Treatment of Major Depressive Disorder With Bilateral Theta Burst Stimulation (TBS-D)

This is a randomized, double-blind, sham-controlled multicenter clinical trial. The aim is to provide evidence for efficacy of TBS in the treatment of patients with major depression. There will be a direct comparison between combined cTBS/iTBS with sham TBS. Overall, 236 patients with major depression will be randomized either to active TBS or sham TBS in a 1:1 ratio. The planned stimulation paradigms will be applied as add-on therapy to standard therapy (antidepressive medication and / or psychotherapy). Patients will receive 30 stimulation sessions in a 6-week treatment period (one session daily from Monday to Friday). Follow up assessments are scheduled 1 and 3 months after end of treatment period.

Study Overview

• Status: Recruiting
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Device: Transcranial Magnetic Stimulation; Device: Sham Transcranial Magnetic Stimulation

• Study Type: Interventional
• Enrollment (Estimated): 236
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Christian Plewnia, Prof., MD; Phone Number: 82311 +49707129; Email: christian.plewnia@uni-tuebingen.de

Study Locations

• Germany
  • Leipzig, Germany
    • Recruiting
    • University of Leipzig, Dept. Psychiatry and Psychotherapy
  • Munich, Germany, 80336
    • Recruiting
    • University of Munich
  • Regensburg, Germany, 93053
    • Recruiting
    • University of Regensburg, Dept. Psychiatry and Psychotherapy
  • Tuebingen, Germany, 72076
    • Recruiting
    • University of Tuebingen, Dept Psychiatry and Psychotherapy
  • Ulm, Germany, 89075
    • Recruiting
    • University of Um, Dept. Psychiatry and Psychotherapy
  • Wuerzburg, Germany
    • Recruiting
    • University of Wuerzburg, Dept. Psychiatry and Psychotherapy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• moderate or severe unipolar depression diagnosed according to criteria of Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5)
• duration of the current episode must be ≥ 6 weeks and ≤ 2 years
• HDRS17 ≥ 18
• mild to moderate treatment resistance according to the Antidepressant Treatment History Form [ATHF-SF]. Treatment resistance is defined as having failed at least one but no more than three adequate antidepressant treatments in this episode
• stable antidepressive medication 4 weeks before treatment or no antidepressive treatment
• no further relevant psychiatric axis-I and/or axis-II disorder except for anxiety disorders (according to DSM-5 and SCID-5-PD)
• no comorbid psychotic symptoms
• ability to give consent

Exclusion Criteria:

• acute suicidality (MADRS item 10 score > 4)
• antiepileptic drugs and/or benzodiazepines corresponding to > 1mg lorazepam / day
• history of brain surgery, significant and clinically relevant brain malformation or neoplasm, head injury, stroke, dementia or other neurodegenerative disorder
• history of seizures
• previous rTMS treatment
• lifetime history of non-response to adequate electroconvulsive therapy (minimum of eight treatments)
• deep brain stimulation
• cardiac pacemakers, intracranial implant, or metal in the cranium
• substance dependence or abuse in the past 3 months (with the exception of tobacco)
• severe somatic comorbidity as judged by the study physician
• pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: combined iTBS/cTBS; Combined theta burst stimulation (TBS) of the left (intermittent TBS, iTBS) and right (continuous TBS, cTBS) dorsolateral prefrontal cortex (dlPFC; F3 and F4 according to EEG10/20 system). Each stimulation session will comprise 2 trains of 600 stimuli each applied in bursts of three pulses at 50 Hz given every 200 ms. iTBS will be applied 20 times for 2 s every 10 s. In the same session, stimulation with cTBS will be applied continuously for 40 s. Intensity of iTBS/cTBS will be standardized at 80 % of the resting motor threshold (rMT). Additionally, patients receive an electrical co-stimulation of the forehead. One electrode is fixed to FZ and the 2nd one is either fixed to the left forehead (iTBS) or the right forehead (cTBS), rectangular aligned to the upper edge of the FZ-electrode with a distance of 0.5 cm. Intensity of the co-stimulation is applied with 50% of TBS-intensity.	Device: Transcranial Magnetic Stimulation; MagVenture Coil Cool B70 A/P
Sham Comparator: sham stimulation; Setup is identical to combined active iTBS/cTBS but TBS is not actively delivered	Device: Sham Transcranial Magnetic Stimulation; MagVenture Coil Cool B70 A/P without TMS being actively delivered

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate of Montgomery-Asberg Depression Rating Scale (MADRS)	MADRS reduction of at least 50% of baseline value after end of treatment period between active combined iTBS / cTBS and the sham condition. (rater questionnaire; MADRS raw score ranges between 0 and 60; the higher the score, the more severe depression)	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Remission rate after treatment	Montgomery-Asberg Depression Rating Scale (MADRS) </= 10 after treatment (rater questionnaire; MADRS raw score ranges between 0 and 60; the higher the score, the more severe depression)	6 weeks
Reduction of raw score: Montgomery-Asberg Depression Rating Scale (MADRS)	The reduction of the raw score after treatment will be compared between active TBS and sham TBS (rater questionnaire; range between 0 and 60; higher score indicates higher level of severity)	6 weeks
Reduction of raw score: Hamilton Depression Rating Scale 17 items (HDRS17)	The reduction of the raw score after treatment will be compared between active TBS and sham TBS (rater questionnaire; score ranges from 0-53;higher score indicates higher level of severity)	6 weeks
Reduction of raw score: Clinical Global Impression (CGI)	The reduction of the raw score after treatment will be compared between active TBS and sham TBS (rater questionnaire; score ranges from 0-7; higher score indicates higher level of severity)	6 weeks
Reduction of raw score: Beck Depression Inventory (BDI-II)	The reduction of the raw score during follow-up will be compared between active TBS and sham TBS (self-rating questionnaire; score ranges from 0-63; higher score indicates higher level of severity)	10 and 18 weeks
Reduction of raw score: WHO-5 well-being index	The reduction of the raw score during follow-up will be compared between active TBS and sham TBS (self-rating questionnaire; score ranges from 0-25; lower score indicates higher level of severity)	10 and 18 weeks
Work Productivity and Activity Impairment Questionnaire (WPAI)	Functionality will be assessed by Work Productivity and Activity Impairment Questionnaire (WPAI; self-rating questionnaire) at baseline, after treatment period as well as during follow-up; contains 6 questions about the effect of health problems on the ability to work and perform regular activities. Health problems are defined as any physical or emotional problem or symptom. Patients are asked to fill in the blanks or circle a number; there is no overall score;	6 and 18 weeks
Frequency of adverse events	Comparison of both arms in respect to number of adverse events during treatment period	6 weeks
Deterioration rate after treatment period	Deterioration is defined as an increase of MADRS (Montgomery-Asberg Depression Rating Scale) score of 25% compared to baseline score (rater questionnaire; range between 0 and 60; higher score indicates higher level of severity)	6 weeks
Examination of the influence of Childhood Trauma Questionnaire (CTQ) at baseline as possible predictor for change of MADRS	It will be examined whether the CTQ can be used for predicting treatment effect, measured by Montgomery-Asberg Depression Rating Scale (MADRS, see above)	6 weeks
Examination of the influence of cognitive performance at baseline as possible predictor for change of MADRS	It will be examined whether cognitive performance measured by THINC-Integrated Tool (Thinc-it -tool; includes 4 different test covering different aspects of cognition) at baseline can be used for predicting treatment effect, measured by Montgomery-Asberg Depression Rating Scale (MADRS, see above)	6 weeks

Collaborators and Investigators

• Sponsor: University Hospital Tuebingen
• Collaborators: Federal Ministry of Health, Germany; University of Ulm; Department of Psychiatry and Psychotherapy, University Munich (LMU), Germany; Institute of Clinical Epidemiology and applied Biometry, University Tuebingen, Germany; Center of Clinical Trials, University Tuebingen, Germany; Department of Psychiatry and Psychotherapy, University Regensburg, Germany; Department of Psychiatry and Psychotherapy, University Wuerzburg, Germany; Department of Psychiatry and Psychotherapy, University Leipzig, Germany
• Investigators: Principal Investigator: Christian Plewnia, Prof., MD, Department of Psychiatry and Psychotherapy, University of Tuebingen

Publications and helpful links

General Publications

• Plewnia C, Brendel B, Schwippel T, Nieratschker V, Ethofer T, Kammer T, Padberg F, Martus P, Fallgatter AJ. Treatment of major depressive disorder with bilateral theta burst stimulation: study protocol for a randomized, double-blind, placebo-controlled multicenter trial (TBS-D). Eur Arch Psychiatry Clin Neurosci. 2021 Oct;271(7):1231-1243. doi: 10.1007/s00406-021-01280-w. Epub 2021 Jun 19.

Study record dates

Study Major Dates

• Study Start (Actual): September 29, 2020
• Primary Completion (Estimated): May 1, 2025
• Study Completion (Estimated): September 1, 2025

Study Registration Dates

• First Submitted: May 8, 2020
• First Submitted That Met QC Criteria: May 13, 2020
• First Posted (Actual): May 19, 2020

Study Record Updates

• Last Update Posted (Actual): March 25, 2024
• Last Update Submitted That Met QC Criteria: March 22, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: multicenter; randomized; major depression; dorsolateral prefrontal cortex; theta burst stimulation; sham-controlled
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Major
• Other Study ID Numbers: 01KG2003

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No