DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

The INjury and TRaumatic STress (INTRuST) Clinical Consortium Brings Together Scientists to Further Posttraumatic Stress Disorder (PTSD) and Traumatic Brain Injury (TBI) Research

Posted October 25, 2016
Murray Stein, M.D., M.P.H., University of California, San Diego

The INjury and TRaumatic STress (INTRuST) Clinical Consortium was established to combine the research efforts of the Nation's leading experts on PTSD and TBI to develop innovative treatments or interventions for those who suffer from PTSD and/or TBI. The INTRuST Consortium was composed of the Coordinating Center, located at the University of California, San Diego (UCSD); 10 competitively selected clinical sites; a Biorepository Core; a Neuroimaging Repository Core; a Biostatistics Core; an Informatics Core; and 19 additional military treatment and Veterans' facilities-all conducting clinical trials or collecting samples for clinical studies in PTSD and/or TBI.

The INTRuST Consortium completed three randomized controlled clinical trials, a prospective cohort study and seven pilot studies. The portfolio spans psychotherapies to drug therapies to telephone-delivered psychotherapy to device therapy. All trials were designed to decrease the impact of military-relevant PTSD and TBI for the benefit of Service Members, their families, their caregivers, and the American public. See http://intrust.sdsc.edu/clinicalTrials.html for more information about the studies listed below:

Randomized Controlled Trials
Title Purpose Gaps Addressed Impact/Results
Randomized Controlled Trial of Acceptance and Commitment Therapy (ACT) for Deployment-Related Distress and Impairment

Dr. Ariel Lang, University of California, San Diego
Compared ACT to Present Centered Therapy (PCT) determine if ACT, which is a psycho¬therapeutic approach used widely to treat emotional distress, is effective as effective as good nonspecific psychotherapy for treating transdiagnostic distress in Veterans and military personnel Treatment and Intervention of PTSD Participants in ACT or in PCT both displayed clinically significant improvement, regardless of head injury status. Within the small subgroup of women, ACT was associated with greater reductions in general distress and PTSD symptoms versus PCT.
Ganaxolone in PTSD: Proof-of-Concept Randomized Controlled Trial Investigating a Neuroactive Steroid Analog

Dr. Christine Marx, Duke University Medical Center
Investigate a mechanistically novel compound for which safety, tolerability, mechanism of action, and pre-clinical studies have demonstrated anxiolytic, anti-aggressive and antidepressant-like effects that may have utility in treating PTSD Treatment and Intervention of PTSD Although efficacy for ganaxolone not demonstrated, ongoing analyses indicate that subpopulations of patients experienced different blood concentrations of ganaxolone, and therefore, it may not have been sufficiently concentrated in the brain to affect PTSD symptoms. The research team continues to evaluate these results in order to determine appropriate next steps.
Concussion Treatment after Combat Trauma (CONTACT): The Effect of Telephone Follow-up on Outcome for Service Members with Mild TBI/PTSD

Dr. Kathleen Bell, University of Washington (now at University of Texas Southwestern, Dallas)
Determine if a telephone-based counseling intervention, called problem solving treatment (PST), will treat the persisting psychological and physical symptoms of concussion and thus improve recovery and overall quality of life Treatment and Intervention of PTSD

Treatment and Clinical Management of TBI
As compared to usual care, PST led to improvements in psychological distress, but not post-concussive symptoms, at 6 months post-PST, with effects no longer present at 12 months. There was a significant beneficial effect on depression, PTSD symptoms, sleep and physical functioning. Further study is needed to evaluate strategies such as more prolonged treatment or relapse-prevention to sustain improvements.


Observational Study
Title Purpose Gaps Addressed Impact/Results
Brain Indices of Risk for PTSD after Mild TBI

Dr. Connie Duncan, Uniformed Services University of the Health Sciences
Evaluate associations between baseline measures of brain structure and function and PTSD symptoms 6 months post injury in Service members with mild TBI, extracranial injuries without TBI and healthy controls Neurobiology/ Genetics of PTSD (and TBI) Results of preliminary analyses are still pending.


Pilot Studies
Title Purpose Gaps Addressed Impact/Results
A Pilot and Feasibility Study of High Dose Left Prefrontal Transcranial Magnetic Stimulation (TMS) to Rapidly Stabilize Suicidal Patients with PTSD

Dr. Mark George, Medical University of South Carolina
Evaluate safety and feasibility of high dose, short duration left prefrontal TMS on suicidal ideation in patients with depression and either PTSD or mild TBI, or both Treatment and Intervention of PTSD Delivering repetitive TMS over 3 days to suicidal inpatients is possible and safe, with few side effects and no worsening of suicidal thinking. TMS appears to lead to earlier symptom reduction versus placebo; however the rapid anti-suicide effect needs to be replicated in a larger sample before implementation.
Randomized Controlled Trial of Galantamine, Methylphenidate, and Placebo for the Treatment of Cognitive Symptoms in Patienst with Mild TBI and/or PTSD

Dr. Thomas McAllister, Dartmouth College (now at Indiana University School of Medicine)
Test pharmaceutical compounds for cognitive complaints in PTSD or mild TBI that may ameliorate executive function problems with fewer side effects than existing treatments Treatment and Intervention of PTSD

Treatment and Clinical Management of TBI
The study found clinically and statistically significant effects in improved attention and cognitive processing speed with methyl-phenidate in contrast to galantamine and placebo, with the most notable effects in PTSD patients. Future examination of methylphenidate is warranted.
A Randomized Controlled Trial of Glyburide for TBI

Dr. Howard Eisenberg, University of Maryland
Determine the efficacy of glyburide as a TBI therapeutic and evaluate its safety and tolerability in subjects with complicated mild, moderate or severe TBI Treatment and Clinical Management of TBI Preliminary magnetic resonance imaging (MRI) analyses reveal that brain edema increased less rapidly in patients that took glyburide over a 72-hour period, within 10 hours of sustaining injury, versus those who received placebo. Other outcome measures need to be assessed and a larger sample size should be studied.
Improving Walking and Balance in Veterans with TBI

Dr. Stacy Fritz, University of South Carolina
Improve therapeutic interventions for recovery of gait and balance following TBI by assessing feasibility and efficacy of different doses of Intensive Mobility Training Re-integration Strategies for TBI Individuals with chronic TBI demonstrated gains in fast gait speed, mobility, and dynamic, functional balance activities following IMT, with gains improving with the number of 3 hour treatment sessions, but not doubling outcomes assessed after 20 days of therapy versus 10 days. Rehabilitative gains in fast gait speed and mobility were sustained at 3 months.
A Double-Blind, Placebo-Controlled, Flexible-Dose Pilot Clinical Trial of Once-Daily Extended-Release Tramadol for the Treatment of PTSD

Dr. Thomas Geracioti, University of Cincinnati Medical Center
Determine if tramadol extended release 100 to 300 mg daily for 6 weeks will reduce symptoms of PTSD relative to placebo Treatment and Intervention of PTSD There were no overall group differences, but men who received gramadol showed significant reductions in PTSD symptoms at certain time points. Tramadol is a promising medicine for the treatment of PTSD and larger clinical trials should be conducted.
Reliability and Initial Validation of the INTRuST Structured Assessment for Evaluation of TBI (SAFE-TBI)

Dr. Thomas McAllister, Dartmouth College (now at Indiana University School of Medicine)
Develop SAFE-TBI, an instrument to improve and systematize the manner in which information about a potential mild TBI is ascertained, and increase the degree of confidence that someone had a mild TBI Measures in Screening, Detection and Diagnosis of TBI SAFE-TBI showed moderately good test-retest reliability, and good sensitivity and specificity compared to the gold standard of experienced TBI clinicians performing a thorough evaluation shortly after injury. VA cohort data suggested that current screening questions identify an appropriately broad population of military personnel at risk for previous exposure to a mild TBI, but that 24% of those who screen positive have weak or no evidence of TBI on more detailed examination with the SAFE-TBI.
Novel Functional and Structural Biomarkers of Neuroinflammation and White Matter Change in TBI: A Potential New Diagnostic and Therapeutic Approach

Dr. Martha Shenton, Brigham and Women’s Hospital
Correlate inflammation, axonal injury, and micro-hemorrhage in the brain measured by non-conventional neuroimaging tools with cognitive/ neuropsychological and behavioral measures to provide insight into neuro-inflammation associated with TBI and lead to more accurate and specific TBI diagnosis Measures in Screening, Detection and Diagnosis of TBI Imaging biomarkers increased in complicated mild TBI patients compared to healthy controls in the acute phase of injury (1-2 weeks), with the positron emission tomography (PET) marker decreasing after 3 months, suggesting a reversal/recovery process. Increased micro-hemorrhages were observed in complicated mild TBI patients at both time points.

In addition, the imaging- and bio-repositories serve as a resource for future investigators, providing blood and DNA/ribonucleic acid (RNA) samples, as well as neuroimages of study subjects and controls. These data are being shared with the NIMH-funded Psychiatric Genomic Consortium (PGC), and can be shared with other collaborative research groups upon request. A public dataset with TBI and PTSD phenotypes is available. This consortium mechanism provided clinicians with a new understanding of the PTSD-TBI interface, and established valuable resources and scientific collaborations that will continue into the future.

Links:

Public and Technical Abstracts: PTSD/TBI Clinical Consortium Coordinating Center

http://intrust.ucsd.edu/

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Last updated Tuesday, October 25, 2016