Treatment of Depression With Connectivity Guided Robotically Delivered rTMS

Study Overview
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Brief Summary
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The purpose of this study is to determine the clinical effects (if any) of connectivity-guided repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder (MDD) to provide clues about the ideal neural networks to target for more robust clinical outcomes, and to identify potential biomarkers of treatment response including changes in brain network connectivity.

Detailed Description
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The investigators propose a randomized, double-blind, 4-week trial of TMS to the left dorsolateral prefrontal cortex (DLPFC) for subjects with MDD all of whom at the patient's treatment clinic are concurrently receiving pharmaceutical and psychotherapeutic interventions. Arm 1 delivers active rTMS to the left DLPFC using the standard aiming strategy. Arm 2 delivers active rTMS to the left anterior DLPFC using connectivity-based, image-guided aiming. Arm 3 delivers active rTMS to the left posterior DLPFC using connectivity-based, image-guided aiming. In all three arms, rTMS is administered in an image-guided, robotically-positioned TMS (irTMS) manner to ensure therapist blinding and equivalent subject experiences across arms. In all three arms, the following stimulation protocol will be used: 10 Hz irTMS delivered in 4 sec trains with 26 sec inter-train intervals, 37.5 minutes/session (i.e. 3,000 pulses/session), 5 sessions/week, for 4 weeks. Neuroimaging will be used both for treatment planning and to characterize any TMS-induced network plasticity using resting-state functional magnetic resonance imaging (rs-fMRI) at week 4 of each treatment arm. Clinical assessments will be administered weekly throughout treatment (weeks 1-4) at the patient's treatment clinic. Additional psychological tests will be performed at UT Health-San Antonio's Research Imaging Institute (RII) at the baseline and post-treatment visits in order to track patient progress.

Official Title
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Treatment of Depression With Connectivity Guided Robotically Delivered Repetitive Transcranial Magnetic Stimulation

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Device: repetitive transcranial magnetic stimulation
* Device: robotic arm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females with MDD receiving treatment at the iKare Mood Trauma Recovery Clinic between the ages of 18-65 years; Meeting the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criteria for MDD as determined using the Mini-International Psychiatric Interview (MINI) Meeting the Patient Health Questionnaire-9 (PHQ-9 > 14) and/or the Structured Interview Guide for the Montgomery-Ashberg Depression Rating Scale (SIGMA>18) criteria for treatment resistance in MDD despite completing at least one adequate trial of an Selective Serotonin Reuptake Inhibitor (SSRI) or Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) at an FDA-recommended dose for at least 6-8 weeks. Subjects on SSRIs or other antidepressants, hypnotic medications including modulators of Gamma-Aminobutryic Acid (GABA)-A receptor function, trazodone, atypical neuroleptic or other psychotropic medications such as prazosin may enter the study if they are deemed to be on a stable dose of their medication. Able to provide written informed consent. Able to read and write English. Exclusion Criteria: Subjects with a diagnostic history of bipolar disorder, schizophrenia or schizoaffective disorder or currently exhibiting psychotic features as confirmed by MINI. Serious, active suicidal risk as assessed by evaluating psychiatrist. Serious active suicidal risk is determine as imminent risk of suicide reflected in a subject having a plan and intent to end his or her life. History of suicidality in itself is not exclusion for participation in this protocol so long as the evaluating psychiatrist determines that there is an absence of serious active suicidal risk and the means to keep subjects safe. Substance use disorder during the 3 months prior to screening; except for Mild or Moderate Alcohol Use Disorder according to DSM-V criteria. Any history or signs of serious medical or neurological illness including seizure disorders. Except for seizures, a subject with a clinical abnormality may be included only if the study clinician considers the illness will not introduce additional risk and will not interfere with the study procedures. Females will be excluded if they are pregnant (i.e. positive pregnancy test identified after their intake at the treatment clinic). History of traumatic brain injury (TBI) with loss of consciousness for 20 minutes or more as determined by the Brief Traumatic Brain Injury Screen (TBI Screening Tool). Any history or signs of metal objects (e.g. surgical clips, cardiac pacemakers, metal implants, etc.) in the body at the time of screening. MRI can have risks for persons with foreign bodies implanted in their body.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard rTMS Aiming<br>Active repetitive transcranial magnetic stimulation (rTMS) will be delivered to the left DLPFC using the standard aiming strategy with the rTMS coil positioned using a robotic arm. In this arm, rTMS will be delivered at 10 Hz in 4 sec trains with 26 sec inter-train intervals, 37.5 minutes/session (i.e. 3,000 pulses/session), 5 sessions/week, for 4 weeks. | Device: repetitive transcranial magnetic stimulation<br>* The MagPro R30 is an advanced, high performance magnetic stimulator designed primarily for non-invasive clinical use. The non-invasive brain stimulation system will be used to deliver repetitive electromagnetic pulses in this research study's treatment of major depressive disorder.<br>* Other names: rTMS;Device: robotic arm<br>* This robotic system is based on a commercially available neurosurgical robot. The robot is mounted on a mobile (i.e. retractable wheels) cart which holds the robot controller and the TMS power supply and pulse-generation computer. The robotic system will be used for TMS coil positioning/targeting.<br>|
| Active Comparator: Anterior DLPFC targeting<br>Active rTMS will be delivered to the left anterior DLPFC using connectivity-based, image-guided aiming with the rTMS coil positioned using a robotic arm. In this arm, rTMS will be delivered at 10 Hz in 4 sec trains with 26 sec inter-train intervals, 37.5 minutes/session (i.e. 3,000 pulses/session), 5 sessions/week, for 4 weeks. | Device: repetitive transcranial magnetic stimulation<br>* The MagPro R30 is an advanced, high performance magnetic stimulator designed primarily for non-invasive clinical use. The non-invasive brain stimulation system will be used to deliver repetitive electromagnetic pulses in this research study's treatment of major depressive disorder.<br>* Other names: rTMS;Device: robotic arm<br>* This robotic system is based on a commercially available neurosurgical robot. The robot is mounted on a mobile (i.e. retractable wheels) cart which holds the robot controller and the TMS power supply and pulse-generation computer. The robotic system will be used for TMS coil positioning/targeting.<br>|
| Active Comparator: Posterior DLPFC targeting<br>Active rTMS will be delivered to the left posterior DLPFC using connectivity-based, image-guided aiming with the rTMS coil positioned using a robotic arm. In this arm, rTMS will be delivered at 10 Hz in 4 sec trains with 26 sec inter-train intervals, 37.5 minutes/session (i.e. 3,000 pulses/session), 5 sessions/week, for 4 weeks. | Device: repetitive transcranial magnetic stimulation<br>* The MagPro R30 is an advanced, high performance magnetic stimulator designed primarily for non-invasive clinical use. The non-invasive brain stimulation system will be used to deliver repetitive electromagnetic pulses in this research study's treatment of major depressive disorder.<br>* Other names: rTMS;Device: robotic arm<br>* This robotic system is based on a commercially available neurosurgical robot. The robot is mounted on a mobile (i.e. retractable wheels) cart which holds the robot controller and the TMS power supply and pulse-generation computer. The robotic system will be used for TMS coil positioning/targeting.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Depression Severity (MADRS) | Measured by the Montgomery-Ashberg Depression Rating Scale. This is a 10-item diagnostic questionnaire with an overall score range from 0 to 60. A higher score indicates more severe depression: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression >34 - severe depression. | Baseline to four weeks (the conclusion of rTMS treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Depression Severity (MADRS) | Measured by the Montgomery-Ashberg Depression Rating Scale. This is a 10-item diagnostic questionnaire with an overall score range from 0 to 60. A higher score indicates more severe depression: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression >34 - severe depression. | Baseline to sixteen weeks (twelve weeks after the conclusion of rTMS treatment) | 
| Clinically Significant Response (MADRS) | Defined as greater than or equal to a 50% decrease in the Montgomery-Ashberg Depression Rating Scale. This is a 10-item diagnostic questionnaire with an overall score range from 0 to 60. A higher score indicates more severe depression: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression >34 - severe depression. | Baseline to four weeks (the conclusion of rTMS treatment) | 
| Clinically Significant Response (MADRS) | Defined as greater than or equal to a 50% decrease in the Montgomery-Ashberg Depression Rating Scale. This is a 10-item diagnostic questionnaire with an overall score range from 0 to 60. A higher score indicates more severe depression: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression >34 - severe depression. | Baseline to sixteen weeks (twelve weeks after the conclusion of rTMS treatment) | 
| Remission From Depression (MADRS) | Defined as Montgomery-Ashberg Depression Rating Scale score less than or equal to 10. This is a 10-item diagnostic questionnaire with an overall score range from 0 to 60. A higher score indicates more severe depression: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression >34 - severe depression. | Baseline to four weeks (the conclusion of rTMS treatment) | 
| Remission From Depression (MADRS) | Defined as Montgomery-Ashberg Depression Rating Scale score less than or equal to 10. This is a 10-item diagnostic questionnaire with an overall score range from 0 to 60. A higher score indicates more severe depression: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression >34 - severe depression. | Baseline to sixteen weeks (twelve weeks after the conclusion of rTMS treatment) | 
| Functional Connectivity Changes of the Targeted Brain Network(s) Following rTMS Treatment | resting-state fMRI scan will also be used to assess, network-specific functional connectivity differences between each subject's pre-treatment and post-treatment scans. The purpose of the Z score is to standardize distributions so that each has a mean of 0, and standard deviation as 1, so we can then make comparisons. Standard Score, the Z-Score: A way to make a comparison between values on two different normal curves by converting the values to the number of standard deviations above or below the mean. | Baseline to four weeks (the conclusion of rTMS treatment) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Repetitive Transcranial Magnetic Stimulation, Major Depressive Disorder