rTMS for Military TBI-related Depression

Henry M. Jackson Foundation for the Advancement of Military Medicine198 enrolled

Overview

The purpose of this study is to investigate the efficacy, safety, and tolerability of two dorsolateral prefrontal cortex (DLPFC) repetitive transcranial magnetic stimulation (rTMS) protocols to alleviate symptoms of depression in United States (U.S.) military service members and veterans with a history of concussion/mild traumatic brain injury (TBI).

In United States Military personnel, rates of depression may increase after mild traumatic brain injury, or concussion. rTMS may hold a therapeutic potential for alleviating symptoms of depression after concussion. This study is a randomized, double-blind, Bayesian adaptive trial aimed at determining the safety, efficacy, and tolerability of individualized connectome targeted (ICT)-accelerated intermittent Theta Burst Stimulation (aiTBS) and scalp-targeted aiTBS for the treatment of depressive symptoms in a properly powered sample of current and former US military service members with a history of concussion.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

198

Conditions

Depressive Symptoms Mild Traumatic Brain Injury Concussion

Interventions

Repetitive Transcranial Magnetic Stimulation (rTMS)DEVICE

Active rTMS

Sham rTMSDEVICE

Sham comparator to active rTMS

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Age 18-55 at the time of consent. Older individuals will not be enrolled in this initial trial for reasons of safety and expected reduced efficacy. * Current or former US military service member eligible for care at a Military Treatment Facility (MTF) or Veterans Administration Medical Center (VAMC.) * Able to provide written, informed consent in English . * Self-reported or medically diagnosed history of concussion (synonymous with "mild TBI.") \>6 months, but \<26 years prior to consent, defined based on the DoD/VA definition: 1. Positive Loss of Consciousness of \<30 minutes as confirmed by the TBI Screener and/or medical records and/or; 2. Positive Alteration of Consciousness of \<24 hours as confirmed by the TBI Screener and/or medical records and/or; 3. Positive Post-traumatic Amnesia of 0 to 1 day as confirmed by the TBI Screener and/or medical records. * Note: Neuroimaging data or documentation from medical records is not required. * Baseline MADRS \>13 at the time of screening indicating at least mild-moderate depressive symptoms. * Maintained a steady psychotropic medication regimen for six weeks and a steady behavioral therapy regimen for twelve weeks prior to enrollment in the study. * Female participants with child-bearing potential must agree to use an effective method of birth control during the course of the study. * Under the care of a primary care and/or behavioral health provider. Exclusion Criteria: * Elevated risk of seizures at the time of rTMS including any of the following: 1. History of unprovoked seizures. 2. History of seizure within 24 hours of sustaining a concussion(s) or other head injury regardless of whether it was determined to have been related to concussion. 3. Family history of two or more unprovoked seizures in a first degree relative (parent, sibling, or child). 4. History of Moderate, Severe, or Penetrating TBI based on TBI Screener and/or medical records. 5. Intracranial lesion (such as intracranial tumor or intraparenchymal hemorrhage) that, in the opinion of the investigators, would increase seizure risk. 6. Currently taking medication or other substances (such as tricyclic antidepressants or neuroleptics) that, in the opinion of the investigator, lowers the seizure threshold. * Contraindications to awake 3T MRI without contrast at the time of the Baseline MRI according to site radiology department criteria. * Severe claustrophobia interfering with medication/sedation-free 3T closed-bore MRI. * Intracranial lesion that would produce an artifact that would compromise the integrity of rsfMRI data. * History of severe or recent uncontrolled heart disease. * Presence of a cardiac pacemaker or intracardiac lines. * Any implant, prosthesis or other permanent alteration of the body (such as implanted neurostimulators and medication pumps) that, in the opinion of the investigator, would be unsafe with MRI or TMS or that would produce an artifact that would compromise the integrity of data. * Presence of rapidly progressive illnesses such as late-stage cancer, neurodegenerative conditions, major organ failure, etc. * History of Bipolar Disorder or Schizophrenia Spectrum Disorders. * Current evidence of substance-induced mood disorder, active psychosis, or depression secondary to general medical illness other than TBI. * Severe or uncontrolled substance use. * Concomitant or lifetime history of receiving open-label TMS, due to issues preserving blinding. * Concomitant or recent history (within 12 weeks prior to enrollment) of receiving other neurostimulatory treatment, including but not limited to transcranial direct current (tDCS), transcranial alternating current (tACS), alpha stim, or electroconvulsive therapy. * Suicide attempt within six months prior to enrollment. * Right upper extremity amputation or other condition precluding left motor threshold calibration. * Unable to complete timeline of study (e.g., planned hospitalization partway through the study period.) * Prisoner, or other legally restricted freedom of movement and participation. * Any other considerations that, in the opinion of the investigators, may adversely affect participant safety, participation, or the scientific validity of the data being collected (e.g., erratic or unreliable responses, inconsistent communication, inability to remain on a steady neurotropic medication and/or behavioral therapy regimen over the course of the Randomization phase of the study.)

Locations (3)

VA Palo Alto Health Care System

Palo Alto, California, United States

RECRUITING

William Beaumont Army Medical Center

Fort Bliss, Texas, United States

RECRUITING

Alexander T. Augusta Military Medical Center

Fort Belvoir, Virginia, United States

RECRUITING

Outcomes

Primary Outcomes

Change from Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Scores

Change in Montgomery-Asberg Depression Rating Scale scores from baseline to post-intervention between groups. The Scale is designed to measure depression severity and consists of 10 items, each of which is scored on a Likert scale from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.

Time frame: Baseline to post-intervention, within 10 working days of the final rTMS session

Change from Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Scores in a Subgroup

Change in Montgomery-Asberg Depression Rating Scale scores between groups from Baseline to post-intervention in participants who complete ≥80% of rTMS sessions. The Scale is designed to measure depression severity and consists of 10 items, each of which is scored on a Likert scale from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.

Time frame: Baseline to post-intervention, within 10 working days of the final rTMS session

Change in Montgomery-Asberg Depression Rating Scale (MADRS) Scores from Baseline to 6-month follow-up

Change in Montgomery-Asberg Depression Rating Scale scores from baseline to 6-month follow-up between groups. The Scale is designed to measure depression severity and consists of 10 items, each of which is scored on a Likert scale from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.

Time frame: Baseline to 6 months

Comparison of Treatment Response or Remission in Montgomery-Asberg Depression Rating Scale (MADRS) Scores

Comparison of proportion of participants in each condition achieving treatment response ≥50% improvement in MADRS) or remission (MADRS ≤10)

Time frame: Baseline to post-intervention, within 10 working days of the final rTMS session

Central Contacts

Elizabeth N Diaz Nelson, MPH

CONTACT

832-671-9532 elizabeth.nelson.ctr@usuhs.edu

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Secondary Outcomes

Comparison of Change in Inventory of Depressive Symptomatology-Self Report (IDS-SR) Scores from Baseline to post-intervention

Change in Inventory of Depressive Symptomatology-Self Report scores between groups. The Report is a 30-item self-report depressive symptom severity rating scale, with each question on a scale of 0 to 4; and a score range between 0 to 84, with a higher score reflecting higher symptom severity in depression.

Time frame: Baseline to post-intervention, within 10 working days of the final rTMS session

Comparison of Change in Symptoms of Major Depressive Disorder Scale (SMDDS) Scores from Baseline to Post-intervention

Change in Symptoms of Major Depressive Disorder Scale scores between groups. The Scale is a 16-question scale, with each question using a rating scale between 0 ("Not at all" or "Never") to 4 ("Extremely" or "Always"); the total score ranges from 0 to 60 with a higher score indicating more severe depressive symptomatology.

Time frame: Baseline to post-intervention, within 10 working days of the final rTMS session

Comparison of Change in Inventory of Depressive Symptomatology-Self Report (IDS-SR) Scores from Baseline to 6-month follow-up

Time frame: Baseline to 6-month follow-up

Comparison of Change in Symptoms of Major Depressive Disorder Scale (SMDDS) Scores from Baseline to 6-month follow-up

Time frame: Baseline to 6-month follow-up

Comparison of Change in TBI Quality of Life Scale (TBI-QOL) Subtest Scores from Baseline to Post-intervention

Change in subtest scores between groups Anxiety ranges Raw Score (RS) 10-50, T-score 36.0-85.1; higher = worse Communication ranges RS 9-45, T-score 12.8-67.2; higher = better Depression ranges RS 10-50, T-score 38.3-82.6; higher = worse Emotional \& Behavioral Dyscontrol ranges RS 10-50, T-score 33.1-84.6; higher = worse Executive Function range RS 10-50, T-score 12.3-58.0; higher = better Fatigue ranges RS 10-50, T-score 32.7-80.7; higher = worse General Concerns ranges RS 10-50, T-score 17.3-59.6; higher = better Grief - Loss ranges RS 9-45, T-score 32.9-75.0; higher = worse Headache ranges RS 10-50, T-score 38.9-72.6; higher = worse Independence ranges RS 8-40, T-score 21.2-66.2; higher = better Pain Interference ranges RS 10-50, T-score 40.4-78.8; higher = worse Resilience ranges RS 10-50, T-score 15.3-69.2; higher = better Self-Esteem ranges RS 10-50, T-score 20.0-64.9; higher = better Cognitive Function ranges RS 8-40, T-score 22.5-67.0; higher = better

Time frame: Baseline to post-intervention, within 10 working days of the final rTMS session

Comparison of Change in TBI Quality of Life Scale (TBI-QOL) Subtest Scores from Baseline to 6-month follow-up

Time frame: Baseline to 6-month follow-up

Comparison of Change in PTSD Checklist for DSM-5 (PCL-5) Scores from Baseline to Post-intervention

Change in PTSD Checklist for DSM-5 scores between groups. The Checklist is a self-reported measure of PTSD symptom severity, with a score range of 0-84 in which a higher score represents greater severity.

Time frame: Baseline to post-intervention, within 10 working days of the final rTMS session

Comparison of Change in PTSD Checklist for DSM-5 (PCL-5) Scores from Baseline to 6-month Follow-up

Time frame: Baseline to 6-month follow-up

Compliance Assessment

Proportion of participants who achieve at least 80% compliance, defined as having completed ≥16 rTMS sessions

Time frame: Post-intervention, within 10 working days of the final rTMS session

Comparison of Change in rsfMRI Connectivity from Baseline to Post-intervention

Compare change in rsfMRI connectivity, focusing on brain networks relevant to mood regulation between groups

Time frame: Baseline to post-intervention, within 10 working days of the final rTMS session

Comparison of Change in rsfMRI Connectivity from Baseline to 6-month Follow-up

Compare change in rsfMRI connectivity, focusing on brain networks relevant to mood regulation between groups

Time frame: Baseline to 6-month follow-up