Efficacy of Active vs Sham Intermittent Theta Burst Transcranial Magnetic Stimulation for Patients With Bipolar Depression

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. (continued) Key Points Question Is intermittent theta burst stimulation (iTBS) transcranial magnetic stimulation targeting the left dorsolateral prefrontal cortex safe and efficacious in acute bipolar depression? Findings This randomized clinical trial including 37 adults was terminated for futility. There was no evidence of antidepressant superiority for active iTBS over sham iTBS, and safety is uncertain because 1 hypomanic switch occurred with active iT...

Intermittent Theta-Burst Stimulation Transcranial Magnetic Stimulation Increases GABA in the Medial Prefrontal Cortex: A Preliminary Sham-Controlled Magnetic Resonance Spectroscopy Study in Acute Bipolar Depression

“…Moreover, we did not observe associations between mPFC GABA and clinical features such as anhedonia, a replicated finding in MDD ( 18 ). While it is possible that the physiological effect we observe precedes symptomatic improvement, the 4 week open label extension of this trial for non-responders also had a low rate of clinical response ( 9 ).…”

“…The primary outcomes are described elsewhere ( 9 ). Briefly, the trial was terminated for futility after 37 participants were randomized due to the absence of an efficacy signal and overall low rates of clinical response (15.7% sham-iTBS vs. 16.6% active-iTBS).…”

“…Accordingly, they are often considered in acute bipolar depression, however the literature in BD is small ( 4 , 5 ). Newer TMS protocols, such as intermittent theta-burst stimulation (iTBS), are efficacious in MDD ( 6 , 7 ) but have not demonstrated efficacy in BD to date ( 8 , 9 ). Given lack of efficacy in BD, this may provide an opportunity to dissociate physiological effects that are and are not treatment mechanisms.…”

“…To our knowledge, mPFC GABA concentrations during rTMS treatment in acute bipolar depression have not been measured. Therefore, in a randomized sham-controlled trial that examined the efficacy of iTBS in comparison to sham-iTBS ( 9 ), we used magnetic resonance spectroscopy (MRS) to assess mPFC GABA in the study patients. We hypothesized that mPFC GABA would be related to anhedonia, would increase with active-iTBS but not sham-iTBS, and that the change would be related to antidepressant response.…”

Repetitive transcranial magnetic stimulation for major depressive disorder: basic principles and future directions

“… 57 Of note, a recent sham-controlled iTBS RCT for bipolar depression was negative. 58 This study can be criticized for its small sample size ( N = 37), recruitment issues and low total number of sessions. 27 Participants were also not asked to discontinue anticonvulsants prior to treatment, which have been shown to alter cortical excitability in preclinical and clinical studies.…”