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
Keywords:
Depressive disorder, major, Electric stimulation therapy, Citalopram, Randomized controlled trial, Biological markersAbstract
CONTEXT AND OBJECTIVE: Major depressive disorder (MDD) is a common psychiatric condition, mostly treated with antidepressant drugs, which are limited due to refractoriness and adverse effects. We describe the study ratio-nale and design of ELECT-TDCS (Escitalopram versus Electric Current Therapy for Treating Depression Clinical Study), which is investigating a non-pharmacological treatment known as transcranial direct current stimulation (tDCS). DESIGN AND SETTING: Phase-III, randomized, non-inferiority, triple-arm, placebo-controlled study, ongoing in São Paulo, Brazil. METHODS: ELECT-TDCS compares the efficacy of active tDCS/placebo pill, sham tDCS/escitalopram 20 mg/day and sham tDCS/placebo pill, for ten weeks, randomizing 240 patients in a 3:3:2 ratio, respectively. Our primary aim is to show that tDCS is not inferior to escitalopram with a non-inferiority margin of at least 50% of the es-citalopram effect, in relation to placebo. As secondary aims, we investigate several biomarkers such as genetic polymorphisms, neurotrophin serum markers, motor cortical excitability, heart rate variability and neuroimaging. RESULTS: Proving that tDCS is similarly effective to antidepressants would have a tremendous impact on clinical psychiatry, since tDCS is virtually devoid of adverse effects. Its ease of use, portability and low price are further compelling characteristics for its use in primary and secondary healthcare. Multimodal investigation of biomark-ers will also contribute towards understanding the antidepressant mechanisms of action of tDCS. CONCLUSION: Our results have the potential to introduce a novel technique to the therapeutic arsenal of treat-ments for depression. CLINICAL TRIAL REGISTRATION: ClinicalTrials.Gov NCT01894815.
Downloads
References
Bromet E, Andrade LH, Hwang I, et al. Cross-national epidemiology of DSM-IV major depressive episode. BMC Med. 2011;9:90.
Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet. 1997;349(9064):1498-504.
Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006; 163(11):1905-17.
Anderson IM, Ferrier IN, Baldwin RC, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines. J Psychopharmacol. 2008;22(4):343-96.
Rosa MA, Lisanby SH. Somatic treatments for mood disorders. Neuropsychopharmacology. 2012;37(1):102-16.
George MS, Lisanby SH, Avery D, et al. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Arch Gen Psychiatry. 2010;67(5):507-16.
Schutter DJ. Antidepressant efficacy of high-frequency transcranial magnetic stimulation over the left dorsolateral prefrontal cortex in double-blind sham-controlled designs: a meta-analysis. Psychol Med. 2009;39(1):65-75.
Priori A, Hallett M, Rothwell JC. Repetitive transcranial magnetic stimulation or transcranial direct current stimulation? Brain Stimul. 2009;2(4):241-5.
Brunoni AR, Nitsche MA, Bolognini N, et al. Clinical research with transcranial direct current stimulation (tDCS): challenges and future directions. Brain Stimul. 2012;5(3):175-95.
Brunoni AR, Amadera J, Berbel B, et al. A systematic review on reporting and assessment of adverse effects associated with transcranial direct current stimulation. Int J Neuropsychopharmacol. 2011;14(8):1133-45.
Nitsche MA, Paulus W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol. 2000;527 Pt 3:633-9.
Purpura DP, McMurtry JG. Intracellular activities and evoked potential changes during polarization of motor cortex. J Neurophysiol. 1965;28:166-85.
Radman T, Ramos RL, Brumberg JC, Bikson M. Role of cortical cell type and morphology in subthreshold and suprathreshold uniform electric field stimulation in vitro. Brain Stimul. 2009;2(4): 215-28, 228. e1-3.
Batsikadze G, Moliadze V, Paulus W, Kuo MF, Nitsche MA. Partially non-linear stimulation intensity-dependent effects of direct current stimulation on motor cortex excitability in humans. J Physiol. 2013;591(Pt 7):1987-2000.
Rahman A, Reato D, Arlotti M, et al. Cellular effects of acute direct current stimulation: somatic and synaptic terminal effects. J Physiol. 2013;591(Pt 10):2563-78.
Mayberg HS, Brannan SK, Tekell JL, et al. Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry. 2000;48(8):830-43.
Moffa AH, Valiengo L, Shiozawa P, Brunoni AR. Novas neuroterapêuticas em psiquiatria: racional e uso da estimulação transcraniana por corrente contínua no transtorno depressivo maior [Novel neurotherapeutics in psychiatry: use and rationale of transcranial direct current stimulation in major depressive disorder]. Rev Psiquiatr Clín. (Sao Paulo). 2014;41(1):15-20.
Ferrucci R, Bortolomasi M, Brunoni A, et al. Comparative benefits of transcranial direct current stimulation (tDCS) treatment in patients with mild/moderate vs. severe depression. Clinical Neuropsychiatry. 2009;6(6):246-51. Available from: http://www.clinicalneuropsychiatry.org/pdf/03%20ferrucci.pdf. Accessed in 2015 (Jan 7).
Schutter DJ. Quantitative review of the efficacy of slow-frequency magnetic brain stimulation in major depressive disorder. Psychol Med. 2010;40(11):1789-95.
Brunoni AR, Ferrucci R, Fregni F, Boggio PS, Priori A. Transcranial direct current stimulation for the treatment of major depressive disorder: a summary of preclinical, clinical and translational findings. Prog Neuropsychopharmacol Biol Psychiatry. 2012;39(1):9-16.
Fregni F, Boggio PS, Nitsche MA, et al. Treatment of major depression with transcranial direct current stimulation. Bipolar Disord. 2006;8(2):203-4.
Loo CK, Alonzo A, Martin D, et al. Transcranial direct current stimulation for depression: 3-week, randomised, sham-controlled trial. Br J Psychiatry. 2012;200(1):52-9.
Brunoni AR, Valiengo L, Baccaro 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(4):383-91.
Shiozawa P, Fregni F, Benseens IM, et al. Transcranial direct current stimulation for major depression: an updated systematic review and meta-analysis. Int J Neuropsychopharmacol. 2014;17(9):1443-52.
Loo CK, Sachdev P, Martin D, et al. A double-blind, sham-controlled trial of transcranial direct current stimulation for the treatment of depression. Int J Neuropsychopharmacol. 2010;13(1):61-9.
Palm U, Schiller C, Fintescu Z, et al. Transcranial direct current stimulation in treatment resistant depression: a randomized double-blind, placebo-controlled study. Brain Stimul. 2012;5(3):242-51.
Blumberger DM, Tran LC, Fitzgerald PB, Hoy KE, Daskalakis ZJ. A randomized double-blind sham-controlled study of transcranial direct current stimulation for treatment-resistant major depression. Front Psychiatry. 2012;3:74.
Brunoni 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(1):90-8.
Koch A, Roch AJ. Hypothesis testing in the “gold standard” design for proving the efficacy of an experimental treatment relative to placebo and a reference. J Biopharm Stat. 2004;14(2):315-25.
Gamalo MA, Muthukumarana S, Ghosh P, Tiwari RC. A generalized p-value approach for assessing noninferiority in a three-arm trial. Stat Methods Med Res. 2013;22(3):261-77.
Pigeot I, Schafer J, Rohmel J, Hauschke D. Assessing non-inferiority of a new treatment in a three-arm clinical trial including a placebo. Stat Med. 2003;22(6):883-99.
Binkley N, Bolognese M, Sidorowicz-Bialynicka A, et al. A phase 3 trial of the efficacy and safety of oral recombinant calcitonin: the Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) trial. J Bone Miner Res. 2012;27(8):1821-9.
Gandiga PC, Hummel FC, Cohen LG. Transcranial DC stimulation (tDCS): a tool for double-blind sham-controlled clinical studies in brain stimulation. Clin Neurophysiol. 2006;117(4):845-50.
Nitsche MA, Cohen LG, Wassermann EM, et al. Transcranial direct current stimulation: State of the art 2008. Brain Stimul. 2008;1(3):206-23.
Brunoni AR, Schestatsky P, Lotufo PA, Benseñor IM, Fregni F. Comparison of blinding effectiveness between sham tDCS and placebo sertraline in a 6-week major depression randomized clinical trial. Clin Neurophysiol. 2014;125(2):298-305.
Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373(9665):746-58.
Rabkin JG, Markowitz JS, Ocepek-Welikson K, Wager SS. General versus systematic inquiry about emergent clinical events with SAFTEE: implications for clinical research. J Clin Psychopharmacol. 1992;12(1):3-10.
Baccaro A, Brunoni AR, Benseñor IM, Fregni F. Hypomanic episode in unipolar depression during transcranial direct current stimulation. Acta Neuropsychiatrica. 2010;22(6):316-8. Available from: http:// onlinelibrary.wiley.com/doi/10.1111/j.1601-5215.2010.00495.x/ abstract. Accessed in 2015 (Jan 7).
Brunoni AR, Valiengo L, Zanao T, et al. Manic psychosis after sertraline and transcranial direct-current stimulation. J Neuropsychiatry Clin Neurosci. 2011;23(3):E4-5.
Arul-Anandam AP, Loo C, Mitchell P. Induction of hypomanic episode with transcranial direct current stimulation. J ECT. 2010;26(1):68-9.
Gálvez V, Alonzo A, Martin S, et al. Hypomania induction in a patient with bipolar II disorder by transcranial direct current stimulation (tDCS). J ECT. 2011;27(3):256-8.
Kemp AH, Quintana DS, Gray MA. Impact of depression and antidepressant treatment on heart rate variability: a review and meta-analysis. Biol Psychiatry. 2010;67(11):1067-74.
Kemp AH, Brunoni AR, Santos IS, et al. Effects of depression, anxiety, comorbidity, and antidepressants on resting-state heart rate and its variability: an ELSA-Brasil cohort baseline study. Am J Psychiatry. 2014;171(2):1328-34.
Brunoni AR, Kemp AH, Dantas EM, et al. Heart rate variability is a trait marker of major depressive disorder: evidence from the sertraline vs. electric current therapy to treat depression clinical study. Int J Neuropsychopharmacol. 2013;16(9):1937-49.
Crisafulli C, Fabbri C, Porcelli S, et al. Pharmacogenetics of antidepressants. Front Pharmacol. 2011;16;2:6.
Kato M, Serretti A. Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Mol Psychiatry. 2010;15(5):473-500.
Zanardi R, Magri L, Rossini D, et al. Role of serotonergic gene polymorphisms on response to transcranial magnetic stimulation in depression. Eur Neuropsychopharmacol. 2007;17(10):651-7.
Bocchio-Chiavetto L, Bagnardi V, Zanardini R, et al. Serum and plasma BDNF levels in major depression: a replication study and meta-analyses. World J Biol Psychiatry. 2010;11(6):763-73.
Malaguti A, Rossini D, Lucca A, et al. Role of COMT, 5-HT(1A), and SERT genetic polymorphisms on antidepressant response to Transcranial Magnetic Stimulation. Depress Anxiety. 2011;28(7):568-73.
Brunoni AR, Kemp AH, Shiozawa P, et al. Impact of 5-HTTLPR and BDNF polymorphisms on response to sertraline versus transcranial direct current stimulation: implications for the serotonergic system. Eur Neuropsychopharmacol. 2013;23(11):1530-40.
Du L, Bakish D, Lapierre YD, Ravindran AV, Hrdina PD. Association of polymorphism of serotonin 2A receptor gene with suicidal ideation in major depressive disorder. Am J Med Genet. 2000;96(1):56-60.
Van Oekelen D, Luyten WH, Leysen JE. 5-HT2A and 5-HT2C receptors and their atypical regulation properties. Life Sci. 2003;72(22):2429-49.
McMahon FJ, Buervenich S, Charney D, et al. Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet. 2006;78(5):804-14.
Jonsson EG, Goldman D, Spurlock G, et al. Tryptophan hydroxylase and catechol-O-methyltransferase gene polymorphisms: relationships to monoamine metabolite concentrations in CSF of healthy volunteers. Eur Arch Psychiatry Clin Neurosci. 1997;247(6):297-302.
Ventimiglia R, Mather PE, Jones BE, Lindsay RM. The neurotrophins BDNF, NT-3 and NT-4/5 promote survival and morphological and biochemical differentiation of striatal neurons in vitro. Eur J Neurosci. 1995;7(2):213-22.
Kuipers SD, Trentani A, Den Boer JA, Ter Horst GJ. Molecular correlates of impaired prefrontal plasticity in response to chronic stress. J Neurochem. 2003;85(5):1312-23.
Domschke K, Lawford B, Laje G, et al. Brain-derived neurotrophic factor (BDNF) gene: no major impact on antidepressant treatment response. Int J Neuropsychopharmacol. 2010;13(1):93-101.
Bocchio-Chiavetto L, Miniussi C, Zanardini R, et al. 5-HTTLPR and BDNF Val66Met polymorphisms and response to rTMS treatment in drug resistant depression. Neurosci Lett. 2008;437(2):130-4.
Stagg CJ, Nitsche MA. Physiological basis of transcranial direct current stimulation. Neuroscientist. 2011;17(1):37-53.
Kobayashi M, Pascual-Leone A. Transcranial magnetic stimulation in neurology. Lancet Neurol. 2003;2(3):145-56.
Hasler G, Northoff G. Discovering imaging endophenotypes for major depression. Mol Psychiatry. 2011;16(6):604-19.
Bajbouj M, Lisanby SH, Lang UE, et al. Evidence for impaired cortical inhibition in patients with unipolar major depression. Biol Psychiatry. 2006;59(5):395-400.
Levinson AJ, Fitzgerald PB, Favalli G, et al. Evidence of cortical inhibitory deficits in major depressive disorder. Biol Psychiatry. 2010;67(5):458-64.
Croarkin PE, Nakonezny PA, Husain MM, et al. Evidence for increased glutamatergic cortical facilitation in children and adolescents with major depressive disorder. JAMA Psychiatry. 2013;70(3):291-9.
Lai CH. Gray matter volume in major depressive disorder: a meta-analysis of voxel-based morphometry studies. Psychiatry Res. 2013;211(1):37-46.
Du MY, Wu QZ, Yue Q, et al. Voxelwise meta-analysis of gray matter reduction in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2012;36(1):11-6.
Bora E, Fornito A, Pantelis C, Yucel M. Gray matter abnormalities in Major Depressive Disorder: a meta-analysis of voxel based morphometry studies. J Affect Disord. 2012;138(1-2):9-18.
Smith R, Chen K, Baxter L, Fort C, Lane RD. Antidepressant effects of sertraline associated with volume increases in dorsolateral prefrontal cortex. J Affect Disord. 2013;146(3):414-9.
Liao Y, Huang X, Wu Q, et al. Is depression a disconnection syndrome? Meta-analysis of diffusion tensor imaging studies in patients with MDD. J Psychiatry Neurosci. 2013;38(1):49-56.
Kozel FA, Johnson KA, Nahas Z, et al. Fractional anisotropy changes after several weeks of daily left high-frequency repetitive transcranial magnetic stimulation of the prefrontal cortex to treat major depression. J ECT. 2011;27(1):5-10.
Peng H, Zheng H, Li L, et al. High-frequency rTMS treatment increases white matter FA in the left middle frontal gyrus in young patients with treatment-resistant depression. J Affect Disord. 2012;136(3):249-57.
Wang L, Hermens DF, Hickie IB, Lagopoulos J. A systematic review of resting-state functional-MRI studies in major depression. J Affect Disord. 2012;142(1-3):6-12.
Posner J, Hellerstein DJ, Gat I, et al. Antidepressants normalize the default mode network in patients with dysthymia. JAMA Psychiatry. 2013;70(4):373-82.
Brunoni AR, Lopes M, Fregni F. A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. Int J Neuropsychopharmacol. 2008;11(8):1169-80.
Molendijk ML, Spinhoven P, Polak M, et al. Serum BDNF concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations (N=9484). Mol Psychiatry. 2014;19(7):791-800.
Brunoni AR, Baeken C, Machado-Vieira R, Gattaz WF, Vanderhasselt MA. BDNF blood levels after electroconvulsive therapy in patients with mood disorders: a systematic review and meta-analysis. World J Biol Psychiatry. 2014;15(5):411-8.
Brunoni AR, Machado-Vieira R, Zarate CA Jr., et al. BDNF plasma levels after antidepressant treatment with sertraline and transcranial direct current stimulation: results from a factorial, randomized, sham-controlled trial. Eur Neuropsychopharmacol. 2014;24(7):1144-51.
Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med. 2008;358(3):252-60.
Rothmann MD, Wiens BL, Chan ISF. Design and analysis of non-inferiority trials. Boca Raton: Taylor & Francis Group; 2012.
Huitfeldt B, Hummel J, European Federation of Statisticians in the Pharmaceutical Industry (EFSPI). The draft FDA guideline on non-inferiority clinical trials: a critical review from European pharmaceutical industry statisticians. Pharm Stat. 2011;10(5):414-9.
Nutt D, Allgulander C, Lecrubier Y, Peters T, Wittchen U. Establishing non-inferiority in treatment trials in psychiatry: guidelines from an Expert Consensus Meeting. J Psychopharmacol. 2008;22(4):409-16.
Middleton H, Shaw I, Hull S, Feder G. NICE guidelines for the management of depression. BMJ. 2005;330(7486):267-8.
Guidance for Industry Non-Inferiority Clinical Trials; 2010. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM202140.pdf. Accessed in 2015 (Jan 7).
European Medicines Agency. Pre-authorisation Evaluation of Medicines for Human Use. Guideline on the choice of the non-inferiority margin; 2004. Available from: http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003636.pdf. Accessed in 2015 (Jan 7).
Mulla SM, Scott IA, Jackevicius CA, You JJ, Guyatt GH. How to use a noninferiority trial: users’ guides to the medical literature. JAMA. 2012;308(24):2605-11.
Vigod S, Dennis CL, Daskalakis Z, et al. Transcranial direct current stimulation (tDCS) for treatment of major depression during pregnancy: study protocol for a pilot randomized controlled trial. Trials. 2014;15:366.
Knotkova H, Rosedale M, Strauss SM, et al. Using Transcranial Direct Current Stimulation to Treat Depression in HIV-Infected Persons: The Outcomes of a Feasibility Study. Front Psychiatry. 2012;3:59.
Valiengo LC, Benseñor IM, Lotufo PA, Fraguas R Jr, Brunoni AR. Transcranial direct current stimulation and repetitive transcranial magnetic stimulation in consultation-liaison psychiatry. Braz J Med Biol Res. 2013;46(10):815-23.
Palm U, Keeser D, Schiller C, et al. Skin lesions after treatment with transcranial direct current stimulation (tDCS). Brain Stimul. 2008;1(4):386-7.
Palm U, Fintescu Z, Obermeier M, et al. Serum levels of brain-derived neurotrophic factor are unchanged after transcranial direct current stimulation in treatment-resistant depression. J Affect Disord. 2013;150(2):659-63.
Brunoni AR, Machado-Vieira R, Zarate CA Jr., et al. Assessment of non-BDNF neurotrophins and GDNF levels after depression treatment with sertraline and transcranial direct current stimulation in a factorial, randomized, sham-controlled trial (SELECT-TDCS): An exploratory analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2015;56:91-6.
Player M, Taylor J, Weickert CS, et al. Increase in PAS-induced neuroplasticity after a treatment course of transcranial direct current stimulation for depression. J Affect Disord. 2014;167:140-7.
Powell TY, Boonstra TW, Martin DM, Loo CK, Breakspear M. Modulation of cortical activity by transcranial direct current stimulation in patients with affective disorder. PLoS One. 2014;9(6):e98503.
Wolkenstein L, Plewnia C. Amelioration of cognitive control in depression by transcranial direct current stimulation. Biol Psychiatry. 2013;73(7):646-51.
Oliveira JF, Zanao TA, Valiengo L, et al. Acute working memory improvement after tDCS in antidepressant-free patients with major depressive disorder. Neurosci Lett. 2013;537:60-4.
Zanao TA, Moffa AH, Shiozawa P, et al. Impact of Two or Less Missing Treatment Sessions on tDCS Clinical Efficacy: Results From a Factorial, Randomized, Controlled Trial in Major Depression. Neuromodulation. 2014;17(8):737-742.
