Repetitive Transcranial Magnetic Stimulation as Maintenance Treatment of Depression: The MAINT-R Randomized Clinical Trial

Abstract

Importance: Depression relapse poses significant medical and economic challenges. Repetitive transcranial magnetic stimulation (rTMS) as maintenance treatment may prevent relapse of treatment-resistant depression (TRD).

Objective: To compare the effectiveness between low-frequency rTMS and lithium in preventing TRD relapse.

Design, setting, and participants: This randomized clinical trial was conducted from September 1, 2018, to May 31, 2023, at Keio University Hospital and Shinjuku-Yoyogi Mental Lab Clinic, Tokyo, Japan, among 75 participants with TRD aged 18 years or older with moderate-to-severe depressive symptoms despite at least 2 adequate antidepressant treatments who subsequently responded to an acute course of bilateral rTMS.

Interventions: Participants were randomly assigned at a 1:1 ratio to receive right dorsolateral prefrontal 1-Hz rTMS (24 weekly sessions; 120% of the resting motor threshold, 900 pulses in 15 minutes) or 24-week maintenance treatment with lithium pharmacotherapy. Participants were maintained on the same venlafaxine dose (150-225 mg/d) as the acute-phase dose.

Main outcomes and measures: The primary outcome was the between-group difference in baseline-adjusted Montgomery-Åsberg Depression Rating Scale (MADRS) scores (range, 0-60, where 0 indicates no symptoms and 60 indicates most severe symptoms) at week 24, which was analyzed using a linear mixed-effects model for repeated measures in an intention-to-treat sample. The secondary outcome was the time to relapse (defined as a MADRS score ≥22), which was analyzed using Kaplan-Meier survival curves. Adverse events were also compared between groups.

Results: Among the 75 participants, 38 were assigned to the rTMS group (mean [SD] age, 44.1 [11.7] years; 21 male participants [55.3%]; baseline mean [SD] MADRS score, 8.9 [4.7]), and 37 were assigned to the lithium group (mean [SD] age, 44.1 [11.1] years; 19 male participants [51.4%]; baseline mean [SD] MADRS score, 7.9 [4.5]). There was no significant between-group difference in the primary outcome at week 24 (0.3 points [95% CI, -2.7 to 3.3 points]; P = .84). Survival analysis showed no meaningful between-group difference in relapse rates. During the 24-week maintenance phase, there were 7 patients who relapsed in each group. There was a higher number of adverse events among participants in the lithium group (n = 16) than in the rTMS group (n = 3; odds ratio, 7.10 [95% CI, 1.84-27.49]; P = .005).

Conclusions and relevance: In this randomized clinical trial, low-frequency rTMS of the right prefrontal cortex as maintenance treatment showed comparable efficacy, as well as better safety and tolerance, compared with lithium. Maintenance low-frequency rTMS could be a promising relapse prevention strategy for patients with TRD.

Trial registration: Japan Registry of Clinical Trials: jRCTs032180188.

Figure 1.. Flowchart for the Maintenance Phase

In this study, 88 participants showed remission or response to the acute Bilateral TMS [Transcranial Magnetic Stimulation] Effectiveness for Adult Depression study (BEAT-D study), and 75 of them participated in the maintenance phase of the study. Subsequently, 38 participants were assigned to the low-frequency right dorsolateral prefrontal cortex repetitive transcranial magnetic stimulation (rTMS) treatment group and 37 participants were assigned to the lithium treatment group using adaptive dynamic allocation. The number of participants was not exactly assigned at a 1:1 ratio because the adaptive dynamic allocation method used an algorithm for between-group matching according to age, sex, and depression severity. In the rTMS group, 1 participant was lost to follow-up during the course of the study, and 3 patients discontinued due to adverse events. Therefore, data from 38 participants were included in the intention-to-treat analysis, and data from 34 participants were included in the per-protocol analysis. In the lithium group, 4 participants discontinued due to adverse events during the course of the study. Therefore, data from 37 participants were included in the intention-to-treat analysis, and data from 33 participants were included in the per-protocol analysis.

Figure 2.. Changes in Depression Scale Scores and Relapse Rates

A, Longitudinal changes in Montgomery-Åsberg Depression Rating Scale (MADRS) scores between the repetitive transcranial magnetic stimulation (rTMS) and lithium groups during the maintenance phase: no significant between-group difference was observed in the baseline-adjusted MADRS scores at 24 weeks (0.3 points [95% CI, −2.7 to 3.3 points]; P = .84). In addition, there were 7 relapse cases in each group. B, The Kaplan-Meier survival curve evaluating the relapse rate in the rTMS and lithium groups: the Kaplan-Meier estimates did not show any substantial between-group difference in the relapse-free periods. The log-rank test showed no meaningful between-group difference in the survival curves (P = .92).