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SDR 09-128 – HSR&D Study

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SDR 09-128
Marine Resiliency Study
Dewleen G Baker MD
VA San Diego Healthcare System, San Diego, CA
San Diego, CA
Funding Period: October 2009 - September 2012

BACKGROUND/RATIONALE:
Combat is emotionally and physically challenging. Post-war adaptation ranges from trajectories of successful post-war function or even growth, to functional disability and chronic PTSD. Prior research has been retrospective, cross-sectional and insular, predominantly focusing on single systems (psychiatric, psychosocial or biological), which constrains causal inference and limits useful information.

OBJECTIVE(S):
The objective of this program was to complete a series of three prospective, longitudinal, interrelated projects that seek to better understand risk and resilience in a cohort of ~2500 Marines bound for Iraq or Afghanistan. The primary programmatic aim was, first, to identify the individual, social, and deployment factors that predict trajectories of mental health response, particularly posttraumatic stress disorder (PTSD), and second, by integrating and analyzing data across studies, to accomplish a broader multi-system understanding of the phenomenology of adaptation to stress. The overarching program hypothesis predicted that there will be different trajectories of posttraumatic adaptation to war-zone trauma, ranging from enduring resilience to a chronic unremitting course of PTSD. We also predicted that different sets of risk and resilience factors, operating at multiple levels of the organism and environment, will predict different trajectories of outcome. Our objective was to examine the data across projects iteratively to discover sets of variables that act synergystically.

The objectives of project 1 were to determine the different mental health (MH) trajectories resulting from deployment, and identify psychiatric and psychosocial factors that predict healthy (resilient and inoculated) versus PTSD (chronic, delayed and recovery) trajectories. The objectives of project 2 were to collect longitudinal biological data (startle thresholds, reactivity, habituation, sensorimotor gating, heart rate variability) to determine if the biological trajectories can be defined, and if measures of biological endophenotypes predict PTSD trajectory. The objectives of project 3 were to assess a number of aspects of autonomic/cardiovascular physiology, and to collect saliva, urine and blood for assay.

METHODS:
Subjects for this study were ~2600 consenting Marines from infantry battalions from the 1st Marine Division. Inclusion criteria were all deploying Marines in units selected for the study; exclusion criteria were none, except that Marines who did not want to participate were not included. Data were collected on-site at 29 Palms or Camp Pendleton, pre-deployment, post-deployment at one week (questionnaires only), 3 months, and 6 months. Data were also compiled from the Naval Health Research Center CHAMPS database (Career History Archival Medical and Personnel System) and integrated with data collected from Marines on-site for data analysis.

FINDINGS/RESULTS:
Pre-deployment:
Characteristics of participating Marines at pre-deployment have been described in detail in the methods paper published in the journal Preventing Chronic Disease (Baker et al., 2012, cited in the reference section). Notable are: Participant age ranges from 18-47 years; mean (SD) is 22.3 (3.5). Most are enlisted, with junior enlisted 68%, senior enlisted including non-commissioned officers 29%, and officers 2.4%. Approximately half (51.3%) of Marines had at least 1 prior deployment at the time of enrollment in this Marine Resiliency Study (MRS). Previously deployed Marines accounted for 46.1% to 55.3% of each battalion. Whereas for all Marines enrolled in MRS battalions at pre-deployment, the mean (SD) physical health component (PHC) SF-12 score was 53.7 (6.16) and mental health component (MHC) SF-12 score was 50.15 (8.09), mean (SD) PHC scores were slightly lower for previously deployed (53.27 [6.13]) compared with never-deployed Marines (54.17 [6.10]) (N = 2,514; F1 = 13.92; P < .001; p2 = .01), but the effect size was very small. However, we found no deployment-related differences in age-adjusted MHC scores. Of the 1,562 Marines who reported prior head injury, 57% incurred at least 1 head injury with combined loss of consciousness (LOC) and altered mental state (AMS) symptoms. Small but significant variations in rates of TBI were found in those with LOC and AMS with deployment history; 54.1% of previously deployed Marines self-reported TBI with LOC and AMS compared with 60.4% of never-deployed Marines. Duration of unconsciousness did not vary significantly with deployment history. ICD-9-CM mental disorder diagnoses retrieved from the CHAMPS database showed that 193 (7.4%) of the 2,593 enrolled Marines had either 1 diagnosis (3.7%) or multiple (3.7%) diagnoses. After controlling for time spent in the military before deployment, there were no significant differences in the number of mental health diagnoses per subject between previously deployed and never-deployed Marines. We did, however, find moderately significant relationships between deployment history and rates of diagnosed PTSD and diagnosed suicidal ideation, with rates of PTSD being higher in the previously deployed Marines, whereas fewer of the previously deployed Marines had ICD-9 codes for suicidal ideation in comparison to never-deployed Marines. See manuscript for more detail.

The MRS team has begun iterative analysis of data aimed at characterization of the sample pre-deployment and longitudinally within sets of variables, with gradual preparation of reports and papers across sets of variables. This work is in progress; described below is work from papers under review and in preparation for submission. This work will continue as the team works toward a gradually more across-domain, integrated analysis. Listed below are some findings (so far) and potential recommendations:

1) One analysis sought to examine the extent to which self-reported pre-deployment and deployment-related TBI confers increased risk of PTSD when accounting for combat intensity and pre-deployment mental health symptoms. Participants were 1372 active-duty Marine and Navy servicemen who completed pre- and post-deployment assessments. Reasons for exclusions were non-deployment (n=32), invalid neuropsychological tests (n=182), missing data (n=258), and rank of non-commissioned and commissioned officers (n=57). The primary outcome was the Clinician-Administered PTSD Scale (CAPS) 3-month post-deployment total score. At the pre-deployment assessment, 57.0% of participants reported prior TBI; at post-deployment assessment, 20.1% reported sustaining TBI between pre- and post-deployment assessments (i.e., "deployment-related TBI"). Approximately 86.9% of deployment-related TBI were mild; 209 of 243 (86.0%) who reported post-traumatic amnesia (PTA) reported < 24 hours PTA (33 reported > 24 hours PTA), and 95 of 97 (97.9%) who lost consciousness reported < 30 minutes LOC. The results support the conclusion that even when accounting for pre-deployment symptoms, prior TBI, and combat intensity, deployment-related TBI during the most recent deployment was the strongest predictor of post-deployment PTSD and may be a significant risk factor for combat-related PTSD. These conclusions support cross-sectional studies that show high rates of PTSD associated with TBI, and would suggest intensified mental health screening in service members who sustained a deployment-related TBI.

2) An analysis sought to determine optimally efficient cutoff scores on the Posttraumatic Stress Disorder Checklist (PCL) used in MRS for identifying full and partial PTSD (P-PTSD) in active-duty Marines. PCL cutoffs were tested against three CAPS-based classifications: full PTSD, stringent P-PTSD, and lenient P-PTSD. PCL scores of 39 and 37 were found to be optimally efficient for identifying full PTSD at three- and six-months post-deployment, respectively. Scores ranging from 28-37 were found to be optimally efficient for identifying P-PTSD. The findings suggest that the PCL cutoff scores that are optimally efficient for detecting PTSD in active-duty Marines are substantially lower than the cutoff score of 50 commonly used.

3) There are early convergent findings using MRS data that suggest that blood immune-biomarkers may be predictors of post-deployment PTSD risk. In one of the analyses, gene-expression levels were assayed in peripheral blood samples from 50 U.S. Marines (25 eventual PTSD cases and 25 non-PTSD comparison subjects) prior to their deployment overseas to war-zones in Iraq or Afghanistan. The panel of biomarkers dysregulated in peripheral blood cells of eventual PTSD cases prior to deployment was significantly enriched for immune genes, achieved 70% prediction accuracy in an independent sample based on the expression of 23 full-length transcripts, and attained 80% accuracy in an independent sample based on the expression of one exon from each of five genes. In the other analysis, MRS data were used to ask whether baseline plasma levels of the inflammatory marker, C-reactive protein (CRP), help predict the emergence and severity of post-deployment PTSD symptoms, as measured by the Clinician Administered PTSD Scale (CAPS), after adjustment for trauma exposure and other relevant covariates. Findings show a significant effect of baseline CRP on post-deployment PTSD symptom emergence, and a trend for an effect on PTSD severity. CRP was not correlated with baseline CAPS or baseline measures of depression and anxiety, indicating that it is not a mediator or proxy for one of these latter predictors.

IMPACT:
This study has the potential to reduce future rates of chronic PTSD by: 1) providing answers about specific vulnerability factors potentially amenable to modification by improved training methods or early intervention, and 2) providing scientific information to support the rational application of secondary prevention and tertiary treatment strategies.


PUBLICATIONS:

Journal Articles

  1. Yurgil KA, Clifford RE, Risbrough VB, Geyer MA, Huang M, Barkauskas DA, Vasterling JJ, MRS Team, Baker DG. Prospective Associations Between Traumatic Brain Injury and Postdeployment Tinnitus in Active-Duty Marines. The Journal of head trauma rehabilitation. 2016 Jan 1; 31(1):30-9.
  2. Breen MS, Maihofer AX, Glatt SJ, Tylee DS, Chandler SD, Tsuang MT, Risbrough VB, Baker DG, O'Connor DT, Nievergelt CM, Woelk CH. Gene networks specific for innate immunity define post-traumatic stress disorder. Molecular Psychiatry. 2015 Dec 1; 20(12):1538-45.
  3. Minassian A, Maihofer AX, Baker DG, Nievergelt CM, Geyer MA, Risbrough VB, Marine Resiliency Study Team. Association of Predeployment Heart Rate Variability With Risk of Postdeployment Posttraumatic Stress Disorder in Active-Duty Marines. JAMA psychiatry (Chicago, Ill.). 2015 Oct 1; 72(10):979-86.
  4. Dickstein BD, Weathers FW, Angkaw AC, Nievergelt CM, Yurgil K, Nash WP, Baker DG, Litz BT, Marine Resiliency Study Team. Diagnostic Utility of the Posttraumatic Stress Disorder (PTSD) Checklist for Identifying Full and Partial PTSD in Active-Duty Military. Assessment. 2015 Jun 1; 22(3):289-97.
  5. Acheson DT, Geyer MA, Baker DG, Nievergelt CM, Yurgil K, Risbrough VB, MRS-II Team. Conditioned fear and extinction learning performance and its association with psychiatric symptoms in active duty Marines. Psychoneuroendocrinology. 2015 Jan 1; 51:495-505.
  6. Nievergelt CM, Maihofer AX, Mustapic M, Yurgil KA, Schork NJ, Miller MW, Logue MW, Geyer MA, Risbrough VB, O'Connor DT, Baker DG. Genomic predictors of combat stress vulnerability and resilience in U.S. Marines: A genome-wide association study across multiple ancestries implicates PRTFDC1 as a potential PTSD gene. Psychoneuroendocrinology. 2015 Jan 1; 51:459-71.
  7. Tylee DS, Chandler SD, Nievergelt CM, Liu X, Pazol J, Woelk CH, Lohr JB, Kremen WS, Baker DG, Glatt SJ, Tsuang MT, Marine Resiliency Study Investigators. Blood-based gene-expression biomarkers of post-traumatic stress disorder among deployed marines: A pilot study. Psychoneuroendocrinology. 2015 Jan 1; 51:472-94.
  8. Mustapic M, Maihofer AX, Mahata M, Chen Y, Baker DG, O'Connor DT, Nievergelt CM. The catecholamine biosynthetic enzyme dopamine ß-hydroxylase (DBH): first genome-wide search positions trait-determining variants acting additively in the proximal promoter. Human Molecular Genetics. 2014 Dec 1; 23(23):6375-84.
  9. Agorastos A, Pittman JO, Angkaw AC, Nievergelt CM, Hansen CJ, Aversa LH, Parisi SA, Barkauskas DA, Marine Resiliency Study Team, Baker DG. The cumulative effect of different childhood trauma types on self-reported symptoms of adult male depression and PTSD, substance abuse and health-related quality of life in a large active-duty military cohort. Journal of psychiatric research. 2014 Nov 1; 58:46-54.
  10. Minassian A, Geyer MA, Baker DG, Nievergelt CM, O'Connor DT, Risbrough VB, Marine Resiliency Study Team. Heart rate variability characteristics in a large group of active-duty marines and relationship to posttraumatic stress. Psychosomatic medicine. 2014 May 1; 76(4):292-301.
  11. Eraly SA, Nievergelt CM, Maihofer AX, Barkauskas DA, Biswas N, Agorastos A, O'Connor DT, Baker DG, Marine Resiliency Study Team. Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. JAMA psychiatry (Chicago, Ill.). 2014 Apr 1; 71(4):423-31.
  12. Yurgil KA, Barkauskas DA, Vasterling JJ, Nievergelt CM, Larson GE, Schork NJ, Litz BT, Nash WP, Baker DG, Marine Resiliency Study Team. Association between traumatic brain injury and risk of posttraumatic stress disorder in active-duty Marines. JAMA psychiatry (Chicago, Ill.). 2014 Feb 1; 71(2):149-57.
  13. Glatt SJ, Tylee DS, Chandler SD, Pazol J, Nievergelt CM, Woelk CH, Baker DG, Lohr JB, Kremen WS, Litz BT, Tsuang MT, Marine Resiliency Study Investigators. Blood-based gene-expression predictors of PTSD risk and resilience among deployed marines: a pilot study. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 2013 Jun 1; 162B(4):313-26.
  14. Nash WP, Marino Carper TL, Mills MA, Au T, Goldsmith A, Litz BT. Psychometric evaluation of the Moral Injury Events Scale. Military medicine. 2013 Jun 1; 178(6):646-52.
  15. Zhang K, Rao F, Miramontes-Gonzalez JP, Hightower CM, Vaught B, Chen Y, Greenwood TA, Schork AJ, Wang L, Mahata M, Stridsberg M, Khandrika S, Biswas N, Fung MM, Waalen J, Middelberg RP, Heath AC, Montgomery GW, Martin NG, Whitfield JB, Baker DG, Schork NJ, Nievergelt CM, O'Connor DT. Neuropeptide Y (NPY): genetic variation in the human promoter alters glucocorticoid signaling, yielding increased NPY secretion and stress responses. Journal of the American College of Cardiology. 2012 Oct 23; 60(17):1678-89.
  16. Baker DG, Nash WP, Litz BT, Geyer MA, Risbrough VB, Nievergelt CM, O'Connor DT, Larson GE, Schork NJ, Vasterling JJ, Hammer PS, Webb-Murphy JA, MRS Team. Predictors of risk and resilience for posttraumatic stress disorder among ground combat Marines: methods of the Marine Resiliency Study. Preventing chronic disease. 2012 May 10; 9:E97.
Conference Presentations

  1. Powell S, Baker D, Geyer M, Nievergelt C, Yurgil K, Acheson D, Risbrough V, MRS Team. Early Life Trauma Effects on Psychophysiological Responses in Active Duty Marines. Poster session presented at: Anxiety and Depression Association of America Anxiety Disorders and Depression Conference; 2013 Apr 5; La Jolla, CA.
  2. Baker DG, Nievergelt CN, O’Connor DT, MRS Team. Biomarker selection in the Marine Resiliency Study, a prospective study of Risk and Resilience. Paper presented at: American College of Neuropsychopharmacology Annual Meeting; 2012 Dec 4; Waikoloa, HI.
  3. Baker DG, Nash WP, Litz BT, O'Connor DT, Geyer MA, Risbrough VB, Nievergelt CM, Larson GE, MRS Team. Marine Resiliency Study. Paper presented at: U.S. Navy and Marine Corps Combat and Operational Stress Control Conference; 2012 Apr 24; San Diego, CA.
  4. Risbrough VB, Baker DG, Nievergelt CM, Goldsmith A, Litz BT, Nash WP, Geyer M. Psychophysiological predictors of PTSD risk in Active Duty Marines: Preliminary Findings from the Marine Resiliency Study. Poster session presented at: American College of Neuropsychopharmacology Annual Meeting; 2011 Dec 5; Waikoloa, HI.
  5. Dickstein BD, Marino-Carper T, Weathers F, Goldsmith A, Baker D, Litz BT. A diagnostic utility analysis of the PTSD Checklist in active duty Marines. Poster session presented at: International Society for Traumatic Stress Studies Annual Meeting; 2011 Nov 3; Baltimore, MD.
  6. Barnes JB, Dickstein BD, Adler AB, Litz BT. Perceived Organizational Support during a Peacekeeping Mission Moderates the Effect of PTSD Symptom Severity on Later Aggression. Poster session presented at: Association for Behavioral and Cognitive Therapies Annual Convention; 2011 Oct 11; Toronto, Canada.
  7. Risbrough VB, Baker D, Nievergelt C, Goldsmith A, Carper T, Litz BT, Nash W, Geyer M. Psychophysiological predictors of PTSD risk in Active Duty Marines: Preliminary Findings from the Marine Resiliency Study. Poster session presented at: VA Mental Health Annual Conference; 2011 Aug 25; Baltimore, MD.
  8. Baker DG, Litz B, Nash W, Geyer M, Risbrough V, Nievergelt C, Yurgil K, Goldsmith A, Vasterling J, Larson J, Schork N, Murphy J, Hammer P, MRS team. Marine Resiliency Study: Overview and Early Findings. Presented at: VA / Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury Workshop; 2011 Jul 29; Falls Church, VA.
  9. Baker D, Nievergelt C, Yurgil K, Goldsmith A, Litz BT, Nash W, Geyer M, Risbrough V, O’Connor D, Vasterling J, Larson J, Murphy J, Hammer P, Marine Resiliency Study. Prior deployments; impact on post-deployment reports of perceived threat and PTSD status. Paper presented at: AcademyHealth Annual Research Meeting; 2011 Jun 12; Seattle, WA.
  10. Nash WP, Baker D, Litz BT, Marine Resiliency Study. Marine Resiliency Study: How Can Science Help the Marine Corps Reduce Risk for Posttraumatic Stress? Paper presented at: Department of Defense Journal Club Meeting; 2011 Jun 8; Washington, DC.
  11. Nash WP, Baker D, Litz BT, Marine Resiliency Study Team. Marine Resiliency Study: How Can Science Help the Marine Corps Reduce Risk for Posttraumatic Stress? Paper presented at: U.S. Navy and Marine Corps Combat and Operational Stress Control Pre-Conference; 2011 Apr 25; San Diego, CA.
  12. Baker DG, Nash WP, Litz BT, O'Connor DT, Geyer MA, Risbrough VB, Nievergelt CM, Larson GE, Marine Resiliency Study Team. Marine Resiliency Study (MRS): Prospective, Longitudinal Assessment of Risk and Resilience Factors for Stress Injuries and Illnesses in Ground Combat Marines. Paper presented at: U.S. Navy and Marine Corps Combat and Operational Stress Control Conference; 2010 May 14; San Diego, CA.
  13. Risbrough VB, Baker D, Litz BT, Nash W, Geyer M, O’Connor D, Vasterling J, Nievergelt C, Schork N, Murphy J, Hammer P, Marine Resiliency Study. Marine Resiliency Study: A longitudinal study of physiological, biological and psychological factors contributing to risk and resiliency for operational combat stress. Paper presented at: Australasian Society for Psychiatric Research Annual Conference; 2009 Dec 3; Canberra, Australia.


DRA: Military and Environmental Exposures, Mental, Cognitive and Behavioral Disorders
DRE: Etiology, Pathology, Prevention, Prognosis, Epidemiology
Keywords: Adjustment Disorders, Deployment, PTSD, Reintegration Post-Deployment, Risk factors
MeSH Terms: none