End of the Road for tDCS as an Adjunct in Major Depression?

End of the Road for tDCS as an Adjunct in Major Depression?

Transcranial direct current stimulation (tDCS) provides no additional benefit when added to selective serotonin reuptake inhibitor (SSRI) therapy for adults with major depressive disorder (MDD), results of a triple-blind, randomized, sham-controlled trial show.

The study showed no difference in mean improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) scores at 6 weeks between active and sham tDCS.

“Our trial does not support the efficacy of tDCS as an additional treatment to SSRIs in adults with MDD,” the investigators, led by Frank Padberg, MD, Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Germany, write.

The study was published online July 3 in The Lancet.

Rigorous Trial

Because it neurophysiologically modulates prefrontal cortex connectivity, tDCS has been proposed as a potential treatment for MDD.

Yet evidence for its efficacy has been inconsistent, and there is a scarcity of multicenter trial data, the researchers note.

The DepressionDC trial assessed the efficacy of tDCS in combination with SSRIs in 160 adults with MDD. Participants had a score of at least 15 on the Hamilton Depression Rating Scale (21-item version); their conditions had not responded to at least one antidepressant trial in their current depressive episode; and they had received treatment with an SSRI at a stable dose for at least 4 weeks. The SSRI was continued at the same dose during stimulation.

Eighty-three patients were allocated to undergo 30 min of 2-mA bifrontal tDCS every weekday for 4 weeks, then two tDCS sessions per week for 2 weeks; 77 patients were assigned to receive matching sham stimulation. Randomization was stratified by baseline MADRS score of <31 or ≥31.

In intention-to-treat analysis, there was no between-group difference in mean improvement on the MADRS at week 6 (–8.2 with active and –8.0 with sham tDCS; difference, 0.3; 95% CI, –2.4 to 2.9).

There was also no significant difference for all secondary outcomes, including response and remission rates, patient-reported depression, and functioning, as well as at 18-week and 30-week follow-up visits.

There were significantly more mild adverse events reported in the active tDCS group than in the sham group (60% vs 43%; P = .028). The most common adverse events were headaches, local skin reactions, and sleep-related problems.

Still Reason for Optimism

These findings call into question the efficacy of tDCS as add-on therapy to SSRI treatment for individuals with MDD and highlight the need for supportive evidence from multicenter studies, the investigators write.

Yet Padberg told Medscape Medical News it’s not the end of the road for tDCS for depression.

tDCS exerts a “rather subtle and nonfocal effect on neuronal activity. Thus, tDCS may need to be combined with specific behavioral or cognitive interventions which functionally involve the brain region, where tDCS is targeted at,” Padberg said.

Another “promising avenue” is personalization of tDCS by “individual MRI-based computational modeling of tDCS-induced electric fields,” he noted.

The co-authors of an accompanying commentary note that the DepressionDC trial was “carefully designed” and “well executed.”

And while the results did not show the superiority of active tDCS over sham stimulation as an additional treatment to SSRI therapy, “clinicians and researchers should not disregard this treatment for people with MDD,” write Daphne Voineskos, MD, PhD, and Daniel Blumberger, MD, with the University of Toronto, Ontario, Canada.

“Specifically, further exploration of placebo response in less heterogeneous MDD samples and the evaluation of tDCS as an earlier treatment option for people with MDD are important areas of future research,” they suggest.

“Moreover, elucidating the effects of interindividual anatomical variability on electrical current distribution might lead to tDCS protocols that individualize treatment to optimize therapeutic effects as opposed to a so-called one-size-fits-all approach.

“Overall, there is reason for optimism about the potential to individualize tDCS and deliver it outside of the clinical setting,” Voineskos and Blumberger conclude.

Funding for the study was provided by the German Federal Ministry of Education and Research. Several authors disclosed relationships with the pharmaceutical industry. A complete list of disclosures of authors and comment writers is available with the original article.

Lancet. Published online July 3, 2023. Abstract, Comment

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