Treatment of Major Depressive Disorder With Bilateral Theta Burst Stimulation

Study Overview
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Brief Summary
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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.

Official Title
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Treatment of Major Depressive Disorder With Bilateral Theta Burst Stimulation

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Device: Transcranial Magnetic Stimulation
* Device: Sham Transcranial Magnetic Stimulation


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: combined iTBS/cTBS<br>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<br>* MagVenture Coil Cool B70 A/P<br>|
| Sham Comparator: sham stimulation<br>Setup is identical to combined active iTBS/cTBS but TBS is not actively delivered | Device: Sham Transcranial Magnetic Stimulation<br>* MagVenture Coil Cool B70 A/P without TMS being actively delivered<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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randomized, major depression, theta burst stimulation, dorsolateral prefrontal cortex, sham-controlled, multicenter