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.
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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Muthén B, Shedden K. Finite mixture modeling with mixture outcomes using the EM algorithm. Biometrics. 1999;55:463–9.
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.
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.
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.
Meinshausen N, Bühlmann P. Stability selection. J R Stat Soc Ser B Stat Methodol. 2010;72:417–73.
Zou H, Hastie T. Regularization and variable selection via the elastic net. J R Stat Soc B. 2005;67:301–20.
Rencher AC, Pun FC. Inflation of R2 in Best Subset Regression. Technometrics. 1980;22:49–53.
Fagerland MW, Hosmer DW. Tests for goodness of fit in ordinal logistic regression models. J Stat Comput Simul. 2016;86:3398–418.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Ziemann U. Pharmaco-transcranial magnetic stimulation studies of motor excitability. Handb Clin Neurol. 2013;116:387–97.
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.
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.
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.
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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
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