Intermittent Brain Stim Flopped for Bipolar Depression

Intermittent theta-burst stimulation (iTBS) wasn’t much help for people struggling with bipolar depression, according to a new study.

In a randomized trial of 37 adults with type I or type II bipolar disorder experiencing an acute major depressive episode, those who received iTBS didn’t have any fewer depressive symptoms than those who received a sham iTBS measured by Montgomery-Asberg Depression Rating Scale (MADRS) scores (least squares mean difference between groups -1.36, 95% CI -8.92 to 6.19, P=0.91 in favor of sham iTBS), reported Lakshmi Yatham, MBBS, MBA, of the University of British Columbia Hospital in Vancouver, and colleagues.

Only three patients in each group had a clinical response; this equated to 16% of the active iTBS group versus 17% of the sham group during the double-blind phase, the group wrote in JAMA Network Open.

One patient who received active iTBS therapy experienced treatment-emergent hypomania, but no seizures or major adverse events occurred.

“On the basis of efficacy data from samples including both [bipolar disorder] and MDD [major depressive disorder], [repetitive] TMS [transcranial magnetic stimulation] was approved by the FDA and Health Canada for the treatment of major depressive episodes regardless of primary diagnosis,” the researchers noted.

Some newer TMS protocols that involve theta burst stimulation — and in particular intermittent theta bust stimulation — are gaining popularity as of late. Yatham’s group also pointed out that recent studies have shown iTBS to evoke sustained neurophysiological changes, particularly beneficial for reducing depressive symptoms in MDD, and was even noninferior to high-frequency stimulation in MDD.

“This is important, because iTBS is a short protocol that could result in a drastic shift in the cost curve of this treatment,” they explained.

The 4-week trial included adults ages 18 to 70 currently being treated with either a mood stabilizer or an atypical antipsychotic — or a combination of the two — who hadn’t had a clinical benefit. All participants had been diagnosed with bipolar disorder type I or type II according to DSM-5 criteria, and were experiencing a depressive episode with a score of at least 18 on the 17-item Hamilton Depression Rating Scale, but didn’t respond to first-line treatment with lithium, lamotrigine (Lamictal), quetiapine (Seroquel), lurasidone (Latuda) with or without concurrent lithium, or valproate.

Taking place at two Canadian sites, the trial utilized the FDA-cleared antidepressant protocol. MagVenture’s MagPro X100 stimulator was used at both sites, with treatments consisting of 600 total pulses per session delivered as triplets at 50 Hz repeated at 5 Hz (2 seconds on and 8 seconds off) at 120% resting motor threshold. The stimulation was targeted to the left dorsolateral prefrontal cortex using neuronavigation. The treatments were delivered daily for a total of 20 treatments.

After the 4-week double-blind phase, patients who didn’t see a 50% or greater MADRS score reduction — which was 24 of the 29 participants who completed this phase — were able to opt for another 4 weeks of open-label iTBS.

Among the participants, the average age was 44 and about half had bipolar disorder type I. The average Hamilton Depression Rating Scale score was 22, while the average MADRS score at baseline was 33. About half the participants were on a mood stabilizer plus an atypical antipsychotic.

“A negative trial may be considered an undesired scientific outcome, but this study … has the potential to impact neuromodulation treatment development in bipolar depression,” said Joan Camprodon, MD, MPH, PhD, of Massachusetts General Hospital in Boston, in an accompanying commentary.

Not only does this trial shift focus towards more deeply understanding traditional repetitive TMS protocols, it also “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 suggested.