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

BDep bipolar depression CI confidence interval HAMD Hamilton Depression Rating Scale MDD major depressive disorder PO primary outcome RCT randomized controlled trial rTMS repetitive transcranial magnetic stimulation AD-TRD 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]. 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]. Therefore, maintenance therapy using treatment that improves acute depressive symptoms is necessary to prevent relapse/recurrence [2]. 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]. 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] 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

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]. 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]. Therefore, maintenance therapy using treatment that improves acute depressive symptoms is necessary to prevent relapse/recurrence [2].
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]. 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] 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 J o u r n a l P r e -p r o o f treatment for at least 6 months after remission is recommended to prevent relapse [5,6]. Other outcomes were relapse rate (remission) and Hamilton Depression Rating Scale (HDRS) score [7] 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]. 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 [8][9][10]. The risk of bias [3] is described in Fig. S2.
Benadhira et al. [8] 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 HDRS scores at the endpoint (PO) between the rTMS and sham groups.  Table S1). All participants (N=24) received at least one psychotropic drug (antidepressant, mood stabilizer, and/or benzodiazepine). No significant differences in HDRS 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 HDRS 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]. 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] in our meta-analysis was double-blind [2]. Moreover, two trials included both MDD and adults with BDep in their study [8,10]. The efficacy and safety of J o u r n a l P r e -p r o o f antidepressants in BDep differ from those in MDD [2]. Moreover, the overall risk of bias for two trials was evaluated as high [9,10] (Fig. S2). Therefore, to replicate our results, further larger, highquality, double-blind, randomized, sham-controlled trials on continuation rTMS for adults with a specific psychiatric disorder are needed.

Declaration of interests
☐ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.