Major Depressive Disorder (MDD) is a leading cause of disability worldwide, often preceding suicide. First-line treatments include antidepressants and psychological therapies, but a significant portion of individuals don't achieve remission. Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique, has shown promise as a new treatment modality. Anodal tDCS enhances cortical excitability, while cathodal stimulation decreases it. Previous research suggests that tDCS, particularly with anode placement over the left dorsolateral prefrontal cortex (DLPFC) and cathode over the right DLPFC, is effective in treating MDD. While clinic-based studies demonstrate tDCS efficacy, the need for daily clinic visits poses a significant barrier. The portability and safety of tDCS make home-based treatment feasible. However, previous home-based trials had limitations, including small sample sizes and shorter durations, failing to show significant effects. This study aimed to evaluate the efficacy and safety of a 10-week home-based tDCS treatment for MDD with remote supervision, addressing the limitations of prior research. The longer duration is based on a recent meta-analysis indicating that effects of active tDCS continue to increase for up to 10 weeks.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique applying a weak direct current via scalp electrodes. Anodal stimulation depolarizes and increases cortical excitability, while cathodal stimulation hyperpolarizes and decreases it. tDCS modulates resting state potential, affecting cortical excitability without directly triggering action potentials unlike repetitive transcranial magnetic stimulation (rTMS). Effects persist beyond stimulation. Anodal tDCS enhances cortical excitability via NMDA receptors and calcium channels, leading to long-term potentiation-like changes. Conversely, cathodal tDCS decreases excitability and facilitates long-term depression-like changes. Neurophysiological studies demonstrate effects on cortical electric fields and network-level modulation, with left DLPFC anodal tDCS influencing default mode, self-referential, and frontoparietal networks, potentially extending to deeper limbic regions like the amygdala – key areas in MDD neurocircuitry. A meta-analysis showed active tDCS significantly increased clinical response and remission rates compared to sham in MDD patients. tDCS is safe and well-tolerated, offering potential as a first-line treatment. However, most studies were clinic-based, requiring daily visits. Previous home-based tDCS trials in MDD, while demonstrating potential, had small sample sizes and shorter durations and no significant difference between active and sham tDCS. A recent meta-analysis suggests that the effects of active tDCS continue to increase for up to 10 weeks.

This was a multisite, double-blind, placebo-controlled, randomized, superiority trial of 10-week home-based tDCS for MDD, followed by a 10-week open-label phase. Participants (18+) with MDD (moderate to severe severity on the Hamilton Depression Rating Scale (HDRS) were recruited from England, Wales, and Texas. Inclusion criteria included being treatment-free or on stable medication/psychotherapy for at least 6 weeks. Exclusion criteria included treatment-resistant depression, high suicide risk, comorbid psychiatric disorders, and medications affecting cortical excitability. Participants were randomized 1:1 to active (2 mA) or sham (0 mA) tDCS using the Flow FL-100 device, with anode over F3 (left DLPFC) and cathode over F4 (right DLPFC). The 10-week RCT involved five sessions/week for 3 weeks, then three sessions/week for 7 weeks. Remote monitoring ensured compliance. The primary outcome was the change in HDRS scores from baseline to week 10. Secondary outcomes included MADRS, MADRS-s, clinical response/remission rates, and quality of life (EQ-5D-3L). Exploratory outcomes assessed anxiety (HAM-A), hypomania (YMRS), and neuropsychological function (RAVLT, SDMT). Adverse events were monitored throughout the trial. Blinding was maintained by using a sham device that mimicked active tDCS sensations. Statistical analysis utilized mixed-model repeated measures (MMRM) to account for missing data.

A total of 174 participants were enrolled (120 women, 54 men). There were no significant differences in discontinuation rates between active and sham groups. The primary outcome showed a significant improvement in depressive symptoms in the active tDCS group compared to the sham group at week 10, as measured by the HDRS (9.41 points improvement in active vs. 7.14 points in sham; 95% CI = 0.51-4.01, P=0.012). Secondary outcomes revealed significantly greater clinical response (58.3% active vs. 37.8% sham; P=0.017) and remission rates (44.9% active vs. 21.8% sham; P=0.004) in the active tDCS group compared to the sham group based on HDRS. Similar significant improvements in favor of active tDCS were observed using the MADRS and MADRS-s scales. There were no significant differences in quality of life between the groups. Exploratory analyses showed no significant difference in anxiety symptoms, but a significant difference in hypomanic symptoms, with lower scores in the active group. There were no significant differences in neuropsychological tests between groups. Regarding adverse events, the active tDCS group had higher rates of skin redness, irritation, and trouble concentrating. Two participants in the active group reported minor skin burns, possibly due to dry sponges, which fully healed without leaving scars. There were no serious adverse events.

This study demonstrates the efficacy and safety of a 10-week home-based tDCS treatment for MDD with remote supervision. The significant improvements in depressive symptoms, response, and remission rates in the active tDCS group compared to the sham group support the use of this treatment modality. The findings are consistent with previous clinic-based studies showing tDCS efficacy in MDD but overcome limitations of prior home-based trials by employing a longer treatment duration and larger sample size. The inclusion of participants with treatment-resistant depression, based on the UK NICE guidelines, expands the generalizability of the findings. The high acceptability and safety profile of the home-based approach further strengthens its potential as a first-line treatment option. While some adverse events were observed, they were mostly mild and manageable. The success of blinding procedures indicates that the results were unlikely biased by placebo effect.

This large, randomized controlled trial provides strong evidence for the efficacy and safety of a 10-week home-based tDCS treatment for MDD. The remote supervision model enhances accessibility and convenience. Further research is needed to optimize treatment parameters and explore integration with other therapeutic approaches, particularly for subgroups such as those with treatment-resistant depression. Continued safety monitoring in larger, long-term studies is warranted.

The study's limitations include limited ethnic diversity and the exclusion of participants with a history of hospital admission. While efforts were made to ensure blinding, the possibility of residual bias cannot be entirely ruled out. Individual variations in head size and electrode placement may have influenced the electric field distribution and treatment response. All clinical assessments were conducted via videoconferencing, which could introduce subtle differences compared to in-person assessments. Finally, the relatively high baseline quality of life scores may have limited the ability to detect significant differences between groups.