| Depression is a mood disorder disease with core symptoms including depressed mood,slow thinking,decreased volition.Second-Generation antidepressants are the first-line treatments for patients with depression.However,drug treatment is characterized by delayed onset,insufficient curative effect,and high recurrence rate.Repetitive transcranial magnetic stimulation(r TMS),as a non-invasive neurostimulation technique,can significantly improve the symptoms of depression.At present,the systematic review of r TMS combined with antidepressant drugs in the treatment of depression failed to analyze the effects of antidepressant drug types,r TMS parameters,depression type,and treatment course on outcomes.In addition,this study hopes to compare the effects of different types of antidepressants combined with r TMS in order to provide information for clinical practice.Objective:1.We used Meta analysis to explore the effectiveness and safety of r TMS combined with antidepressants in the treatment of depression,as well as the effects of antidepressants types,r TMS parameters,depression types,and r TMS course on the treatment effect.2.we observe the behavioral changes of sertraline,venlafaxine,mirtazapine combined with r TMS on chronic unpredictable mild stress model(CUMS)mice to further explored the antidepressant effect of different antidepressants combined with r TMS,aim to provide theoretical support for clinical practice.Methods:1.Computer retrievals of domestic and foreign databases(The Cochrane Library,Pub Med,OVID,CNKI,Wanfang database,Weipu database)and the document search were carried out before December 2020.By collecting randomized controlled trials of repetitive transcranialmagnetic stimulation combined with antidepressants for depression treatment,the relevant literatures were collected for literature screening,quality evaluation and data collection.Meta-analysis was performed using Rev Man5.3 software with the response rate and remission rate as the outcome indicators.2.64 male mice were randomly divided into 8 groups:sham group,CUMS group,CUMS+sham–r TMS+Ser group,CUMS+r TMS+Ser group,CUMS+sham–r TMS+Ven group,CUMS+r TMS+Ven group,CUMS+sham–r TMS+Mir group,CUMS+r TMS+Mir group.The depression model of mice was established by CUMS.The changes of depression-like behaviors of mice were tested by sucrose preference test,open field test,forced swimming test and tail suspension test.Results:1.Total of 48 clinical trials involving 2886 patients were included,all of which were randomized controlled trials.There were 1,526 patients in the r TMS combined with antidepressants group(experimental group)and 1,360 patients in the sham stimulation combined with antidepressants group(control group).The Meta-analysis results showed that the response rate(RR=1.83,95%CI(1.59,2.11),p<0.001)and remission rate(RR=2.25,95%CI(1.66,3.06),p<0.001)of the experimental group and the control group for treatment of depression had significant statistical differences,but there was significant heterogeneity in various randomized controlled trials(I~2=57%,P<0.00001;I~2=54%,P=0.0001).In addition,the study found that there was no statistical difference in the drop-off rate between the experimental group and the control group(RR=0.89,95%CI(0.65,1.23),p=0.47)and there was no heterogeneity in the randomized controlled trials(I~2=0%,P=0.98).Subgroup analysis found that the response rate of patients receiving specific drugs or non-specific drugs during r TMS treatment(RR=1.65,95%CI(1.43,1.90),p<0.00001;RR=2.58,95%CI(1.89,3.51),p<0.001)and remission rate(RR=2.01,95%CI(1.42,2.84),p<0.0001;RR=2.73,95%CI(1.67,4.46),p<0.001)compared with the control group all have significant statistical significance(p<0.001);the subgroup receiving specific drugs has significant heterogeneity(I~2=60%,P<0.0001;I~2=62%,P=0.0002),and the subgroup receiving non-specific drugs has low heterogeneity(I~2=25%,P=0.14;I~2=7%,P=0.62).During r TMS treatment,patients were treated with high-frequency left DLPFC stimulation,low-frequency right DLPFC stimulation,or bilateral(low-frequency right DLPFC first,then high-frequency left DLPFC)stimulation,the experimental group response rate(RR=1.80,95%CI(1.51,2.14)),p<0.001;RR=2.07,95%CI(1.68,2.56),p<0.001;RR=3.45,95%CI(1.70,6.99),p<0.001)and remission rate(RR=2.13,95%CI(1.59,2.85),p<0.001;RR=3.78,95%CI(1.10,13.01),p=0.04;RR=5.73,95%CI(1.89,17.36),p=0.002)were statistically significant,except for the remission rate of the right DLPFC stimulation which was not statistically significant.;the high-frequency left DLPFC stimulation subgroup(I~2=54%,P=0.0002;I~2=42%,P=0.01)and the low-frequency right the DLPFC stimulation subgroup(I~2=59%,P=0.01;I~2=74%,P=0.004)have higher heterogeneity,and the bilateral stimulation subgroup has lower heterogeneity(I~2=0%,P=0.88;I~2=0%,P=0.63).In patients with major depression(MDD),first-episode depression,and treatment-resistant depression(TRD),the experimental group response rate(RR=1.94,95%CI(1.34,2.82)),p=0.0005;RR=1.49,95%CI(1.31,1.69),p<0.001;RR=2.31,95%CI(1.37,3.89),p=0.002)and remission rate(RR=2.16,95%CI(1.14,4.08),p=0.02;RR=1.77,95%CI(1.32,2.38),p=0.001;RR=3.50,95%CI(1.36,9.01),p=0.009)are statistically significant compared with the control group;MDD subgroups has heterogeneous high sexuality(I~2=56%,P=0.009;I~2=61%,P=0.009),and the first-episode depression subgroup has low heterogeneity(I~2=4%,P=0.40;I~2=0%,P=0.80),the TRD subgroup has higher response rates and lower response rates(I~2=55%,P=0.06;I~2=0%,P=0.65).In patients receiving different courses of r TMS(2 weeks,3 weeks,4 weeks,6 weeks),the test group response rate(RR=1.89,95%CI(1.55,2.31),P<0.001;RR=1.86,95%CI(1.11,3.12),p=0.02;RR=1.74,95%CI(1.47,2.06),p<0.001;RR=1.81,95%CI(1.20,2.71),p=0.004)and remission rate(RR=2.35,95%CI(1.32,4.17),p=0.004;RR=3.76,95%CI(1.34,10.56),p=0.01;RR=2.52,95%CI(1.67,3.80),p<0.0001;RR=2.46,95%CI(1.27,4.77),p=0.008)compared with the control group were statistically significant except for the 6-week remission rate,which was not statistically significant;the patient received 2 weeks(I~2=0%,P=0.76;I~2=0%,P=0.73)or 3 weeks(I~2=24%,P=0.24;I~2=0%,P=0.89)of r TMS treatment subgroups have low heterogeneity,patients received 4weeks(I~2=41%,P=0.04;I~2=33%,P=0.12)or 6 weeks(I~2=78%,P<0.0001;I~2=66%,P=0.003)r TMS treatment subgroups have higher heterogeneity.2.The results of animal experiments showed that compared with the sham group,the sucrose preference rate,the number of crossing grids and the number of standing uprights in the open field experiment were significantly reduced,and the immobility time in the forced swimming and tail suspension experiments were significantly increased(p<0.05),indicating that the modeling was successful;compared with the CUMS group,after r TMS and/or drug treatment,the mice’s sucrose preference rate,the number of crossing grids and the number of standing uprights in the open field experiment were significantly increased,forced swimming and tail suspension.The immobility time of the experiment was significantly shortened(p<0.05),and the improvement of the depressive state of mice by r TMS combined with the drug was better than that of the drug group(p<0.05).Sertraline,venlafaxine,mirtazapine combined with r TMS had no statistical difference in improving the depressive behavior of mice.Conclusions:r TMS combined with antidepressants in the treatment of depression,compared with sham-r TMS combined with antidepressants,can significantly improve the efficacy,relieve the clinical symptoms of patients,and do not increase the occurrence of adverse reactions.Different treatment parameters(such as patients with different types of depression,whether they receive specific drugs,using different r TMS parameters,and receiving different r TMS courses),the efficacy of r TMS combined with antidepressants is still significantly better than sham-r TMS combined with antidepressants.Different classes of antidepressants(SSRIs:sertraline,SNRIs:venlafaxine,Na SSAs:mirtazapine)combined with r TMS have comparable efficacy in the treatment of depression. |
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