Abstract
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. To determine whether iTBS to the left dorsolateral prefrontal cortex (LDLPFC) is safe and efficacious in the treatment of acute bipolar depression. 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. 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. 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. 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. 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. ClinicalTrials.gov Identifier: NCT02749006.
Highlights
Bipolar disorder (BD) is a common lifetime condition that affects up to 2% of the population.[1,2,3] episodes of mania and hypomania are defining features of the disorder, syndromal and subsyndromal depressive symptoms account for the major disease burden and a substantial proportion of disability.[4,5] Patients are reported to spend as much as half of their lives with mood symptoms, with depressive symptoms accounting for 70% to 82% of the symptomatic periods.[6]
There were no significant differences in Montgomery-Asberg Depression Rating Scale score changes, and rates of clinical response were low in both the double-blind phase (3 of 19 participants [15.8%] in the sham intermittent theta burst stimulation (iTBS) group and 3 of 18 participants [16.7%] in the active iTBS group) and open-label phase (5 of 21 participants [23.8%])
Additional research is required to understand how transcranial magnetic stimulation treatment protocols differ in efficacy between unipolar and bipolar depression
Summary
Bipolar disorder (BD) is a common lifetime condition that affects up to 2% of the population.[1,2,3] episodes of mania and hypomania are defining features of the disorder, syndromal and subsyndromal depressive symptoms account for the major disease burden and a substantial proportion of disability.[4,5] Patients are reported to spend as much as half of their lives with mood symptoms, with depressive symptoms accounting for 70% to 82% of the symptomatic periods.[6]. There are several US Food and Drug Administration (FDA)–approved medications with level 1 evidence for efficacy in the management of acute mania. To date, only 4 treatments with level 1 or level 2 evidence (ie, olanzapine and fluoxetine combination, quetiapine, lurasidone, and cariprazine) have been approved by the FDA for treatment of acute bipolar depression.[8] many patients with bipolar depression either do not respond or have difficulty tolerating the adverse effects of these medications. Novel treatments are urgently needed for management of acute bipolar depression to address this unmet clinical need
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