Intermittent TBS to left dorsolateral prefrontal cortex not effective for acute bipolar depression

Intermittent theta burst stimulation (iTBS) transcranial magnetic stimulation targeting the left dorsolateral prefrontal cortex (LDLPFC) is not effective in the treatment of acute bipolar depression, according to a recent study that was terminated for futility. Instead, researchers found that this treatment may, in fact, cause mood episode switches despite concomitant treatment with antipsychotics or mood stabilizing medications.

Results are published in JAMA Network Open.

Alexander McGirr, MD, PhD, of the University of Calgary, Alberta, Canada, and fellow researchers explained the rationale behind transcranial magnetic stimulation treatment.

“Repetitive transcranial magnetic stimulation (rTMS) therapy is a noninvasive neurostimulation treatment that has been adopted as a first-line treatment for pharmacotherapy-resistant major depressive disorder (MDD). rTMS induces electrical activity in the cortex using magnetic fields generated outside of the head. Repetitive magnetic pulses delivered using high-frequency, low-frequency, bilateral, priming, and theta burst protocols have demonstrated efficacy in improving depression in MDD. However, the evidence for antidepressant efficacy of rTMS in the treatment of bipolar depression is limited and derived primarily from small trials and subsets of trials in major depression that included individuals with BD,” they wrote.

For this small, double-blind, randomized trial, they included 37 patients (mean age: 43.86 years; 62% women) with bipolar disorder (type I or II) who had experienced acute major depressive episodes iand for whom first-line treatment was ineffective.

All patients were taking either a mood stabilizer, an atypical antipsychotic, or a combination of the two, and they were randomized to 4-week treatment with iTBS or sham; non-responders were eligible for 4 weeks of open-label iTBS. The primary outcome of the study was change in the Montgomery-Asberg Depression Rating Scale from baseline, and secondary outcomes included clinical response, remission, and treatment-emergent mania or hypomania.

Researchers saw no significant changes in Montgomery-Asberg Depression Rating Scale scores, in favor of the sham iTBS (least squares mean difference between groups: −1.36; 95% CI −8.92 to 6.19; P=0.91). In addition, clinical response rates were low in both the double-blind phase (15.8% of the 19 patients in the sham group, and 16.7% of 18 patients in the active iTBS group) and in the open-label phase (23.8% of 21 patients).

One patient treated with active iTBS experienced treatment-emergent hypomania, and a second episode during open-label treatment.

“iTBS targeting the LDLPFC does not appear to be clinically efficacious in the treatment of bipolar depression in conjunction with an antimanic agent. Although iTBS does not appear to be associated with increases in manic symptoms in general, we cannot eliminate the possibility that it may result in increased risk of treatment-emergent affective switches,” wrote McGirr and colleagues.

“This negative RCT highlights the importance of standardizing protocols and testing the efficacy of neurostimulation treatments proven in MDD in BD. Furthermore, standardizing protocols and sham-controlled designs to account for spontaneous response is necessary to determine what, if any, role TMS has in the treatment of bipolar depression,” they concluded.

In her accompanying editorial, Joan A. Camprodon, MD, MPH, PhD, of Massachusetts General Hospital, Harvard Medical School, Boston, explained that TMS has been shown to effect lasting neuroplastic changes, and is currently approved by the FDA for the treatment of major depressive disorder, migraine headaches, obsessive compulsive disorder, and smoking cessation. In 2020, the FDA granted TMS breakthrough device designation for the treatment of bipolar depression.

“This is not a formal approval, but it indicates interest, is generally supported by evidence, and provides an expedited path for FDA review,” wrote Camprodon.

Camprodon stated that the phenotypical similarities of major depressive episodes in both major depressive and bipolar disorders suggest that the same TMS protocol could be efficacious for both conditions.

“A number of previous positive trials and meta-analyses of TMS in bipolar depression, predominantly using high-frequency or low-frequency TMS over the [dorsolateral prefrontal cortex] DLPFC, may have suggested this was, in fact, true, but the current findings from McGirr et al seem to contradict this hypothesis,” she wrote, adding that pathophysiological research has begun to “suggest distinct patterns that differentiate 2 otherwise similar clinical phenotypes…”

Nevertheless, Camprodon was quick to defend this study, despite the fact that it was terminated early for futility.

“A negative trial may be considered an undesired scientific outcome, but this study by McGirr et al has the potential to impact neuromodulation treatment development in bipolar depression,” she wrote.

“Clinically, it may focus the next steps in the exploration of traditional repetitive TMS protocols. Perhaps more critically, however, it emphasizes the need to deepen our characterization of circuit pathophysiology, the identification of anatomical treatment targets, and the focus on oscillatory physiological dynamics to understand both disease mechanisms and the distinct mechanisms of action (and clinical indications) of different TMS frequency interventions,” Camprodon concluded.

  1. This randomized clinical trial was terminated for futility; researchers found no evidence of antidepressant superiority for active iTBS over sham iTBS.

  2. The safety of intermittent theta burst stimulation remains uncertain due to a hypomanic switch that occurred in one patient after active treatment and a second episode during the open-label phase.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

This study was supported by a philanthropic donation through the University of British Columbia.

McGirr reported no disclosures.

Camprodon has served on the scientific advisory board of Hyka and Feelmore Labs and has received consultation honoraria from Neuronetics. His research is currently funded by the National Institutes of Health, the AE foundation, the Solinsky Foundation and the Gerstner foundation.

Cat ID: 54

Topic ID: 87,54,730,130,192,54,55,921,925