iTBS Study for Depression in Patients With Multiple Sclerosis

Study Overview
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Brief Summary
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Multiple sclerosis (MS) is a chronic and demyelinating disease of the central nervous system. It is one of the most common cause of neurological disability in young adults. Depression is a common symptom in MS patients, with lifetime prevalence rates going up to 50%. Depression not only reduces the response to treatment, delays the recovery of neurological function and social ability, but also significantly increases the risk of disability in patients with MS. Transcranial magnetic stimulation (TMS) is a non-invasive method of brain stimulation that is based on electromagnetic induction. Intermittent theta burst stimulation (TBS), a newer form of rTMS, delivers 600 pulses in just 3 min, versus 37.5 min for conventional rTMS, but it has been shown to produce similar effects in patient with treatment-resistant depression. To observe the effect and safety of iTBS on patients with MS and depression, we design a double-blind, randomized controlled study. Results of this research will inform on the efficiency of the TMS for the treatment of depression in MS patients, which will reduce the risk of disability and improve the quality of life.

Detailed Description
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Multiple sclerosis (MS) is a chronic and demyelinating disease of the central nervous system. It is one of the most common cause of neurological disability in young adults. Depression is a common symptom in MS patients, with lifetime prevalence rates going up to 50%. Depression not only reduces the response to treatment, delays the recovery of neurological function and social ability, but also significantly increases the risk of disability in patients with MS. It is worth noting that depression remains widely underdiagnosed and untreated in MS patients. The investigators aim to treat the depression in MS patients using a non-invasive method, which will help improve life quality and reduce the risk of disability in patients. Transcranial magnetic stimulation (TMS) is a non-invasive method of brain stimulation that uses magnetic fields to stimulate nerve cells in brain. Repetitive TMS (rTMS) is usually applied in antidepressant-resistant depression. Furthermore, some clinical trials show that rTMS also significantly improve Parkinson's related depression and postpartum depression. Intermittent theta burst stimulation (TBS), a newer form of rTMS, delivers 600 pulses in just 3 min, versus 37.5 min for conventional rTMS, but it has been shown to produce similar effects in patient with treatment-resistant depression. In this study, thirty patients who meet the criteria will be included. They will then be randomly assigned into the SHAM or iTBS group for the study intervention. Patients and outcome assessors will be masked to treatment allocation. SHAM or iTBS will be delivered to stimulate left dorsalateral prefrontal cortex (DLPFC). The protocol includes 600 pulses per session: triplet 50 Hz bursts, repeated at 5 Hz; 2 s on and 8 s off. Each patient will receive 2 sessions per day over a period of 10 days (total of 20 sessions). After the treatment phase, patients will be followed up once after two weeks. The presence and severity of side effects will be assessed by the physician from the Department of Neurology. Before and after the iTBS or SHAM intervention and after two weeks of follow-up, primary and secondary measurements will be performed. Results of this study will inform on the efficiency of the TMS for the treatment of depression in MS patients, which will reduce the risk of disability and improve the quality of life.

Official Title
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Intermittent Theta Burst Stimulation (iTBS) for the Treatment of Depression in Patients With Multiple Sclerosis: a Randomized Controlled Study

Conditions
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Multiple Sclerosis, Depression, Anxiety

Intervention / Treatment
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* Device: intermittent theta burst stimulation using a MagPro X100
* Device: sham intermittent theta burst stimulation using a MagPro X100


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1) Age 18 to 65 2) Male and female patients with clinically definite MS according to 2017 McDonald criteria 3) EDSS 0 to 6 4) Score between 11 and 30 on the Montgomery-Asberg Depression Rating Scale (MADRS) and stable antidepressants therapy > 1 months before enrollment and during the follow-up period 5) Informed consent of patients Exclusion Criteria: 1) History of seizures (personal or family) 2) Comedication with neuroleptics or tricyclic antidepressants 3) bipolar disorder 4) Presence of other diseases of the nervous system (history of stroke, brain injury, brain tumor, increased intracranial pressure) 5) Significant neurologic, psychiatric, cardiovascular, hepatic, renal, gastrointestinal, metabolic, or other systemic comorbidities. 6) History of drug or alcohol abuse 7) Cardiac pacemakers 8) Metal implants in the head 9) 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: iTBS stimulation<br>iTBS stimulation to left dorsolateral prefrontal cortex (DLPFC), twice daily, 10 days | Device: intermittent theta burst stimulation using a MagPro X100<br>* Patients randomized to receive iTBS in left dorsolateral prefrontal cortex, each treatment will consist of 600 stimuli (triplet 50 Hz bursts, repeated at 5 Hz; 2 s on and 8 s off; total duration of 3 min 12 s). Simulated iTBS will be administered using Magventure static cooling MCF-B65 coil.<br>|
| Sham Comparator: sham iTBS stimulation<br>sham iTBS stimulation to left dorsolateral prefrontal cortex (DLPFC), twice daily, 10 days | Device: sham intermittent theta burst stimulation using a MagPro X100<br>* Patients randomized to receive sham iTBS will undergo the same procedure to patients receiving real iTBS. Sham iTBS will be administered using Magventure static cooling MCF-P-B65 coil that shares the same mechanical outline and produces identical sound level to MCF-B65 coil without stimulating the cerebral cortex.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Montgomery-Asberg Depression Rating Scale (MADRS) | The MADRS is a 0-60 point scale to measure depression severity with a higher number indicating more severe depression. A score of 0-6 indicates symptoms absent, 7-19 indicates mild depression, 20-34 moderate, and > 34 severe. | 0 (baseline), 10 days and 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presence and changes in severity of side effects | Adverse events will be assessed by the physician from Department of Neurology weekly. | 0 (baseline), 10 days and 4 weeks | 
| Change in Beck Depressive Inventory (BDI) | BDI is a widely utilized to assess depression in MS patients. It is a 21-item self-reporting questionnaire for evaluating the severity of depression. The score range is 0-63 with higher scores indicating higher intensity. | 0 (baseline), 10 days and 4 weeks | 
| Change in 21-item Beck's Anxiety Inventory (BAI) | BAI is a self-report test for measuring anxiety severity and level. It contains 21 multiple-choice questions. The score range is 0-63 with higher scores indicating higher intensity. | 0 (baseline), 10 days and 4 weeks | 
| Change in Fatigue Severity Scale (FSS) | The FSS is a 9-item scale which measure the severity of fatigue and its effect on an individual's daily living and social participation. The total score ranges from 9 to 63, with a higher score indicate greater fatigue severity. | 0 (baseline), 10 days and 4 weeks | 
| Change in Pittsburgh Sleep Quality Index (PSQI) | PSQI is a self-rated questionnaire designed to evaluate overall sleep quality during the past month. Each of the questionnaire's 19 self-reported items belongs to one of seven subcategories: sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbance, use of sleep medication, degree of daytime dysfunction. | 0 (baseline), 10 days and 4 weeks | 
| Change in Expand Disability Status Scale (EDSS) | EDSS is a standardized method used to classify the severity and progression of multiple sclerosis. It provides a total score on a scale that ranges from 0 to 10. | 0 (baseline), 10 days and 4 weeks | 
| Change in Cortical silent period (CSP) duration | CSP duration will be measured by Magventure X100 + option. | 0 (baseline), 10 days and 4 weeks | 
| Change in short-interval intracortical inhibition (SICI) | SICI will be measured by Magventure X100 + option. | 0 (baseline), 10 days and 4 weeks | 
| Change in intracortical facilitation (ICF) | ICF will be measured by Magventure X100 + option. | 0 (baseline), 10 days and 4 weeks | 
| Changes in long-interval intracortical inhibition (LICI) | LICI will be measured by Magventure X100 + option. | 0 (baseline), 10 days and 4 weeks | 
| Change in slow-wave/fast-wave (theta/beta) ratio from resting-state electroencephalograph (EEG) recording | Resting-state EEG will be recorded by Nicolet EEG system. | 0 (baseline), 10 days and 4 weeks | 
| Serum biomarker | Serum biomarker such as BDNF, TNF-alpha, IL-1 beta, S100 beta will be examined before and after TMS treatment. | 0 (baseline), 10 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Sclerosis, Depression, Transcranial Magnetic Stimulation