Effectiveness of sequential bilateral repetitive transcranial stimulation versus bilateral theta burst stimulation for patients with treatment-resistant depression (BEAT-D): A randomized non-inferiority clinical trial

Masataka Wada¹, Shinichiro Nakajima², Keita Taniguchi², Shiori Honda³, Yu Mimura², Ryo Takemura⁴, Kevin E Thorpe⁵, Sakiko Tsugawa², Ryosuke Tarumi², Sotaro Moriyama², Naohiro Arai⁶, Ryosuke Kitahata⁷, Hiroyuki Uchida², Shinsuke Koike⁸, Zafiris J Daskalakis⁹, Masaru Mimura¹⁰, Daniel M Blumberger¹¹, Yoshihiro Noda¹²

Affiliations

¹ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 94305, USA; Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan.
² Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan.
³ Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan; Graduate School of Media and Governance, Keio University, 5322 Endo, Fujisawa-shi, Kanagawa, 252-0882, Japan.
⁴ Division of Biostatistics, Clinical and Translational Research Center, Keio University Hospital, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan.
⁵ Dalla Lana School of Public Health, University of Toronto, 155 College St, Toronto, ON, M5T 3M7, Canada; Applied Health Research Centre, Li Ka Shing Knowledge Institute of St. Michael's Hospital, 30 Bond St., Toronto, ON, M6R 1B5, Canada.
⁶ Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan; Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, 2-39-1 Kurokami Chuo-ku, Kumamoto, 860-8555, Japan.
⁷ Shinjuku-Yoyogi Mental Lab Clinic, 5-27-5 Sendagaya, Shibuyaku, Tokyo, 151-0051, Japan.
⁸ University of Tokyo Institute for Diversity and Adaptation of Human Mind, The University of Tokyo, 3-8-1, Komaba, Meguroku, Tokyo, 153-8902, Japan; Center for Evolutionary Cognitive Sciences, Graduate School of Art and Sciences, The University of Tokyo, 3-8-1, Komaba, Meguroku, Tokyo, 153-8902, Japan; The International Research Center for Neurointelligence, University of Tokyo Institutes for Advanced Study (UTIAS), 3-8-1, Komaba, Meguroku, Tokyo, 153-8902, Japan.
⁹ Department of Psychiatry, University of California, San Diego Health, 8950 Villa La Jolla Dr., La Jolla, CA, 92037, USA.
¹⁰ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 94305, USA.
¹¹ Temerty Centre for Therapeutic Brain Intervention, Campbell Family Research Institute, Centre for Addiction and Mental Health, 1025 Queen St. W, Toronto, ON, M6J 1H4, Canada; Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, 250 College Street, Toronto, ON, M5T 1R8, Canada.
¹² Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan; Shinjuku-Yoyogi Mental Lab Clinic, 5-27-5 Sendagaya, Shibuyaku, Tokyo, 151-0051, Japan; Department of Psychiatry, International University of Health and Welfare, Mita Hospital, 1-4-3 Mita, Minato-ku, Tokyo, 108-8329, Japan. Electronic address: yoshi-tms@keio.jp.

PMID: 39725000
DOI: 10.1016/j.brs.2024.12.1474

Free article

Multicenter Study

Effectiveness of sequential bilateral repetitive transcranial stimulation versus bilateral theta burst stimulation for patients with treatment-resistant depression (BEAT-D): A randomized non-inferiority clinical trial

Masataka Wada et al. Brain Stimul. 2025 Jan-Feb.

Free article

. 2025 Jan-Feb;18(1):25-33.

doi: 10.1016/j.brs.2024.12.1474. Epub 2024 Dec 25.

Authors

Affiliations

¹ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 94305, USA; Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan.
² Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan.
³ Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan; Graduate School of Media and Governance, Keio University, 5322 Endo, Fujisawa-shi, Kanagawa, 252-0882, Japan.
⁴ Division of Biostatistics, Clinical and Translational Research Center, Keio University Hospital, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan.
⁵ Dalla Lana School of Public Health, University of Toronto, 155 College St, Toronto, ON, M5T 3M7, Canada; Applied Health Research Centre, Li Ka Shing Knowledge Institute of St. Michael's Hospital, 30 Bond St., Toronto, ON, M6R 1B5, Canada.
⁶ Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan; Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, 2-39-1 Kurokami Chuo-ku, Kumamoto, 860-8555, Japan.
⁷ Shinjuku-Yoyogi Mental Lab Clinic, 5-27-5 Sendagaya, Shibuyaku, Tokyo, 151-0051, Japan.
⁸ University of Tokyo Institute for Diversity and Adaptation of Human Mind, The University of Tokyo, 3-8-1, Komaba, Meguroku, Tokyo, 153-8902, Japan; Center for Evolutionary Cognitive Sciences, Graduate School of Art and Sciences, The University of Tokyo, 3-8-1, Komaba, Meguroku, Tokyo, 153-8902, Japan; The International Research Center for Neurointelligence, University of Tokyo Institutes for Advanced Study (UTIAS), 3-8-1, Komaba, Meguroku, Tokyo, 153-8902, Japan.
⁹ Department of Psychiatry, University of California, San Diego Health, 8950 Villa La Jolla Dr., La Jolla, CA, 92037, USA.
¹⁰ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 94305, USA.
¹¹ Temerty Centre for Therapeutic Brain Intervention, Campbell Family Research Institute, Centre for Addiction and Mental Health, 1025 Queen St. W, Toronto, ON, M6J 1H4, Canada; Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, 250 College Street, Toronto, ON, M5T 1R8, Canada.
¹² Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan; Shinjuku-Yoyogi Mental Lab Clinic, 5-27-5 Sendagaya, Shibuyaku, Tokyo, 151-0051, Japan; Department of Psychiatry, International University of Health and Welfare, Mita Hospital, 1-4-3 Mita, Minato-ku, Tokyo, 108-8329, Japan. Electronic address: yoshi-tms@keio.jp.

PMID: 39725000
DOI: 10.1016/j.brs.2024.12.1474

Abstract

Background: Bilateral repetitive transcranial magnetic stimulation (BL-rTMS) over the dorsolateral prefrontal cortex is effective for treatment-resistant depression (TRD). Owing to a shorter treatment time, bilateral theta burst stimulation (BL-TBS) can be more efficient protocol. The non-inferiority of BL-TBS to BL-rTMS was established in late-life TRD; however, this has not been determined in adults of other age groups. Therefore, we investigated the non-inferiority in efficacy of BL-TBS versus BL-rTMS for TRD across a wide range of ages in a randomized, single-blind, multicenter trial.

Methods: The study included 180 participants with major depressive disorder (moderate or greater severity) who were unresponsive to at least one antidepressant treatment between September 2018 and July 2022. Following venlafaxine treatment, patients were randomly assigned to BL-rTMS or BL-TBS (1:1 ratio). The primary outcome was baseline-adjusted Montgomery-Åsberg Depression Rating Scale scores at 6 weeks. The non-inferiority margin of -3.86 was compared against the baseline-adjusted difference. Secondary outcomes included other depression rating scales.

Results: Seventy-seven patients were randomly assigned to BL-rTMS and 81 to BL-TBS, of whom 73 and 76 were assessed for the primary outcome, respectively. There was a -2.44 point difference, favoring BL-rTMS (one-tailed lower 95 % CI = -4.19, p = 0.091 for non-inferiority), and non-inferiority of BL-TBS was not established. However, non-inferiority was observed for secondary outcomes. The all-cause dropout rates and number of adverse effects were similar between them.

Conclusion: Our study could not establish the non-inferiority of BL-TBS compared to BL-rTMS in terms of efficacy for patients with TRD across the adult lifespan.

Keywords: Major depressive disorder; Non-inferiority study; Randomized controlled study; Repetitive transcranial magnetic stimulation; Theta burst stimulation; Treatment resistant depression.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yoshihiro Noda reports financial support was provided by Teijin Pharma Limited. Masataka Wada reports a relationship with Japan Society for the Promotion of Science that includes: funding grants. Masataka Wada reports a relationship with Takeda Science Foundation that includes: funding grants. Masataka Wada reports a relationship with Nakatani Foundation for Advancement of Measuring Technologies in Biomedical Engineering that includes: funding grants. Masataka Wada reports a relationship with Sumitomo Pharma Co Ltd that includes: speaking and lecture fees. Masataka Wada reports a relationship with Eisai Inc that includes: speaking and lecture fees. Masataka Wada reports a relationship with Takeda Pharmaceutical Company Limited that includes: speaking and lecture fees. Shinichiro Nakajima reports a relationship with Japan Agency for Medical Research and Development that includes: funding grants. Shinichiro Nakajima reports a relationship with Japan Research Foundation for Clinical Pharmacology that includes: funding grants. Shinichiro Nakajima reports a relationship with Naito Foundation that includes: funding grants. Shinichiro Nakajima reports a relationship with Takeda Science Foundation that includes: funding grants. Shinichiro Nakajima reports a relationship with Watanabe foundation that includes: funding grants. Shinichiro Nakajima reports a relationship with Osake-no-Kagaku Foundation that includes: speaking and lecture fees. Shinichiro Nakajima reports a relationship with Astellas Foundation for Research on Metabolic Disorders that includes: funding grants. Shinichiro Nakajima reports a relationship with Asahi Quality and Innovations Ltd that includes: funding grants. Shinichiro Nakajima reports a relationship with Sumitomo Pharma Co Ltd that includes: speaking and lecture fees. Shinichiro Nakajima reports a relationship with Meiji Seika Pharma Co Ltd that includes: speaking and lecture fees. Shinichiro Nakajima reports a relationship with Otsuka Holdings Co Ltd that includes: speaking and lecture fees. Shinichiro Nakajima reports a relationship with PDR pharma that includes: speaking and lecture fees. Shinichiro Nakajima reports a relationship with Merck & Co Inc that includes: speaking and lecture fees. Naohiro Arai reports a relationship with Japan Society for the Promotion of Science that includes: funding grants. Naohiro Arai reports a relationship with Meiji Yasuda Life Foundation of Health and Welfare that includes: funding grants. Naohiro Arai reports a relationship with Sumitomo Pharma Co Ltd that includes: speaking and lecture fees. Hiroyuki Uchida reports a relationship with Daiichi Sankyo Inc that includes: funding grants. Hiroyuki Uchida reports a relationship with Eisai Inc that includes: funding grants and speaking and lecture fees. Hiroyuki Uchida reports a relationship with Mochida Pharmaceutical Co Ltd that includes: funding grants. Hiroyuki Uchida reports a relationship with Otsuka Holdings Co Ltd that includes: funding grants and speaking and lecture fees. Hiroyuki Uchida reports a relationship with Sumitomo Pharma Co Ltd that includes: funding grants and speaking and lecture fees. Shinsuke Koike reports a relationship with Japan Agency for Medical Research and Development Department of Innovative Drug Discovery and Development that includes: funding grants. Zafiris J. Daskalakis reports a relationship with BrainsWay Ltd that includes: consulting or advisory and non-financial support. Zafiris J. Daskalakis reports a relationship with MagVenture Inc that includes: non-financial support. Zafiris J. Daskalakis reports a relationship with National Institute of Mental Health that includes: funding grants. Zafiris J. Daskalakis reports a relationship with Canadian Institutes of Health Research that includes: funding grants. Zafiris J. Daskalakis reports a relationship with Brain Canada Foundation that includes: funding grants. Masaru Mimura reports a relationship with Biogen Inc that includes: speaking and lecture fees. Masaru Mimura reports a relationship with BYERLYS PHARMACY that includes: speaking and lecture fees. Daniel M. Blumberger reports a relationship with Canadian Institutes of Health Research that includes: funding grants. Daniel M. Blumberger reports a relationship with National Institutes of Health that includes: funding grants. Daniel M. Blumberger reports a relationship with Brain Canada Foundation that includes: funding grants. Daniel M. Blumberger reports a relationship with BrainsWay Ltd that includes: funding grants and non-financial support. Daniel M. Blumberger reports a relationship with MagVenture Inc that includes: non-financial support. Yoshihiro Noda reports a relationship with Japan Society for the Promotion of Science that includes: funding grants. Yoshihiro Noda reports a relationship with Japan Agency for Medical Research and Development that includes: funding grants. Japan Agency for Medical Research and Development reports a relationship with Teijin Pharma Limited that includes: funding grants. Japan Agency for Medical Research and Development reports a relationship with Inter Reha Co Ltd that includes: funding grants and non-financial support. Japan Agency for Medical Research and Development reports a relationship with MagVenture Inc that includes: non-financial support. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Effectiveness of sequential bilateral repetitive transcranial stimulation versus bilateral theta burst stimulation for patients with treatment-resistant depression (BEAT-D): A randomized non-inferiority clinical trial

Affiliations

Effectiveness of sequential bilateral repetitive transcranial stimulation versus bilateral theta burst stimulation for patients with treatment-resistant depression (BEAT-D): A randomized non-inferiority clinical trial

Authors

Affiliations

Abstract

Conflict of interest statement

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MeSH terms

LinkOut - more resources

Full Text Sources