Transcranial Direct Current Stimulation Promising for Major Depressive Disorder

Transcranial direct current stimulation (tDCS) is an investigative modality for major depressive disorder (MDD) that has shown some promising results.¹ Though it has a while before it is approved by the US Food and Drug Administration, clinicians and patients have been clamoring for an effective treatment for MDD that is not associated with harmful adverse effects.¹ As 6.7% of the world’s population has MDD, which is resistant to pharmacotherapy in approximately one-third of cases, the push is on to identify treatment with lasting effects to combat this disabling disorder.¹ 

tDCS refers to the use of a noninvasive, weak electrical current (1 to 2 mA) applied to electrodes on the scalp that modify cortical excitability.^1,2 tDCS has been tested with favorable outcomes in individuals with stroke, Alzheimer disease, movement disorders, schizophrenia, and addiction.^1,2  

A Small but Emerging Body of Evidence

tDCS has produced mixed results in patients with MDD.³ Brunoni and colleagues performed a meta-analysis of individual patient data on 289 participants with MDD (mean age, 47.2 years; 62.3% women) in 6 randomized, sham-controlled studies.³ tDCS significantly improved response compared with sham procedures (34% vs 19%, respectively; odds ratio [OR], 2.44; 95% confidence interval [CI], 1.38-4.32; P=.002). Remission rates were also favorable (23.1% vs 12.7%, respectively; OR, 2.38; 95% CI, 1.22-4.64; P=.002). The trials did not uniformly categorize adverse events, but the researchers noted that both the tDCS and sham groups had similar drop-out rates.

“tDCS efficacy is still small, and it should be optimized,” noted lead author André Russowsky Brunoni, MD, PhD, associate professor at the Institute of Psychiatry at the University of São Paulo Medical School in Brazil. “There are some approaches for increasing its efficacy, such as combining with other therapies and/or increasing the dose, although this has not been systematically tested yet.”

Combination tDCS and Antidepressant Therapy

The SELECT-TDCS trial (ClinicalTrials.gov Identifier: NCT01033084) examined the cognitive effects of tDCS on 120 patients with MDD (mean age, 42 years; 68% women) in a 6-week trial of sertraline 50 mg/d vs placebo and tDCS vs sham procedure.⁴ As assessed by a battery of neuropsychological tests, such as the Mini-Mental Status Exam and the Montreal Cognitive Assessment, patients in the trial neither benefited nor regressed in their cognitive functioning with treatment.

tDCS for Treatment-Resistant MDD

Martin and colleagues sought to determine whether tDCS could be used for patients for whom 2 different pharmacotherapies were ineffective for MDD.⁵ In the open-label study, 20 patients (mean age, 47.4 years; 50% women) received tDCS during cognitive emotional therapy sessions 3 times a week for 6 weeks. The 17 completers had their mood, cognition, and emotion processing assessed at baseline, 3 weeks, and 6 weeks. At the end of the study, 41% of the participants experienced a ≥50% improvement in their depression score and none reported serious adverse events. During the stimulation, patients reported mild burning, redness, and tingling, which diminished by the end of the study.

“Current evidence suggests that tDCS when given by itself has limited antidepressant efficacy compared to standard medication treatment and that it is also not effective in more treatment-resistant patients,” said lead author Donel Martin, PhD, clinical neuropsychologist from the School of Psychiatry at the University of New South Wales in Sydney, Australia. “What our results suggest is that if patients complete a task during tDCS, which simultaneously activates relevant dysfunctional brain regions instead of doing nothing at all, better antidepressant effects may be achieved.”

Filling the tDCS Research Gaps

Scientists have yet to clearly elucidate the mechanism of action of low-current electrical stimulation with tDCS.² Still to be discovered: how tDCS modulates neurons, how it affects the neural networks, and how the currents change behavior. When clinicians have a better understanding of the underlying mechanisms, they will be better equipped to select the appropriate patients, administer optimal dosages, pair with synergistic antidepressants, and accurately place the electrodes.

Co-author Opher Donchin, PhD, head of the biomedical engineering department at Ben-Gurion University of the Negev, Be’er Sheva, Israel, acknowledges that researchers and clinicians still need additional information for tDCS to progress. “[Functional magnetic resonance imaging] of the brain region before applying tDCS will assist in delivering tDCS with spatiotemporal accuracy,” he said. “Focal stimulation using small electrodes (with high-definition tDCS) is crucial in intensifying and restricting current flow around the intended region. Also, an individual’s genetic test to assess the sensitivity towards tDCS will determine subject-specific adjustment of stimulation strength.”

In animal studies, tDCS has demonstrated long-term changes in brain plasticity in subjects with depression, but scientists still do not know how this occurs.⁶ Although many studies extrapolated from depression trials, more needs to be elucidated about depressive phenotypes (eg, anxious, melancholic).  

“The goal of the paper was to provide a rigorous framework so that future research may one day impact clinical care,” explained co-author Sarah H. Lisanby, MD, director of the Division of Translational Research and the Noninvasive Neuromodulation Unit at the National Institute of Mental Health in Bethesda, Maryland. “There is a need for better characterization/phenotyping of patients in a heterogeneous disorder, for rigorous trial designs, for optimizing spatial targeting and dosing such that the stimulation delivered to the brain is well characterized, and opportunities for combining tDCS with established efficacious interventions as an augmentation strategy.”

Summary and Clinical Applicability

The application of tDCS may ameliorate depression in patients with MDD. Despite some positive signals, tDCS remains an investigative therapy in the United States. More rigorous studies — including randomized, sham-controlled, and dose-ranging trials — are needed to determine optimal patient selection.

References

1. Bennabi D, Haffen E. Transcranial direct current stimulation (tDCS): a promising treatment for major depressive disorder? Brain Sci. 2018;8(5):81.
2. Das S, Holland P, Frens MA, Donchin O. Impact of transcranial direct current stimulation (tDCS) on neuronal functions. Front Neurosci. 2016;10:550.
3. Brunoni AR, Moffa AH, Fregni F, et al. Transcranial direct current stimulation for acute major depressive episodes: meta-analysis of individual patient data. Br J Psychiatry. 2016;208(6):522-531.
4. Brunoni AR, Tortella G, Benseñor IM, Lotufo PA, Carvalho AF, Fregni F. Cognitive effects of transcranial direct current stimulation in depression: results from the SELECT-TDCS trial and insights for further clinical trials. J Affect Disord. 2016;202:46-52. doi: 10.1016/j.jad.2016.03.066
5. Martin DM, Teng JZ, Lo TY, et al. Clinical pilot study of transcranial direct current stimulation combined with Cognitive Emotional Training for medication resistant depression. J Affect Disord. 2018;232:89-95.
6. Bikson M, Brunoni AR, Charvet LE, et al. Rigor and reproducibility in research with transcranial electrical stimulation: an NIMH-sponsored workshop. Brain Stimul. 2018;11(3):465-480.