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Cited by 76Transcranial Magnetic Stimulation StudiesElectroconvulsive Therapy StudiesTreatment of Major Depression

Efficacy of Active vs Sham Intermittent Theta Burst Transcranial Magnetic Stimulation for Patients With Bipolar Depression: A Randomized Clinical Trial

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McGirr, Alexander, Vila-Rodriguez, Fidel, Cole, Jaeden, Torres, Ivan J., Arumugham, Shyam Sundar, Keramatian, Kamyar, Saraf, Gayatri, Lam, Raymond W. +2 more·2021·JAMA Network Open
DOI 10.1001/jamanetworkopen.2021.0963PMC PMC7955269
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Abstract

Importance: Major depressive episodes in bipolar disorder are common and debilitating. Repetitive transcranial magnetic stimulation is well established in the treatment of major depressive disorder, and the intermittent theta burst stimulation (iTBS) protocol is replacing conventional protocols because of noninferiority and reduced delivery time. However, iTBS has not been adequately studied in bipolar disorder and, therefore, its efficacy is uncertain. Objective: To determine whether iTBS to the left dorsolateral prefrontal cortex (LDLPFC) is safe and efficacious in the treatment of acute bipolar depression. Design, Setting, and Participants: This study was a double-blind, 4-week, randomized clinical trial of iTBS targeting the LDLPFC. Two Canadian academic centers recruited patients between 2016 and 2020. Adults with bipolar disorder type I or type II experiencing an acute major depressive episode were eligible if they had not benefited from a first-line treatment for acute bipolar depression recommended by the Canadian Network for Mood and Anxiety Treatments and were currently treated with a mood stabilizer, an atypical antipsychotic, or their combination. Seventy-one participants were assessed for eligibility, and 37 were randomized to daily sham iTBS or active iTBS using a random number sequence, stratified according to current pharmacotherapy. Data analysis was performed from April to September 2020. Interventions: Four weeks of daily active iTBS (120% resting motor threshold) or sham iTBS to the LDLPFC. Nonresponders were eligible for 4 weeks of open-label iTBS. Main Outcomes and Measures: The primary outcome was the change in score on the Montgomery-Asberg Depression Rating Scale from baseline to study end. Secondary outcomes included clinical response, remission, and treatment-emergent mania or hypomania. Results: The trial was terminated for futility after 37 participants (23 women [62%]; mean [SD] age, 43.86 [13.87] years; age range, 20-68 years) were randomized, 19 to sham iTBS and 18 to active iTBS. There were no significant differences in Montgomery-Asberg Depression Rating Scale score changes (least squares mean difference between groups, -1.36 [95% CI, -8.92 to 6.19; P = .91] in favor of sham iTBS), and rates of clinical response were low in both the double-blind phase (3 of 19 participants [15.8%] in the sham iTBS group and 3 of 18 participants [16.7%] in the active iTBS group) and open-label phase (5 of 21 participants [23.8%]). One active iTBS participant had a treatment emergent hypomania, and a second episode occurred during open-label treatment. Conclusions and Relevance: iTBS targeting the LDLPFC is not efficacious in the treatment of acute bipolar depression in patients receiving antimanic or mood stabilizing agents. Additional research is required to understand how transcranial magnetic stimulation treatment protocols differ in efficacy between unipolar and bipolar depression. Trial Registration: ClinicalTrials.gov Identifier: NCT02749006.

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  • There is not yet a TMS protocol for treating bipolar disorder that is in widespread clinical use, with recent protocols showing mixed results.

    “There is not yet a TMS protocol for treating bipolar disorder that is in widespread clinical use, with recent protocols showing mixed results (Goldwaser et al., 2020; McGirr et al., 2016; McGirr et al., 2021; Myczkowski et al., 2018).”

    From A double-blind, randomized, sham-controlled clinical trial of cerebellar intermittent theta burst stimulation for bipolar disorder: Safety, tolerability, mood and cognitive effects (2025) · cites this paper as McGirr et al., 2021

    The Discussion (page unavailable) describes preliminary evidence for several rTMS protocols in bipolar depression, inconclusive findings for theta-burst protocols, and this trial’s negative result. The Conclusions (page unavailable) say further standardized trials are needed to determine TMS’s role in bipolar depression. The paper does not establish whether any TMS protocol is in widespread clinical use, so that part of the claim remains unsupported. (LLM, conf=0.86)

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Authors
McGirr, A., Vila-Rodriguez, F., Cole, J., Torres, I. J., Arumugham, S. S., Keramatian, K., Saraf, G., Lam, R. W., Chakrabarty, T., & Yatham, L. N.
Affiliations
  • University of Calgary (CA)
  • Non-Invasive Neurostimulation Therapies Laboratory, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada
  • University of British Columbia (CA)
Corresponding author
Yatham, Lakshmi N.
ORCID
Venue
JAMA Network Open
Publisher
American Medical Association (AMA)
Published
2021-03-12
Volume
4
Issue
3
Pages
e210963
ISSN
2574-3805 (ISSN-L)
DOI
10.1001/jamanetworkopen.2021.0963
PMC
PMC7955269
OpenAlex
W3134799943
Cited by
76
References
47
Citations by year
2026: 9 · 2025: 16 · 2024: 20 · 2023: 15 · 2022: 10 · 2021: 6
FWCI
5.11
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • JAMA Network Open (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Pfizer
  • Sanofi
  • Sunovion
  • Wellcome Trust
  • Canadian Network for Mood and Anxiety Treatments
  • Department of Biotechnology, Ministry of Science and Technology, India
  • Mitacs
  • University of British Columbia
  • The Wellcome Trust DBT India Alliance
  • H. Lundbeck A/S
  • Administration for Community Living
  • Allergan
  • University Health Network Foundation
  • Canadian Institutes of Health Research
Topics
  • Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
  • Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
intermittent theta burst stimulation, bipolar depression, repetitive transcranial magnetic stimulation, dorsolateral prefrontal cortex, sham stimulation, treatment-resistant depression, futility, mania, hypomania, mood stabilizers, antipsychotic drugs, treatment response and remission, safety and tolerability, non-inferiority, Montgomery-Asberg Depression Rating Scale
MeSH terms
Adult, Aged, Bipolar Disorder, Double-Blind Method, Female, Humans, Male, Middle Aged, Treatment Outcome, Prefrontal Cortex, Transcranial Magnetic Stimulation, Young Adult

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