Treatment of major depressive disorder with bilateral theta burst stimulation: study protocol for a randomized, double-blind, placebo-controlled multicenter trial (TBS-D)

Christian Plewnia,Tobias Schwippel,Thomas Ethofer,Frank Padberg,Vanessa Nieratschker,Andreas J Fallgatter,Bettina Brendel,Thomas Kammer,Peter Martus

doi:10.1007/s00406-021-01280-w

Abstract

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (dlPFC) is currently evolving as an effective and safe therapeutic tool in the treatment of major depressive disorder (MDD). However, already established rTMS treatment paradigms are rather time-consuming. With theta burst stimulation (TBS), a patterned form of rTMS, treatment time can be substantially reduced. Pilot studies and a randomized controlled trial (RCT) demonstrate non-inferiority of TBS to 10 Hz rTMS and support a wider use in MDD. Still, data from placebo-controlled multicenter RCTs are lacking. In this placebo-controlled multicenter study, 236 patients with MDD will be randomized to either intermittent TBS (iTBS) to the left and continuous TBS (cTBS) to the right dlPFC or bilateral sham stimulation (1:1 ratio). The treatment will be performed with 80% resting motor threshold intensity over six consecutive weeks (30 sessions). The primary outcome is the treatment response rate (Montgomery-Asberg Depression Rating Scale reduction ≥ 50%). The aim of the study is to confirm the superiority of active bilateral TBS compared to placebo treatment. In two satellite studies, we intend to identify possible MRI-based and (epi-)genetic predictors of responsiveness to TBS therapy. Positive results will support the clinical use of bilateral TBS as an advantageous, efficient, and well-tolerated treatment and pave the way for further individualization of MDD therapy.Trial registration: ClinicalTrials.gov (NCT04392947).

Highlights

Major depressive disorder (MDD) is one of the leading causes of disease burden, severely impairs quality of life, autonomy, social integration, and life expectancy
We selected the difference in treatment response-rates (MADRS reduction of at least 50% of baseline value after the end of treatment period) between active combined intermittent TBS (iTBS)/ continuous TBS (cTBS) and the placebo condition as the primary endpoint
In a recent large clinical trial [18] comparing iTBS (n = 193) with 10 Hz repetitive transcranial magnetic stimulation (rTMS) (n = 192) the outcome criterion of HDRS-17 ≤ 50% of baseline was achieved by 49% of patients treated with iTBS

Summary

Introduction

Major depressive disorder (MDD) is one of the leading causes of disease burden, severely impairs quality of life, autonomy, social integration, and life expectancy. Psychotherapy and medication are effective treatments, a large proportion of patients do not tolerate or sufficiently respond to the initial treatment [1]. Approximately 50% will experience a recurrent or chronic course of illness for which long-term treatment is recommended [2]. The implementation of additional effective and tolerable interventions is highly desirable to expand and individualize treatment options. In the last two decades, modern noninvasive brain stimulation (NIBS) techniques, repetitive transcranial magnetic stimulation (rTMS), have emerged as effective new means of MDD treatment [3, 4]. Treatment effects are mediated by several mechanisms of action.

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