title: Efficacy of intermittent Theta Burst Stimulation (iTBS) and 10-Hz high-frequency repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant unipolar depression: study protocol for a randomised controlled trial.
abstract: The treatment of depression remains a challenge since at least 40% of patients do not respond to initial antidepressant therapy and 20% present chronic symptoms (more than 2 years despite standard treatment administered correctly). Repetitive transcranial magnetic stimulation (rTMS) is an effective adjuvant therapy but still not ideal. Intermittent Theta Burst Stimulation (iTBS), which has only been used recently in clinical practice, could have a faster and more intense effect compared to conventional protocols, including 10-Hz high-frequency rTMS (HF-rTMS). However, no controlled study has so far highlighted the superiority of iTBS in resistant unipolar depression.
  
  
  
  This paper focuses on the design of a randomised, controlled, double-blind, single-centre study with two parallel arms, carried out in France, in an attempt to assess the efficacy of an iTBS protocol versus a standard HF- rTMS protocol. Sixty patients aged between 18 and 75 years of age will be enrolled. They must be diagnosed with major depressive disorder persisting despite treatment with two antidepressants at an effective dose over a period of 6 weeks during the current episode. The study will consist of two phases: a treatment phase comprising 20 sessions of rTMS to the left dorsolateral prefrontal cortex, localised via a neuronavigation system and a 6-month longitudinal follow-up. The primary endpoint will be the number of responders per group, defined by a decrease of at least 50% in the initial score on the Montgomery and Asberg Rating Scale (MADRS) at the end of rTMS sessions. The secondary endpoints will be: response rate 1 month after rTMS sessions; number of remissions defined by a MADRS score of <8 at the endpoint and 1 month after; the number of responses and remissions maintained over the next 6 months; quality of life; and the presence of predictive markers of the therapeutic response: clinical (dimensional scales), neuropsychological (evaluation of cognitive functions), motor (objective motor testing) and neurophysiological (cortical excitability measurements).
  
  
  
  The purpose of our study is to check the assumption of iTBS superiority in the management of unipolar depression and we will discuss its effect over time. In case of a significant increase in the number of therapeutic responses with a prolonged effect, the iTBS protocol could be considered a first-line protocol in resistant unipolar depression.
  
  
  
  ClinicalTrials.gov, Identifier NCT02376491 . Registered on 17 February 2015 at http://clinicaltrials.gov .
authors.affiliation: CHU de Nantes, Clinical Investigation Unit 18, Department of Addictology and Consultation-liaison Psychiatry, F-44000, Nantes, France. samuel.bulteau@chu-nantes.fr.|University of Nantes, University of Tours, INSERM, SPHERE U1246, F-44000, Nantes, France. samuel.bulteau@chu-nantes.fr.
authors.forename: Samuel
authors.initials: S
authors.lastname: Bulteau
authors.affiliation: University of Nantes, University of Tours, INSERM, SPHERE U1246, F-44000, Nantes, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Sébille
authors.affiliation: CHU de Nantes, Department of Clinical Neurophysiology, F-44000, Nantes, France.
authors.forename: Guillemette
authors.initials: G
authors.lastname: Fayet
authors.affiliation: University of Nantes, Laboratory 'Movement, Interactions, Performance' (E.A. 4334), F-44000, Nantes, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Thomas-Ollivier
authors.affiliation: University of Nantes, Laboratory 'Movement, Interactions, Performance' (E.A. 4334), F-44000, Nantes, France.
authors.forename: Thibault
authors.initials: T
authors.lastname: Deschamps
authors.affiliation: CHU de Nantes, Clinical Investigation Unit 18, Department of Addictology and Consultation-liaison Psychiatry, F-44000, Nantes, France.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Bonnin-Rivalland
authors.affiliation: CHU de Nantes, Clinical Investigation Unit 18, Department of Addictology and Consultation-liaison Psychiatry, F-44000, Nantes, France.
authors.forename: Edouard
authors.initials: E
authors.lastname: Laforgue
authors.affiliation: CHU de Nantes, Clinical Investigation Unit 18, Department of Addictology and Consultation-liaison Psychiatry, F-44000, Nantes, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Pichot
authors.affiliation: CHU de Nantes, Clinical Investigation Unit 18, Department of Addictology and Consultation-liaison Psychiatry, F-44000, Nantes, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Valrivière
authors.affiliation: CHU de Nantes, Department of Neuroradiology, F-44000, Nantes, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Auffray-Calvier
authors.affiliation: CHU de Nantes, Delegation of Clinical Research and Innovation, F-44000, Nantes, France.
authors.forename: June
authors.initials: J
authors.lastname: Fortin
authors.affiliation: CHU de Nantes, Department of Clinical Neurophysiology, F-44000, Nantes, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Péréon
authors.affiliation: CHU de Nantes, Clinical Investigation Unit 18, Department of Addictology and Consultation-liaison Psychiatry, F-44000, Nantes, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Vanelle
authors.affiliation: CHU de Nantes, Clinical Investigation Unit 18, Department of Addictology and Consultation-liaison Psychiatry, F-44000, Nantes, France.|University of Nantes, University of Tours, INSERM, SPHERE U1246, F-44000, Nantes, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Sauvaget
mesh_terms: D000293:Adolescent; D000328:Adult; D000339:Affect; D000368:Aged; D001921:Brain / Q000503:physiopathology*; D002985:Clinical Protocols; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000503:physiopathology / Q000523:psychology / Q000628:therapy*; D061218:Depressive Disorder, Treatment-Resistant / Q000175:diagnosis / Q000503:physiopathology / Q000523:psychology / Q000628:therapy*; D004311:Double-Blind Method; D004569:Electroencephalography; D005260:Female; D005602:France; D006801:Humans; D008297:Male; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D012107:Research Design; D011795:Surveys and Questionnaires; D013826:Theta Rhythm; D050781:Transcranial Magnetic Stimulation / Q000009:adverse effects / Q000379:methods*; D055815:Young Adult
keywords: Intermittent Theta Burst Stimulation (iTBS); Relapse; Repetitive transcranial magnetic stimulation (rTMS); Treatment-resistant depression