Repetitive Transcranial Magnetic Stimulation in Obsessive Compulsive Disorder

Study Overview
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Brief Summary
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Evaluate the therapeutic effect of a functional Magnetic Resonance Imaging (fMRI)-guided and robotized neuronavigated theta burst Transcranial Magnetic Stimulation (TMS) targeting right inferior frontal region in resistant obsessive compulsive disorder (OCD) in a double-blind, randomized, placebo-controlled, monocentric study.

Detailed Description
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This study evaluates the therapeutic effect of a fMRI-guided and robotized neuronavigated theta burst Transcranial Magnetic Stimulation (TMS) targeting right inferior frontal region in resistant obsessive compulsive disorder (OCD) in a double-blind, randomized, placebo-controlled, monocentric study. The study will also assess the interest of some clinical, neuropsychological, neuroimaging, electrophysiological variables in response prediction, besides physiopathological information. There is an increasing interest in developping treatments for resistant OCD, which are not responding to the conventional treatment, represented by pharmacotherapy associated to cognitive behavioral therapy. Repetitive TMS represents a promising non invasive brain stimulation approach, but efficacy, best available brain target, optimal responder profile and stimulation parameters need to be further documented. In this study, the included patients will be randomly assigned to an active (theta burst TMS) or sham-placebo treatment group. TMS will be added to their stable pharmacotherapy. The brain target, the right inferior frontal region, involved in the inhibition control brain network, will be defined in a personalized manner via a fMRI paradigm for each patient. TMS will be delivered daily for 2 successive weeks. Measures of different clinical, neuropsychological , electrophysiological (cortical excitability) variables will be performed at baseline, as well as at the end of the TMS course, and 1 week after. Other assessments are planned at 3 and 6 months, in order to highlight the evolution of the potential benefit.

Official Title
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Stimulation magnétique transcrânienne répétitive Dans le Traitement Des Troubles Obsessionnels Compulsifs

Conditions
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Obsessive-Compulsive Disorder

Intervention / Treatment
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* Device: Active Repetitive Transcranial Magnetic Stimulation
* Device: Placebo Repetitive Transcranial Magnetic Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Volunteer subjects with Obsessive Compulsive Disorders (OCD) according to the Diagnostic and Statistical Manual of Mental Disorders (DSM IV-TR) criteria and validated by an experimented clinician following instruments like SCID (Structured Clinical Interview for DSM IV) or MINI (Mini-International Neuropsychiatric Interview) with or without associated tics (Gilles de la Tourette Syndrome) Age > 18 years old Y-BOCS score > 20 and CGI (Clinical Global Impression Scale) score ≥ 4 Resistant patients to standard treatments - where treatment resistance is defined by partial but insufficient response (Global Assessment of Functioning score GAF score < 60 and/or reduction of Yale Brown Obsessions and Compulsion Scale score < 35%) or lack of response to previous well conducted treatment including: pharmacotherapy : optimal tolerated dose and adequate duration (> 12 weeks) of at least 2 Serotonin Reuptake Inhibitors (selective serotonin reuptake inhibitors, clomipramine), and one augmentation strategy (adjunction of an antipsychotic - such as risperidone or olanzapine or aripiprazole - or lithium or buspirone) ; psychotherapy (at least 6 months of cognitive and behavioral therapy) Exclusion Criteria: other primary diagnosis than OCD (comorbid tics and depression are tolerated) comorbid diagnosis of schizophrenia/ psychotic disorder, bipolar disorder, substance abuse or dependance medical condition involving cognitive decline and affecting brain structures such as Parkinson disease, dementia, multiple sclerosis, HIV (human immunodeficiency virus) infection, lupus etc. Magnetic Resonance Imaging exclusion criteria (ferromagnetic implants etc) common TMS exclusion criteria (neurological condition with an increased risk of seizure, cardiac pacemakers, implanted medication pumps, intracardiac lines, or acute, unstable cardiac disease, intracranial implants (e.g. cochlear implants, electrodes, aneurysm clips, stimulators... ) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed will be excluded Current use of any investigational drug pregnancy / breast feeding patients visual or auditive important deficit

Ages Eligible for Study
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Minimum Age: 18 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: active Transcranial Magnetic Stimulation<br>Active Transcranial Magnetic Stimulation (TMS) targeting the right frontal inferior gyrus, 2 sessions per day, each session 5min30 day, during 10 consecutive days, Using theta burst stimulation and using Transcranial Magnetic Stimulation navigator and robot | Device: Active Repetitive Transcranial Magnetic Stimulation<br>* modulation of the electrical activity of the right inferior frontal gyrus cortex in order to reduce Obsessive Compulsive Disorders symptoms by Active Transcranial Magnetic Stimulation (TMS) targeting the right frontal inferior gyrus, 2 sessions per day, each session 5min30 day, during 10 consecutive days, using theta burst stimulation and using a TMS neuronavigated robot<br>|
| Placebo Comparator: Placebo<br>Placebo comparator, using non active magnetic coil, targeting the right frontal inferior gyrus, 2 sessions per day, each session 5min30 day, during 10 consecutive days, using theta burst stimulation and using Transcranial Magnetic Stimulation navigator and robot | Device: Placebo Repetitive Transcranial Magnetic Stimulation<br>* Sham rTMS will be delivered using non active magnetic coil, targeting the right frontal inferior gyrus, 2 sessions per day, each session 5min30 day, during 10 consecutive days, using TMS neuronavigated robot. A subjective sensation will be obtained via frontal dermic electrical stimulation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline of the score at the Yale - Brown Obsessive and Compulsive Scale | Evaluation of Obsessive Compulsive Disorder symptoms using the Yale - Brown Obsessive and Compulsive Scale, at day 21, corresponding to 7 days after the end of the TMS cure, compared to baseline. | at baseline and at day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Score of Montgomery and Asberg Depression Rating Scale, as a Measure of effects on Mood (depression) | Evaluation of Mood using Montgomery Asberg Depression Rating Scale | At baseline, at day 21, day 90, day 180 | 
| Score of Young Mania Rating Scale, as a Measure of effects on Mood (hyperthymia) | Evaluation of Mood using Young Mania Rating Scale | At baseline, at day 21, day 90, day 180 | 
| Score of Multidimensional Assessment of Thymic States Scale as a Measure of effects on Emotional Reactivity | Evaluation of Emotional Reactivity using Multidimensional Assessment of Thymic States Scale | At baseline, at day 21, day 90, day 180 | 
| Number of patients with Side effects as a measure of Safety and Tolerability | collection of the side effects of the Transcranial Magnetic Stimulation, after each session, during the entire TMS cure | for each session of Transcranial Magnetic Stimulation, at day 15, day 21, day 90, day 180 | 
| Inferior Frontal Region Activity (percentage of the BOLD signal change (parameter estimates beta) | Performing a functional Magnetic Resonance Imaging, looking for biomarkers of response to the TMS cure. Especially studying the right inferior cortex activation in functional Magnetic Resonance Imaging using a Signal Stop Task. | at baseline (day 0) | 
| Fractional Anisotropy (FA), mean and radial diffusivity (MD, RD), tracti integrity of the inhibition network, | looking for anatomical biomarkers of response, or anatomical differences between the subjects on the inhibition network using Diffusing Tensor Imaging data | at day 0 (baseline) | 
| Yale - Brown Obsessive and Compulsion Scale score after the TMS treatment as an evaluation of the persistence of the clinical benefit | The Yale - Brown Obsessive and Compulsion Scale will also be performed at day 15, day 90 and day 180 after the inclusion in order to assess the kinetics of clinical changes in Obsessive Compulsive symptoms after the TMS cure. | day 15, day 90 and day 180 after the inclusion. | 
| Cortical Excitability | assessing a new biomarker linked to OCD and monitoring its evolution with the TMS cure, testing its predictive value for the clinical response | baseline - day 15 - day 21 - day 90 - day 180 | 
| Evaluation of Impulsivity using specific scales | Evaluation of impulsivity using UPPS (Urgency, Premeditation, and Sensation Seeking) Impulsive Behavior Scale. | At baseline, at day 21, day 90, day 180 | 
| Evaluation of the Clinical global State | Using Clinical Global Impression scale we will assess the evolution of the clinical global status | at baseline, day 15, day 21, day 90, day 180 | 
| type of side effects (pain, paresthesia, other) as a measure of Safety and Tolerability | collection of the side effects of the Transcranial Magnetic Stimulation, after each session, during the entire TMS cure | for each session of Transcranial Magnetic Stimulation, at day 15, day 21, day 90, day 180 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obsessive-Compulsive Disorder, Transcranial Magnetic Stimulation