Coupling Repetitive Transcranial Magnetic Stimulation With a Neuronavigation System in Treatment Resistant Depression

Study Overview
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Brief Summary
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Repetitive Transcranial Magnetic Stimulation (rTMS) is a non invasive technique which was shown to be effective in the treatment of major depression. The dorsolateral prefrontal cortex (DLPFC) is the anatomic target in rTMS studies and the standard (manual) '5-cm method' for positioning the coil over DLPFC is the reference. Nevertheless, it has been criticized due to poor targeting accuracies attributed to inter-subject variability. Such an inaccuracy could have any therapeutic consequences as a decrease in rTMS efficacy. Preliminary findings suggest that a more reproductible and accurate method, based upon a neuronavigation system could allow for a better efficacy. This finding has to be replicated with sound methodology. Investigator's objective is to compare efficacy on mood of coil positioning based upon a neuronavigation device versus coil positioning based upon the standard method.

Detailed Description
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Background : Repetitive Transcranial Magnetic Stimulation (rTMS) is a new tool for major depressive disorder. rTMS is a non invasive technique allowing for a localized stimulation of cerebral tissue cortex. rTMS uses electromagnetic induction to induce weak electric currents using a rapidly changing magnetic field; this can modify activity in specific or general parts of the brain. Meta-analyses have stated that rTMS appeared to be effective in the treatment of major depression despite any limits concerning sample sizes and methodological concerns. Studies have shown that this technique potentiates antidepressants treatment in combination therapy. It has received FDA approval for the management of major depressive disorder. Stimulation parameters are numerous (frequency, intensity, number of pulses) and their effects are increasingly better understood in order to predict a better balance between efficacy and tolerability. The dorsolateral prefrontal cortex (DLPFC) is the target in repetitive transcranial magnetic stimulation and the standard (manual) '5-cm method' for positioning the transcranial magnetic stimulation coil over DLPFC is the reference. It has been criticized due to poor targeting accuracies attributed to inter-subject variability. Such an inaccuracy could have consequences as a decrease in rTMS efficacy. Any preliminary findings suggest that a more reproductible and accurate method, based upon a neuronavigation system could allow for a better efficacy. This finding has to be replicated with sound methodology. Objectives: To compare efficacy on mood of coil positioning based upon a neuronavigation device versus coil positioning based upon the standard method. Investigators hypothesized that an accurate localization and stimulation of DLPFC using neuronavigation would be more effective than the less accurate standard method. A secondary objective is to compare the efficacy on patient's self perception, on psychomotor symptoms and the tolerability of the two methods.

Official Title
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Assessment of the Neuronavigation System Coupled With Repetitive Transcranial Magnetic Stimulation. A Randomized Double Blind Study

Conditions
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Treatment Resistant Depression

Intervention / Treatment
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* Device: Neuronavigation system
* Device: Standard localisation method


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients giving their consent; Right handed; Age > 18 and < 65; With a DSM-IV diagnosis of MDD, single episode or recurrent; With an antidepressant treatment unchanged in the 3 last weeks; With an MADRS score ≥ 21; Benzodiazepine treatments have to be avoided; Exclusion Criteria: Major depressive episode with psychotic characteristics; A lifetime of the following axis 1 diagnoses: schizophrenia or substance use disorder (alcohol or other substance); Stade 5 of Thase and Rush classification ; Involuntary hospitalizations; Patients under guardianship; Outpatients in case of an increased risk of suicide as assessed by a MADRS item 10 > 3; Contraindication for MRI or rTMS: a personal history of a seizure disorder, presence of neurologic or neurosurgical disorder, presence of ferromagnetic material (including intraocular) or metallic medical devices (pacemakers); Pregnancy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neuronavigation system<br>10 sessions of rTMS coupled with a neuronavigation system Description of 1 session of the rTMS protocol : Frequency: 20Hz Intensity: 110% of motor threshold 80 train of 2 seconds duration 10 seconds between two trains 3200 pulses Devices : rTMS: System Mag Pro (Magventure, Denmark) Neuronavigation system: Syneika One (Syneika, France) | Device: Neuronavigation system<br>* Neuronavigation<br>* Other names: Syneika One (Syneika, France);|
| Sham Comparator: Standard localisation method<br>10 sessions of rTMS with manual localisation of the DLPFC using the standard localisation method (i.e. the '5-cm method') Description of 1 session of the rTMS protocol : Frequency: 20Hz Intensity: 110% of motor threshold 80 train of 2 seconds duration 10 seconds between two trains 3200 pulses Devices : - rTMS: System Mag Pro (Magventure, Denmark) | Device: Standard localisation method<br>* Manual localisation of the DLPFC using the standard localisation method (i.e. the '5-cm method')<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response | Response defined as at least 50% reduction in the MADRS score. | Day 44 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response | Response is defined as at least 50% reduction in the MADRS score. | Day 14 | 
| Remission | Remission is defined as a MADRS score ≤ 8. | Day 14 Day 44 | 
| MADRS | Description: It is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders. | Day 0, day 14 and day 44 | 
| BDI | It is a multiple-choice self-report inventory and one of the most widely used instruments for measuring the severity of depression. | Day 0 Day 14 Day 14 | 
| ERD | It is a 14-item questionnaire which psychiatrists use to measure the intensity of motor retardation. | Day 0 Day 14 day 44 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rTMS, Major depressive disorder, Neuronavigation