Efficacy of rTMS in Bipolar Depression

Study Overview
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Brief Summary
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Bipolar Disorder is a common condition that is characterized by periods of mood elevation however periods of chronic and recurring depressive episodes are more common and can be severely disabling. Effective treatments exist, however a significant portion of bipolar depressed patients do not respond to, or have difficulty tolerating many of these interventions. Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive neuromodulatory technique that is effective in major depression and there is evidence for its efficacy in bipolar depression which needs to be assessed in larger randomized controlled trials. This study is a randomised, double-blind, sham-controlled trial over four weeks. The primary objective is to assess improvement in depressive symptoms in acute bipolar depressed patients on treatment with intermittent Theta-Burst Stimulation (iTBS) in comparison to sham-rTMS.

Detailed Description
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rTMS is a treatment that involves stimulating a certain area of the brain with magnetic field pulses. Over time, the magnetic field pulses can gradually change the activity level of the stimulated brain region and help symptoms of bipolar depression. The device used in this study has been approved by Health Canada for therapeutic use since 2002. Participants will complete a screen visit to determine eligibility based on the inclusion/exclusion criteria. If the participants are not eligible, no further study procedures will be conducted. Eligible subjects will be randomized to receive either active iTBS-rTMS or sham rTMS treatment (scalp stimulation with no magnetic pulse) daily for four weeks (20 sessions) to the left dorsolateral prefrontal cortex (DLPFC). All participants will complete a MRI (to target the left DLPFC region of the brain and functional activity), EEG & fNIRS, lab work, and neurocognitive testing prior to the commencement and post rTMS treatment. Efficacy, safety and tolerability will be evaluated at screen visit, during daily rTMS treatments, clinic visits and post rTMS treatment. All participants will have a phone interview two weeks post rTMS treatment.

Official Title
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A Randomized Double-blind Sham-controlled Trial of Repetitive Transcranial Magnetic Stimulation (rTMS) in Acute Bipolar Depression

Conditions
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Bipolar Depression

Intervention / Treatment
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* Device: iTBS repetitive Transcranial Magnetic Stimulation (rTMS)
* Device: Sham rTMS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are a male or female aged 18 to 70 years. Have a diagnosis of Bipolar Disorder with a current ongoing episode of depression. Are not currently experiencing a mania. Have failed to achieve a clinical response or have been unable to tolerate an adequate dose of at least one of the medications used for treating Bipolar depression Are taking an anti-manic agent (lithium or valproate) or an atypical antipsychotic (quetiapine, lurasidone, aripiprazole, ziprasidone, risperidone, olanzapine), or a combination of the above, or a combination of any of them with lamotrigine 100-400 mg daily. Lamotrigine alone for bipolar II disorder is permitted. current medications have been at a stable dose in the 2 weeks prior to randomization Are capable of understanding, consenting to, and complying with the requirements of the study Exclusion criteria: Have an alcohol or substance abuse or dependence within the last 3 months. Are at a significant risk of harm to themselves or others Are pregnant or planning on becoming pregnant in near future or lactating. Have a personal or family history of seizures. Have a history of unstable or inadequately treated medical illnesses, including moderate to severe brain injury or head trauma. Have a primary diagnosis of other psychiatric disorders (other than Bipolar) or personality disorders that are of primary concern and causing greater impairment other than bipolar disorder. are currently taking more than 3 of the antipsychotics. Have failed a course of ECT in the current episode. History of non-response to rTMS treatment. If participating in psychotherapy, you must have been in stable treatment for at least 3 months prior to entry into the study, Currently (or in the last 4 weeks) taking more than 2 mg daily (or equivalent) of lorazepam or any dose of medication for seizures Have a pacemaker, or an implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or near the head, excluding the mouth that cannot be safely removed. Have a non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to cooperate with interview).

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: Active iTBS rTMS<br>The active arm involves magnetic stimulation of the brain to the left dorsolateral prefrontal cortex (DLPFC) daily for four weeks. The active arm will be receiving intermittent Theta-Burst (iTBS) repetitive Transcranial Magnetic Stimulation (rTMS) to deliver magnetic pulses. | Device: iTBS repetitive Transcranial Magnetic Stimulation (rTMS)<br>* rTMS is a non-invasive procedure in which cerebral electrical activity is influenced by a rapidly changing magnetic field. The magnetic field is created by a plastic-encased coil which is placed over the patient's scalp. The magnetic field can be directed onto specific areas of the brain. rTMS can modulate cerebral activity by low or high frequencies. Over time, the magnetic field pulses can gradually change the activity level of the stimulated brain region and help symptoms of bipolar depression.<br>* Other names: MAGPRO X100 stimulator;|
| Sham Comparator: Sham rTMS<br>sham rTMS treatment involves scalp stimulation with no magnetic pulse daily for four weeks (20 sessions). Sham rTMS involves only the click replicating the sound of the magnetic discharge, without any magnetic pulse being delivered. | Device: Sham rTMS<br>* Sham rTMS involves a click replicating the sound of the magnetic discharge, without any magnetic pulse being delivered.<br>* Other names: MAGPRO X100 stimulator;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in depressive symptoms as measured by MADRS scale score from baseline to week-4 (post rTMS treatment) with iTBS-rTMS as compared to sham treatment group | Compared to sham-rTMS, active-iTBS rTMS is anticipated to show Higher rates of clinical remission (score ≤12 on the MADRS) and Higher rates of clinical response (≥50% reduction in MADRS scores) in patients with acute bipolar depression. | Baseline to 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in mood from baseline to week 4 (post rTMS treatment) with iTBS-rTMS as compared to sham treatment group. | Young Mania Rating Scale (YMRS) will be used to assess changes in mood from baseline to Week 4. | Baseline to 4 weeks | 
| Improvement in overall psychiatric status from baseline to week 4 (post rTMS treatment) with iTBS-rTMS as compared to sham treatment group. | Clinical Global Impression severity and change scale - bipolar version (CGI-BP) is a clinician rated scale to capture any change in participants mania, depression, over well being in a a single scale 1 (normal not at all ill) to 7 (very severely ill). | Baseline to 4 weeks | 
| Improvement in overall well being from baseline to week 4 (post rTMS treatment) with iTBS-rTMS as compared to sham treatment group. | The visual analog scale (VAS) is self report measure captures the over all being from of 0-worst health to 100- best health. We are only the sub scale of VAS to capture the over all well being. | Baseline to 4 weeks | 
| BFIS self report questionnaire that captures the difficulty in functioning major life activities from baseline to week 4 (post rTMS treatment) with iTBS-rTMS as compared to sham treatment group. | Brief Illness Perception Questionnaire that captures the difficulty in functioning major life activities on a scale of 0 (not at all ) to 9 (severely). | Baseline to 4 weeks | 
| Improvement in neurocognitive function from baseline to week-4 (post rTMS treatment) with iTBS-rTMS as compared to sham | Cognitive improvement will be measured by changes in cognitive score on The International Society for Bipolar Disorders-Battery for Assessment of Neurocognition (ISBD-BANC) from baseline to week-4 (post rTMS treatment). | Baseline to 4 weeks | 
| Cognitive Failures Questionnaire (CFQ)is a self report questionnaire to capture daily cognitive measures from baseline to week-4 (post rTMS treatment) with iTBS-rTMS as compared to sham | CFQ captures minor mistakes of daily functioning at a scale of 0 (never) to 4 (very often) making mistakes. | Baseline to 4 weeks | 
| Sheehan Disability Scale (SDS) is a self report questionnaire to assess everyday functioning will be assessed from baseline to week-4 (post rTMS treatment) with iTBS-rTMS as compared to sham. | Sheehan Disability Scale is to capture everyday functioning at work/school, social life, family life and home responsibilities captured in a scale of 0 to 10 (not at all to extremely disruptive). | Baseline to 4 weeks | 
| Quality of Life questionnaire is a self report questionnaire improvement in life quality to assess baseline to week-4 (post rTMS treatment) with iTBS-rTMS as compared to sham. | Quality of Life in Bipolar Disorder (QoL.BD) captures a range of experiences, behaviors, felling related questions scaled from 1 (strongly disagree) to 5 (strongly agree). | Baseline to 4 weeks | 
| Patient Global Impression Rating Scale: Severity and Improvement | Patient Global Impression Rating Scale: Severity and Improvement is a self-rated scale to capture any change in participants mood rating 1-4 (1 is normal and 4 is severe) and improvement rating of 1-7 (1 is very much better and 7 is very much worse). | Baseline to 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bipolar disorder, Depression, intermittent Theta-Burst Stimulation (rTMS), neuromodulatory technique