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When added to stable selective serotonin reuptake inhibitors (SSRI) treatment, transcranial direct current stimulation (tDCS) was not superior to sham stimulation for major depressive disorder (MDD), results from a sham-controlled indicated.

After 6 weeks in the study, mean change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) scores hardly differed between an active stimulation group (-8.2, SD 7.2) and patients assigned to sham stimulation (-8.0, SD 9.3; P=0.85), according to Frank Padberg, MD, of Ludwig-Maximilians-Universität in Munich, Germany, and co-authors.

Notably, more participants had at least one mild adverse event in the active stimulation group when compared with the sham (60% vs 43%, P=0.028), they reported in .

Padberg and colleagues noted that the active stimulation group experienced higher rates of headaches, sleep-related problems, and local reactions at the treatment site, such as a burning sensation. However, they also emphasized that no one experienced clinically meaningful changes in their vital signs, BMI, or cognitive function.

In addition to the mild adverse events, the authors identified three serious events during the trial. Only one -- development of acute onset mania with psychotic symptoms -- was potentially related to treatment.

Unlike most other trials of tDCS, this was not sponsored by a device maker but rather by the German government.

"Our results suggest that active tDCS is not associated with any unacceptable harms, but they question its efficacy as an addition to SSRI treatment in individuals with MDD," the authors wrote.

"[W]e found no significant difference in the change in MADRS scores in patients with MDD at week 6 after either active tCDS or sham tCDS," Padberg and colleagues added. "We also found no significant difference for all secondary outcomes, including response and remission rates, patient-reported depression, and functioning and at 18-week and 30-week follow-up visits."

In particular, while the active treatment showed numerical advantages in secondary measures, they did not reach statistical significance:

• 1.5 points in MADRS response (95% CI 0.8-3.0, P=0.25)
• 1.2 points in MADRS remission (95% CI 0.6-2.6, P=0.59)
• -2.3 points in self-reported depression scores (BDI-II score; 95% CI –5.0 to 0.6, P=0.18)

"These findings highlight the need for supportive evidence from multicentre studies, which are currently missing for most applications of tDCS," the authors wrote. "Future research should focus on advancing the neurobiological understanding of the effects of tDCS on depressive symptoms and incorporating technological developments to establish individualised tDCS as an alternative to a so-called one-size-fits-all approach."

In an , Daphne Voineskos, MD, PhD, and Daniel Blumberger, MD, of the Centre for Addiction and Mental Health and the University Health Network, respectively, both in Toronto, said the study was well designed to answer "several remaining unknowns about tDCS as a therapeutic intervention for people with MDD."

"Although the results of the DepressionDC trial did not show the superiority of active tDCS over sham stimulation as an additional treatment to SSRI pharmacotherapy, clinicians and researchers should not disregard this treatment for people with MDD," Voineskos and Blumberger wrote.

While the study findings suggest that tDCS is not effective in clinical settings, the editorialists argued that it would have missed potential benefits for individual patients in nonclinical settings.

"[F]urther 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 wrote. "Moreover, elucidating the effects of interindividual anatomical variability on electrical current distribution might lead to tDCS protocols that individualise treatment to optimise therapeutic effects...."

"Overall, there is reason for optimism about the potential to individualise tDCS and deliver it outside of the clinical setting," Voineskos and Blumberger concluded.

Study Details

Padberg's group enrolled 150 patients who were on stable SSRI doses for at least 4 weeks prior to inclusion but with continuing MDD symptoms (score of at least 15 on the 21-item Hamilton Depression Rating Scale). In total, 77 were randomized to the active tDCS group and 73 to sham stimulation.

Participants received 24 sessions during the 6-week study period, consisting of one session per day on weekdays for 4 weeks and two sessions per week for the final 2 weeks. SSRIs were continued at pre-enrollment doses.

DepressionDC was conducted at eight hospitals in Germany from January 2016 to June 2020. Among the 150 patients, 59% were women and nearly all were white. The patients had to be 18-65 years old with an MDD diagnosis. They also had to have had no response to at least one antidepressant during their current depressive episode.

To triple-blind the trial, the investigators used a tDCS device (DC-Stimulator PLUS from neuroConn) programmed to deliver active or sham stimulation without displaying any treatment information to the participants, raters, or operators.

Besides the limitations cited by the editorialists, Padberg and colleagues listed the sample size and numbers of dropouts as potentially reducing the ability to detect positive treatment effects. Also, they acknowledged that the active tDCS dosages used in the trial might have been suboptimal.

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