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Repetitive transcranial magnetic stimulation for preventing relapse in antidepressant treatment-resistant depression: A systematic review and meta-analysis of randomized controlled trials
Corresponding author. Department of Psychiatry, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.
The guidelines for the treatment of major depressive disorder (MDD) recommends that, with insufficient treatment of symptoms with antidepressants, neurostimulation treatments such as repetitive transcranial magnetic stimulation (rTMS) are recommended [
Canadian network for mood and anxiety treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 4. Neurostimulation treatments.
]. The relapse/recurrence rate is >80% within a decade of an index depressive episode and an average of >50% within 6 months of apparent clinical remission if the initially effective treatment is discontinued [
There are three relapse-prevention, randomized, controlled trials (RCTs) with rTMS in antidepressant treatment-resistant depression (AD-TRD) (Table S1), but they have shown that rTMS did not prevent relapse in the patients. However, the small sample sizes of these trials may have contributed to the negative results. Combining the results of multiple studies with a meta-analysis can increase the statistical power, which is often inadequate in smaller studies [
]. Therefore, we conducted this systematic review and meta-analysis to examine whether rTMS prevented relapse in individuals with AD-TRD.
The systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines (Table S2) [
] and registered with the Open Science Framework (https://osf.io/f8g9k). The literature search, data transfer accuracy, and statistical analysis were each double-checked by at least two of the authors.
The patient was adults with AD-TRD. Because only a few trials exclusively evaluated individuals with MDD, we included studies on both individuals with MDD and those with bipolar depression (BDep) (Table S1). The intervention was rTMS. The control conditions involved a placebo or treatment as usual (i.e., treatment group without rTMS was included as a control). The primary outcome (PO) was the relapse rate (response) at 6 months because recent meta-analyses of antidepressant treatment for adults with MDD in the maintenance phase suggest that maintenance treatment for at least 6 months after remission is recommended to prevent relapse [
] at 6 months, all-cause discontinuation, discontinuation due to adverse events, and serious adverse events. The definitions for remission and response used by each study were retained (Table S3). Raw data for all outcomes included in our meta-analysis were shown in Table S4. We included only RCTs with an enrichment design in which patients were stabilized on rTMS during the open-label study and then randomized to receive the rTMS or a sham (or no rTMS).
To perform the pairwise meta-analysis, we used the Comprehensive Meta-Analysis software version 4 (Biostat Inc., Englewood, NJ, USA). Given the potential for heterogeneity across the included studies, we used a random-effects model [
Can medication free, treatment-resistant, depressed patients who initially respond to TMS Be maintained off medications? A prospective, 12-month multisite randomized pilot study.
Maintenance deep transcranial magnetic stimulation sessions are associated with reduced depressive relapses in patients with unipolar or bipolar depression.
] conducted an 11-month, double-blind, randomized, sham-controlled trial of continuation rTMS for adults with MDD (82.4%) or BDep (17.6%) (Table S1). All participants (n = 17) received at least one psychotropic drug (antidepressant, antipsychotic, mood stabilizer, and/or benzodiazepine receptor agonist) during the study. No significant differences were observed in HAMD scores at the endpoint (PO) between the rTMS and sham groups.
Can medication free, treatment-resistant, depressed patients who initially respond to TMS Be maintained off medications? A prospective, 12-month multisite randomized pilot study.
] conducted a 47-week, open-label, RCT on continuation rTMS for adults with MDD (Table S1). No participants (N = 49) received antidepressants during the study. No significant difference was observed in the number of patients who did not require rTMS reintroduction at the endpoint (PO) between the rTMS and no rTMS groups.
Maintenance deep transcranial magnetic stimulation sessions are associated with reduced depressive relapses in patients with unipolar or bipolar depression.
] conducted a 12-month, open-label, RCT on continuation rTMS for adults with MDD (37.5%) or BDep (62.5%) (Table S1). All participants (N = 24) received at least one psychotropic drug (antidepressant, mood stabilizer, and/or benzodiazepine). No significant differences in HAMD scores were noted at the endpoint (possibly the PO of this study) between the rTMS and no rTMS groups.
Our meta-analysis demonstrated that rTMS outperformed the control in relapse rate (response) (Fig. 1). Moreover, rTMS was also marginally superior to the control on HAMD score (Fig. 1). The result could be interpreted as a type II error; however, no significant differences were observed in relapse rate (remission) and all-cause discontinuation between the rTMS and control groups (Fig. 1). No participants discontinued due to or had serious adverse events in either treatment group.
This is the first systematic review and meta-analysis of RCTs to compare relapse rates in clinically stable adults with AD-TRD continuing or discontinuing rTMS. Our meta-analysis suggests that continuation rTMS prevented relapse in adults with AD-TRD. In the three RCTs, rTMS did not outperform the control in all efficacy outcomes (Table S1). Thus, rTMS for preventing relapse is not recommended based on current treatment guidelines [
Canadian network for mood and anxiety treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 4. Neurostimulation treatments.
]. However, the number of patients included in the three RCTs was small (Table S1). One reason for failing to obtain a significant difference in the relapse rates between the rTMS and control groups might be the low statistical power of these studies, considering an insufficient sample size in all three RCTs. In fact, our meta-analysis showed that rTMS lowered the relapse rate in clinically stable adults with AD-TRD, thereby offering novel insights into brain stimulation treatment for adults with AD-TRD in the maintenance phase.
Although a double-blind design must be implemented in assessing individuals with depression, only one trial [
Maintenance deep transcranial magnetic stimulation sessions are associated with reduced depressive relapses in patients with unipolar or bipolar depression.
Can medication free, treatment-resistant, depressed patients who initially respond to TMS Be maintained off medications? A prospective, 12-month multisite randomized pilot study.
Maintenance deep transcranial magnetic stimulation sessions are associated with reduced depressive relapses in patients with unipolar or bipolar depression.
] (Fig. S2). Therefore, to replicate our results, further larger, high-quality, double-blind, randomized, sham-controlled trials on continuation rTMS for adults with a specific psychiatric disorder are needed.
Authors’ contributions
YM, KS and TK were involved in the study conception and design and performed the statistical analysis. YM, and KS performed the acquisition and interpretation of the data. All the authors wrote the manuscript. SK, NI and MS supervised the review.
Disclosure of ethical statements
The authors have no conflicts of interest to declare in relation to this study. We further declare herein the potential competing interests within the past 3 years.
YM has received speaker's honoraria from Meiji, Otsuka, Sumitomo, Takeda, Teijin, and Viatris.
KS has received speaker's honoraria from Eisai, Meiji, Otsuka, and Sumitomo and has received Grant-in-Aid for Young Scientists (B)(19K17099) and a grant from the Japan Agency for Medical Research and Development (JP22dk0307107).
TK has received speaker's honoraria from Sumitomo, Eisai, Janssen, Otsuka, Meiji, MSD, Yoshitomiyakuhin, Viatris, and Takeda, as well as research grants from Eisai, the Japanese Ministry of Health, Labour and Welfare (21GC1018), Grant-in-Aid for Scientific Research (C) (19K08082), and a grant from the Japan Agency for Medical Research and Development (JP22dk0307107 and JP22wm0525024).
KE has no previous competing interests with any company.
SK has received research grants and personal fees from Century Medical, Inter-Riha, Lundbeck, Sumitomo, and Teijin.
MS has received speaker's honoraria from Daiichi Sankyo and Eisai and research grants from Eisai.
NI has received speaker's honoraria from Sumitomo, Eisai, Eli Lilly, Janssen, Takeda, Meiji, Tanabe-Mitsubishi, Otsuka, and Viatris, as well as research grants from Daiichi Sankyo, Eisai, Takeda, Sumitomo, Meiji, Mitsubishi-Tanabe, and Otsuka.
Funding
This work was supported by the Japan Agency for Medical Research and Development (JP22dk0307107).
Declaration of competing interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors have no conflicts of interest to declare in relation to this study. We further declare herein the potential competing interests within the past 3 years.
Canadian network for mood and anxiety treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 4. Neurostimulation treatments.
Can medication free, treatment-resistant, depressed patients who initially respond to TMS Be maintained off medications? A prospective, 12-month multisite randomized pilot study.
Maintenance deep transcranial magnetic stimulation sessions are associated with reduced depressive relapses in patients with unipolar or bipolar depression.
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