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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Vila-Rodriguez reported receiving honoraria from Janssen and in-kind equipment support from MagVenture. Dr Torres reported serving as a consultant for Community Living British Columbia. Dr Arumugham reported receiving a research grant from DBT/Wellcome Trust India Alliance. Dr Saraf reported receiving salary support from the Institute of Mental Health’s Marshall fellowship. Dr Lam reported receiving honoraria or research funds from Allergan, Asia-Pacific Economic Cooperation, BC Leading Edge Foundation, CIHR, CANMAT, Canadian Psychiatric Association, Hansoh, Healthy Minds Canada, Janssen, Lundbeck, Lundbeck Institute, MITACS, Ontario Brain Institute, Otsuka, Pfizer, St Jude Medical, University Health Network Foundation, and VGH-UBCH Foundation. Dr Yatham reported receiving honoraria or research grants from Allergan, CANMAT, Lundbeck, Otsuka, DSP, Sanofi, Intracellular Therapies, AbbVie, Merck, and Sunovion. No other disclosures were reported.

Figures

Figure 1.. Participant Enrollment Flowchart

COVID-19 indicates coronavirus disease 2019; iTBS, intermittent theta burst stimulation; ITT, intention to treat.

Figure 2.. Clinical Outcomes in Patients Who Received Sham and Active Intermittent Theta Burst Stimulation (iTBS)

Panel A shows the change in Montgomery-Asberg Depression Rating Scale (MADRS) score from baseline to study end at 4 weeks. Panel B shows the change in scores on the Clinical Global Impression (CGI) Scale. Circles denote means, and error bars denote standard error of the mean.