How effective is transcranial direct current stimulation? – Authors' reply
Authors: Gerrit Burkhardt, Stephan Goerigk, Frank Padberg
Journal: The Lancet (2024)

We appreciate the interest of Stephane Perrey in our randomised controlled trial (RCT) on transcranial direct current stimulation (tDCS) as an additional treatment to selective serotonin reuptake inhibitors in adults with major depressive disorder (MDD),1Burkhardt G Kumpf U Crispin A et al.Transcranial direct current stimulation as an additional treatment to selective serotonin reuptake inhibitors in adults with major depressive disorder in Germany (DepressionDC): a triple-blind, randomised, sham-controlled, multicentre trial.Lancet. 2023; 402: 545-554Summary Full Text Full Text PDF Google Scholar and welcome his Correspondence on the limitations and perspectives of precision approaches in transcranial electrical stimulation (tES). As Perrey aptly notes, a challenge in developing tDCS as an antidepressant treatment is the lack of a comprehensive understanding of its neurophysiological mechanisms of action. In the absence of such knowledge, tDCS parameters have largely evolved towards standard protocols informed by clinical data from pilot trials.2Brunoni AR Valiengo L Baccaro A et al.Sertraline vs. electrical current therapy for treating depression clinical trial—SELECT TDCS: design, rationale and objectives.Contemp Clin Trials. 2011; 32: 90-98Crossref PubMed Scopus (0) Google Scholar Our RCT represents an effort to confirm the efficacy of such a standard tDCS protocol in MDD.1Burkhardt G Kumpf U Crispin A et al.Transcranial direct current stimulation as an additional treatment to selective serotonin reuptake inhibitors in adults with major depressive disorder in Germany (DepressionDC): a triple-blind, randomised, sham-controlled, multicentre trial.Lancet. 2023; 402: 545-554Summary Full Text Full Text PDF Google Scholar Recently, two multicentre RCTs on home-based tDCS for MDD have been published;3Borrione L Cavendish BA Aparicio LVM et al.Home-use transcranial direct current stimulation for the treatment of a major depressive episode: a randomized clinical trial.JAMA Psychiatry. 2024; (published online Jan 3.)https://doi.org/10.1001/jamapsychiatry.2023.4948Crossref Scopus (2) Google Scholar, 4Woodham RD Selvaraj S Lajmi N et al.Home-based transcranial direct current stimulation RCT in major depression.bioRxiv. 2023; (published online Nov 27.) (preprint).https://doi.org/10.1101/2023.11.27.23299059Google Scholar the results of one of these trials were negative,3Borrione L Cavendish BA Aparicio LVM et al.Home-use transcranial direct current stimulation for the treatment of a major depressive episode: a randomized clinical trial.JAMA Psychiatry. 2024; (published online Jan 3.)https://doi.org/10.1001/jamapsychiatry.2023.4948Crossref Scopus (2) Google Scholar but the other obtained positive results (available as a preprint).4Woodham RD Selvaraj S Lajmi N et al.Home-based transcranial direct current stimulation RCT in major depression.bioRxiv. 2023; (published online Nov 27.) (preprint).https://doi.org/10.1101/2023.11.27.23299059Google Scholar Notably, all three RCTs applied the same tDCS protocol—ie, 2 mA intensity, 30 min stimulation, anode F3, and cathode F4 (10–20 electroencephalography system). These trials do not fully clarify whether this standard protocol is effective in MDD, and meta-analyses are needed. At the same time, it is surprising that clinical tES research has predominantly focused on a single set of tDCS parameters, even though the dose–response relationships are largely unknown. Although Perrey suggests precision approaches for tES, we advise caution against endorsing such methods prematurely in clinical trials. Such an endorsement might carry a similar risk of narrowing the potential array of protocols before obtaining robust preclinical and early clinical validation. The evidence for and maturity of such precision methods might differ; for example, personalising stimulation intensity by individual MRI-based computational modelling of tDCS-induced electric fields could be close to clinical application.5Mizutani-Tiebel Y Takahashi S Karali T et al.Differences in electric field strength between clinical and non-clinical populations induced by prefrontal tDCS: a cross-diagnostic, individual MRI-based modeling study.NeuroImage: Clinical. 2022; 34103011 Crossref Scopus (15) Google Scholar Complex approaches, such as precisely targeting individual connectivity and temporal dynamics, modulating oscillatory activity, and introducing closed-loop methods, might require more substantial translational research. Such research involves establishing connections between neurophysiological modifications and behavioural changes at the symptomatic level, rather than addressing a heterogeneous diagnosis as a whole. Novel tES protocols should be evaluated at an early clinical stage, because it took a decade from the initial description of the tDCS protocol tested in our study2Brunoni AR Valiengo L Baccaro A et al.Sertraline vs. electrical current therapy for treating depression clinical trial—SELECT TDCS: design, rationale and objectives.Contemp Clin Trials. 2011; 32: 90-98Crossref PubMed Scopus (0) Google Scholar to the publication of the current RCTs.1Burkhardt G Kumpf U Crispin A et al.Transcranial direct current stimulation as an additional treatment to selective serotonin reuptake inhibitors in adults with major depressive disorder in Germany (DepressionDC): a triple-blind, randomised, sham-controlled, multicentre trial.Lancet. 2023; 402: 545-554Summary Full Text Full Text PDF Google Scholar, 2Brunoni AR Valiengo L Baccaro A et al.Sertraline vs. electrical current therapy for treating depression clinical trial—SELECT TDCS: design, rationale and objectives.Contemp Clin Trials. 2011; 32: 90-98Crossref PubMed Scopus (0) Google Scholar, 3Borrione L Cavendish BA Aparicio LVM et al.Home-use transcranial direct current stimulation for the treatment of a major depressive episode: a randomized clinical trial.JAMA Psychiatry. 2024; (published online Jan 3.)https://doi.org/10.1001/jamapsychiatry.2023.4948Crossref Scopus (2) Google Scholar Drawing from oncology, innovative platform trial designs6Blackwell SE Woud ML Margraf J Schönbrodt FD Introducing the leapfrog design: a simple Bayesian adaptive rolling trial design for accelerated treatment development and optimization.Clin Psychol Sci. 2019; 7: 1222-1243Crossref Scopus (18) Google Scholar offer a promising means to systematically compare novel interventions, including dose–response relationships, and benchmark optimised treatments with established interventions for MDD. Instead of relying on indirect comparisons of effect sizes between tES modalities, researchers could use such comparative, flexible trial designs to make data-informed decisions about the selection of treatment candidates for resource-intensive confirmatory multicentre RCTs. GB, SG, and FP were investigators of the DepressionDC trial, which was funded by the German Federal Ministry of Education and Research as part of the German Center for Brain Stimulation research consortium (FKZ 01EE1403G). FP has received further grants from the German Research Foundation (BR 4264/6-1) and the German Federal Ministry of Education and Research (01EW1903); consulting fees from Brainsway as a member of the European Scientific Advisory Board and from Sooma as a member of the International Scientific Advisory Board; honoraria for workshops from Mag&More and for lectures from the NeuroCare Group and Brainsway; and technical support and equipment from Mag&More, the NeuroCare Group, and Brainsway. GB was supported by two internal grants for young researchers from the Medical Faculty of Ludwig-Maximilians-Universität Munich (FöFoLe, grant number 1127; FöFoLe+, grant number CS063). Transcranial direct current stimulation as an additional treatment to selective serotonin reuptake inhibitors in adults with major depressive disorder in Germany (DepressionDC): a triple-blind, randomised, sham-controlled, multicentre trialActive tDCS was not superior to sham stimulation during a 6-week period. Our trial does not support the efficacy of tDCS as an additional treatment to SSRIs in adults with MDD. Full-Text PDF