Repetitive Transcranial Magnetic Stimulation as Maintenance Treatment of Depression
Yoshihiro Noda, Masataka Wada, Yu Mimura, Keita Taniguchi, Ryosuke Tarumi, Sotaro Moriyama, Naohiro Arai, Sakiko Tsugawa, Kevin E. Thorpe, Zafiris J. Daskalakis, Hiroyuki Uchida, Masaru Mimura, Daniel M. Blumberger, Shinichiro Nakajima
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.