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Escitalopram and transcranial direct current stimulation in major depressive disorder: a double blind, placebo-controlled, randomized, non-inferiority trial

Abstract

Major depressive disorder (MDD) is a common psychiatric condition, mostly treated with antidepressant drugs, which are limited for issues such as refractoriness and adverse effects. In this context, we investigate a non-pharmacological treatment known as transcranial direct current stimulation (tDCS). In a prior clinical trial with 120 patients with MDD, we demonstrated that the combination of tDCS with sertraline 50mg/day had increased, faster effects on depressive symptoms (Brunoni et al., JAMA Psychiatry, 2013). However, although we suggested that tDCS vs. sertraline had similar efficacy, such comparison was compromised due to the low sertraline dose and also because the comparison of sertraline vs. placebo was not significant. To prove that tDCS is similarly effective than antidepressants would have a tremendous impact in clinical psychiatry, since tDCS is virtually absent of adverse effects. Its ease of use, portability and low price are also interesting characteristics for using in primary and secondary health care. Thus, our aim is to compare tDCS against a fully dosed, effective antidepressant. The study will be a non-inferiority, randomized, double-blinded, placebo-controlled, three-arm trial comparing active tDCS/placebo pill, sham tDCS/escitalopram 20mg/day and sham tDCS/placebo pill for ten weeks, randomizing 240 patients with MDD in a 3:3:2 ratio (less to placebo). Our primary aim is to show that tDCS is not inferior to escitalopram 20mg/day with a non-inferiority margin of at least 50% of the escitalopram-placebo effect. As secondary aims, we will investigate putative biomarkers for tDCS response. This is important considering the large sample size of this study and also the paucity of tDCS studies - therefore, the identification of such biomarkers could generate new hypothesis for future studies and for tDCS' mechanisms of action. The biomarkers will be: genetic polymorphisms (BDNF, SLC6A4, THP1, 5HT2A); serum markers (BDNF); motor cortical excitability (cortical silent period, intracortical inhibition, intracortical facilitation); heart rate variability; and neuroimaging (structural volume of the dorsolateral prefrontal and anterior cingulate cortex, white matter tracts of the prefrontal cortex and posterior cingulate cortex connectivity). This project represents a novel research line in our Institution, and we thereby propose the onset of a new center denominated C.I.N.A. (Interdisciplinary Center for Applied Neuromodulation) that will foment the use and development of projects using neuromodulation techniques. This new center will also interact with other centers on the fields of clinical research, neurosciences and neuropsychiatry. (AU)

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Scientific publications (33)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
SUEN, PAULO J. C.; GOERIGK, STEPHAN; RAZZA, LAIS B.; PADBERG, FRANK; PASSOS, IVES CAVALCANTE; BRUNONI, ANDRE R. Classification of unipolar and bipolar depression using machine learning techniques. PSYCHIATRY RESEARCH, v. 295, JAN 2021. Web of Science Citations: 0.
BULUBAS, LUCIA; PADBERG, FRANK; MEZGER, EVA; SUEN, PAULO; BUENO, V, PRISCILA; DURAN, FABIO; BUSATTO, GERALDO; AMARO JR, EDSON; BENSENOR, ISABELA M.; LOTUFO, PAULO A.; GOERIGK, STEPHAN; GATTAZ, WAGNER; KEESER, DANIEL; BRUNONI, ANDRE R. Prefrontal resting-state connectivity and antidepressant response: no associations in the ELECT-TDCS trial. EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE, v. 271, n. 1, SI SEP 2020. Web of Science Citations: 0.
SUEN, PAULO J. C.; DOLL, SARAH; BATISTUZZO, MARCELO C.; BUSATTO, GERALDO; RAZZA, LAIS B.; PADBERG, FRANK; MEZGER, EVA; BULUBAS, LUCIA; KEESER, DANIEL; DENG, ZHI-DE; BRUNONI, ANDRE R. Association between tDCS computational modeling and clinical outcomes in depression: data from the ELECT-TDCS trial. EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE, v. 271, n. 1, SI APR 2020. Web of Science Citations: 3.
KAMBEITZ, JOSEPH; GOERIGK, STEPHAN; GATTAZ, WAGNER; FALKAI, PETER; BENSENOR, ISABELA M.; LOTUFO, PAULO A.; BUEHNER, MARKUS; KOUTSOULERIS, NIKOLAOS; PADBERG, FRANK; BRUNONI, ANDRE R. 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. Journal of Affective Disorders, v. 265, p. 460-467, MAR 15 2020. Web of Science Citations: 0.
BRUNONI, ANDRE R.; CARRACEDO, ANGEL; AMIGO, OLALLA M.; PELLICER, ANA L.; TALIB, LEDA; CARVALHO, ANDRE F.; LOTUFO, PAULO A.; BENSENOR, ISABELA M.; GATTAZ, WAGNER; CAPPI, CAROLINA. Association of BDNF, HTR2A, TPH1, SLC6A4, and COMT polymorphisms with tDCS and escitalopram efficacy: ancillary analysis of a double-blind, placebo-controlled trial. Revista Brasileira de Psiquiatria, v. 42, n. 2, p. 128-135, MAR-APR 2020. Web of Science Citations: 0.
MORENO, MARINA L.; GOERIGK, STEPHAN A.; BERTOLA, LAISS; SUEMOTO, CLAUDIA K.; RAZZA, LAIS B.; MOFFA, ADRIANO H.; VERONEZI, BEATRIZ P.; TORT, LUARA; NOGUEIRA, BARBARA S.; GATTAZ, WAGNER F.; FRAGUAS, RENERIO; PADBERG, FRANK; LOTUFO, PAULO A.; BENSENOR, ISABELA M.; BRUNONI, ANDRE R. Cognitive changes after tDCS and escitalopram treatment in major depressive disorder: Results from the placebo-controlled ELECT-TDCS trial. Journal of Affective Disorders, v. 263, p. 344-352, FEB 15 2020. Web of Science Citations: 0.
BRUNONI, ANDRE R.; SUPASITTHUMRONG, THITIPORN; TEIXEIRA, ANTONIO LUCIO; VIEIRA, ERICA L. M.; GATTAZ, WAGNER F.; BENSENOR, ISABELA M.; LOTUFO, PAULO A.; LAFER, BENY; BERK, MICHAEL; CARVALHO, ANDRE F.; MAES, MICHAEL. Differences in the immune-inflammatory profiles of unipolar and bipolar depression. Journal of Affective Disorders, v. 262, p. 8-15, FEB 1 2020. Web of Science Citations: 0.
ANDRE R. BRUNONI; ANGEL CARRACEDO; OLALLA M. AMIGO; ANA L. PELLICER; LEDA TALIB; ANDRE F. CARVALHO; PAULO A. LOTUFO; ISABELA M. BENSEÑOR; WAGNER GATTAZ; CAROLINA CAPPI. Association of BDNF, HTR2A, TPH1, SLC6A4, and COMT polymorphisms with tDCS and escitalopram efficacy: ancillary analysis of a double-blind, placebo-controlled trial. Revista Brasileira de Psiquiatria, v. 42, n. 2, p. 128-135, Abr. 2020.
APARICIO, LUANA V. M.; ROSA, VIVIANNE; RAZZA, LAIS M.; SAMPAIO-JUNIOR, BERNARDO; BORRIONE, LUCAS; VALIENGO, LEANDRO; LOTUFO, PAULO A.; BENSENOR, ISABELA M.; FRAGUAS, RENERIO; MOFFA, ADRIANO H.; GATTAZ, WAGNER F.; BRUNONI, ANDRE RUSSOWSKY. Transcranial direct current stimulation (tDCS) for preventing major depressive disorder relapse: Results of a 6-month follow-up. DEPRESSION AND ANXIETY, v. 36, n. 3, p. 262-268, MAR 2019. Web of Science Citations: 1.
ANDRE R. BRUNONI; ANGEL CARRACEDO; OLALLA M. AMIGO; ANA L. PELLICER; LEDA TALIB; ANDRE F. CARVALHO; PAULO A. LOTUFO; ISABELA M. BENSEÑOR; WAGNER GATTAZ; CAROLINA CAPPI. Association of BDNF, HTR2A, TPH1, SLC6A4, and COMT polymorphisms with tDCS and escitalopram efficacy: ancillary analysis of a double-blind, placebo-controlled trial. Revista Brasileira de Psiquiatria, n. ahead, p. -, 2019.
FIQUER, JULIANA TEIXEIRA; MORENO, RICARDO ALBERTO; BRUNONI, ANDRE R.; BARROS, VIVIAN BOSCHESI; FERNANDES, FERNANDO; GORENSTEIN, CLARICE. What is the nonverbal communication of depression? Assessing expressive differences between depressive patients and healthy volunteers during clinical interviews. Journal of Affective Disorders, v. 238, p. 636-644, OCT 1 2018. Web of Science Citations: 0.
BRUNONI, ANDRE R.; PADBERG, FRANK; MARCIANO VIEIRA, ERICA LEANDRO; TEIXEIRA, ANTONIO LUCIO; CARVALHO, ANDRE F.; LOTUFO, PAULO ANDRADE; GATTAZ, WAGNER F.; BENSENOR, ISABELA MARTINS. Plasma biomarkers in a placebo-controlled trial comparing tDCS and escitalopram efficacy in major depression. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 86, p. 211-217, AUG 30 2018. Web of Science Citations: 8.
HAYASHI, CINTYA YUKIE; NEVILLE, IURI SANTANA; RODRIGUES, PRISCILA APARECIDA; GALHARDONI, RICARDO; BRUNONI, ANDRE RUSSOWSKY; ZANINOTTO, ANA LUIZA; DE PAULA GUIRADO, VINICIUS MONTEIRO; CUEVA, ANA SOFIA; DE ANDRADE, DANIEL CIAMPI; TEIXEIRA, MANOEL JACOBSEN; PAIVA, WELLINGSON SILVA. Altered Intracortical Inhibition in Chronic Traumatic Diffuse Axonal Injury. FRONTIERS IN NEUROLOGY, v. 9, MAR 28 2018. Web of Science Citations: 0.
BRUNONI, A. R.; MOFFA, A. H.; SAMPAIO-JUNIOR, B.; BORRIONE, L.; MORENO, M. L.; FERNANDES, R. A.; VERONEZI, B. P.; NOGUEIRA, B. S.; APARICIO, L. V. M.; RAZZA, L. B.; CHAMORRO, R.; TORT, L. C.; FRAGUAS, R.; LOTUFO, P. A.; GATTAZ, W. F.; FREGNI, F.; BENSENOR, I. M.; INVESTIGATORS, ELECT-TDCS. Trial of Electrical Direct-Current Therapy versus Escitalopram for Depression. New England Journal of Medicine, v. 376, n. 26, p. 2523-2533, JUN 29 2017. Web of Science Citations: 67.
ESMAEILPOUR, ZEINAB; SCHESTATSKY, PEDRO; BIKSON, MAROM; BRUNONI, ANDRE R.; PELLEGRINELLI, ADA; PIOVESAN, FERNANDA X.; SANTOS, MARIANA M. S. A.; MENEZES, RENATA B.; FREGNI, FELIPE. Notes on Human Trials of Transcranial Direct Current Stimulation between 1960 and 1998. FRONTIERS IN HUMAN NEUROSCIENCE, v. 11, FEB 23 2017. Web of Science Citations: 11.
VALIENGO, LEANDRO C. L.; GOULART, ALESSANDRA C.; DE OLIVEIRA, JANAINA F.; BENSENOR, ISABELA M.; LOTUFO, PAULO A.; BRUNONI, ANDRE R. Transcranial direct current stimulation for the treatment of post-stroke depression: results from a randomised, sham-controlled, double-blinded trial. JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, v. 88, n. 2, p. 170-175, FEB 2017. Web of Science Citations: 18.
BRUNONI, ANDRE RUSSOWSKY; TORTELLA, GABRIEL; BENSENOR, ISABELA MARTINS; LOTUFO, PAULO ANDRADE; CARVALHO, ANDRE FERRER; FREGNI, FELIPE. Cognitive effects of transcranial direct current stimulation in depression: Results from the SELECT-TDCS trial and insights for further clinical trials. Journal of Affective Disorders, v. 202, p. 46-52, SEP 15 2016. Web of Science Citations: 15.
VERONEZI, B. P.; MOFFA, A. H.; CARVALHO, A. F.; GALHARDONI, R.; SIMIS, M.; BENSENOR, I. M.; LOTUFO, P. A.; MACHADO-VIEIRA, R.; DASKALAKIS, Z. J.; BRUNONI, A. R. Evidence for increased motor cortical facilitation and decreased inhibition in atypical depression. ACTA PSYCHIATRICA SCANDINAVICA, v. 134, n. 2, p. 172-182, AUG 2016. Web of Science Citations: 5.
DIMOV, LUIZ FABIO; FRANCIOSI, ADRIANO CARDOZO; PINHEIRO CAMPOS, ANA CAROLINA; BRUNONI, ANDRE RUSSOWSKY; PAGANO, ROSANA LIMA. Top-Down Effect of Direct Current Stimulation on the Nociceptive Response of Rats. PLoS One, v. 11, n. 4 APR 12 2016. Web of Science Citations: 4.
VALIENGO, LEANDRO; CASATI, ROBERTA; BOLOGNINI, NADIA; LOTUFO, PAULO A.; BENSENOR, ISABELA M.; GOULART, ALESSANDRA C.; BRUNONI, ANDRE R. Transcranial direct current stimulation for the treatment of post-stroke depression in aphasic patients: a case series. NEUROCASE, v. 22, n. 2, p. 225-228, MAR 3 2016. Web of Science Citations: 6.
WOODS, A. J.; ANTAL, A.; BIKSON, M.; BOGGIO, P. S.; BRUNONI, A. R.; CELNIK, P.; COHEN, L. G.; FREGNI, F.; HERRMANN, C. S.; KAPPENMAN, E. S.; KNOTKOVA, H.; LIEBETANZ, D.; MINIUSSI, C.; MIRANDA, P. C.; PAULUS, W.; PRIORI, A.; REATO, D.; STAGG, C.; WENDEROTH, N.; NITSCHE, M. A. A technical guide to tDCS, and related non-invasive brain stimulation tools. CLINICAL NEUROPHYSIOLOGY, v. 127, n. 2, p. 1031-1048, FEB 2016. Web of Science Citations: 240.
SLYEPCHENKO, A.; BRUNONI, A. R.; MCINTYRE, R. S.; QUEVEDO, J.; CARVALHO, A. F. The Adverse Effects of Smoking on Health Outcomes in Bipolar Disorder: A Review and Synthesis of Biological Mechanisms. CURRENT MOLECULAR MEDICINE, v. 16, n. 2, p. 187-205, 2016. Web of Science Citations: 4.
NEVILLE, IURI SANTANA; HAYASHI, CINTYA YUKIE; EL HAJJ, SIMONE ALVES; COSTA ZANINOTTO, ANA LUIZA; SABINO, JULIANA PEREZ; SOUSA, JR., LEONARDO MOURA; NAGUMO, MARCIA MITIE; BRUNONI, ANDRE RUSSOWSKY; SILVA SHIEH, BARBARA DAL FORNO; OLIVEIRA AMORIM, ROBSON LUIS; TEIXEIRA, MANOEL JACOBSEN; PAIVA, WELLINGSON SILVA. Repetitive Transcranial Magnetic Stimulation (rTMS) for the cognitive rehabilitation of traumatic brain injury (TBI) victims: study protocol for a randomized controlled trial. Trials, v. 16, OCT 5 2015. Web of Science Citations: 6.
BRUNONI, A. R.; LOTUFO, P. A.; SABBAG, C.; GOULART, A. C.; SANTOS, I. S.; BENSENOR, I. M. Decreased brain-derived neurotrophic factor plasma levels in psoriasis patients. Brazilian Journal of Medical and Biological Research, v. 48, n. 8, p. 711-714, AUG 2015. Web of Science Citations: 8.
MORENO, MARINA L.; VANDERHASSELT, MARIE-ANNE; CARVALHO, ANDRE F.; MOFFA, ADRIANO H.; LOTUFO, PAULO A.; BENSENOR, ISABELA M.; BRUNONI, ANDRE R. Effects of acute transcranial direct current stimulation in hot and cold working memory tasks in healthy and depressed subjects. Neuroscience Letters, v. 591, p. 126-131, MAR 30 2015. Web of Science Citations: 19.
VANDERHASSELT, MARIE-ANNE; DE RAEDT, RUDI; NAMUR, VICTORIA; LOTUFO, PAULO A.; BENSENOR, ISABELA M.; BOGGIO, PAULO S.; BRUNONI, ANDRE R. Transcranial electric stimulation and neurocognitive training in clinically depressed patients: A pilot study of the effects on rumination. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 57, p. 93-99, MAR 3 2015. Web of Science Citations: 29.
BRUNONI, ANDRE R.; BAEKEN, CHRIS; MACHADO-VIEIRA, RODRIGO; GATTAZ, WAGNER F.; VANDERHASSELT, MARIE-ANNE. BDNF blood levels after non-invasive brain stimulation interventions in major depressive disorder: A systematic review and meta-analysis. WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY, v. 16, n. 2, p. 114-122, FEB 2015. Web of Science Citations: 0.
BRUNONI, ANDRE R.; BAEKEN, CHRIS; MACHADO-VIEIRA, RODRIGO; GATTAZ, WAGNER F.; VANDERHASSELT, MARIE-ANNE. BDNF blood levels after electroconvulsive therapy in patients with mood disorders: A systematic review and meta-analysis. WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY, v. 15, n. 5, p. 411-418, JUL 2014. Web of Science Citations: 3.
BRUNONI, ANDRE R.; MACHADO-VIEIRA, RODRIGO; ZARATE, CARLOS A.; VALIENGO, LEANDRO; VIEIRA, ERICA L. M.; BENSENOR, ISABELA M.; LOTUFO, PAULO A.; GATTAZ, WAGNER F.; TEIXEIRA, ANTONIO L. Cytokines plasma levels during antidepressant treatment with sertraline and transcranial direct current stimulation (tDCS): results from a factorial, randomized, controlled trial. Psychopharmacology, v. 231, n. 7, p. 1315-1323, APR 2014. Web of Science Citations: 25.
BRUNONI, ANDRE RUSSOWSKY; SCHESTATSKY, PEDRO; LOTUFO, PAULO ANDRADE; BENSENOR, ISABELA MARTINS; FREGNI, FELIPE. Comparison of blinding effectiveness between sham tDCS and placebo sertraline in a 6-week major depression randomized clinical trial. CLINICAL NEUROPHYSIOLOGY, v. 125, n. 2, p. 298-305, FEB 2014. Web of Science Citations: 38.
BRUNONI, ANDRE R.; FRAGUAS JUNIOR, RENERIO; KEMP, ANDREW H.; LOTUFO, PAULO A.; BENSENOR, ISABELA M.; FREGNI, FELIPE. Differential improvement in depressive symptoms for tDCS alone and combined with pharmacotherapy: an exploratory analysis from The Sertraline Vs. Electrical Current Therapy For Treating Depression Clinical Study. INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, v. 17, n. 1, p. 53-61, JAN 2014. Web of Science Citations: 14.
ADRIANO H. MOFFA; LEANDRO VALIENGO; PEDRO SHIOZAWA; ANDRÉ RUSSOWSKY BRUNONI. Novel neurotherapeutics in psychiatry: use and rationale of transcranial direct current stimulation in major depressive disorder. ARCHIVES OF CLINICAL PSYCHIATRY, v. 41, n. 1, p. 15-20, Abr. 2014.
MOFFA, ADRIANO H.; VALIENGO, LEANDRO; SHIOZAWA, PEDRO; BRUNONI, ANDRE RUSSOWSKY. Novel neurotherapeutics in psychiatry: use and rationale of transcranial direct current stimulation in major depressive disorder. ARCHIVES OF CLINICAL PSYCHIATRY, v. 41, n. 1, p. 15-20, Abr. 2014. Web of Science Citations: 2.

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