| Major depressive disorder(MDD)is one of the most common mental disorders worldwide and leadingly affect the human health in the forefront of chronic diseases.By2020,MDD is becoming the second most general disease and public health problem.Anti-depressants are still the main maneuvers for the treatment of MDD.However,there is still two thorny problems for these medications.One is these anti-depressants only work in 50%to 80%patients.Furthermore,although anti-depressants maintenance therapy is the mainstay in the prevention against the relapse and recurrence of MDD,many patients still experience more than one depressive episodes throughouttheir life time.Thus,there is still need more effective maneuver for the treatment of MDD.Repetitive trancranial magnetic stimulation(rTMS)is a new noninvasive brain stimulation treatment,which has been widely used to treat psychiatric and neurological disorders.It also has been approved for the treatment of treatment resistance depression in2006 and 2008,respectively.The acute and short-term efficacy of rTMS treatment against MDD has been well established by more and more clinical trials,even against TRD.Our previous study has detected the combination of rTMS treatment obviously improve the effect of venlafaxine in the acute phase of depression.This indicate us that rTMS may produce its anti-depressive effect via the mechanism different with the current medications.Objective:In this trial,we designed a one center,assessor-blind,randomized,parallel controlled trial to evaluate the efficacy and safety profile of rTMS as a mono-or combination treatment compared with anti-depressants alone in a 12-month maintainance treatment period.Methods:This trial was conducted in the Department of Psychiatry of Xijing Hospital inAir Force Military Medical University at Xi'an,Shannxi,China between January 2013 and May 2015.The in-or out-patients of either gender who are currently experiencing a moderate or sever depressive episode and fulfill the include criteria of this trial were eligible to participate in this study.The study was divided into two parts,one is the 6-month run-in treatment,another is 12-month maintainance treatment.When all eligible MDD patients were instructed to start a 6-month run-in period,the choice of anti-depressive medications was based on their medication history and current condition,also on the psychiatric doctors'direction.Generally,paroxetine was prescribed for patients who were experiencing the first depressive episode without any medication before(initiated at 10mg per day and escalated to an optimal dose within 2 weeks based on the individual patients'response.The maximum dose is 40 mg per day).Patients with relapsed depressive episode were selected anti-depressants based on their previous treatment.During the run-in period,the severity of the depressive symptoms was assessed using the Hamilton Depression Rating Scale-17(HAMD-17)biweekly to determine the degree of depression(full remission was defined as a HAMD-17 score of?7,partial remission was defined as a HAMD-17 score of 8-14).If the remission was maintained for at least 3months over six consecutive evaluation time points,the stabilization was considered has been achieved.The stabilization patients were randomly divided into three groups:an anti-depressants drug treatment group(ADP),an rTMS treatment group(rTMS),and an antidepressant drug combined with rTMS treatment(rTMS+ADP).Participants who were assigned to the ADP and rTMS+ADP groups continued their anti-depressants regimen in run-in period as maintenance treatment for 12 months.The rTMS treatment group needed to gradually withdraw their anti-depressants within 2 weeks,dependedon the pharmacokinetic properties of each anti-depressant taken.Patients who were assigned to the rTMS and rTMS plus ADP groups received clustered rTMS maintainance treatment monthly.The procedure was involved 10 sessions over a 5-day period for the first 3months and 5 sessions over a 3-day period thereafter.The rTMS stimulation site was dorsolateral to the left prefrontal lobe(DLPFC)with a stimulation frequency of 10 Hz and an intensity of 110%individual's resting motor threshold(RMT).The efficacy was assessed based on the intention-to-treat population.The survival analysis was conducted to evaluate the differences of the time to relapse at 6 months among three groups.The dose of anti-depressants,anti-insomnia medications and the risk of adverse effects were also evaluated.Results:A total of 391 patients were successfully enrolled in the study during the run-in period.A total of 223 patients were treated with paroxetine,which accounted for57%of the total number of patients.The average use dose was 25.32±7.81 mg.The remaining antidepressants used were venlafaxine(n=58,mean drug dose 169.17±42.58mg),escitalopram(n=47,average dose 13.08±3.21 mg),and fluoxetine(n=27,average dose 27.50±5.32 mg).Sertraline(n=17,mean dose 132.45±42.17 mg),fluvoxamine(n=11,average dose 135.73±31.30 mg)and duloxetine hydrochloride(n=8,mean dose83.48±31 mg)were also used.Finally,281 patients successfully entered the maintenance period,including 108 patients in the ADP group,91 in the rTMS group,and 82 in the rTMS+ADP group.The scores of HAMD in each group during the maintenance period were 5.8±4.1 in the ADP group,5.9±3.0 in the rTMS group and 6.5±2.2 in the rTMS+ADP group.After the 12-months maintainance period,the study found that the rTMS and rTMSplusantidepressantswereassociatedwiththedecreaseddepressive recurrence/relapse rates in both groups compared with the antidepressant mono-treatment group.The risk of depressive recurrence/relapse rate in rTMS and the combination group was significantly lower than that in the antidepressants mono-treatment group,respectively(24.2%for rTMS mono-treatment,15.9%for rTMS plus antidepressants,and44.4%for antidepressants mono-treatment;?~2=20.165,d.f.=2,P<0.001).The difference in depressive recurrence/reactivation rate between rTMS+APDtreatment and antidepressants mono-therapy was 28.5%(?~2=16.192,d.f.=1,P=0.001).While the difference in depressive recurrence/reactivation rate between rTMS treatment and antidepressants mono-therapy was 20.2%(?~2=8.031,d.f.=1,P=0.005).However,there was no statistically significant difference in the depressive recurrence/relapse rate of depression between the combination group and rTMS mono-therapy group.During the12-month maintenance period of depression,a total of 5 patients showed manifestations of manic episodes.Among them,3 patients with manic episode appeared in the rTMS combined with antidepressant drug treatment group,and 2 patients with depressive drug treatment alone.Conclusions:This study shows that rTMS,either alone or as a complementary treatment for antidepressants,is an effective maintenance therapy and is superior to antidepressants in preventing depressive recurrence/relapse,especially in patients with first-episode depression.There is no increase in the risk of manic episodes.Although it is possible to increase the risk of certain aspects such as adverse reactions of the nervous system,rTMS is effective and is a potent preventive maintenance therapy for the prevention of depressive recurrence/relapse. |
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