Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Distinct trajectories of response to prefrontal tDCS in major depression: results from a 3-arm randomized controlled trial

Abstract

Transcranial direct current stimulation (tDCS) is a safe, effective treatment for major depressive disorder (MDD). While antidepressant effects are heterogeneous, no studies have investigated trajectories of tDCS response. We characterized distinct improvement trajectories and associated baseline characteristics for patients treated with prefrontal tDCS, an active pharmacotherapy (escitalopram), and placebo. This is a secondary analysis of a randomized, non-inferiority, double-blinded trial (ELECT-TDCS, N = 245). Participants were diagnosed with an acute unipolar, nonpsychotic, depressive episode, and presented Hamilton Depression Rating Scale (17-items, HAM-D) scores ≥17. Latent trajectory modeling was used to identify HAM-D response trajectories over a 10-week treatment. Top-down (hypothesis-driven) and bottom-up (data-driven) methods were employed to explore potential predictive features using, respectively, conservatively corrected regression models and a cross-validated stability ranking procedure combined with elastic net regularization. Three trajectory classes that were distinct in response speed and intensity (rapid, slow, and no/minimal improvement) were identified for escitalopram, tDCS, and placebo. Differences in response and remission rates were significant early for all groups. Depression severity, use of benzodiazepines, and age were associated with no/minimal improvement. No significant differences in trajectory assignment were found in tDCS vs. placebo comparisons (38.3, 34, and 27.6%; vs. 23.3, 43.3, and 33.3% for rapid, slow, and no/minimal trajectories, respectively). Additional features are suggested in bottom-up analyses. Summarily, groups treated with tDCS, escitalopram, and placebo differed in trajectory class distributions and baseline predictors of response. Our results might be relevant for designing further studies.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Distinct trajectories of change in depressive symptoms over 10 weeks of treatment with tDCS + placebo, escitalopram + sham tDCS, and placebo + sham tDCS.

References

  1. 1.

    Liu Q, He H, Yang J, Feng X, Zhao F, Lyu J. Changes in the global burden of depression from 1990 to 2017: findings from the global burden of disease study. J Psychiatr Res. 2019. https://doi.org/10.1016/j.jpsychires.2019.08.002.

  2. 2.

    Carvalho AF, Sharma MS, Brunoni AR, Vieta E, Fava GA. The safety, tolerability and risks associated with the use of newer generation antidepressant drugs: a critical review of the literature. Psychother Psychosom. 2016;85:270–88.

    PubMed  Google Scholar 

  3. 3.

    Cuijpers P. Four decades of outcome research on psychotherapies for adult depression: an overview of a series of meta-analyses. Can Psychol/Psychologie Canadienne. 2017;58:7–19.

    Google Scholar 

  4. 4.

    Brunoni AR, Sampaio-Junior B, Moffa AH, Aparício LV, Gordon P, Klein I, et al. Noninvasive brain stimulation in psychiatric disorders: a primer. Braz J Psychiatry. 2019;41:70–81.

    PubMed  Google Scholar 

  5. 5.

    Mutz J, Vipulananthan V, Carter B, Hurlemann R, Fu CHY, Young AH. Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis. BMJ. 2019;364:l1079.

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Rossi S, Hallett M, Rossini PM, Pascual-Leone A. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol. 2009;120:2008–39.

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Bikson M, Brunoni AR, Charvet LE, Clark VP, Cohen LG, Deng Z-D, et al. Rigor and reproducibility in research with transcranial electrical stimulation: an NIMH-sponsored workshop. Brain Stimul. 2018;11:465–80.

    PubMed  Google Scholar 

  8. 8.

    Aparício LVM, Guarienti F, Razza LB, Carvalho AF, Fregni F, Brunoni AR. A systematic review on the acceptability and tolerability of transcranial direct current stimulation treatment in neuropsychiatry trials. Brain Stimul. 2016;9:671–81.

    Google Scholar 

  9. 9.

    Brunoni AR, Moffa AH, Sampaio-Junior B, Borrione L, Moreno ML, Fernandes RA, et al. Trial of electrical direct-current therapy versus escitalopram for depression. N. Engl J Med. 2017;376:2523–33.

    CAS  PubMed  Google Scholar 

  10. 10.

    Loo CK, Husain MM, McDonald WM, Aaronson S, O’Reardon JP, Alonzo A, et al. International randomized-controlled trial of transcranial Direct Current Stimulation in depression. Brain Stimul. 2018;11:125–33.

    PubMed  Google Scholar 

  11. 11.

    Brunoni AR, Valiengo L, Baccaro A, Zanão TA, de Oliveira JF, Goulart A, et al. The sertraline vs. electrical current therapy for treating depression clinical study: results from a factorial, randomized, controlled trial. JAMA Psychiatry. 2013;70:383–91.

    CAS  PubMed  Google Scholar 

  12. 12.

    Moffa AH, Martin D, Alonzo A, Bennabi D, Blumberger DM, Benseñor IM, et al. Efficacy and acceptability of transcranial direct current stimulation (tDCS) for major depressive disorder: An individual patient data meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2019;99:109836.

    PubMed  Google Scholar 

  13. 13.

    Razza LB, Palumbo P, Moffa AH, Carvalho AF, Solmi M, Loo CK, et al. A systematic review and meta‐analysis on the effects of transcranial direct current stimulation in depressive episodes. Depress Anxiety. 2020;3:74.

    Google Scholar 

  14. 14.

    Brunoni AR, Nitsche MA, Bolognini N, Bikson M, Wagner T, Merabet L, et al. Clinical research with transcranial direct current stimulation (tDCS): challenges and future directions. Brain Stimul. 2012;5:175–95.

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    McTeague LM, Rosenberg BM, Lopez JW, Carreon DM, Huemer J, Jiang Y, et al. Identification of common neural circuit disruptions in emotional processing across psychiatric disorders. Am J Psychiatry. 2020;177:411–21.

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Padmanabhan JL, Cooke D, Joutsa J, Siddiqi SH, Ferguson M, Darby RR, et al. A human depression circuit derived from focal brain lesions. Biol Psychiatry. 2019;86:749–58.

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Fitzgerald PB, Oxley TJ, Laird AR, Kulkarni J, Egan GF, Daskalakis ZJ. An analysis of functional neuroimaging studies of dorsolateral prefrontal cortical activity in depression. Psychiatry Res. 2006;148:33–45.

    PubMed  Google Scholar 

  18. 18.

    Blumberger DM, Vila-Rodriguez F, Thorpe KE, Feffer K, Noda Y, Giacobbe P, et al. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet. 2018;391:1683–92.

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Kaster TS, Downar J, Vila-Rodriguez F, Thorpe KE, Feffer K, Noda Y, et al. Trajectories of response to dorsolateral prefrontal rTMS in major depression: a THREE-D Study. Am J Psychiatry. 2019;176:367–75.

    PubMed  Google Scholar 

  20. 20.

    Stulz N, Thase ME, Klein DN, Manber R, Crits-Christoph P. Differential effects of treatments for chronic depression: a latent growth model reanalysis. J Consult Clin Psychol. 2010;78:409–19.

    PubMed  Google Scholar 

  21. 21.

    Smagula SF, Butters MA, Anderson SJ, Lenze EJ, Dew MA, Mulsant BH, et al. Antidepressant response trajectories and associated clinical prognostic factors among older adults. JAMA Psychiatry. 2015;72:1021–8.

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Brunoni AR, Sampaio-Junior B, Moffa AH, Borrione L, Nogueira BS, Aparício LVM, et al. The Escitalopram versus Electric Current Therapy for Treating Depression Clinical Study (ELECT-TDCS): rationale and study design of a non-inferiority, triple-arm, placebo-controlled clinical trial. Sao Paulo Med J 2015;133:252–63.

    PubMed  Google Scholar 

  23. 23.

    Fuentes D, Tavares H, Camargo CHP, Gorenstein C. Inventário de Temperamento e de Caráter de Cloninger–Validação da versão em Português. Lemos: Escalas de Avaliação Clínica Em Psiquiatria E Psicofarmacologia São Paulo; 2000. p. 363–76.

    Google Scholar 

  24. 24.

    Pires P, Filgueiras A, Ribas R, Santana C. Positive and negative affect schedule: psychometric properties for the Brazilian Portuguese version. Span J Psychol. 2013;16:E58.

    PubMed  Google Scholar 

  25. 25.

    Gorenstein C, Andrade LHSG. Validation of a Portuguese version of the Beck Depression Inventory and State-Trait anxiety inventory in Brazilian subjects. Braz J Med Biol Res. 1996. 1996.

  26. 26.

    Berlim MT, Turecki G. Definition, assessment, and staging of treatment-resistant refractory major depression: a review of current concepts and methods. Can J Psychiatry. 2007;52:46–54.

    PubMed  Google Scholar 

  27. 27.

    R Development Core Team R, others. R: a language and environment for statistical computing. 2011. https://www.gbif.org/tool/81287/r-a-language-and-environment-for-statistical-computing. Assessed 10 Dec 2020.

  28. 28.

    Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Stat Methodol. 1995;57:289–300.

    Google Scholar 

  29. 29.

    Proust-Lima C, Philipps V, Liquet B. Estimation of extended mixed models using latent classes and latent processes: the R package lcmm. 2015. https://arxiv.org/abs/1503.00890. Assessed 10 Dec 2020.

  30. 30.

    Muthén B, Shedden K. Finite mixture modeling with mixture outcomes using the EM algorithm. Biometrics. 1999;55:463–9.

    PubMed  Google Scholar 

  31. 31.

    Proust C, Jacqmin-Gadda H. Estimation of linear mixed models with a mixture of distribution for the random effects. Comput Methods Prog Biomed. 2005;78:165–73.

    Google Scholar 

  32. 32.

    Klijn SL, Weijenberg MP, Lemmens P, van den Brandt PA, Passos VL. Introducing the fit-criteria assessment plot – A visualisation tool to assist class enumeration in group-based trajectory modelling. Stat Methods Med Res. 2017;26:2424–36.

    PubMed  Google Scholar 

  33. 33.

    Lennon H, Kelly S, Sperrin M, Buchan I, Cross AJ, Leitzmann M, et al. Framework to construct and interpret latent class trajectory modelling. BMJ Open. 2018;8:e020683.

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Meinshausen N, Bühlmann P. Stability selection. J R Stat Soc Ser B Stat Methodol. 2010;72:417–73.

    Google Scholar 

  35. 35.

    Zou H, Hastie T. Regularization and variable selection via the elastic net. J R Stat Soc B. 2005;67:301–20.

  36. 36.

    Rencher AC, Pun FC. Inflation of R2 in Best Subset Regression. Technometrics. 1980;22:49–53.

    Google Scholar 

  37. 37.

    Fagerland MW, Hosmer DW. Tests for goodness of fit in ordinal logistic regression models. J Stat Comput Simul. 2016;86:3398–418.

    Google Scholar 

  38. 38.

    Jay M. Generalhoslem: goodness of fit tests for logistic regression models. R package version 1.2. 5. 2017. https://cran.r-project.org/web/packages/generalhoslem/generalhoslem.pdf. Assessed 10 Dec 2020.

  39. 39.

    Uher R, Muthén B, Souery D, Mors O, Jaracz J, Placentino A, et al. Trajectories of change in depression severity during treatment with antidepressants. Psychol Med. 2010;40:1367–77.

    CAS  PubMed  Google Scholar 

  40. 40.

    Sampaio-Junior B, Tortella G, Borrione L, Moffa AH, Machado-Vieira R, Cretaz E, et al. Efficacy and safety of transcranial direct current stimulation as an add-on treatment for bipolar depression: a randomized clinical trial. JAMA Psychiatry. 2018;75:158–66.

    PubMed  Google Scholar 

  41. 41.

    Valiengo L, da CL, Goerigk S, Gordon PC, Padberg F, Serpa MH, Koebe S, et al. Efficacy and safety of transcranial direct current stimulation for treating negative symptoms in schizophrenia: a randomized clinical trial. JAMA Psychiatry. 2019. https://doi.org/10.1001/jamapsychiatry.2019.3199.

  42. 42.

    Bajbouj M, Aust S, Spies J, Herrera-Melendez A-L, Mayer SV, Peters M, et al. PsychotherapyPlus: augmentation of cognitive behavioral therapy (CBT) with prefrontal transcranial direct current stimulation (tDCS) in major depressive disorder-study design and methodology of a multicenter double-blind randomized placebo-controlled trial. Eur Arch Psychiatry Clin Neurosci. 2018;268:797–808.

    PubMed  Google Scholar 

  43. 43.

    Brunoni AR, Ferrucci R, Bortolomasi M, Scelzo E, Boggio PS, Fregni F, et al. Interactions between transcranial direct current stimulation (tDCS) and pharmacological interventions in the Major Depressive Episode: findings from a naturalistic study. Eur Psychiatry. 2013;28:356–61.

    CAS  PubMed  Google Scholar 

  44. 44.

    Brunoni AR, Moffa AH, Fregni F, Palm U, Padberg F, Blumberger DM, et al. Transcranial direct current stimulation for acute major depressive episodes: meta-analysis of individual patient data. Br J Psychiatry. 2016;208:522–31.

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Hunter AM, Minzenberg MJ, Cook IA, Krantz DE, Levitt JG, Rotstein NM, et al. Concomitant medication use and clinical outcome of repetitive Transcranial Magnetic Stimulation (rTMS) treatment of Major Depressive Disorder. Brain Behav. 2019;9:e01275.

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    Turco CV, El-Sayes J, Locke MB, Chen R, Baker S, Nelson AJ. Effects of lorazepam and baclofen on short-and long-latency afferent inhibition. J Physiol. 2018;596:5267–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Ziemann U. Pharmaco-transcranial magnetic stimulation studies of motor excitability. Handb Clin Neurol. 2013;116:387–97.

    PubMed  Google Scholar 

  48. 48.

    Huedo-Medina TB, Kirsch I, Middlemass J, Klonizakis M, Siriwardena AN. Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration. BMJ. 2012;345:e8343.

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Kambeitz J, Goerigk S, Gattaz W, Falkai P, Benseñor IM, Lotufo PA, et al. Clinical patterns differentially predict response to transcranial direct current stimulation (tDCS) and escitalopram in major depression: a machine learning analysis of the ELECT-TDCS study. J Affect Disord. 2020;265:460–7.

  50. 50.

    Hastie T, Tibshirani R, Friedman J. The elements of statistical learning, data mining, inference, and prediction. New York, Springer, 2001. p. 16–533. ISBN 0-387-95284-5.

Download references

Acknowledgements

The authors thank Roberta Ferreira de Mello for administrative support.

Author information

Affiliations

Authors

Contributions

All authors have contributed substantially to the conception, data acquisition, analysis, or interpretation of data for the work; SG, FP, and ARB conceptualized the study, analyzed the data, and interpreted the results. LB and LBR were involved in data acquisition and interpretation of the findings. MB, NS, TSK, ZJD, and DMB were involved in the interpretation of the findings. All authors participated in the critical revision and finalization of the article and gave final approval for the version to be published.

Corresponding author

Correspondence to Andre R. Brunoni.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Goerigk, S.A., Padberg, F., Bühner, M. et al. Distinct trajectories of response to prefrontal tDCS in major depression: results from a 3-arm randomized controlled trial. Neuropsychopharmacol. 46, 774–782 (2021). https://doi.org/10.1038/s41386-020-00935-x

Download citation

Further reading

Search

Quick links