iTBS in Refractory Pediatric Depression

Study Overview
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Brief Summary
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This work will mark the first step in understanding the neural targets for rTMS in youth with difficult to treat depressive symptoms, creating benchmarks for optimizing the safety and efficacy of rTMS for pediatric populations through precision targeting, and encourage funding applications for larger sham- controlled randomized clinical studies.

Detailed Description
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Problem Statement: Depression is a global health problem with limited novel and targeted solutions. Currently available interventions (medication and psychotherapy) have failed to provide adequate clinical improvement in 40% of adolescents with depression and only produce remission in 30% of youth. There is a clear need to develop better targeted interventions for this growing population of youth. Specific Aims Aim 1: To examine the efficacy of a targeting strategy to optimize repetitive transcranial magnetic stimulation (rTMS) delivered to the left dorsolateral prefrontal cortex (DLPFC) to reduce depressive symptoms in adolescents between 12-17 years of age. Hypothesis 1: Six weeks of open-label daily intermittent theta-burst stimulation (iTBS) sessions delivered to the left DLPFC will be effective at reducing depressive symptoms between baseline and 10- week follow-up. Hypothesis 2: iTBS over left DLPFC will decrease functional connectivity between left DLPFC and subcallosal cingulate cortex (SCC) and will reduce depression-related hyperconnectivity between nodes of the default mode network (DMN). Hypothesis 3: Higher anti-correlation between left DLPFC and SCC and lower cingulate glutamate concentrations will predict better clinical outcome following iTBS. Aim 2: To determine the tolerability of iTBS in adolescents between 12-17 years of age. Hypothesis 1: iTBS will be well tolerated without any more than minimal side effects. Hypothesis 2: iTBS will result in sufficient cortical excitability, as measured by 64-channel-EEG pre, during, and post iTBS, to induce an antidepressant effect but not induce seizures or other adverse events.

Official Title
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Evaluating the Efficacy and Tolerability of Targeted Transcranial Magnetic Stimulation in Youth

Conditions
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Depression

Intervention / Treatment
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* Device: Intermittent Theta Burst Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 10 participants ages 12-21 years of age with at least moderate to severe depressive symptoms confirmed by the Children's Depression Rating Scale-Revised (CDRS-R>40) or Hamilton Rating Scale for Depression (HRSD-17 ≥ 18) able to commit to protocol schedule and provide Informed consent by a legal guardian and assent by a youth participant have had at least one prior antidepressant treatment failure with adequate dose and duration Exclusion Criteria: prior neurological diagnosis (neurodevelopmental disorders, strokes/traumatic brain injuries, brain tumor, epilepsy) contraindications for TMS or MRI e.g. have any implanted metal unstable medical conditions acute suicide risk, defined as an attempt in past 6 months that required medical treatment, or history of ≥2 suicide attempts in the past 12 months, or has a clear cut plan for suicide pregnancy, suspected pregnancy or not on birth control if sexually active; 6) Inability to locate and quantify a motor threshold any factor that the PI determines to be reason for exclusion.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 21 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open Label<br>Open-label rTMS sessions will occur within  2 days after the baseline session with daily sessions delivered to left DLPFC over 2-6 weeks. | Device: Intermittent Theta Burst Stimulation<br>* Stimulation will be administered using the MagVenture MagPro rTMS Research System at currently FDA approved parameters (www.magvitatms.com). The TBS parameters will be 3-pulse 50-Hz bursts given every 200 ms (at 5 Hz) and an intensity of 80% active motor threshold, as measured from the right first dorsal interosseous muscle by a hand-held 700-mm figure-of-eight coil. rTMS will be applied for 9 min delivering a total of 1800 pulses/session.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Children's Depression Rating Scale - Revised (CDRS-R) Score From | Standardized assessment to determine depression severity. The CDRS-R total score is the sum of the responses to 17 questions. Each question is graded on a 5- or 7-point scale. Total score ranges from 17-113. In general, higher values of CDRS-R total score represent greater severity of illness. Response to treatment is determined by a ≥ 50% reduction in score from baseline to end of treatment. | Baseline and week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hamilton Depression Rating Scale (HDRS-17) | Standardized assessment to determine depression severity. HDRS-17, a clinician-rated measure of depressive symptoms that consists of 17 items rated using a semi-structured interview. Eight of the 17 HDRS-17 items are rated on a 5-point scale (0=absent; 1=doubtful or mild; 2=mild to moderate; 3=moderate to severe; 4=very severe), while the remaining 9 items are rated on a 3-point scale (0=absent; 1=doubtful or mild; 2=clearly present), yielding a minimum total score of 0 (least severe) and a maximum score of 52 (most severe). Response to treatment is determined by a ≥ 50% reduction in score from baseline to end of treatment. | Baseline and week 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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depression, transcranial magnetic stimulation, adolescent, treatment refractory