No Support for Routine Use of Direct Brain Stimulation for MDD

Megan Brooks

July 05, 2017

A trial that tested the noninferiority of transcranial direct-current stimulation (tDCS) against the selective serotonin reuptake inhibitor (SSRI) escitalopram (Lexapro, Forest Labs) has failed.

In the single-center trial, tDCS for the treatment of major depressive disorder (MDD) did not show noninferiority compared to escitalopram over a 10-week period and was associated with more adverse events.

"This study shows that tDCS is less effective than escitalopram for depression treatment. Therefore, it should not be routinely used," first author Andre R. Brunoni, MD, PhD, University Hospital, University of São Paulo, in Brazil, told Medscape Medical News.

The study was published online June 28 in the New England Journal of Medicine.

Active Area of Research

The antidepressant efficacy of tDCS has been an area of active research, and a recent meta-analysis by Dr Brunoni's group provides support for its use. In addition, a previous trial by the researchers showed the superiority of tDCS plus sertraline (Zoloft, Pfizer) over tDCS alone, sertraline alone, and placebo. However, that trial was not designed to directly compare tDCS with drug therapy.

The Escitalopram versus Electrical Current Therapy for Treating Depression Clinical Study (ELECT-TDCS) compared the efficacy of tDCS with that of escitalopram in 245 patients with MDD.

Ninety-four patients were randomly assigned to receive active tDCS plus oral placebo (tDCS group), 60 to sham tDCS plus oral placebo (placebo group), and 91 to sham tDCS plus escitalopram (escitalopram group).

tDCS was administered in 30-minute, 2-mA prefrontal stimulation sessions for 15 consecutive weekdays, followed by 7 weekly treatments. Escitalopram was given at a dose of 10 mg daily for 3 weeks and 20 mg daily thereafter.

The primary outcome measure was the change in score on the 17-item Hamilton Depression Rating Scale (HDRS-17) (range, 0 to 52, with higher scores indicating more depression). Noninferiority of tDCS vs escitalopram was defined by a lower boundary of the confidence interval for the difference in the decreased score that was at least 50% of the difference in the scores with placebo vs escitalopram.

In this three-arm trial of patients with MDD, tDCS "did not show noninferiority to escitalopram in the intention-to-treat and per-protocol analyses in reducing depression," the authors write.

In the intention-to-treat analysis, the average decrease in the HDRS-17 score from baseline was 11.3 points in the escitalopram group, 9.0 points in the tDCS group, and 5.8 points in the placebo group.

The lower boundary of the confidence interval for the difference in the decrease for tDCS vs escitalopram (difference, -2.3 points; 95% confidence interval, -4.3 to -0.4; P = .69) was lower than the noninferiority margin of -2.75 (50% of placebo minus escitalopram), "so noninferiority could not be claimed," the investigators note.

In secondary-outcome superiority analyses, escitalopram was superior to tDCS and placebo, and tDCS was superior to placebo.

Knowledge Gaps Remain

Two patients who received tDCS experienced new-onset mania, and tDCS was associated with higher rates of local adverse events than escitalopram, including skin redness, tingling, nervousness, and tinnitus. All of these adverse events have been seen previously in trials of tDCS.

Escitalopram was associated with higher rates of sleepiness and obstipation than was tDCS or placebo. The total number of adverse events was similar among the three groups. There were no serious adverse events during the trial.

"This finding highlights the need for new trials that explore optimized parameters for tDCS, which are more effective than the current ones," said Dr Brunoni.

Sarah Lisanby, MD, of the National Institute of Mental Health, Bethesda, Maryland, agrees.

"We cannot know whether the tDCS dose that was used in this trial successfully engaged the intended cerebral target circuits, but future work could provide such a test. As with all forms of noninvasive brain stimulation, the most effective tDCS dosing is not known, and more is not always better," she writes in an accompanying editorial.

"Although uncertainty remains regarding the antidepressant efficacy of tDCS, this trial shows key knowledge gaps in the dose-response relationship and physiologic mechanisms for tDCS and other forms of noninvasive brain stimulation that need to be addressed in order for an effective therapy to be developed.

"Ultimately, the more we know about the ways in which noninvasive brain stimulation influences brain activity at a mechanistic level, the closer we come to determining the clinical usefulness of these new therapies," she writes.

The study had no commercial funding. Dr Brunoni received grant support from the São Paulo Research State Foundation and nonfinancial support from Soterix Medical and Libbs during the conduct of the study; personal fees from Delta Medical; and personal fees and nonfinancial support from the IBSA Foundation and the National Institute of Mental Health outside the submitted work. A complete list of authors' relevant financial relationships is available at

N Engl J Med. 2017;376:2523-2533, 2593-2594. Abstract, Editorial


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