Accelerated Intermittent Theta-Burst Stimulation (aiTBS) in Treatment-Resistant Depression of Bipolar II Disorder

Study Overview
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Brief Summary
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The purpose of this study is to investigate the effectiveness of accelerated intermittent theta-burst transcranial magnetic stimulation (aiTBS) in inducing anti-depressant responses in individuals with treatment-resistant depression of bipolar II disorder. This is a double-blind, randomized, sham-controlled trial that targets a single location on the left dorsolateral prefrontal cortex (LDLPFC) using the MagPro rTMS system.

Detailed Description
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The aim of this study is to assess the efficacy of aiTBS applied to the left dorsolateral prefrontal cortex (L-DLPFC) in reducing depressive symptoms in individuals with bipolar II disorder, and to determine the neural functional connectivity changes that underlie treatment response. A total of 60 individuals with bipolar II disorder who are currently experiencing a depressive episode will be recruited for the study. The accelerated iTBS (aiTBS) treatment will consist of 10 sessions, administered daily over a period of 5 consecutive days. Before and after the stimulation, magnetic resonance imaging (MRI) scans, electroencephalograms (EEG), and heart rate variability (HRV) will be collected. The severity of depressive symptoms will be evaluated using both clinician-rated and self-report assessments.

Official Title
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Accelerated Intermittent Theta-Burst Stimulation (aiTBS) in Treatment-Resistant Depression of Bipolar II Disorder

Conditions
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Bipolar II Disorder, Most Recent Episode Major Depressive, Current Depressive Episode, Treatment Resistant Depression

Intervention / Treatment
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* Device: Active Comparator: Active aiTBS
* Device: Sham Comparator: Sham aiTBS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants aged 18 years old to 80 years old with a primary diagnosis of bipolar affective disorder II in a current major depressive episode, according to the criteria defined in the Diagnosis and Statistical Manual of Mental Disorders, Fifth Fourth Edition, Text Revision (DSM-V). Able to read, understand, and provide written, dated informed consent prior to screening. Participants will be deemed likely to comply with study protocol and communicate with study personnel about adverse events and other clinically important information. Meet the criteria by Maudsley Staging Method score >=7 Not in a current state of hypomania (as assessed by the Young Mania Rating Scale) or psychosis In good general health, as ascertained by medical history. Must have a stable psychiatrist during study enrollment, who confirms diagnosis of bipolar II disorder. Must be on a mood stabilizer regimen for 6 weeks prior to study enrollment and agree to continue this regimen during study period Meet the threshold on the MADRS, with a total score of >/=20 at screening/baseline. TMS Naive 11. For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation. 12. Agreement to adhere to Lifestyle Considerations throughout study duration. Lifestyle considerations: Abstain from becoming pregnant from the screening visit (Visit 1) until after the final study visit (Visit 9). Continue usual intake patterns of caffeine- or xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) without significant change for the duration of the study. Abstain from alcohol for at least 24 hours before the start of each MRI and TMS session. Participants who use tobacco products will be informed that use will be allowed only in between intervention sessions. Exclusion Criteria: Primary diagnosis other than bipolar II disorder Any structural lesion e.g. structural neurological condition, more subcortical lesions than would be expected for age, stroke effecting stimulated area or connected areas or any other clinically significant abnormality that might affect safety, study participation, or confound interpretation of study results. Metal implant in brain (e.g. deep brain stimulation), cardiac pacemaker, or cochlear implants History of epilepsy or seizures Shrapnel or any ferromagnetic item in the head Pregnancy Autism Spectrum disorder Any current or past history of any physical condition which in the investigator's opinion might put the subject at risk or interfere with study results interpretation Active substance abuse (<1 week) or intoxication verified by toxicology screen--of cocaine, amphetamines, benzodiazepines Cognitive impairment (including dementia) Current severe insomnia (must sleep a minimum of 5 hours the night before stimulation) Current hypomania or psychosis Showing symptoms of withdrawal from alcohol or benzodiazepines A diagnosis of intellectual disability Parkinsonism or other movement disorder determined by Principal Investigator to interfere with treatment Any other indication the Principal Investigator feels would comprise data. Current active suicidal ideation or suicide attempt or suicidal behaviors in the last 6 months Any history of psycho surgery for depression Any history of ECT (greater than 8 sessions) without meeting responder criteria Recent (within 4 weeks of any clinical effect) or concurrent use of rapid acting antidepressant agent (i.e., ketamine or a course of ECT) 22. Any history of myocardial infarction, CABG, CHF, or other cardiac history 23. The presence or diagnosis of prominent anxiety disorder, personality disorder or dysthymia 24. History of intractable migraine 25. Hypomania in the past 6 months. 26. Depth-adjusted aiTBS treatment dose > 65% maximum stimulator output (MSO) 27. Unstable symptoms between screening and baseline as defined by a 30% change in MADRS-C score. 28. Any other condition deemed by the PI to interfere with the study or increase risk to the participant

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active aiTBS<br>Participants will be randomized to active or sham aiTBS condition, and receive 10 aiTBS to left DLPFC (LDLPFC) sessions a day for 5 days of course. | Device: Active Comparator: Active aiTBS<br>* Participants will be randomized to active or sham aiTBS condition, and receive 10 aiTBS to left DLPFC (LDLPFC) sessions a day for 5 days of course.<br>|
| Sham Comparator: Sham aiTBS<br>Participants will be randomized to active or sham aiTBS condition, and receive 10 aiTBS to left DLPFC (LDLPFC) sessions a day for 5 days of course. | Device: Sham Comparator: Sham aiTBS<br>* Participants will be randomized to active or sham aiTBS condition, and receive 10 aiTBS to left DLPFC (LDLPFC) sessions a day for 5 days of course.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline Montgomery Asberg Depression Rating Scale (MADRS) | A ten item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. The MADRS uses a 0 to 6 severity scale, scored following the interview. Scoring/Interpretation: Higher scores indicate increasing depressive symptoms. Cut-off points include: 0 to 6 - symptom absent, 7 to 19 - mild depression, 30 to 34 - moderate, 35 to 60 - severe depression. | Baseline and immediately post-treatment, 1-month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline Young Mania Rating Scale (YMRS) | The Young Mania Rating Scale (YMRS) is one of the most frequently utilized rating scales to assess manic symptoms. The scale has 11 items and is based on the patient's subjective report of his or her clinical condition. There are four items that are graded on a 0 to 8 scale (irritability, speech, thought content, and disruptive/aggressive behavior), while the remaining seven items are graded on a 0 to 4 scale. These four items are given twice the weight of the others to compensate for poor cooperation from severely ill patients. Typical YMRS baseline scores can vary a lot. They depend on the patients' clinical features such as mania (YMRS = 12), depression (YMRS = 3), or euthymia (YMRS = 2). | Baseline and immediate post-treatment, 1-month | 
| Change in resting-state functional connectivity | Resting-state fMRI scans will be conducted before and after the course of aiTBS to examine changes in resting-state functional connectivity. | After all stimulation sessions have been completed (approximately 48 hours after the final session) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bipolar II Disorder, Treatment Resistant Depression, Transcranial Magnetic Stimulation (TMS), Theta Burst