Trial Design

The trial design has been published previously.10 The trial was conducted at the University Hospital and Department and Institute of Psychiatry, University of São Paulo, with a recruitment period from October 2013 through July 2016. The trial was approved by the local ethics committee. All the patients provided written informed consent. All the authors affirm that the trial was conducted, and all analyses were performed, per the original protocol, which is available with the full text of this article at NEJM.org. The authors vouch for the accuracy and completeness of the data and analyses reported.

Soterix Medical provided five tDCS devices (1×1 tDCS-CT) free of charge, and Libbs provided escitalopram oxalate (Reconter, 10-mg pills) free of charge. These companies were not involved in any aspect of the conduct, analysis, or reporting of the trial. The funder, Fundação de Amparo à Pesquisa do Estado de São Paulo, had no role in any aspect of the trial.

In this noninferiority, parallel, placebo-controlled trial, patients were randomly assigned in a 2:3:3 ratio, with the use of a permuted-block design, according to a computer-generated list, to receive one of three regimens: sham tDCS plus placebo (placebo group), sham tDCS plus escitalopram (escitalopram group), and active tDCS plus placebo (tDCS group).

Patients

We included patients 18 to 75 years of age who had unipolar depression that had been diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), criteria and confirmed by psychiatrists by means of the Mini-International Neuropsychiatric Interview (MINI).11 Patients had to have a score of 17 points or more on the 17-item Hamilton Depression Rating Scale (HDRS-17; scores range from 0 to 52, with higher scores indicating more depression; a score of 24 or more indicates severe depression; minimal clinically significant difference, 3 points) as well as a low risk of suicide (evaluated with the use of the MINI). The exclusion criteria were bipolar disorder, substance abuse or dependence, dementia, personality disorder, brain injury, pregnancy, specific contraindications to tDCS (e.g., cranial plates), current or previous escitalopram use, and previous or concomitant participation in other trials of tDCS. Patients who presented with an anxiety disorder (generalized anxiety disorder, specific phobia, panic disorder, or social anxiety disorder) as a coexisting condition were not excluded.

Participants were recruited by means of advertisements and physician referrals and were prescreened by means of telephone and e-mail. Persons who met the inclusion criteria underwent on-site screening. Before the onset of the trial, the patients either were not using antidepressants or underwent a drug washout and remained free of antidepressant medications for five or more drug half-lives. Benzodiazepines were allowed but were tapered to a maximum dose of 20 mg per day of a diazepam equivalent; the dose remained stable during the trial.

Interventions

Anode and cathode electrodes were placed over the left and right dorsolateral prefrontal cortexes, respectively, with the use of the Omni-Lateral-Electrode system.12 In a total of 22 sessions that lasted 30 minutes per day, 2 mA of direct-current stimulation were administered in each session. The first 15 sessions took place daily, except for weekends, and the remaining 7 sessions took place once a week, until week 10. The tDCS protocol that was used in this trial had more sessions than in earlier trials because recent studies have suggested that more sessions could produce greater clinical effects.13,14

Trained nurses administered the tDCS regimen. The same protocol was used for active and sham tDCS, but the current was turned off automatically after 30 seconds in patients receiving sham tDCS by devices that were programmed to deliver active or sham stimulation according to the randomized code.

Patients received 10 mg per day of escitalopram (or matching placebo) for the first 3 weeks and 20 mg per day thereafter. The School of Pharmaceutical Sciences of the University of São Paulo produced the placebo pills. They had the same size, color, appearance, and taste as the escitalopram pills and were stored in identical bottles. Escitalopram was chosen as representative of a first-line therapy for major depressive disorder,15 with the maximally effective dose (20 mg per day) administered close to the initial dose (10 mg per day), which thus allowed the maximum dose to be reached within weeks after the initiation of the intervention if necessary.

To assess the integrity of trial-group blinding, patients were asked to guess which intervention they had received and to rate the confidence in their prediction. Adherence to the escitalopram and placebo regimens was determined by means of pill count and was considered to be acceptable if less than 10% of the pills were returned.

Outcomes

All the assessments were performed by trained psychiatrists and psychologists who were unaware of the trial-group assignments. Efficacy and safety were measured during screening, at baseline, and at the end of weeks 3, 6, 8, and 10. The primary outcome was the change in the HDRS-17 score from baseline to 10 weeks.

Secondary outcomes included the changes from baseline in the Montgomery–Åsberg Depression Rating Scale (MADRS) score (range, 0 to 60, with higher scores indicating more severe depression; minimal clinically significant difference, 1.6 to 1.9 points),16 the Beck Depression Inventory score (range, 0 to 63, with higher scores indicating more severe depression; minimal clinically significant difference, 5 points),17,18 and several other scales that are listed in the protocol, the Supplementary Appendix (available at NEJM.org), and previous publications.19,20 Additional secondary outcomes were early improvement (defined as a change in the score from baseline to week 3 on the HDRS-17),21 clinical response (defined as a >50% reduction from the baseline HDRS-17 or MADRS score), and remission (defined as an HDRS-17 score ≤7 or a MADRS score ≤10) at week 10.

Adverse Events

Adverse events were assessed with the use of the Systematic Assessment for Treatment Emergent Effects questionnaire22 and a commonly used questionnaire regarding 39 adverse events that have been associated with tDCS.23 At the end of weeks 3 and 10, patients were asked to fill out these questionnaires, describing the presence of an adverse event, its severity, and their opinion regarding its relationship to the trial regimen. We report data on all mild, moderate, and severe adverse events that were considered by the patients to be at least remotely associated with the intervention.

The Young Mania Rating Scale (range, 0 to 60, with higher scores indicating a greater degree of manic features; minimal score to define new-onset mania or hypomania, 8 points) was used at the end of weeks 3 and 10 to assess mania or hypomania during the trial.24 Other events that were considered by the investigators to be potentially serious adverse events were hospitalization for a psychiatric cause, suicidality or attempted suicide, or events leading to major incapacity or a life-threatening condition. A brief neuropsychological evaluation consisting of seven tests (listed in the trial-design publication10 and Table S12 in the Supplementary Appendix) was performed at baseline and at 10 weeks to determine whether tDCS was associated with cognitive impairment.

Biologic Markers

Several biologic markers were investigated as predictors and mediators of clinical response. Two of these biologic markers have been analyzed so far: heart-rate variability and motor cortical excitability (see the Supplementary Appendix). Other planned analyses have not yet been done.

Statistical Analysis

The sample size was estimated on the basis of results from our previous study, the Sertraline versus Electrical Current Therapy for Treating Depression Clinical Study (SELECT-TDCS),8 with the use of an attrition rate of 13%25 and a noninferiority margin of 50% of the comparative efficacy of placebo versus escitalopram. The noninferiority margin was based on our hypothesis that tDCS would be associated with at least 50% of the difference in efficacy of escitalopram as compared with placebo (see the Supplementary Appendix).26

For our primary hypothesis, we compared the decrease in the HDRS-17 score (the baseline score minus the score at 10 weeks, with a decrease in score indicating less depression) among the three groups. A modified t-test was used to assess whether the difference in the scores between the tDCS group and the placebo group was more than 50% of the mean difference between the scores in the escitalopram group and the placebo group.25 The noninferiority margin was based on the point estimate of 50% of the difference in the mean change in the HDRS-17 score in the comparison of placebo with escitalopram. This approach was chosen because our hypothesis was that tDCS would be associated with at least 50% of the effectiveness of escitalopram. If the lower boundary of the confidence interval around the mean difference between the scores in the tDCS group versus the escitalopram group exceeded this value, then noninferiority could be claimed (see the statistical analysis plan provided with the protocol). After the noninferiority assessment, t-tests were used for superiority analyses, comparing the decrease in the HDRS-17 score for escitalopram versus tDCS, for escitalopram versus placebo, and for tDCS versus placebo.

A mixed-model analysis of variance was conducted to assess a reduction in symptoms over time. Logistic regression was performed to assess the rates of response and remission between groups. The chi-square test or Fisher’s exact test was used to compare the frequency and severity of adverse events, new-onset mania or hypomania, and serious adverse events between groups. The number of adverse events between groups at 10 weeks was compared with the use of the Kruskal–Wallis test. General linear models were used to assess predictors of response. These exploratory analyses were not corrected for multiple comparisons (see the protocol).

For biomarker analyses, 78 analyses were performed, and 3 or 4 positive results were expected by chance (see the Supplementary Appendix). For the clinical, demographic, neuropsychological, psychological,27 and adverse-event analyses, 4 or 5 positive results were expected by chance, because 85 analyses were performed.

We performed noninferiority analyses in the intention-to-treat and per-protocol populations.28 Analysis was also performed in the population of patients who had high adherence to the trial visits (patients who had <2 missing visits). Missing data were considered to be missing at random and were imputed with the use of regression models, in which baseline depression and main demographic characteristics were used as variables.