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...

Background: Magnetic resonance spectroscopy (MRS) has been used to identify gamma-aminobutyric acid (GABA) alterations in mood disorders, particularly in the medial prefrontal cortex (mPFC) where decreased concentrations have been associated with anhedonia. In major depressive disorder (MDD), prior work suggests that repetitive transcranial magnetic stimulation (rTMS) increases mPFC GABA concentrations proportional to antidepressant response. To our knowledge, this has not been examined in acute bipolar depression.Methods: As part of a multicentre 4-week randomized, double-blind, sham-controlled trial using intermittent theta-burst stimulation (iTBS) of the left dorsolateral prefrontal cortex (DLPFC) in individuals with acute bipolar depression, we quantified mPFC GABA and Glx (glutamate+glutamine) concentrations using a 3T MRS scan at baseline and after the intervention. Depressive symptoms were measured using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating Scale-17 (HRDS-17), and anhedonia was measured using the Snaith-Hamilton Pleasure Scale (SHAPS).Results: The trial was terminated for futility and magnetic resonance spectroscopy data was acquired for 18 participants. At baseline, there were no associations between GABA or Glx concentrations and anhedonia, however GABA was negative correlated with depressive symptom severity on the HRDS-17. Compared to the sham-iTBS group, participants receiving active-iTBS had a significant increase in mPFC GABA concentrations. This was unrelated to antidepressant outcomes or improvements in anhedonia.Conclusion: Our data suggests that iTBS targeting the DLPFC is associated with physiological changes in the mPFC. In acute bipolar depression, our preliminary data suggests that mPFC GABA is dissociated from antidepressant iTBS treatment outcomes and anhedonia.

ImportanceThe antidepressant effects of transcranial magnetic stimulation protocols for major depressive disorder (MDD) are thought to depend on synaptic plasticity. The theta-burst stimulation (TBS) protocol synaptic plasticity is known to be N-methyl-D-aspartate (NMDA)–receptor dependent, yet it is unknown whether enhancing NMDA-receptor signaling improves treatment outcomes in MDD.ObjectiveTo test whether low doses of the NMDA-receptor partial-agonist, D-cycloserine, would enhance intermittent TBS (iTBS) treatment outcomes in MDD.Design, Setting, and ParticipantsThis was a single-site 4-week, double-blind, placebo-controlled, randomized clinical trial conducted from November 6, 2019, to December 24, 2020, including 50 participants with MDD. Participants were recruited via advertisements and referral. Inclusion criteria were as follows: age 18 to 65 years with a primary diagnosis of MDD, a major depressive episode with score of 18 or more on the 17-item Hamilton Depression Rating Scale, a Young Mania Rating Scale score of 8 or less, and normal blood work (including complete blood cell count, electrolytes, liver function tests, and creatinine level).InterventionsParticipants were randomly assigned 1:1 to either iTBS plus placebo or iTBS plus D-cycloserine (100 mg) for the first 2 weeks followed by iTBS without an adjunct for weeks 3 and 4.Main Outcomes and MeasuresThe primary outcome was change in depressive symptoms as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) at the conclusion of treatment. Secondary outcomes included clinical response, clinical remission, and Clinical Global Impression (CGI) scores.ResultsA total of 50 participants (mean [SD] age, 40.8 [13.4] years; 31 female [62%]) were randomly assigned to treatment groups: iTBS plus placebo (mean [SD] baseline score, 30.3 [4.2]) and iTBS plus D-cycloserine (mean [SD] baseline score, 30.4 [4.5]). The iTBS plus D-cycloserine group had greater improvements in MADRS scores compared with the iTBS plus placebo group (mean difference, −6.15; 95% CI, −2.43 to −9.88; Hedges g = 0.99; 95% CI, 0.34-1.62). Rates of clinical response were higher in the iTBS plus D-cycloserine group than in the iTBS plus placebo group (73.9% vs 29.3%), as were rates of clinical remission (39.1% vs 4.2%). This was reflected in lower CGI-severity ratings and greater CGI-improvement ratings. No serious adverse events occurred.Conclusions and RelevanceFindings from this clinical trial indicate that adjunctive D-cycloserine may be a promising strategy for enhancing transcranial magnetic stimulation treatment outcomes in MDD using iTBS requiring further investigation.Trial RegistrationClinicalTrials.gov Identifier: NCT03937596

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Background: Cost-efficient and non-invasive predictors of antidepressant response to repetitive transcranial magnetic stimulation (rTMS) are required. The personality vulnerabilities—neuroticism and self-criticism—are associated with antidepressant outcomes in other modalities; however, self-criticism has not been examined in response to rTMS, and the literature on neuroticism and rTMS is inconsistent. Methods: This naturalistic, 4-week study involved daily dorsolateral prefrontal cortex (DLFPC) rTMS for major depression (15 unipolar, 2 bipolar). Participants completed the Big Five Inventory (neuroticism) and the Depressive Experiences Questionnaire (self-criticism) at baseline and at the end of treatment. Changes in depressive symptoms, as rated by the clinician, were quantified using the 21-item Hamilton Depression Rating Scale. Given the inconsistencies in data regarding the stability of neuroticism in patients receiving rTMS, we performed a systematic review and quantitative meta-analysis of trials examining rTMS and neuroticism. Results: rTMS significantly improved depressive symptoms, and this was predicted by higher levels of self-criticism but not neuroticism. Self-criticism was stable over the 4 weeks of rTMS; however, neuroticism decreased, and this was not related to decreases in depressive symptoms. Our quantitative meta-analysis of 4 rTMS trials in major depression ( n = 52 patients) revealed decreases in neuroticism, with a moderate effect size. Limitations: Our results are limited by a small sample size, and the absence of a sham-rTMS group. Our meta-analysis included only 4 trials. Conclusion: Highly self-critical patients appear to benefit more from rTMS than less self-critical patients. Neuroticism, a conceptually similar but distinct personality domain, does not appear to predict antidepressant response, yet this vulnerability factor for depression decreases after rTMS.

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