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Prefrontal transcranial direct current stimulation (tDCS) as treatment for major depression: study design and methodology of a multicenter triple blind randomized placebo controlled trial (DepressionDC)

European Archives of Psychiatry and Clinical Neuroscience volume 267, pages 751–766 (2017)Cite this article

Abstract

Transcranial direct current stimulation (tDCS) has been proposed as novel treatment for major depressive disorder (MDD) based on clinical pilot studies as well as randomized controlled monocentric trials. The DepressionDC trial is a triple-blind (blinding of rater, operator and patient), randomized, placebo controlled multicenter trial investigating the efficacy and safety of prefrontal tDCS used as additive treatment in MDD patients who have not responded to selective serotonin reuptake inhibitors (SSRI). At 5 study sites, 152 patients with MDD receive a 6-weeks treatment with active tDCS (anode F3 and cathode F4, 2 mA intensity, 30 min/day) or sham tDCS add-on to a stable antidepressant medication with an SSRI. Follow-up visits are at 3 and 6 months after the last tDCS session. The primary outcome measure is the change of the Montgomery-Asberg Depression Rating Scale (MADRS) scores at week 6 post-randomisation compared to baseline. Secondary endpoints also cover other psychopathological domains, and a comprehensive safety assessment includes measures of cognition. Patients undergo optional investigations comprising genetic testing and functional magnetic resonance imaging (fMRI) of structural and functional connectivity. The study uses also an advanced tDCS technology including standard electrode positioning and recording of technical parameters (current, impedance, voltage) in every tDCS session. Aside reporting the study protocol here, we present a novel approach for monitoring technical parameters of tDCS which will allow quality control of stimulation and further analysis of the interaction between technical parameters and clinical outcome. The DepressionDC trial will hopefully answer the important clinical question whether prefrontal tDCS is a safe and effective antidepressant intervention in patients who have not sufficiently responded to SSRIs.

Trial registry: ClinicalTrials.gov Identifier NCT0253016.

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References

  1. Murray C, Lopez A (1996) The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries and risk factors in 1990 and projected to 2020, ed. H.S.o.P. Health. Harvard School of Public Health, Cambridge

    Google Scholar 

  2. Greden JF (2001) The burden of recurrent depression: causes, consequences, and future prospects. J Clin Psychiatry 62(Suppl 22)5–9

    Google Scholar 

  3. Bschor T (2008) Definition, klinisches Bild und Epidemiologie. In: Behandlungsmanual therapieresistente Depression. Pharmakotherapie—Somatische Therapieverfahren—Psychotherapie. Kohlhammer Verlag, Stuttgart, pp 11–16

  4. Trivedi MH et al (2006) Factors associated with health-related quality of life among outpatients with major depressive disorder: a STAR*D report. J Clin Psychiatry 67(2):185–195

    Article  PubMed  Google Scholar 

  5. Rush AJ et al (2006) Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 354(12):1231–1242

    Article  CAS  PubMed  Google Scholar 

  6. Boggio PS et al (2008) A randomized, double-blind clinical trial on the efficacy of cortical direct current stimulation for the treatment of major depression. Int J Neuropsychopharmacol 11(2):249–254

    Article  PubMed  Google Scholar 

  7. Brunoni AR et al (2011) Transcranial direct current stimulation (tDCS) in unipolar vs. bipolar depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 35(1):96–101

    Article  CAS  PubMed  Google Scholar 

  8. Dell’Osso B et al (2012) Transcranial direct current stimulation for the outpatient treatment of poor-responder depressed patients. Eur Psychiatry 27(7):513–517

    Article  PubMed  Google Scholar 

  9. Ferrucci R et al (2009) Transcranial direct current stimulation in severe, drug-resistant major depression. J Affect Disord 118(1–3):215–219

    Article  CAS  PubMed  Google Scholar 

  10. Fregni F et al (2006) Treatment of major depression with transcranial direct current stimulation. Bipolar Disord 8(2):203–204

    Article  PubMed  Google Scholar 

  11. Martin DM et al (2011) Fronto-extracephalic transcranial direct current stimulation as a treatment for major depression: an open-label pilot study. J Affect Disord 134(1–3):459–463

    Article  PubMed  Google Scholar 

  12. Insel T et al (2010) Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry 167(7):748–751

    Article  PubMed  Google Scholar 

  13. Glannon W (2015) Research domain criteria: a final paradigm for psychiatry? Front Hum Neurosci 9:488

    Article  PubMed  PubMed Central  Google Scholar 

  14. Bikson M et al (2016) Safety of transcranial direct current stimulation: evidence based update 2016. Brain Stimul

  15. De Raedt R, Vanderhasselt MA, Baeken C (2015) Neurostimulation as an intervention for treatment resistant depression: From research on mechanisms towards targeted neurocognitive strategies. Clin Psychol Rev 41:61–69

    Article  PubMed  Google Scholar 

  16. Plewnia C, Schroeder PA, Wolkenstein L (2015) Targeting the biased brain: non-invasive brain stimulation to ameliorate cognitive control. Lancet Psychiatry 2(4):351–356

    Article  PubMed  Google Scholar 

  17. Mayberg HS et al (1999) Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry 156(5):675–682

    CAS  PubMed  Google Scholar 

  18. Bench CJ et al (1992) The anatomy of melancholia–focal abnormalities of cerebral blood flow in major depression. Psychol Med 22(3):607–615

    Article  CAS  PubMed  Google Scholar 

  19. Soares JC, Mann JJ (1997) The functional neuroanatomy of mood disorders. J Psychiatr Res 31(4):393–432

    Article  CAS  PubMed  Google Scholar 

  20. Baxter LR Jr., et al (1989) Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatry 46(3):243–250

    Article  CAS  PubMed  Google Scholar 

  21. Ishizaki J et al (2008) Changes in regional cerebral blood flow following antidepressant treatment in late-life depression. Int J Geriatr Psychiatry 23(8):805–811

    Article  PubMed  Google Scholar 

  22. Berlim MT et al (2014) Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials. Psychol Med 44(2):225–239

    Article  CAS  PubMed  Google Scholar 

  23. Padberg F, George MS (2009) Repetitive transcranial magnetic stimulation of the prefrontal cortex in depression. Exp Neurol 219(1):2–13

    Article  PubMed  Google Scholar 

  24. Nitsche MA, Paulus W (2000) Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol 527(3):633–639

  25. Pathak Y et al (2013) The role of electrode location and stimulation polarity in patient response to cortical stimulation for major depressive disorder. Brain Stimul 6(3):254–260

    Article  PubMed  Google Scholar 

  26. Price JL, Drevets WC (2012) Neural circuits underlying the pathophysiology of mood disorders. Trends Cogn Sci 16(1):61–71

    Article  PubMed  Google Scholar 

  27. Grimm S et al (2008) Imbalance between left and right dorsolateral prefrontal cortex in major depression is linked to negative emotional judgment: an fMRI study in severe major depressive disorder. Biol Psychiatry 63(4):369–376

    Article  PubMed  Google Scholar 

  28. Brunoni AR et al (2013) The sertraline vs. electrical current therapy for treating depression clinical study: results from a factorial, randomized, controlled trial. JAMA Psychiatry 70(4):383–391

    Article  CAS  PubMed  Google Scholar 

  29. Palm U et al (2012) Transcranial direct current stimulation in treatment resistant depression: a randomized double-blind, placebo-controlled study. Brain Stimul 5(3):242–251

    Article  CAS  PubMed  Google Scholar 

  30. Bai S et al (2014) A computational modelling study of transcranial direct current stimulation montages used in depression. Neuroimage 87:332–344

    Article  PubMed  Google Scholar 

  31. Bikson M et al (2010) Electrode montages for tDCS and weak transcranial electrical stimulation: role of “return” electrode’s position and size. Clin Neurophysiol 121(12):1976–1978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shiozawa P et al (2014) Transcranial direct current stimulation for major depression: an updated systematic review and meta-analysis. Int J Neuropsychopharmacol 17(9):1443–1452

    Article  PubMed  Google Scholar 

  33. Brunoni AR et al (2016) Transcranial direct current stimulation for acute major depressive episodes: meta-analysis of individual patient data. Br J Psychiatry 208(6):522–531

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kalu UG et al (2012) Transcranial direct current stimulation in the treatment of major depression: a meta-analysis. Psychol Med 42(9):1791–1800

    Article  CAS  PubMed  Google Scholar 

  35. Meron D et al (2015) Transcranial direct current stimulation (tDCS) in the treatment of depression: Systematic review and meta-analysis of efficacy and tolerability. Neurosci Biobehav Rev 57:46–62

    Article  PubMed  Google Scholar 

  36. Berlim MT, Van den Eynde F, Daskalakis ZJ (2013) Clinical utility of transcranial direct current stimulation (tDCS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials. J Psychiatr Res 47(1):1–7

    Article  PubMed  Google Scholar 

  37. Loo CK et al (2012) Transcranial direct current stimulation for depression: 3-week, randomised, sham-controlled trial. Br J Psychiatry 200(1):52–59

    Article  PubMed  Google Scholar 

  38. Loo CK et al (2010) A double-blind, sham-controlled trial of transcranial direct current stimulation for the treatment of depression. Int J Neuropsychopharmacol 13(1):61–69

    Article  PubMed  Google Scholar 

  39. Blumberger DM et al (2012) A randomized double-blind sham-controlled study of transcranial direct current stimulation for treatment-resistant major depression. Front Psychiatry 3:74

    Article  PubMed  PubMed Central  Google Scholar 

  40. Segrave RA et al (2014) Concurrent cognitive control training augments the antidepressant efficacy of tDCS: a pilot study. Brain Stimul 7(2):325–331

    Article  CAS  PubMed  Google Scholar 

  41. Bennabi D et al (2015) Pilot study of feasibility of the effect of treatment with tDCS in patients suffering from treatment-resistant depression treated with escitalopram. Clin Neurophysiol 126(6):1185–1189

    Article  CAS  PubMed  Google Scholar 

  42. Nitsche MA et al (2009) Serotonin affects transcranial direct current-induced neuroplasticity in humans. Biol Psychiatry 66(5):503–508

    Article  CAS  PubMed  Google Scholar 

  43. Kuo HI et al (2016) Chronic enhancement of serotonin facilitates excitatory transcranial direct current stimulation-induced neuroplasticity. Neuropsychopharmacology 41(5):1223–1230

    Article  CAS  PubMed  Google Scholar 

  44. Brunoni AR et al (2014) 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. Int J Neuropsychopharmacol 17(1):53–61

    Article  CAS  PubMed  Google Scholar 

  45. Brunoni AR et al (2013) Impact of 5-HTTLPR and BDNF polymorphisms on response to sertraline versus transcranial direct current stimulation: implications for the serotonergic system. Eur Neuropsychopharmacol 23(11):1530–1540

    Article  CAS  PubMed  Google Scholar 

  46. Levkovitz Y et al (2015) Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial. World. Psychiatry 14(1):64–73

    Google Scholar 

  47. Palm U et al (2014) The role of contact media at the skin-electrode interface during transcranial direct current stimulation (tDCS). Brain Stimul 7(5):762–764

    Article  PubMed  Google Scholar 

  48. Derogatis L (1993) BSI brief symptom inventory: administration, scoring, and procedure manual, 4th edn. National Computer Systems, Minneapolis, MN

  49. Bernstein DP, Fink L (1998) CTQ Childhood Trauma questionnaire. A retrospective self-report. Manual. The Psychological Corporation, San Antonio

    Google Scholar 

  50. Cohen S et al (1997) Social ties and susceptibility to the common cold. JAMA 277(24):1940–1944

    Article  CAS  PubMed  Google Scholar 

  51. Fuge P et al (2014) Assessment of age-related changes in cognitive functions using EmoCogMeter, a novel tablet-computer based approach. J Vis Exp 84:e50942

  52. Keeser D et al (2011) Prefrontal transcranial direct current stimulation changes connectivity of resting-state networks during fMRI. J Neurosci 31(43):15284–15293

    Article  CAS  PubMed  Google Scholar 

  53. Keeser D et al (2011) Prefrontal direct current stimulation modulates resting EEG and event-related potentials in healthy subjects: a standardized low resolution tomography (sLORETA) study. Neuroimage 55(2):644–657

    Article  CAS  PubMed  Google Scholar 

  54. Bundesen C (1990) A theory of visual attention. Psychol Rev 97(4):523–547

    Article  CAS  PubMed  Google Scholar 

  55. Bundesen C, Habekost T, Kyllingsbaek S (2005) A neural theory of visual attention: bridging cognition and neurophysiology. Psychol Rev 112(2):291–328

    Article  PubMed  Google Scholar 

  56. Desimone R, Duncan J (1995) Neural mechanisms of selective visual attention. Annu Rev Neurosci 18:193–222

    Article  CAS  PubMed  Google Scholar 

  57. Chechlacz M et al (2015) Structural variability within frontoparietal networks and individual differences in attentional functions: an approach using the theory of visual attention. J Neurosci 35(30):10647–10658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Smoller JW (2015) The genetics of stress-related disorders: PTSD, depression, and anxiety disorders. Neuropsychopharmacology

  59. Gong Q, Y. He, Depression (2015) neuroimaging and connectomics: a selective overview. Biol Psychiatry 77(3):223–235

    Article  PubMed  Google Scholar 

  60. Won E, Ham BJ (2016) Imaging genetics studies on monoaminergic genes in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 64:311–319

    Article  CAS  PubMed  Google Scholar 

  61. Nieratschker V et al (2015) The COMT Val/Met polymorphism modulates effects of tDCS on response inhibition. Brain Stimul 8(2):283–288

    Article  PubMed  Google Scholar 

  62. Lockwood LE, Su S, Youssef NA (2015) The role of epigenetics in depression and suicide: A platform for gene-environment interactions. Psychiatry Res 228(3):235–242

    Article  CAS  PubMed  Google Scholar 

  63. Lopizzo N et al (2015) Gene-environment interaction in major depression: focus on experience-dependent biological systems. Front Psychiatry 6:68

    Article  PubMed  PubMed Central  Google Scholar 

  64. Perahia DG et al (2009) Switching to duloxetine in selective serotonin reuptake inhibitor non- and partial-responders: effects on painful physical symptoms of depression. J Psychiatr Res 43(5):512–518

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the German Center for Brain Stimulation (GCBS) research consortium (FKZ 01EE1403G), funded by the Federal Ministry of Education and Research (BMBF).

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    Authors and Affiliations

    1. Department of Psychiatry and Psychotherapy, Ludwig Maximilian University Munich, Nussbaumstr. 7, 80336, Munich, Germany

      Frank Padberg, Ulrike Kumpf, Ulrich Palm, Jana Nolden, Daniel Keeser, Peter Falkai & Alkomiet Hasan

    2. Institute for Medical Information Processing, Biometry and Epidemiology (IBE), Ludwig Maximilian University Munich, Munich, Germany

      Ulrich Mansmann

    3. Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany

      Christian Plewnia & Andreas Fallgatter

    4. Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany

      Berthold Langguth & Rainer Rupprecht

    5. kbo-Inn-Salzach-Hospital, Wasserburg am Inn, Germany

      Peter Zwanzger

    6. Münchner Studienzentrum, Technical University of Munich, Munich, Germany

      Silvia Egert

    7. Department of Psychiatry and Psychotherapy, Charité-Campus Benjamin Franklin, Berlin, Germany

      Max Burger & Malek Bajbouj

    Authors
    1. Frank Padberg
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    Corresponding author

    Correspondence to Frank Padberg.

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    Conflict of interest

    F.P. has received speaker’s honorarium from Mag&More GmbH and support with equipment from neuroConn GmbH, Ilmenau, Germany, Mag&More GmbH and Brainsway Inc., Jerusalem. A. Hasan has been invited to scientific meetings by Lundbeck, Janssen-Cilag, and Pfizer, and he received paid speakership by Desitin, Otsuka and BAK. He is a member of the Roche Advisory Board. The other authors do not report conflicts of interest.

    Funding

    The clinical trial is funded by the Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung [BMBF]) within the German Center for Brain Stimulation (GCBS, FKZ 01EE1403G).

    Trial status

    Enrolment for this study began in January 2016. At the time of submission, we have enrolled 18 participants.

    Additional information

    Frank Padberg and Ulrike Kumpf contributed equally.

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    Padberg, F., Kumpf, U., Mansmann, U. et al. Prefrontal transcranial direct current stimulation (tDCS) as treatment for major depression: study design and methodology of a multicenter triple blind randomized placebo controlled trial (DepressionDC). Eur Arch Psychiatry Clin Neurosci 267, 751–766 (2017). https://doi.org/10.1007/s00406-017-0769-y

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