Biomarkers in Repetitive Transcranial Magnetic Stimulation (rTMS) for Adolescent Depression

Study Overview
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Brief Summary
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The Researchers are going to gather information regarding the use of rTMS as a treatment for depression in adolescents with Major Depressive Disorder. The researchers also hope to learn if measures of brain activity (cortical excitability and inhibition) collected with transcranial magnetic stimulation (TMS) can be used to identify which patients will benefit from certain types of rTMS treatment.

Detailed Description
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Phase I is a double-blind, randomized, biomarker-stratified trial of 1 Hz vs. 10 Hz rTMS. Phase II is for participants who do not respond to Phase I treatment and is a biomarker guided, double-blind trial of continuous vs intermittent theta burst stimulation (TBS). Please note that transcranial magnetic stimulation (TMS) biomarkers will be collected in this protocol during the course of the proposed interventions. Participants in Phase I will be offered enrollment in a separate protocol with baseline and posttreatment 7 Tesla Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy (MRS) scans

Official Title
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Glutamatergic and GABAergic Biomarkers in rTMS for Adolescent Depression

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Device: NeuroStar TMS Therapy® System
* Device: NeuroStar XPLOR®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Depressed adolescent participants will have a primary diagnoses of MDD based on a clinical and structured interview with the MINI Depression symptoms severity of a 40 or greater based on evaluation with the Children's Depression Rating Scale Revised (CDRS-R) at screening and baseline visits. Further, the total score of the baseline CDRS-R score must not have had a 25% or greater decrease from the screening CDRS-R score The duration of the current episode of depression must be 4 weeks or more but 3 years or less. For any participant currently receiving antidepressant medication, the referring clinician must determine that insufficient benefit is being received from this treatment and it is clinically appropriate to discontinue the existing antidepressant. Participants in psychotherapy are eligible provided that this was initiated 4 weeks prior to enrollment and that the frequency of visits will be maintained during study participation. Exclusion criteria: The following psychiatric comorbidities are exclusionary: psychotic disorders, bipolar disorders, anorexia nervosa, bulimia nervosa, and substance use disorders within the past year (with the exception of caffeine and tobacco) A positive urine drug screen at baseline Seizure history Family history of epilepsy in a first degree relative Head trauma with loss of consciousness for greater than 5 minutes Any true positive findings on the rTMS safety screening form. Any concurrent psychotropic medications (for potential participants receiving antidepressants or psychotropic medications, the referring clinician must determine that insufficient benefit is being received from the treatment and if clinically appropriate, discontinue existing antidepressants and other psychotropic medications) Prohibited concomitant medications (See Appendix A) Pregnancy or suspected pregnancy in female Participants (assessed with urine pregnancy test) Conductive, ferromagnetic, or other magnetic-sensitive metals implanted in the subject's head within 30 cm of the treatment coil excluding the mouth that cannot safely be removed. Examples include cochlear implants, implanted electrodes/stimulators, aneurysm clips or coils, stents, bullet fragments, jewelry and hair barrettes. Prior brain surgery Risk for increased intracranial pressure such as a brain tumor Any unstable medical condition History of treatment with ECT or TMS Therapy for any disorder Use of any investigational drug within 4 weeks of the baseline visit Initiation of a new psychotherapeutic treatment within the past 4 weeks Suicide attempt within the previous 6 months that required medical treatment or ≥ 2 attempts in the past 12 months, or has a clear cut plan for suicide and states that he/she cannot guarantee that he/she will inform a family member or call his/her psychiatrist or the investigator if the impulse to implement the plan becomes substantial during the study; or, in the investigator's opinion, is likely to attempt suicide within the next 6 months.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1 Hz left prefrontal rTMS<br>36 sessions of 1 Hz rTMS at 120% motor threshold applied to the left prefrontal cortex. Each session is 2400 continuous pulses. | Device: NeuroStar TMS Therapy® System<br>* The NeuroStar TMS Therapy® System is a computerized electromechanical instrument that produces and delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce electrical currents in localized regions of the cerebral cortex. It is a non-invasive tool used for the treatment of Participants with MDD who have not achieved sufficient clinical benefit from antidepressant pharmacotherapy.<br>Device: NeuroStar XPLOR®<br>* NeuroStar XPLOR® is a clinical research option for the NeuroStar TMS Therapy System that provides features necessary to conduct randomized controlled trials and other TMS research.<br>|
| Active Comparator: 10 Hz left prefrontal rTMS<br>36 sessions of 10 Hz rTMS at 120% motor threshold applied to the left prefrontal cortex. Each session is 2400 pulses with 4 seconds on and 36 seconds off. | Device: NeuroStar TMS Therapy® System<br>* The NeuroStar TMS Therapy® System is a computerized electromechanical instrument that produces and delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce electrical currents in localized regions of the cerebral cortex. It is a non-invasive tool used for the treatment of Participants with MDD who have not achieved sufficient clinical benefit from antidepressant pharmacotherapy.<br>Device: NeuroStar XPLOR®<br>* NeuroStar XPLOR® is a clinical research option for the NeuroStar TMS Therapy System that provides features necessary to conduct randomized controlled trials and other TMS research.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Children's Depression Rating Scale, Revised (CDRS-R) score | The children's depression Rating Scale-Revised (CDRS-R) (Poznanski and Mokros 1996) has become the most widely used rating scale for assessing severity of depression and change in depressive symptoms for clinical research trials in children and adolescents with depression. The CDRS-R, which was based on the adult Hamilton Depression Rating Scale, was originally developed as a rating scale for children aged 6-12 years. It is a 17-item scale, with items ranging from 1 to 5 or 1 to 7 (possible total score from 17 to 113), rated by a clinician via interviews with the child and parent. A score of ≥40 is indicative of depression, whereas a score ≤28 is often used to define remission (minimal or no symptoms) | up to 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intracortical Facilitation ICF | Intracortical Facilitation will be the secondary continuous outcome measure. A within-Participants linear mixed model analysis of repeated measures will be used to examine the change in ICF over 6 weeks of rTMS treatment in depressed adolescents. We will consider the inclusion of pubertal state and treatment resistance (as defined by ATHF score) during the study period as a covariate in the mixed model. A mixed model analysis will be conducted on ICF for those who receive 6 weeks of low frequency (1 Hz) rTMS treatment (Hypothesis 2a) and, in a separate model, for those who receive 6 weeks of high frequency (10 Hz) rTMS treatment (Hypothesis 2c). | Weekly for 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adolescent, biomarkers