Repetitive transcranial magnetic stimulation for preventing relapse in antidepressant treatment-resistant depression: A systematic review and meta-analysis of randomized controlled trials

bipolar depression confidence interval Hamilton Depression Rating Scale major depressive disorder primary outcome randomized controlled trial repetitive transcranial magnetic stimulation antidepressant treatment-resistant depression 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 [[1]Milev R.V. Giacobbe P. Kennedy S.H. Blumberger D.M. Daskalakis Z.J. Downar J. et al.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 J Psychiatr. 2016; 61: 561-575Crossref PubMed Scopus (364) Google Scholar]. 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 [[2]Herrman H. Patel V. Kieling C. Berk M. Buchweitz C. Cuijpers P. et al.Time for united action on depression: a lancet-world psychiatric association commission.Lancet. 2022; 399: 957-1022Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar]. Therefore, maintenance therapy using treatment that improves acute depressive symptoms is necessary to prevent relapse/recurrence [[2]Herrman H. Patel V. Kieling C. Berk M. Buchweitz C. Cuijpers P. et al.Time for united action on depression: a lancet-world psychiatric association commission.Lancet. 2022; 399: 957-1022Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar]. 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 [[3]Higgins J. Thomas J. Chandler J. Cumpston M. Li T. Page M. et al.Cochrane handbook for systematic reviews of interventions.2021Version: version 6.2Google Scholar]. 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) [[4]Page M.J. McKenzie J.E. Bossuyt P.M. Boutron I. Hoffmann T.C. Mulrow C.D. et al.The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.BMJ. 2021; 372: n71Crossref PubMed Scopus (18549) Google Scholar] 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 [[5]Kishi T. Ikuta T. Sakuma K. Okuya M. Hatano M. Matsuda Y. et al.Antidepressants for the treatment of adults with major depressive disorder in the maintenance phase: a systematic review and network meta-analysis.Mol Psychiatr. 2022; Google Scholar,[6]Kishi T. Sakuma K. Hatano M. Okuya M. Matsuda Y. Kato M. et al.Relapse and its modifiers in major depressive disorder after antidepressant discontinuation: meta-analysis and meta-regression.Mol Psychiatr. 2022; Crossref Scopus (5) Google Scholar]. Other outcomes were relapse rate (remission) and Hamilton Depression Rating Scale (HAMD) score [[7]Hamilton M. A rating scale for depression.J Neurol Neurosurg Psychiatr. 1960; 23: 56-62Crossref PubMed Scopus (26705) Google Scholar] 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 [[3]Higgins J. Thomas J. Chandler J. Cumpston M. Li T. Page M. et al.Cochrane handbook for systematic reviews of interventions.2021Version: version 6.2Google Scholar]. We calculated the risk ratios for dichotomous outcomes and the standardized mean difference for continuous outcomes with 95% confidence intervals. The literature search results are shown in Fig. S1. We reviewed three studies involving a total of 90 individuals [8Benadhira R. Thomas F. Bouaziz N. Braha S. Andrianisaina P.S. Isaac C. et al.A randomized, sham-controlled study of maintenance rTMS for treatment-resistant depression (TRD).Psychiatr Res. 2017; 258: 226-233Crossref PubMed Scopus (34) Google Scholar, 9Philip N.S. Dunner D.L. Dowd S.M. Aaronson S.T. Brock D.G. Carpenter L.L. et al.Can medication free, treatment-resistant, depressed patients who initially respond to TMS Be maintained off medications? A prospective, 12-month multisite randomized pilot study.Brain Stimul. 2016; 9: 251-257Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 10Rapinesi C. Bersani F.S. Kotzalidis G.D. Imperatori C. Del Casale A. Di Pietro S. et al.Maintenance deep transcranial magnetic stimulation sessions are associated with reduced depressive relapses in patients with unipolar or bipolar depression.Front Neurol. 2015; 6: 16Crossref PubMed Scopus (40) Google Scholar]. The risk of bias [[3]Higgins J. Thomas J. Chandler J. Cumpston M. Li T. Page M. et al.Cochrane handbook for systematic reviews of interventions.2021Version: version 6.2Google Scholar] is described in Fig. S2. Benadhira et al. [[8]Benadhira R. Thomas F. Bouaziz N. Braha S. Andrianisaina P.S. Isaac C. et al.A randomized, sham-controlled study of maintenance rTMS for treatment-resistant depression (TRD).Psychiatr Res. 2017; 258: 226-233Crossref PubMed Scopus (34) Google Scholar] 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. Philip et al. [[9]Philip N.S. Dunner D.L. Dowd S.M. Aaronson S.T. Brock D.G. Carpenter L.L. et al.Can medication free, treatment-resistant, depressed patients who initially respond to TMS Be maintained off medications? A prospective, 12-month multisite randomized pilot study.Brain Stimul. 2016; 9: 251-257Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar] 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. Rapinesi et al. [[10]Rapinesi C. Bersani F.S. Kotzalidis G.D. Imperatori C. Del Casale A. Di Pietro S. et al.Maintenance deep transcranial magnetic stimulation sessions are associated with reduced depressive relapses in patients with unipolar or bipolar depression.Front Neurol. 2015; 6: 16Crossref PubMed Scopus (40) Google Scholar] 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 [[1]Milev R.V. Giacobbe P. Kennedy S.H. Blumberger D.M. Daskalakis Z.J. Downar J. et al.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 J Psychiatr. 2016; 61: 561-575Crossref PubMed Scopus (364) Google Scholar]. 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 [[8]Benadhira R. Thomas F. Bouaziz N. Braha S. Andrianisaina P.S. Isaac C. et al.A randomized, sham-controlled study of maintenance rTMS for treatment-resistant depression (TRD).Psychiatr Res. 2017; 258: 226-233Crossref PubMed Scopus (34) Google Scholar] in our meta-analysis was double-blind [[2]Herrman H. Patel V. Kieling C. Berk M. Buchweitz C. Cuijpers P. et al.Time for united action on depression: a lancet-world psychiatric association commission.Lancet. 2022; 399: 957-1022Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar]. Moreover, two trials included both MDD and adults with BDep in their study [[8]Benadhira R. Thomas F. Bouaziz N. Braha S. Andrianisaina P.S. Isaac C. et al.A randomized, sham-controlled study of maintenance rTMS for treatment-resistant depression (TRD).Psychiatr Res. 2017; 258: 226-233Crossref PubMed Scopus (34) Google Scholar,[10]Rapinesi C. Bersani F.S. Kotzalidis G.D. Imperatori C. Del Casale A. Di Pietro S. et al.Maintenance deep transcranial magnetic stimulation sessions are associated with reduced depressive relapses in patients with unipolar or bipolar depression.Front Neurol. 2015; 6: 16Crossref PubMed Scopus (40) Google Scholar]. The efficacy and safety of antidepressants in BDep differ from those in MDD [[2]Herrman H. Patel V. Kieling C. Berk M. Buchweitz C. Cuijpers P. et al.Time for united action on depression: a lancet-world psychiatric association commission.Lancet. 2022; 399: 957-1022Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar]. Moreover, the overall risk of bias for two trials was evaluated as high [[9]Philip N.S. Dunner D.L. Dowd S.M. Aaronson S.T. Brock D.G. Carpenter L.L. et al.Can medication free, treatment-resistant, depressed patients who initially respond to TMS Be maintained off medications? A prospective, 12-month multisite randomized pilot study.Brain Stimul. 2016; 9: 251-257Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar,[10]Rapinesi C. Bersani F.S. Kotzalidis G.D. Imperatori C. Del Casale A. Di Pietro S. et al.Maintenance deep transcranial magnetic stimulation sessions are associated with reduced depressive relapses in patients with unipolar or bipolar depression.Front Neurol. 2015; 6: 16Crossref PubMed Scopus (40) Google Scholar] (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. 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. 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. This work was supported by the Japan Agency for Medical Research and Development (JP22dk0307107).

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