| Objective1、To evaluate the clinical efficacy of "soothing the liver and regulating the mind"integrated acupuncture in the treatment of moderate depressive disorder(MDD)through a randomized controlled trial.2、The neurocognitive paradigm emotional go/n o-go(AGN)paradigm was used to evaluate the effect of integrated acupuncture on the emotional cognitive function of patients with moderate depressive disorder.3、The seed point based functional connectivity analysis method was used to evaluate the effect of integrated acupuncture and moxibustion on the whole brain connectivity of CEN,DMN and SN central nodes in patients with moderate depression.Methods1 Study 1:Efficacy of the Integrative Acupuncture and Moxibustion Treatment in Patients With Major Depressive Disorder:a Multicenter,Single-Blinded,Randomized Trial in ChinaFrom November 2020 to April 2022,subjects with moderate depressive disorder aged 18 to 65 were recruited from 4 centers,including the Second Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine,Hainan Hospital of Traditional Chinese Medicine,the First Affiliated Hospital of Guangxi University of Traditional Chinese Medicine and Shenzhen Bao’an Hospital(Group)of Traditional Chinese Medicine.A total of 154 patients with MDD with moderate symptoms were recruited and randomly assigned with a ratio of 2:2:2:1 into 4 groups:an active integrative acupuncture and moxibustion treatment protocol and sertraline(hereafter referred to as combined treatment group),an active integrative acupuncture and moxibustion treatment protocol and placebo(ie,iAM-only group),a sham integrative acupuncture and moxibustion treatment protocol and sertraline(ie,sertraline-only group),and a sham integrative acupuncture and moxibustion treatment protocol and placebo(ie,placebo group).1.1 Interventions1.1.1 Integrated acupuncture and moxibustion protocol①Point selection:a Acupuncture:Baihui,Yintang,Touwei(Shuang),Jiuwei,Zhongwan,Qihai,Taichong(Shuang),Hegu(Shuang),Sanyinjiao(Shuang);b.Fine moxibustion:alternate use of bilateral Feishu,Geshu,Danshu,Yongquan and bilateral Pohu,Geguan,Yanggang and Yongquan;c.Ear acupuncture points:the left and right ears of the heart,liver and kidney are used alternately.②Operation:a Acupuncture:φ,zero point two five ×25 mm acupuncture needle tube needle insertion method,acupuncture Taichong,Hegu,Sanyinjiao,Baihui,Yintang,Touwei φ 0.22 mm × The 40 mm acupuncture needle tube is used for needling Jiuwei,Zhongwan and Qihai,and the needling is conducted to get Qi and the needle is kept for 30 minutes.b.Fine moxibustion:fix the acupoints and place them with a diameter of 2 mm after applying kaleidoscope oil × The 3 mm high moxa cone is ignited with incense sticks.After burning two-thirds of the moxa cone,it is pinched away.Each hole is 2 strong.c.Ear acupuncture:point fixing,disinfection φ zero point two zero × 0.6 mm disposable sterile press needle,which is stuck and fixed with tweezers.1.1.2 Sham acupuncture protocol①Point selection:the same as the integrated acupuncture scheme.② Operation:a Comfort acupuncture:Taichong,Hegu,Sanyinjiao,Baihui,Yintang,Touwei and Jiuwei φzero point four zero × 25 mm flat head needle,the needle insertion method does not penetrate the skin,and the needle is used in Zhongwan and Qihai φ 0.40 mm × 40 mm flat head needle,the needle insertion method does not penetrate the skin.The rest processes are the same as the integrated acupuncture scheme.b.Moxibustion with soothing essence:Fix the acupoints,completely soak the moxa cone with kaleidoscope oil,and only light the moxa cone instead of lighting it.Each acupoint is 2 strong.c.Ear comforting needle:set the acupoints,sterilize,use the comfort press needle(no needle inside),and hold the tweezers to paste and fix.1.1.3 Drug protocolSertraline hydrochloride tablets,the first-line antidepressant,were taken by oral administration of 50 mg sertraline hydrochloride tablets immediately after breakfast every day.1.1.4 Placebo protocolThe placebo tablets with starch preparation have the same appearance as sertraline hydrochloride tablets,and the administration method and dosage are the same as the drug scheme.1.2 CourseIntegrated acupuncture or comfort acupuncture treatment is performed 3 times a week,with an interval of ≥ 24 hours,for 12 consecutive weeks,a total of 36 times;Take medicine or placebo once a day for 12 consecutive weeks.The effective case is 80%of the treatment course(≥ 29 times of treatment).1.3 Evaluation time and index:Evaluation time:5 evaluations were conducted before treatment,at the end of the 4th week,the 8th week,the 12th week,and the 20th week(follow-up).MAIN OUTCOME MEASURES:At the end of treatment(the 12th weekend),the total score of Hamilton Depression Scale-17(HAMD-17)and the change value of baseline level.Secondary outcome measures:① change in total score of HAMD-17 scale at each time point after treatment.② change in score of PHQ-9 scale,③ change in score of five dimension factors of H AMD17 scale,and ④ change in response rate(the percentage of cases whose total score of HAMD-17 is reduced by 50%or more than the baseline level).Other indicators:liver and kidney function test indicators before and after treatment,and adverse event/reaction records during treatment for safety evaluation.2 Study 2:Study of integrated acupuncture and moxibustion on emotional cognitive control of MDD2.1 Part 1 Characteristics of emotional cognitive control in MDDFrom May 2021 to January 2022,subjects with moderate depressive disorder aged 1865 were recruited from Guangdong Hospital of Traditional Chinese Medicine,and healthy subjects aged 18-65 were recruited from medical students,hospital staff and the society of Guangzhou University of Traditional Chinese Medicine.A total of 38 healthy subjects and 44 patients with moderate depressive disorder were included.Index collection:All subjects conducted the AGN cognitive psychology paradigm experiment to obtain task behavior indicators,including the rate of missing reports(MA),false reports(FA)and response time(RT).To evaluate the cognitive responses of patients with moderate MDD under different emotional stimuli.2.2 Part 2 Effect of integrated acupuncture and moxibustion on emotional cognitive control of MDDThe subjects were from patients with moderate depressive disorder recruited in the Second Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine in Study One,and the trial group was the same as that in Clinical Study One.Indicator collection:AGN psychological cognitive paradigm experiment was conducted at two time points before and after treatment(the 12th weekend),and cognitive behavior indicators(including MA,FA and RT)of subjects were collected.To evaluate the effect of integrated acupuncture on emotional cognitive control in patients with moderate MDD.3 Study 3:Effect of integrated acupuncture and moxibustion on the whole brain functional connectivity of hub nodes of CEN,DMN and SN in MDD3.1 Part 1 The characteristics of whole brain connectivity of hub nodes of CEN,DMN and SN in MDDThe source of the subjects is the same as that of trial 1 in study 2.Index collection:functional magnetic resonance imaging(fMRI)was performed on all subjects,BOLD sequences of subjects in the resting state with eyes closed were collected,and the central nodes of the executive control network(CEN),default network(DMN)and highlight network(SN)were selected as the regions of interest(ROIs)based on seed point correlation analysis,including:dorsal lateral prefrontal lobe(DLPFC),ventrolateral prefrontal lobe(VLPFC),medial prefrontal lobe(MPFC)The anterior cingulate cortex(ACC),the lateral parietal lobe(LP).the posterior cingulate cortex(PCC)and the anterior insula(AI)were used to construct the whole brain connection model.To explore the characteristics of the whole brain connectivity of CEN,DMN and SN in patients with moderate MDD.3.2 Part 2 Effect of Integrated Acupuncture and Moxibustion on the Whole Brain Functional Connection of hub nodes of CEN.DMN and SN in MDDThe subjects were from patients with moderate depressive disorder recruited in the Second Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine in Study One,and the trial group was the same as that in Clinical Study One.Index collection:fMRI was performed at two time points before and after treatment(at the end of the 12th week of treatment).BOLD sequences of subjects were collected with eyes closed and at rest.Based on the results of experiment 1,different seed points were selected to construct functional connections of the whole brain.To evaluate the effect of integrated acupuncture and moxibustion of "soothing the liver and regulating the mind" on the different functional connections of central nodes in the whole brain in patients with moderate MDD.Results1.Study 1:1.1 Baseline resultsA total of 154 patients were included,including 28 patients who fell off or deviated from the plan during treatment(due to insufficient treatment times due to epidemic situation and other reasons),28 patients who fell off during follow-up,126 patients who completed 80%of the course of treatment,and 98 patients who completed treatment and follow-up.154 cases were included in the full data set(FAS)analysis,including 43 cases in the combined treatment group,44 cases in iAM-only group,45 cases in sertraline-only group,and 22 cases in placebo group.There was no difference between the four groups in baseline general population data,HAMD-17,PHQ-9 scale scores(P>0.05),and the four groups were comparable before treatment.Ninety eight patients were included in the PPS for sensitivity analysis of major outcome indicators and differences between follow-up groups.1.2 Primary outcome:Comparison of changes in HAMD from baseline to the end of the 12th week of treatment.Intra group comparison:HAMD scores of the four groups were lower than the baseline level(all P<0.001).Comparison between groups:The reduction level of HAMD in the iAM-only group was better than that in the sertraline-only group and the placebo group(P=0.007 and P=0.006).There was no statistical difference between the other the two groups in the four groups(both P>0.05),and the results of sensitivity analysis were consistent.1.3 Secondary outcome measures1.3.1 HAMD-17 scoreOverall analysis of repeated measurement:grouping,time and interaction effects were significant(P<0.01).The scores of the four groups decreased with the increase of time,and the difference between the groups was more obvious with the increase of time.Intra group comparison:all time points after treatment in the four groups decreased compared with the baseline period(all P<0.001).Comparison between groups:At the 8th.12th and 20th weekend,the HAMD-17 score in the iAM-only group was lower than that in the sertraline-only group(all P<0.01),and at the 12th and 20th weekend,it was lower than that in the placebo group(all P<0.01).The sensitivity analysis was consistent.At the end of the 8th week,the HAMD-17 score of combined treatment group was lower than that of the sertraline-only group(P=0.003).and the sensitivity analysis showed that it was lower than that of the sertraline-only group at the end of the 20th week(P=0.019).There was no significant difference between the two groups in the four groups at the other each time point after treatment(all P>0.05).1.3.2 PHQ-9 scoreOverall analysis of repeated measurement:time,time*grouping interaction effect was significant(all P<0.001).The scores of the four groups decreased with time,and there was a trend of difference with time.Intra group comparison:all time points after treatment in the four groups decreased compared with the baseline period(all P<0.001).Comparison between groups:At the end of the 20th week,the PHQ-9 score of the iAMonly group was lower than that of the sertraline-only group(P=0.030),and the sensitivity analysis showed that it was lower than that of the sertraline-only group at the end of the 12th and 20th weeks(both P<0.05).There was no significant difference between the other two groups in the four groups at the other each time point after treatment(all P>0.05).1.3.3 HAMD-17 Scale 5 Dimension Factor ScoresOverall analysis of repeated measurement:the time effect of each factor was significant,and the scores decreased with time(all P<0.05).Among them,block,sleep disorder factor grouping effect and time*grouping effect are significant,and the difference between groups is greater with time(both P<0.05).The time*grouping effect of anxiety/somatization factor was significant,and there was an inter group difference with time(P=0.001).The other grouping effect and the interaction effect of time*grouping were not significant(both P>0.05).Intra group comparison:The scores of anxiety/somatization,cognition,block and sleep disorder factors in the four groups at each time point were lower than those in the baseline period(all P<0.05).Body weight factor score:the score of the iAM-only group at the 8th and 12th weekend of treatment was lower than that of the baseline period(both P<0.05);The scores of the sertraline-only group at the end of the 20th week were lower than those of the baseline period(P<0.05);There was no statistical difference between the scores of other time points after treatment and the baseline period in both combined treatment group and placebo group(all P>0.05).Inter group comparison:inter group comparison of each factor at each time point after treatment.Anxiety/somatization:At the 12th and 20th weekend of treatment,the score of the iAMonly group was lower than that of the sertraline-only group(all P<0.05),and there was no difference between the other two groups in four groups at each time point after treatment(all P>0.05).Cognition:At the 8th and 20th weekend of treatment,the score of the iAM-only group was lower than that of the sertraline-only group(P = 0.025 and 0.016 respectively);At the 8th weekend of treatment,the score of combined treatment group was lower than that of the sertraline-only group(P=0.037);There was no difference between the other two groups in four groups at each time point after treatment(all P>0.05).Block:At the 8th and 20th weekend of treatment,the score of the iAM-only group was lower than that of the sertraline-only group(P=0.016 and 0.032 respectively);At the end of the 8th week,the score of the combined treatment group was lower than that of the sertralineonly group(P=0.005);There was no difference between the other two groups in four groups at each time point after treatment(all P>0.05).Sleep disorder:At the 8th,12th and 20th weekend of treatment,the score of the iAMonly group was lower than that of the sertraline-only group(P=0.035,0.044 and 0.001 respectively);At the end of the 20th week,the score of the iAM-only group was lower than that of the placebo group(P=0.008);There was no difference between the other two groups in four groups at each time point after treatment(all P>0.05).Body weight:there was no difference between groups at each time point after treatment(all P>0.05).1.3.4 Inter group comparison of response rate of HAMD-17 scaleOverall analysis of repeated measurements:the response rates of the four groups increased with time(time effect P<0.001),and there was a difference in the response rates between groups(grouping effect P=0.006),but the difference trend did not change significantly with time(time and grouping interaction effect P=0.660).Comparison between groups:At the 8th week of treatment,the response rate of 55.81%in the combined treatment group and 56.82%in the iAM-only group were both higher than that of 24.44%in the sertraline-only group(all P<0.05),and there was no statistical difference between the other two groups in four groups(all P>0.05).At the 12th and 20th weekend of treatment,there were differences between the four groups(P=0.040 and P=0.024),but there was no statistical difference after further analysis and correction(both P>0.05).1.4 Adverse events/reactionsThere were 6 cases of adverse reactions related to taking western medicine and 1 case of adverse reactions related to acupuncture,which can be continued.No clinical abnormality was found in liver and kidney function indexes.2 Study 2:2.1 Part 1A total of 44 patients(32 women)with moderate MDD were enrolled,with an average age of 27.7 ± 6.89;38 healthy subjects(21 females),average age 26.37 ± 2.80.There was comparability between the two groups(P>0.05).The AGN paradigm of healthy people was completely collected,and the AGN paradigm data of patients with moderate MDD were excluded in one case(did not follow the task instructions).The results of inter group comparison showed that:compared with the healthy group,the MR of MDD patients to happy stimuli increased(P=0.041);RT of neutral information was significantly prolonged(P=0.030).Specifically,RT of neutral information was prolonged under the stimulus of fear and sadness distraction(P was 0.020 and 0.022 respectively).There was no difference between groups in the behavioral indicators under the stimulus of residual information(emotional and neutral)(all P>0.05).2.2 Part 2There were 48 cases of AGN task experiment before and after treatment,and 3 cases of kicking did not follow the task instructions.A total of 45 cases were included for analysis.There were 14 cases in the acupuncture and medicine group,14 cases in the acupuncture and moxibustion group,8 cases in the western medicine group,and 9 cases in the comfort group.There was no difference between groups at the baseline of each index(all P>0.05),which was comparable.The results show that:MR:a.the Intra group comparison:in the iAM-only group,the MR of MDD to anger stimulation was decreased(P=0.021),and the MR of other information stimulation did not change significantly(all P>0.05).The other groups had no significant changes in MR of each information stimulus after treatment(all P>0.05).b.The difference-value between before and after treatment:there was no difference between groups(all P>0.05).FA:the Intra group comparison:In the combined treatment group,FA of MDD to fear stimuli were increased significantly(P=0.038).In placebo group,the FA of MDD to neutral information were increased(P=0.007),and for the aspect of specific emotions,the FA to neutral information under the stimulation of fear and sadness goals were increased(P=0.027 and 0.014 respectively).The rest had no significant change(all P>0.05).b.Inter group comparison of difference before and after treatment:There was an inter group difference in FA of total neutral stimulation(P=0.026),but there was no statistical difference after correction(both P>0.05).Specifically,the neutral information FA under fear target stimulation decreased after treatment in the iAM-only group and increased in the placebo group(P=0.008,the iAM-only group[-0.110(-0.220,0.028)],placebo group[0.110(0.000,0.665)]).The FA to neutral information under the stimulation of sad target had no significant change after treatment in the western medicine group,but increased after treatment in the placebo group(P=0.010,the sertraline-only group[0.000(-0.110,0.000)],and the placebo group[0.110(0.055,0.165)]).There was no difference in FA stimulated by other information between groups(all P>0.05).RT:the Intra group comparison:After treatment,RT to total emotional stimulation of MDD in the iAM-only group were reduced(P=0.049).For specific emotions,RT to fear stimulus was reduced(P=0.026);RT to the neutral information under the stimulation of sadness distraction was reduced(P=0.024).In the sertraline-only group,the RT to total neutral stimulation was increased(P=0.031).For specific emotions,the RT to neutral information under the stimulation of anger was increase(P=0.033).The other groups had no significant change in RT to information stimulus after treatment(all P>0.05).b.Inter group comparison of difference before and after treatment:For RT to total neutral information.there was an inter group difference between the four groups before and after treatment(all P>0.05).and there was no difference between the two groups in four groups after further comparison and correction(all P>0.05).3 Study 33.1 Part 1The fMRI examination and collection of 38 healthy people were complete.In 43 patients with moderate MDD,fMRI was missing in data transmission in 1 case.RS-FCs analysis based on seed points:compared with healthy people,the functional connectivity of left posterior cingulate gyrus and right forebrain island in patients with moderate MDD changed.Among them,the RS-FC of left posterior cingulate gyrus and right hippocampus was enhanced(P<0.05);The RS-FC of right anterior insula and right putamen decreased(P<0.05).3.2 Part 2fMRI was performed in 46 cases before and after treatment,including 12 cases in the acupuncture and medicine group,16 cases in the acupuncture and moxibustion group,9 cases in the western medicine group,and 9 cases in the comfort group.Seed point based RS-FCs analysis:After treatment in the iAM-only group,the RS-FC between the right ventral anterior insula and the right anterior cuneiform lobe(posterior)of patients with moderate MDD was enhanced(P<0.05),and the whole brain functional connection with the left posterior cingulate gyrus as the seed point had no significant change(P>0.05).After treatment in the sertraline-only group,the RS FCs of left posterior cingulate gyrus,right anterior cuneiform lobe(posterior)and left cuneiform lobe in patients with moderate MDD were enhanced(P<0.05),and there was no significant change in the whole brain functional connectivity with the right forebrain island as the seed point(P>0.05).After treatment in combined treatment group,the RS-FC of the left posterior cingulate gyrus and the right anterior cuneiform lobe(anterior/posterior DMN)in patients with moderate MDD decreased significantly(P<0.05),and the whole brain functional connectivity with the right forebrain island as the seed point did not change significantly(P>0.05).After treatment in the placebo group,the RS-FC of left posterior cingulate gyrus and right inferior occipital gyrus in patients with moderate MDD decreased,and the RS-FCs of right anterior central gyrus,right posterior central gyrus(right superior marginal gyrus),and right posterior central gyrus(right central sulcus cover)increased(P<0.05);The RS-FCs from the right anterior insula to the left fusiform gyrus and left cuneiform lobe decreased(P<0.05).Conclusion1、The integrated acupuncture and moxibustion treatment protocol improved the total score of HAMD-17,factor scores of all dimensions,and PHQ-9 scale scores of moderate MDD,and the efficacy was better than that of 50mg sertraline and placebo protocol.The efficacy was maintained better after discontinuing treatment.Compared with integrated acupuncture and moxibustion,the combination of low dose sertraline did not show significant therapeutic advantages.2、MDD patients have decreased recognition of happy information,and it is difficult to separate from fear and sadness information.Integrating acupuncture and moxibustion can reduce the difficulty of MDD patients to separate from sad information.Sertraline,combination of acupuncture and medicine and placebo program did not significantly reduce the interference of negative emotions.3、In MDD patients,the internal connection of the default network(posterior cingulate gyrus hippocampus)was enhanced,and the connection of the forebrain island striatum(putamen)was weakened.Integration of acupuncture,sertraline and combination of acupuncture and medicine will change the connection function of anterior cuneiform lobe.Among them,acupuncture enhances the connection between anterior cuneiform lobe(posterior)and forebrain island,sertraline decreases the connection between anterior cuneiform lobe(posterior)and posterior cingulate gyrus,and combination of acupuncture and medicine decreases the connection between anterior cuneiform lobe(anterior/DMN)and posterior cingulate gyrus. |
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