411-419.
[87]Zald DH. The human amygdale and the emotional evaluation of sensory stimuli. Brain Res Rev,2003,41(1):88-123.
[88]Kathleen H, Liu J. The integrated response of the human cerebro-cerebellar and limbic systems to acupuncture stimulation at ST36 as evidenced by fMR. Neuroimage,2005, 27(3):479-496.
[89]Vogt B A. Pain and Emotion interaction in subregions of the cingulated gyrus, focus on pain. Nat Rev Neurosci,2005,6(7):533-544.
[90]王丽,章军建,刘涛.PKA-cREB信号转导通路在大鼠慢性脑缺血所致认知功能障碍中的作用.中国临床神经科学,2006,14(5)：449—452.
[91]Tardito D, Perez J, Tiraboschi E, et al. Signaling pathways regulating gene expression, neuroplasticity, and neurotrophic mechanisms in the action of antidepressants: a critical overview. Pharmacol Rev,2006,58:115-134.
[92]Carlezon WA Jr, Duman RS, Nestler EJ. The many faces of CREB. Trends Neurosci,2005,28:436-445.
[93]Shelton R C. Cellular mechanisms in the vulnerability to depression and response to antidepressants. Psychiatr Clin North Am,2000,23:713-729.
[94]Nestler EJ, Terwilliger RZ, Duman RS. Chronic antidepressant administration alters the subcellular distribution of cyclic AMP-dependent protein kinase in rat frontal cortex. J Neurochem,1989,53:1644-1647.
[95]Solomon DA, Keller MB, Leon AC, et al. Multiple recurrences of major depressive disorder[J]. Am J Psychiatry,2000,157(2):229-233.
[96]韩明飞,高东,孙学礼.应激抑郁动物模型的建立与评价[J].华西医学,2008,23(4)：901-902.
[97]秦琴,刘利学.抑郁症动物模型概述及评价[J].实验动物科学,2010,27(1)：53-59.
[98]Katz RJ, Roth K A, Carroll B J, et al. Acute and chronic stress effects on open field activity in the rat:Implications for a model of depression[J]. Neurosci Biobehav Rev, 1981,5(2):247.
[99]Willner P. Validation criteria for animal models of human mental depression:learned helpless aparadigra case[J]. Psychopharmacology,1985,85(4):387-404.
[100]Willner P, Muscat R, Papp M. Chronic mild stress-induced anhedonia:arealistic animal model of depression[J]. Neurosci Biobehav Rev,1992,16(4):525-534.
[101]Willner P. Validity, reliability and utility of the chronic mild stress model of depression:a 10-year review and evaluation[J]. Psychopharmacology,1997,134(4): 319-329.
[102]McEwen BS, Magarinos AM. Stress and hippocampal plasticity:implications for the pathophysiology of affective disorders [J]. Hum Psychopharmacol.,2001,16(S1):S7-S19.
[103]Schulte-Herbruggen 0, Hellweg R, Chourbaji S, et al. Differential regulation of neurotrophins and serotonergic function in mice with genetically reduced glucocorticoid receptor expression [J]. Exp Neurol,2007,204(1):307-316.
[104]宓轶群,陈一.四关穴为主治疗脑卒中后抑郁证的对照分析[J].中国临床康复,2003,7(31) ： 4250.
[105]俞红五,朱才丰,陈颖.开四关加人中针刺治疗中风后抑郁状态32例[J].中医药临床杂志,2007,19(3)：245.
[106]严德庆.四关穴治疗癔病选案.针灸临床杂志,1999,15(11)：44-45
[107]符文彬,樊莉,朱晓平，等.Depressive Neurosis Treated by Acupuncture for Regulating the Liver-A Report of 176 Cases. Journal of Traditional Chinese Medicine, 2009,29(2):83-86.
[108]符文彬刘健华 白艳甫,等.电针对抑郁症大鼠海马CREB-BDNF受体后信号转导通路的作用.中国老年学杂志,2009,29(23)：3038-3042.
[109]徐叔云.药理实验方法学,北京：人民卫生出版社,1994：641.
[110]郭德玉,陈铁玉,李斌,等.不同年龄大鼠学习一记忆能力及旷场行为比较.中国实验动物学报,1998,6：19-23.
[111]Willner P. Validity, reliability and utility of the chronic mild stress model of depression:a 10-year review and evaluation[J]. Psychopharmacology,1997,134(4): 319-329.
[112]Harro J, Tonissaar M, Eller M, et al. Chronic variable stress and partial 5-HT denervation by parachloroamphetamine treatment in the rat:effects on behavior and monoamine neurochemistry. Brain Research,2001,899:227-239.
[113]Naranjoa CA, Tremblaye LK, Bustob UE. The role of the brain reward system in depression. Progress in Neuro-Psychopharmacology and Biological psychiatry,2001, 25(4):781-823.
[114]Gronli J, Murison R, Bjorvatn B, et al. Chronic mild stress affects sucrose intake and sleep in rats. Behavioral Brain Research,2004,150(1-2):139-147.
[115]Duman RS, Malberg J, Nakagawa S, D'Sa. CNeuronal plasticity and survival in mood disorders. Biol Psychiatry,2000,46:1181-1191.
[116]Ozawa H, Rasenick MM. Chronic electroconvulsive treatment augments coupling of the GTP-binding protein Gs to the catalytic moiety of adenylyl cyclase in a manner similar to that seen with chronic antidepressant drugs. J Neurochem.1991,56:330-338.
[117]Nestler EJ, Terwilliger RZ, Duman RS. Chronic antidepressant administration alters the subcellular distribution of cyclic AMP dependent protein kinase in rat frontal cortex. J Neurochem.1989,53:1644-1647.
[118]Tronson NC, Schrick C, Fischer A, et al. Regulatory mechanisms of fear extinction and depression-like behavior. Neuropsychopharmacology.2008,33(7):1570-83.
[119]时宇静,卢峻,贾宝辉,等.电针对抑郁模型大鼠糖水摄人量和性行为的影响及机理研究。针刺研究,2006；31(1)：27-30.
[120]孙华,张有志,韩毳,等.电针对慢性应激抑郁模型大鼠大脑皮层5-HT1和5-HT2受体 数量和结合活性的影响[J].中国针灸,2003,23(9)：553-555.
[121]李晓白,黄继忠,王祖承.抑郁症与谷氨酸传导[J].中国新药与临床杂志,2005,24：601-604.
[122]陈运平, 孙圣刚,梅元武,等.低频重复经颅磁刺激对抑郁模型大鼠游泳及海马内氨基酸递质的影响[J].中华物理医学与康复杂志,2006,28(8)：507-509.
[123]刘海静,何新芳,陈兴华.针刺对抑郁模型大鼠行为学及海马氨基酸类神经递质的影响。医学研究杂志,2010,39(3)：79-81
[124]Hyunyoung Kim, Hyun-Jung Park, Hyun Soo Shim, et al. The effects of acupuncture (PC6) on chronic mild stress-induced memory loss. Neuroscience Letters 488 (2011) 225-228.
[125]Bombi Lee, Insop Shim, Hye-Jung Lee, et al. Effects of acupuncture on chronic corticosterone-induced depression-like behavior and expression of neuropeptide Y in the rats. Neuroscience Letters.453 (2009) 151-156
[126]钱瑞琴,张春英,杨宇,等.电针与舒血宁联合治疗抑郁症患者免疫功能的影响[J].中国实验方剂学杂志,2001,7(3)：56.
[127]Wachtel H. The second-messenger dysbalance hypothesis of affective disorders[J]. Pharm copsychiatry,1990,17:1.
[128]Perez J, Tardito D,MoriS, et al. Abnormalities of cAMP signaling in affective disorders:implication for pathophysiology and treatment. Bipolar Disoul,2000,2:27-36.
[129]Duman R.. Novel therapeutic approaches beyond the serotonin receptor. Biol Psychiatry,1998,44:324-335.
[130]Donati RJ, Rasenick MM. G Protein signaling and the molecular basis of antidepressant action.LifeSci,2003,73:1-17
[131]孙健,刘健华,王谦,等.电针对抑郁症大鼠海马组织AC-cAMP-PKA信号通路的影响.中国老年学杂志2010,12(30)：3672-3673.
[132]张敏,图娅。电针对慢性应激抑郁模型大鼠学习记忆行为的影响。中医研究。2008,21(3)：15-17
[133]李丽萍,毕颖。针灸对慢性应激抑郁模型大鼠环核苷酸的影响。中华中医药学刊。2008；26(12)：2742
[134]罗文舒,皮敏,饶晓丹,等.针刺督脉和膀胱经促进抑郁症大鼠海马神经元再生的实验研究.广西中医药.2008,31(4)：46-48.
[135]van Wingen GA, van Eijndhoven P, Tendolkar I, et al. Neural basis of emotion recognition deficits in first-episode major depression. Psychol Med.2010 Nov 8:1-9.
[136]Mayberg HS, Brannan SK, Mahurin RK, et al. (21ingulate function in depression: a potential predictor oftreatment response[J]. Neuroreport,1997,8:1057-1061
[137]Videbech P MRI finding in patients with affective disorder:ameta-analysis [J]. Acta PsychiatrSeand,1997,96:157-168.
[138]Georgge MS, Ketter TA. Pose RM. SPECT and PET imaging in mood dizorder[J]. J Clin Psychiatry.1993,54:6
[139]Konarski JZ, Kennedy SH, Mclntyre RS, et al. Relationship between regional brain metabolism,illness severity an d age in depressed subjects[J]. Psychiatry Res,2007, 155(3):203-210.
[140]Veena Kumari MT. Mittersehiffthaler JD, Teasdale GS, et al. Neural abnormalities during cognitive generation of affect in Treatment-Resistant Depression[J]. Biol Psychiatry,2003,54(8):777-791.
[141]Mayberg HS. Modulating dysfunctional limbic-cortical circuits in depression:towards development of brain-based algorithms for diagnosis and optimized treatment [J]. Br Med Bull,2003,65(1):193-207.
[142]冯正直,张大均.抑郁与脑血流量和葡萄糖代谢的研究进展[J].中国行为医学科学,2002,(11)：354-355
[150]Dequervain D J, Roozendaa I B, McGaugh J L. Stress and glucocorticoids impair retrieval of long term spatial memory [J]. Nature,1998,394 (12):787.
[151]符文彬,刘健华,白艳甫,等。电针对抑郁症大鼠海马CREB-BDNF受体后信号转导通路的作用。中国老年学杂志。2009,12(29)：3038-3040.
[152]Wong ML, Licinio J. Nat from monamines to genomic targets:a paradigm shift for drug discovery in depression [J]. Rev Drug Discov,2004,3(2):136-151.
[153]Kempermann G. Regulation of adult hippocampal neurogenesis-implications for novel theories of major depression[J]. Bipolar Disord,2002,4:17-33.
[154]Benninghoff J, Schmitt A, Mossner R, et al. When cells become depressed:focus on neuralstemcells in novel treatment strategies against depression [J]. J Neural Transm,2002,109:947-962.
[155]罗文舒,皮敏,饶晓丹,等。针刺督脉和膀胱经促进抑郁症大鼠海马神经元再生的实验研究。广西中医药。2008,31(4)：45-47.
[156]Qiong Liu, Jin Yu, Wen-Li Mi, et al. Electroacupuncture attenuates the decrease of hippocampal progenitor cell proliferation in the adult rats exposed to chronic unpredictable stress. Life Sciences 81 (2007):1489-1495.
[157]徐世芬,庄礼兴,唐纯志.针刺对抑郁大鼠海马神经因子表达的影响[J].广州中医药大学学报,2009,26(6)：532-534.
[158]FOSSATI P, RADTCH A, BOYER P. Neuroplasticity:from MRI to depressive symptoms. Eur Neuropsychopharmacol.2004;15:s503-s510.
[159]Cotter D, Mackay D, Chana G, Beasley C, Landau S, Everall IP. Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Cereb Cortex.2002,12:386-394.
[160]Rajkowska G, Halaris A, Selemon LD. Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder. Biol Psychiatry.2001,49:741-752.
[161]Webster MJ, Knable MB, Johnston-Wilson N, Nagata K, Inagaki M, YolkenRH. Immunohistochemical localization of phosphorylated glial fibrillary acidic protein in the prefrontal cortex and hippocampus from patients with schizophrenia, bipolar disorder, and depression. Brain Behav Immun.2001,15:388-400.
[162]Johnston-Wilson NL, Sims CD, Hofmann JP, Anderson L, Shore AD, Torrey EF, Yolken RH. Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium. Mol Psychiatry.2000,5:142-149.
[163]Si X, Miguel-Hidalgo JJ,O'Dwyer G, Stockmeier CA, Rajkowska G Age-dependent reductions in the level of glial fibrillary acidic protein in the prefrontal cortex in major depression. Neuropsychopharmacology.2004,29:2088-2096.
[164]Banasr M, Duman R S. Glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors. Biol Psychiatry,2008,64:863-70.
[165]Qiong Liu, Bing Li, Hai-Yan Zhu, et al. Glia atrophy in the hippocampus of chronic unpredictable stress-induced depression model rats is reversed by electroacupuncture treatment. Journal of Affective Disorders.2011,128:309-313.
[166]胡旺平,张健,胡圣望,等.电针对慢性应激所致大鼠空间学习记忆障碍及海马胆碱能功能的影响[J].辽宁中医杂志.2003,30(3)；215-216.
[167]胡旺平,胡圣望,化长林,等.电针对慢性应激大鼠空间学习记忆能力的影响[J].山东中医杂志,2003,22(5)；300-301.
[168]刘建平.随机对照试验的依从性和意向性治疗分析[J].中国中西医结合杂志,2003,23(12)：884-886.
[2]周学东,陈兴宝.抑郁症经济负担研究进展[J].上海医药,2006,27(12)：539-541
[3]周庚生,胡纪明.中西医临床精神病学,中国中医药出版社,1998：316
[4]Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron.2002,34:13-25.
[5]Hampton T. Suicide caution stamped on antidepressants. JAMA.2004,291:2060-2061.
[6]罗和春,Ureil Halbriech,沈渔邮,孟凡强.电针与氟西汀治疗抑郁症疗效的对照研究[J].中华精神科杂志,2003,36：215-219.
[7]吕梅,王玲玲,刘兰英,利达.针药结合治疗抑郁症的临床研究[J].南京中医药大学学报,2004,20：149-151.
[8]俞瑾,李晓艳,曹小定,吴根诚.电针合用抗抑郁药能明显减少小鼠强迫游泳实验中的静止时间[J].针刺研究,2002,27：214-219.
[9]吴绪平,韩肖华,王亚文,刘又香.头穴透刺对急性脑梗塞大鼠脑组织中p-EP与cAMP含量的相关性研究[J].中国中医基础医学杂志,2003,9：47-49.
[10]韩森,.李学武,李晓私,郭顺根.电针对慢性应激抑郁模型大鼠海马BDNF的影响[J].中国中医基础医学杂志,2001,7：55-57.
[11]符文彬.针灸对抑郁症的治疗作用[J].中国临床康复杂志,2002,6：5.
[12]樊莉,符文彬,蒙昌荣.应用汉密顿抑郁量表评估正穴位与非穴位针刺治疗抑郁症的疗效[J].中国临床康复,2005,9：14-16.
[13]符文彬,樊莉,朱晓平等.疏肝调神治疗抑郁症的临床研究[J].针刺研究,2006,31：355-35
[14]中华医学会精神科分会.中国精神障碍分类与诊断标准第三版[M].济南：山东科学技术出版社,2001,87-89
[15]国家中医药管理局发布.中医病证诊断疗效标准[M].南京大学出版社出版,1994,7,第1版;20
[16]张宏耕主编.中西医结合精神病学[M].中国中医药出版社.2005,8,第1版,19
[17]周仲瑛主编.中医内科学[M]..中国中医药出版社.第一版,北京,2003,1,393-395
[18]章洪流,王天芳,郭文,等.抑郁症中医证型的近10年文献分析[J].北京中医药大学学报,2005,28(3)：79-81
[19]赵燕,王天芳,于春光,等.抑郁症中医证候及证候要素分布特点的文献研究[J].中医杂志,2006,47(9)：691-693
[20]周玲,陈文垲,梅晓云,等.抑郁症中医证候的群体分布特点及其相关因素研究[J].中国中西医结合杂志,2006,26(2)：106-109.
[21]胡随瑜,张宏耕,郑林,等.1997例抑郁症患者中医不同证候构成比分析[J].中国医师杂志,2003,5(10)：1312-1313.
[22]张海男,胡随瑜,陈泽奇等.抑郁症常见中医证候类型第一轮专家问卷分析[J].湖南医科大学学报,2002.27(6)：519-521
[23]蔡光生,赵玉庸.中西医结合内科学.中国中医药出版社.2005.916-920
[24]王腾云.丹栀逍遥汤加减治疗抑郁症34例[J].中国中西医结合杂志,2001,21(9)：710-711.
[25]张金茹.小柴胡汤治疗抑郁症40例[J].北京中医,2003,22,(5)：38-39.
[26]朱春山.文拉法辛与消遥丸联合治疗抑郁症的疗效观察.中国中西医结合杂志,2002,22(2)：152
[27]陈建冲.逍遥散加味治疗难治性抑郁症18例.黑龙江中医药,2003,(1)：21-22
[28]杜元濒,李桂平,颜红,等.调神疏肝法治疗郁证的临床研究[J].中国针灸,2005,25(3)：151-154.
[29]张春虹,李金波,王舒,等.在德国运用“醒脑开窍法”治疗郁证的临床观察[J].针刺临床杂志,2002,18(8)：6-7
[30]李静.针刺治疗中风后抑郁症67例[J].上海针灸杂志,2005,24(6)：27.
[31]符文彬,樊莉,朱晓平,等.针刺调肝法治疗抑郁性神经症176例疗效观察[J].新中医,2007,39(12)：42-44.
[32]徐世芬,庄礼兴.电针百会印堂对肝郁型抑郁性神经症的影响.现代中西医结合杂志,2010,19(15)：1835—1838
[33]Andrade L, Caraveo-duaga JJ, Berglund P, et al. The epidemiology of major depressive episodes:results from the International Consortium of Psychiatric Epidemiology(ICPE)Surveys[J]. International Journal of Methods in Psychiatric Research, 2003,12:3-21
[34]Kessler RC. Epidemiology of depression in the Asia pacific region[J]. Australasian Psychiatry,2004,12(suppl):4-10
[35]Kessler RC. Epidemiology of women and depression[J]. Journal of Affective Disorders,2003,74:5-13
[36]严和骏,肖世富,陆余芬,等.综合性医院就诊者的心理障碍[J].上海精神医学,1996,8：65-68
[37]余殿飞,谢铜华.战胜人类第一心理杀手：抑郁症的早期认识和有效防治[M].北京：中国医药科技出版社,2001：28
[38]Udziszewska B, Jaworska-Feil L, kajtaM, et al. Antidepressant Drugs inhibit Glucocorticoid receptor-mediated gene transcription-a possible mechanism[J]. BrJ Pharmaco,2000,130(6):1385-1393
[39]Sweeney JA, Kmiec JA, Kupfer DJ. Neuropsychologic impairments in bipolar and unipolar mood disorders on the CANTAB neurocognitive battery. Biol Psychiatry.2000,48:674-684
[40]Airaksinen E, Larsson M, Lundberg I,Forsell Y. Cognitive functions in depressive disorders:evidence from a population based study. Psyehol Med.2004,34:83-91
[41]Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA.1996,93:3908-3913
[42]Videbech p, Ravnkilde B. Hippocampal volume and depression:a meta-analysis of MRI studies. Am J Psychiatry.2004,161:1957-1966
[43]Cheryl A, Frye, JoAnna W. Effect of prenatal stress and gonadal hormone condition on depressive behaviors of female and male rats[J].Hormones and Behavior,2003,44(4): 319-326.
[44]Owen BM, Eceleston D, Ferrier IN, et al. Raised levels of plasma inierleukin-1 βin major and postviral depression[J]. Acta Psychlatrica Scandinavica,2001,103(3): 226-228.
[45]Levine J, Barak Y, Chengappa KN, et al. Cerebrospinalcytokine levels in Patients with acute depression[J]. NeuroPsychobiology,1999,40(4):171-176.
[46]左玲俊,罗星光.抑郁症的防治[M].上海：复旦大学出版社,2001：90.
[47]唐济生,翟静.吗氯贝胺治疗抑郁症双盲对照研究.中国神经精神疾病杂志,2001,27(1)：69-70.
[48]Breen R, Mc Cormac RJ. A fresh look at management of depression, How to choose and use the newer antidepressant drugs. Postgradmed,2002,112(3):25-40.
[49]陈瑞玲,赵志刚.抗抑郁症类药物的临床应用研究进展.中国临床药理学杂志,2007,23(1)：54-57.
[50]赵志刚,张星虎,张石革.当代神经精神科用药选择[M].北京：人民卫生出版社,2003：45-60.
[51]王巍巍,王春晓,高洪丽.抑郁症药物治疗的研究进展,中国实用医药,2008,3(17)：211-212.
[52]Sanz EJ, De-las-Cuevas C, Kiuru A, Bate A, Edwards R. Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome:a database analysis. Lancet,2005,365:482-487.
[53]Burt T, Lisanby SH, Sackeim HA. Neuropsychiatric applications of transcranial magnetic stimulation:a meta analysis. Int J Neuropsychopharmacol,2002,5:73-103.
[54]Shajahan PM, Glabus MF, Steele JD, et al. Left dorso-lateral repetitive transcranial magnetic stimulation affects cortical excitability and functional connectivity, but does not impair cognition in major depression. ProgNeuropsychopharmacol Biol Psychiatry, 2002,26:945-954.
[55]Dwork AJ, Arango V, Underwood M, et al. Absence of histological lesions in primate models of ECT and magnetic seizure therapy. Am J Psychiatry,2004,161:57.
[56]Kosel M, Friek C, Lisanby SH, Fiseh HU, et al. Magnetic seizure therapy improves mood in refractory major depression. Neuropsychopharmacology,2003,28:2045-2048.
[57]Lisanby SH, Moserip T, Morales 0, et al. Neurophysiological characterization of magnetic seizure therapy(MST) in non-human primates. Suppl Clin Neurophysiol,2003, 56:81-99.
[58]UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders:a systematic review and meta analysis. Lancet,2003,361:799-808. [59]Sackeim HA, Haskett RF, Mulsant BH, et al. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy:a randomized controlled trial. JAMA,2001,285:1299-1307.
[60]White AR, Emst E. A systematic review of randomized controlled trials of acupuncture for neck pain[J]. Rheumatology,1999,38(2):143-147.
[61]刘鸣.系统评价、Meta-分析设计与实施方法[M].人民卫生出版社,北京,2011,68-70.
[62]Higgins JPT, Green S, Eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1. The Cochrane Collaboration 2008.
[63]Allen J, Schnyer RN, HittSK. The efficacy of acupuncture in the treatment of major depression in women[J]. Psychol Sci,1998,9(5):397-401.
[64]Allen J, Schnyer RN, Chambers AS, et al. Acupuncture for depression a randomized controlled trial[J].J Clin Psychiatry,2006,67(11):1665-1673.
[65]樊莉,符文彬,蒙昌荣,等.应用汉密顿抑郁量表评估正穴位与非穴位针治疗抑郁性神经症的疗效[J].中国临床康复,2005,9(28)：14-16.
[66]罗和春,Urei1H,沈渔邨,等.电针与氟西汀治疗抑郁症疗效的对照研究[J].中华精神科杂志,2003,36(4)：215-219.
[67]符文彬,樊莉,朱晓平,等.针刺调肝法治疗抑郁性神经症的临床研究[J].针刺研究,2006,31(6)：355-358.
[68]李颖文.针刺治疗抑郁性神经症的临床研究[D].广州：广州中医药大学学位论文,2005.
[69]Eich H, Agelink MW, Lehman E, Lemmer W, Kliesser E. Acupuncture in patients with minor depression or generalized anxiety disorders-results of a randomized study. Fortschritte Der Neurologie Psychiatrie 2000:68:137-44.
[70]Whiting M, Leavey G, Scammell A, Au S, King M. Using acupuncture to treat depression: a feasibility study. Complementary Therapies in Medicine 2008:16:87-91.
[71]Carmen A, Ronald MG, Chetachi AE, et al. Acupuncture for the treatment of major depressive disorder:A Randomaied controlled trial. J Clin Psychiatry,2011,72 (8): 1129-1135.
[72]Wing-Fai Yeung, BCM, Ka-Fai Chung, et al. Electroacupuncture for Residual Insomnia Associated with Major Depressive Disorder:A Randomized Controlled Trial. Sleep,2011, 34(6):807-900.
[73]Yeung A, Mischoulon D, Alpert J, et al. Acupuncture for major depressive disorder: has its efficacy been disproved[J]. J Clin Psychiatry,2007,68 (10):1617-1618.
[74]Park J, White A, Stevinson C, Ernst E, James M:Validating a new non-penetrating sham acupuncture device:two randomised controlled trials. Acupunct Med 2002, 20(4):168-174.
[75]杨维杰.针灸五输穴应用.世界图书出版公司.1993.
[76]王葳,李坤成,单保慈,等.针刺正常老年人“四关穴”的脑功能MRI研究.中国医学影像技术,2006,22(6)：829-832.
[77]刘永源,陈杰辉.四关穴临床应用概况[J].针灸临床杂志,2003,19(4)：56.
[78]王宁宁,陈俊琦,江晓宇,等.针灸治疗原发性抑郁症取穴规律的文献分析.中医杂志,2011,52(24)：2132-2133.
[79]孙畅,黄东勉,曾令友.针刺治疗抑郁症64例临床观察.中国康复理论与实践.2007,13(12)：1186.
[80]Spiker B. Clinical trials come of age:the development of clinical trial methodology since 1945 has been remarkable. DN&P,1993,6:22.
[81]Park J, White AD, Lee H, et al. Development of a new sham needle. Acupuncture in Medicine,1999,17:110.
[82]张宏伟,唐金陵.针灸临床试验中安慰针的设计与选用. 中国中西医结合杂志.2003,23(4)：247-249.
[83]Marwich C. Acceptance of some acupuncture application. JAMA.1997,278:1725.
[84]刘慧林,张琰,李敬道,等.针灸临床研究安慰对照方法的设计与实践.中国循证医学杂志.2008,8(12)：1133-1135.
[85]Streitberger K.一种用于针刺研究的新安慰法[J].沈嘉怡摘译. 国外医学中医中药分册,2000,22(5)：316.
[86]Kong J, Ma L, Gollub R L, et al. A pilot study of functional magnetic resonance imaging of the brain during manual and electroacupuncture stimulation of acupuncture point (LI-4 Hegu)in normal subjects reveals differential brain activation between methods. J Altern Compl Med,2002,8(4):411-419.
[87]Zald DH. The human amygdale and the emotional evaluation of sensory stimuli. Brain Res Rev,2003,41(1):88-123.
[88]Kathleen H, Liu J. The integrated response of the human cerebro-cerebellar and limbic systems to acupuncture stimulation at ST36 as evidenced by fMR. Neuroimage,2005, 27(3):479-496.
[89]Vogt B A. Pain and Emotion interaction in subregions of the cingulated gyrus, focus on pain. Nat Rev Neurosci,2005,6(7):533-544.
[90]王丽,章军建,刘涛.PKA-cREB信号转导通路在大鼠慢性脑缺血所致认知功能障碍中的作用.中国临床神经科学,2006,14(5)：449—452.
[91]Tardito D, Perez J, Tiraboschi E, et al. Signaling pathways regulating gene expression, neuroplasticity, and neurotrophic mechanisms in the action of antidepressants: a critical overview. Pharmacol Rev,2006,58:115-134.
[92]Carlezon WA Jr, Duman RS, Nestler EJ. The many faces of CREB. Trends Neurosci,2005,28:436-445.
[93]Shelton R C. Cellular mechanisms in the vulnerability to depression and response to antidepressants. Psychiatr Clin North Am,2000,23:713-729.
[94]Nestler EJ, Terwilliger RZ, Duman RS. Chronic antidepressant administration alters the subcellular distribution of cyclic AMP-dependent protein kinase in rat frontal cortex. J Neurochem,1989,53:1644-1647.
[95]Solomon DA, Keller MB, Leon AC, et al. Multiple recurrences of major depressive disorder[J]. Am J Psychiatry,2000,157(2):229-233.
[96]韩明飞,高东,孙学礼.应激抑郁动物模型的建立与评价[J].华西医学,2008,23(4)：901-902.
[97]秦琴,刘利学.抑郁症动物模型概述及评价[J].实验动物科学,2010,27(1)：53-59.
[98]Katz RJ, Roth K A, Carroll B J, et al. Acute and chronic stress effects on open field activity in the rat:Implications for a model of depression[J]. Neurosci Biobehav Rev, 1981,5(2):247.
[99]Willner P. Validation criteria for animal models of human mental depression:learned helpless aparadigra case[J]. Psychopharmacology,1985,85(4):387-404.
[100]Willner P, Muscat R, Papp M. Chronic mild stress-induced anhedonia:arealistic animal model of depression[J]. Neurosci Biobehav Rev,1992,16(4):525-534.
[101]Willner P. Validity, reliability and utility of the chronic mild stress model of depression:a 10-year review and evaluation[J]. Psychopharmacology,1997,134(4): 319-329.
[102]McEwen BS, Magarinos AM. Stress and hippocampal plasticity:implications for the pathophysiology of affective disorders [J]. Hum Psychopharmacol.,2001,16(S1):S7-S19.
[103]Schulte-Herbruggen 0, Hellweg R, Chourbaji S, et al. Differential regulation of neurotrophins and serotonergic function in mice with genetically reduced glucocorticoid receptor expression [J]. Exp Neurol,2007,204(1):307-316.
[104]宓轶群,陈一.四关穴为主治疗脑卒中后抑郁证的对照分析[J].中国临床康复,2003,7(31) ： 4250.
[105]俞红五,朱才丰,陈颖.开四关加人中针刺治疗中风后抑郁状态32例[J].中医药临床杂志,2007,19(3)：245.
[106]严德庆.四关穴治疗癔病选案.针灸临床杂志,1999,15(11)：44-45
[107]符文彬,樊莉,朱晓平，等.Depressive Neurosis Treated by Acupuncture for Regulating the Liver-A Report of 176 Cases. Journal of Traditional Chinese Medicine, 2009,29(2):83-86.
[108]符文彬刘健华 白艳甫,等.电针对抑郁症大鼠海马CREB-BDNF受体后信号转导通路的作用.中国老年学杂志,2009,29(23)：3038-3042.
[109]徐叔云.药理实验方法学,北京：人民卫生出版社,1994：641.
[110]郭德玉,陈铁玉,李斌,等.不同年龄大鼠学习一记忆能力及旷场行为比较.中国实验动物学报,1998,6：19-23.
[111]Willner P. Validity, reliability and utility of the chronic mild stress model of depression:a 10-year review and evaluation[J]. Psychopharmacology,1997,134(4): 319-329.
[112]Harro J, Tonissaar M, Eller M, et al. Chronic variable stress and partial 5-HT denervation by parachloroamphetamine treatment in the rat:effects on behavior and monoamine neurochemistry. Brain Research,2001,899:227-239.
[113]Naranjoa CA, Tremblaye LK, Bustob UE. The role of the brain reward system in depression. Progress in Neuro-Psychopharmacology and Biological psychiatry,2001, 25(4):781-823.
[114]Gronli J, Murison R, Bjorvatn B, et al. Chronic mild stress affects sucrose intake and sleep in rats. Behavioral Brain Research,2004,150(1-2):139-147.
[115]Duman RS, Malberg J, Nakagawa S, D'Sa. CNeuronal plasticity and survival in mood disorders. Biol Psychiatry,2000,46:1181-1191.
[116]Ozawa H, Rasenick MM. Chronic electroconvulsive treatment augments coupling of the GTP-binding protein Gs to the catalytic moiety of adenylyl cyclase in a manner similar to that seen with chronic antidepressant drugs. J Neurochem.1991,56:330-338.
[117]Nestler EJ, Terwilliger RZ, Duman RS. Chronic antidepressant administration alters the subcellular distribution of cyclic AMP dependent protein kinase in rat frontal cortex. J Neurochem.1989,53:1644-1647.
[118]Tronson NC, Schrick C, Fischer A, et al. Regulatory mechanisms of fear extinction and depression-like behavior. Neuropsychopharmacology.2008,33(7):1570-83.
[119]时宇静,卢峻,贾宝辉,等.电针对抑郁模型大鼠糖水摄人量和性行为的影响及机理研究。针刺研究,2006；31(1)：27-30.
[120]孙华,张有志,韩毳,等.电针对慢性应激抑郁模型大鼠大脑皮层5-HT1和5-HT2受体 数量和结合活性的影响[J].中国针灸,2003,23(9)：553-555.
[121]李晓白,黄继忠,王祖承.抑郁症与谷氨酸传导[J].中国新药与临床杂志,2005,24：601-604.
[122]陈运平, 孙圣刚,梅元武,等.低频重复经颅磁刺激对抑郁模型大鼠游泳及海马内氨基酸递质的影响[J].中华物理医学与康复杂志,2006,28(8)：507-509.
[123]刘海静,何新芳,陈兴华.针刺对抑郁模型大鼠行为学及海马氨基酸类神经递质的影响。医学研究杂志,2010,39(3)：79-81
[124]Hyunyoung Kim, Hyun-Jung Park, Hyun Soo Shim, et al. The effects of acupuncture (PC6) on chronic mild stress-induced memory loss. Neuroscience Letters 488 (2011) 225-228.
[125]Bombi Lee, Insop Shim, Hye-Jung Lee, et al. Effects of acupuncture on chronic corticosterone-induced depression-like behavior and expression of neuropeptide Y in the rats. Neuroscience Letters.453 (2009) 151-156
[126]钱瑞琴,张春英,杨宇,等.电针与舒血宁联合治疗抑郁症患者免疫功能的影响[J].中国实验方剂学杂志,2001,7(3)：56.
[127]Wachtel H. The second-messenger dysbalance hypothesis of affective disorders[J]. Pharm copsychiatry,1990,17:1.
[128]Perez J, Tardito D,MoriS, et al. Abnormalities of cAMP signaling in affective disorders:implication for pathophysiology and treatment. Bipolar Disoul,2000,2:27-36.
[129]Duman R.. Novel therapeutic approaches beyond the serotonin receptor. Biol Psychiatry,1998,44:324-335.
[130]Donati RJ, Rasenick MM. G Protein signaling and the molecular basis of antidepressant action.LifeSci,2003,73:1-17
[131]孙健,刘健华,王谦,等.电针对抑郁症大鼠海马组织AC-cAMP-PKA信号通路的影响.中国老年学杂志2010,12(30)：3672-3673.
[132]张敏,图娅。电针对慢性应激抑郁模型大鼠学习记忆行为的影响。中医研究。2008,21(3)：15-17
[133]李丽萍,毕颖。针灸对慢性应激抑郁模型大鼠环核苷酸的影响。中华中医药学刊。2008；26(12)：2742
[134]罗文舒,皮敏,饶晓丹,等.针刺督脉和膀胱经促进抑郁症大鼠海马神经元再生的实验研究.广西中医药.2008,31(4)：46-48.
[135]van Wingen GA, van Eijndhoven P, Tendolkar I, et al. Neural basis of emotion recognition deficits in first-episode major depression. Psychol Med.2010 Nov 8:1-9.
[136]Mayberg HS, Brannan SK, Mahurin RK, et al. (21ingulate function in depression: a potential predictor oftreatment response[J]. Neuroreport,1997,8:1057-1061
[137]Videbech P MRI finding in patients with affective disorder:ameta-analysis [J]. Acta PsychiatrSeand,1997,96:157-168.
[138]Georgge MS, Ketter TA. Pose RM. SPECT and PET imaging in mood dizorder[J]. J Clin Psychiatry.1993,54:6
[139]Konarski JZ, Kennedy SH, Mclntyre RS, et al. Relationship between regional brain metabolism,illness severity an d age in depressed subjects[J]. Psychiatry Res,2007, 155(3):203-210.
[140]Veena Kumari MT. Mittersehiffthaler JD, Teasdale GS, et al. Neural abnormalities during cognitive generation of affect in Treatment-Resistant Depression[J]. Biol Psychiatry,2003,54(8):777-791.
[141]Mayberg HS. Modulating dysfunctional limbic-cortical circuits in depression:towards development of brain-based algorithms for diagnosis and optimized treatment [J]. Br Med Bull,2003,65(1):193-207.
[142]冯正直,张大均.抑郁与脑血流量和葡萄糖代谢的研究进展[J].中国行为医学科学,2002,(11)：354-355
[150]Dequervain D J, Roozendaa I B, McGaugh J L. Stress and glucocorticoids impair retrieval of long term spatial memory [J]. Nature,1998,394 (12):787.
[151]符文彬,刘健华,白艳甫,等。电针对抑郁症大鼠海马CREB-BDNF受体后信号转导通路的作用。中国老年学杂志。2009,12(29)：3038-3040.
[152]Wong ML, Licinio J. Nat from monamines to genomic targets:a paradigm shift for drug discovery in depression [J]. Rev Drug Discov,2004,3(2):136-151.
[153]Kempermann G. Regulation of adult hippocampal neurogenesis-implications for novel theories of major depression[J]. Bipolar Disord,2002,4:17-33.
[154]Benninghoff J, Schmitt A, Mossner R, et al. When cells become depressed:focus on neuralstemcells in novel treatment strategies against depression [J]. J Neural Transm,2002,109:947-962.
[155]罗文舒,皮敏,饶晓丹,等。针刺督脉和膀胱经促进抑郁症大鼠海马神经元再生的实验研究。广西中医药。2008,31(4)：45-47.
[156]Qiong Liu, Jin Yu, Wen-Li Mi, et al. Electroacupuncture attenuates the decrease of hippocampal progenitor cell proliferation in the adult rats exposed to chronic unpredictable stress. Life Sciences 81 (2007):1489-1495.
[157]徐世芬,庄礼兴,唐纯志.针刺对抑郁大鼠海马神经因子表达的影响[J].广州中医药大学学报,2009,26(6)：532-534.
[158]FOSSATI P, RADTCH A, BOYER P. Neuroplasticity:from MRI to depressive symptoms. Eur Neuropsychopharmacol.2004;15:s503-s510.
[159]Cotter D, Mackay D, Chana G, Beasley C, Landau S, Everall IP. Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Cereb Cortex.2002,12:386-394.
[160]Rajkowska G, Halaris A, Selemon LD. Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder. Biol Psychiatry.2001,49:741-752.
[161]Webster MJ, Knable MB, Johnston-Wilson N, Nagata K, Inagaki M, YolkenRH. Immunohistochemical localization of phosphorylated glial fibrillary acidic protein in the prefrontal cortex and hippocampus from patients with schizophrenia, bipolar disorder, and depression. Brain Behav Immun.2001,15:388-400.
[162]Johnston-Wilson NL, Sims CD, Hofmann JP, Anderson L, Shore AD, Torrey EF, Yolken RH. Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium. Mol Psychiatry.2000,5:142-149.
[163]Si X, Miguel-Hidalgo JJ,O'Dwyer G, Stockmeier CA, Rajkowska G Age-dependent reductions in the level of glial fibrillary acidic protein in the prefrontal cortex in major depression. Neuropsychopharmacology.2004,29:2088-2096.
[164]Banasr M, Duman R S. Glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors. Biol Psychiatry,2008,64:863-70.
[165]Qiong Liu, Bing Li, Hai-Yan Zhu, et al. Glia atrophy in the hippocampus of chronic unpredictable stress-induced depression model rats is reversed by electroacupuncture treatment. Journal of Affective Disorders.2011,128:309-313.
[166]胡旺平,张健,胡圣望,等.电针对慢性应激所致大鼠空间学习记忆障碍及海马胆碱能功能的影响[J].辽宁中医杂志.2003,30(3)；215-216.
[167]胡旺平,胡圣望,化长林,等.电针对慢性应激大鼠空间学习记忆能力的影响[J].山东中医杂志,2003,22(5)；300-301.
[168]刘建平.随机对照试验的依从性和意向性治疗分析[J].中国中西医结合杂志,2003,23(12)：884-886.