Personalized High-Definition Transcranial Direct Current Stimulation for the Treatment of Depression: A Randomized Clinical Trial.

Importance: Transcranial direct current stimulation (tDCS) shows promise for treating depression. The precision and focality of stimulation may influence therapeutic outcomes; thus, investigation of personalized focal high-definition (HD) tDCS for treating depression is needed. Objective: To determine whether HD-tDCS therapy can improve mood in patients with moderate to severe depression. Design, Setting, and Participants: This randomized clinical trial used a double-blind, sham-controlled, parallel study design. The trial was conducted from December 1, 2020, to March 7, 2024, at UCLA. Each participant received a 4-week follow-up. Participants were required to meet diagnostic criteria for a current major depressive episode (evaluated using the Mini International Neuropsychiatric Interview), present moderate to severe depressive symptoms (ie, have a 17-item Hamilton Depression Rating Scale [HAMD] score ≥14 and <24), be either treatment naive or receiving a stable standard antidepressant regimen, and be 18 to 65 years of age. Key exclusion criteria included treatment-resistant depression, bipolar disorder, or schizophrenia. Of 560 volunteers screened, 71 were found to be eligible for participation. Interventions: Participants received 20 minutes of active or sham HD-tDCS each day for 12 consecutive working days. Structural magnetic resonance imaging and frameless stereotaxic neuronavigation were used to personalize the HD-tDCS configuration to each participant. Main Outcomes and Measures: Pretreatment to posttreatment change in the HAMD score. Results: Seventy-one participants (44 female [62.0%]; mean [SD] age, 34.3 [10.4] years) were randomized to receive active (n = 40) or sham (n = 31) HD-tDCS therapy. The primary outcome measure, mean (SD) pretreatment to posttreatment change in HAMD score, differed significantly between treatment groups (group difference, -2.2 [4.3]; P = .04; Cohen d, -0.50 [95% CI, -0.99 to -0.01]). Post hoc 2-sample t tests revealed significant decreases in HAMD scores within both groups, with (significantly) greater decreases in the active treatment group (active HD-tDCS group, -7.8 [4.2]; sham HD-tDCS group, -5.6 [4.4]). HD-tDCS was well-tolerated, with mild to no adverse effects. Exploratory analyses indicated a significant active treatment-related improvement in the anxiety dimension of the primary outcome measure (group difference, -0.68 [1.42]; P = .049; Cohen d, -0.48 [95% CI, -0.96 to -0.004]). Conclusions and Relevance: In this randomized clinical trial of HD-tDCS in participants with moderate to severe depression, the 12-day HD-tDCS therapy was observed to significantly improve mood with a moderate effect size. Similar effect sizes in pharmacotherapy, psychotherapy, and conventional tDCS-based therapy have been observed to occur substantially later, highlighting the clinical potential of more precise and focal tDCS in depression. Follow-up studies with appropriate maintenance treatments are needed to clarify the persistence of antidepressant effects, as well as possible therapy optimizations. Exploratory analyses indicated that HD-tDCS therapy also may be salient for treating anxiety disorders. Trial Registration: ClinicalTrials.gov Identifier: NCT04507243.