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Suggested Citation:"Front Matter." Institute of Medicine. 2008. Gulf War and Health: Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress. Washington, DC: The National Academies Press. doi: 10.17226/11922.
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Committee on Gulf War and Health: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress Board on Population Health and Public Health Practice

THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by Contract V101(93)P-2155B between the National Academy of Sciences and the Department of Veterans Affairs. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number = 13: 978-0-309-10177-6 International Standard Book Number = 10: 0-309-10177-8 Library of Congress Control Number: 2008920197 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, NW, Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at www.iom.edu. Copyright 2008 by the National Academy of Sciences. All rights reserved. Printed in the United States of America. The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Suggested citation: IOM (Institute of Medicine). 2008. Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress. Washington, DC: The National Academies Press.

The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org .

COMMITTEE ON GULF WAR AND HEALTH: PHYSIOLOGIC, PSYCHOLOGIC, AND PSYCHOSOCIAL EFFECTS OF DEPLOYMENT- RELATED STRESS RICHARD MAYEUX, MD, MSc (Chair), Gertrude H. Sergievsky Professor of Neurology, Psychiatry, and Epidemiology, Sergievsky Center, and Codirector, Taub Institute, Columbia University KATHRYN KARUSAITIS BASHAM, PhD, MSW, Professor, Smith College School for Social Work EVELYN J. BROMET, PhD, Professor of Psychiatry and Preventive Medicine, State University of New York at Stony Brook GREGORY L. BURKE, MD, MSc, Professor and Chair, Public Health Sciences, Wake Forest University School of Medicine DENNIS S. CHARNEY, MD, Dean, Anne and Joel Ehrenkranz Professor, Mount Sinai School of Medicine MICHAEL DAVIS, PhD, Robert W. Woodruff Professor of Psychiatry, Behavioral Sciences and Psychology, Emory University DOUGLAS A. DROSSMAN, MD, Professor of Medicine and Psychiatry and Codirector, UNC Center for Functional GI and Motility Disorders, University of North Carolina at Chapel Hill DWIGHT L. EVANS, MD, Ruth Meltzer Professor and Chair, Psychiatry, and Professor of Psychiatry, Medicine, and Neuroscience, University of Pennsylvania School of Medicine VINCENT J. FELITTI, MD, Kaiser Permanente Medical Care Program, San Diego, CA JANICE L. KRUPNICK, PhD, Professor, Department of Psychiatry, Georgetown University School of Medicine WILLIAM B. MALARKEY, MD, Professor of Internal Medicine and Molecular Virology, Immunology and Medical Genetics and Director, Clinical Research Center, Ohio State University BRUCE S. MCEWEN, PhD, Alfred E. Mirsky Professor and Head, Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, Rockefeller University THOMAS G. PICKERING, MD, DPhil, Professor of Medicine, Columbia University JERROLD F. ROSENBAUM, MD, Psychiatrist-in-Chief, Massachusetts General Hospital, and Stanley Cobb Professor of Pyschiatry, Harvard Medical School B. TIMOTHY WALSH, MD, William and Joy Ruane Professor of Pediatric Psychopharmacology, College of Physicians and Surgeons, Columbia University, and Chief, Division of Clinical Therapeutics, New York State Psychiatric Institute v

CONSULTANTS KERRY L. KNOX, PhD, Associate Professor, Department of Psychiatry and Community and Preventive Medicine, University of Rochester School of Medicine and Department of Veterans Affairs, Director, VISN 2 Center for Excellence at Canandaigua CAROL NORTH, MD, VA North Texas Health Care System and Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas MIRIAM DAVIS, Independent Medical Writer, Silver Spring, MD STAFF CAROLYN FULCO, Scholar ROBERTA WEDGE, Senior Program Officer SANDRA GOODBODY, Senior Program Officer PETER JAMES, Senior Program Associate DEEPALI M. PATEL, Senior Program Associate MICHAEL SCHNEIDER, Senior Program Associate DAVID J. TOLLERUD, Program Assistant DANIELLE K. STOLL, Program Assistant DAMIKA WEBB, Research Assistant RENEE WLODARCZYK, Senior Program Assistant NORMAN GROSSBLAT, Senior editor ROSE MARIE MARTINEZ, Director, Board on Population Health and Public Health Practice HOPE HARE, Administrative Assistant vi

REVIEWERS This report has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards of objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following for their review of this report: Elissa S. Epel, Department of Psychiatry, University of California, San Francisco Manning Feinleib, Department of Epidemiology, The Johns Hopkins University Edgar Garcia-Rill, Center for Translational Neuroscience, Department of Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences Danny O. Jacobs, Department of Surgery, Duke University Medical Center Karen A. Matthews, Western Psychiatric Institute & Clinic, University of Pittsburgh School of Medicine Eric J. Nestler, Department of Psychiatry, The University of Texas Southwestern Medical Center at Dallas William E. Schlenger, Abt Associates, Inc. Robert D. Sparks, TASER Foundation Ezra S. Susser, Department of Epidemiology, Columbia University Daniel S. Weiss, Department of Psychiatry, University of California, San Francisco Nancy Fugate Woods, School of Nursing, University of Washington Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Dr. Charles E. Phelps, University of Rochester, and Dr. Harold C. Sox, American College of Physicians/Annals of Internal Medicine. Appointed by the National Research Council and the Institute of Medicine, they were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the author committee and the institution. vii

CONTENTS ACRONYMS............................................................................................................................... xiii PREFACE ................................................................................................................................... xvii SUMMARY.....................................................................................................................................1 Committee’s Interpretation of Its Charge ...................................................................................2 Committee’s Approach to Its Charge..........................................................................................2 Evaluation Criteria ......................................................................................................................3 Categories of Association ...........................................................................................................4 Limitations of Veteran Studies ...................................................................................................5 Deployment-Related Stressors ....................................................................................................5 The Stress Response....................................................................................................................6 Posttraumatic Stress Disorder .....................................................................................................6 Health Effects..............................................................................................................................7 Summary of Conclusions ............................................................................................................7 Recommendations .......................................................................................................................9 1 INTRODUCTION ....................................................................................................................11 Demographics ...........................................................................................................................12 Committee’s Interpretation of Its Charge .................................................................................13 Committee’s Approach to Its Charge........................................................................................14 Organization of the Report........................................................................................................15 References .................................................................................................................................16 2 CONSIDERATIONS IN IDENTIFYING AND EVALUATING THE LITERATURE .........17 Identification of the Literature ..................................................................................................17 Types of Evidence.....................................................................................................................18 Inclusion Criteria.......................................................................................................................23 Additional Considerations.........................................................................................................24 Considerations in Assessing the Strength of Evidence .............................................................25 Categories of Association .........................................................................................................26 Limitations of Veteran Studies .................................................................................................28 Summary ...................................................................................................................................28 References .................................................................................................................................29 3 DEPLOYMENT-RELATED STRESSORS .............................................................................31 Stressors During Combat ..........................................................................................................32 Noncombat Stressors.................................................................................................................35 Anticipation of Deployment to a War Zone..............................................................................36 Military Sexual Assault and Harassment ..................................................................................37 Living Conditions .....................................................................................................................38 Environmental and Chemical Stressors ....................................................................................39 Reserve and National Guard Troops .........................................................................................39 Peacekeepers .............................................................................................................................40 ix

x CONTENTS Women ......................................................................................................................................41 Conclusions ...............................................................................................................................43 References .................................................................................................................................43 4 THE STRESS RESPONSE.......................................................................................................49 Central Role of the Brain ..........................................................................................................50 Modifiers of the Stress Response..............................................................................................56 Chronic Stress and Health.........................................................................................................59 Conclusions ...............................................................................................................................66 References .................................................................................................................................66 5 POSTTRAUMATIC STRESS DISORDER .............................................................................75 Diagnosis and Clinical Features................................................................................................76 Prevalence .................................................................................................................................78 Course .......................................................................................................................................81 Comorbidity and Disability.......................................................................................................84 Risk and Protective Factors.......................................................................................................86 Neurobiology ............................................................................................................................94 Conclusions .............................................................................................................................100 References ...............................................................................................................................100 6 HEALTH EFFECTS ...............................................................................................................115 Organization of This Chapter..................................................................................................115 Cancer .....................................................................................................................................117 Endocrine Diseases .................................................................................................................133 Psychiatric Disorders ..............................................................................................................142 Substance-Use Disorders ........................................................................................................158 Neurobehavioral and Neurocognitive Effects.........................................................................167 Chronic Fatigue Syndrome .....................................................................................................174 Sleep Disturbances ..................................................................................................................179 Cardiovascular Diseases .........................................................................................................183 Respiratory System Diseases ..................................................................................................197 Digestive System Disorders ....................................................................................................204 Skin Disorders.........................................................................................................................214 Fibromyalgia and Chronic Widespread Pain ..........................................................................222 Reproductive Effects...............................................................................................................229 Suicide and Accidental Death .................................................................................................237 Symptom Reporting ................................................................................................................248 References ...............................................................................................................................261 7 PSYCHOSOCIAL EFFECTS.................................................................................................283 Marital and Family Conflict....................................................................................................283 Homelessness ..........................................................................................................................299 Incarceration............................................................................................................................304 Employment ............................................................................................................................308 References ...............................................................................................................................312

CONTENTS xi 8 CONCLUSIONS AND RECOMMENDATIONS .................................................................317 Quality of the Studies..............................................................................................................317 Overview of Health Effects.....................................................................................................318 Recommendations ...................................................................................................................321 References ...............................................................................................................................321 INDEX .........................................................................................................................................323 Tables TABLE S-1 Summary of Findings Regarding the Association Between Deployment to a War Zone and Specific Health and Psychosocial Effects............................................................8 TABLE 3-1 Combat Experiences Reported by Members of the U.S. Army and Marine Corps After Deployment to Iraq or Afghanistan............................................................................34 TABLE 3-2 Stressors Experienced by U.S. Forces in the Gulf War...........................................37 TABLE 3-3 Percentage of Active-Duty vs Reserve and National Guard Troops, by War .........40 TABLE 5-1 Prevalence of Traumatic Events and PTSD in Men and Women............................78 TABLE 5-2 Estimated Prevalence of PTSD in U.S. Military Populations .................................82 TABLE 6-1 Cancer ......................................................................................................................128 TABLE 6-2 Endocrine Diseases..................................................................................................141 TABLE 6-3 Psychiatric Disorders ...............................................................................................153 TABLE 6-4 Substance-Use Disorders .........................................................................................164 TABLE 6-5 Neurobehavioral and Neurocognitive Effects .........................................................171 TABLE 6-6 Chronic Fatigue Syndrome ......................................................................................178 TABLE 6-7 Cardiovascular Diseases ..........................................................................................195 TABLE 6-8 Respiratory System Diseases...................................................................................202 TABLE 6-9 Digestive System Disorders.....................................................................................211 TABLE 6-10 Skin Disorders .......................................................................................................220 TABLE 6-11 Fibromyalgia and Chronic Widespread Pain.........................................................228 TABLE 6-12 Reproductive Effects ............................................................................................234 TABLE 6-13 Suicide and Accidental Death................................................................................245 TABLE 6-14 Symptom Reporting...............................................................................................259 TABLE 7-1 Marital and Family Conflict ....................................................................................295 TABLE 7-2 Homelessness...........................................................................................................303 TABLE 7-3 Incarceration ............................................................................................................307 TABLE 7-4 Adverse Employment Outcomes .............................................................................311 TABLE 8-1 Summary of Findings Regarding the Association Between Deployment to a War Zone and Specific Health and Psychosocial Effects............................................................319 Boxes and Figures BOX 4-1 Physiologic Changes During the Stress Response .......................................................50 BOX 5-1 DSM-IV Diagnostic Criteria for Posttraumatic Stress Disorder...................................77 BOX 6-1 Case Definition of Chronic Fatigue Syndrome............................................................174 FIGURE 1-1 Schematic depiction of the relationship between deployment to a war zone and adverse health and psychosocial effects. .............................................................................15 FIGURE 4-1 Stress-response pathways. .....................................................................................52

xii CONTENTS FIGURE 4-2 How chronic stress can affect behavior and health................................................55 FIGURE 4-3 Chronicity of stressors............................................................................................57 FIGURE 4-4 The brain-gut axis and IBS. ...................................................................................65

ACRONYMS ACTH Adrenocorticotrophic hormone, corticotropin APA American Psychiatric Association ASI Anxiety sensitivity index AUDIT Alcohol use disorder identification test BIRLS Beneficiary identification record locator subsystem BNST Bed nucleus of the stria terminalis BSS Body-system symptom CAPS Clinician-Administered PTSD Scale CCEP Comprehensive Clinical Evaluation Program CDC Centers for Disease Control and Prevention CES Combat Exposure Scale CFS Chronic fatigue syndrome CHD Coronary heart disease CI Confidence interval CIDI Composite International Diagnostic Interview CNS Central nervous system COPD Chronic obstructive pulmonary disease CRH Corticotropin-releasing hormone CSF Cerebrospinal fluid CSMs Cerebrospinal malformations CTS Conflict Tactics Scale CVLT California Verbal Learning Test DIS Diagnostic Interview Schedule DMDC Defense Manpower Data Center DoD Department of Defense DSM Diagnostic and Statistical Manual of Mental Disorders III or IV GAD Generalized anxiety disorder GI Gastrointestinal HDL High-density lipoprotein HPA Hypothalamus-pituitary-adrenal HU13 Health Utilities Index Mark 3 HVVP Hawaiian Vietnam Veterans Project IBS Irritable bowel syndrome ICD International Statistical Classification of Diseases and Related Health Problems xiii

xiv ACRONYMS IEDs Improvised explosive devices IOM Institute of Medicine km Kilometer MDD Major depression disorder MHAT Mental Health Advisory Team MHM Military History Measure MMPI Minnesota Multiphasic Personality Inventory MPI Martial Problem Index MRI Magnetic resonance imaging MSAs Metropolitan statistical areas NART National Adult Reading Test NAS National Academy of Sciences NCHS National Center for Health Statistics NCO Noncommissioned officer NCS National Comorbidity Survey NHANES National Health and Nutrition Examination Survey NHL Non-Hodgkin’s lymphoma NSVG National Survey of the Vietnam Generation NVVRS National Vietnam Veterans Readjustment Study OEF Operation Enduring Freedom OIF Operation Iraqi Freedom OR Odds ratio PASAT Paced Auditory Serial Addition Test PB Pyridostigmine bromide PIR Proportional incidence rate PMR Proportional morbidity ratio PPI Parental Problem Index PTSD Posttraumatic stress disorder RR Relative risk SCID Structured Clinical Interview for DSM-III or IV SE Standard error SF-36 36-Item Medical Outcomes Study Short-Form T3 Triiodothyronine T4 Thyroxine TSH Thyroid-stimulating hormone UK United Kingdom UN United Nations VA Department of Veterans Affairs

ACRONYMS xv VES Vietnam Experience Study VET Registry Vietnam-Era Twin Registry vs Versus WAIS-R Wechsler Adult Intelligence Scale-revised WCST Wisconsin Card Sorting Test

PREFACE Deployment to a war zone has a profound impact on the lives of many of the troops who are deployed to foreign soil and on their family members. Needless to say, numerous stressors are associated with deployment, from terrifying concerns about surviving, being taken prisoner, and being tortured to the horrific possibility of seeing friends die, being maimed, and handling dead bodies. Less traumatic but more pervasive stressors include anxiety about home life, such as loss of a job and income, impacts on relationships, and absence from family. The effects of deployment-related stressors on a veteran’s health during and after deployment are numerous. When sudden and life-threatening stressors are encountered, the body will typically react with an acute “flight or fight” response that subsides when the stressor goes away. If the stressor or the acute response persists, the body may react with a more prolonged stress response that can lead to harmful long-term effects on health. The focus of this report, by the Institute of Medicine (IOM) Committee on Gulf War and Health: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress, is the long-term effects of deployment- related stress. What happens to military personnel when they are subjected to the many stressors that occur in a war zone? The U.S. Department of Veterans Affairs and Congress have secured the assistance of IOM in evaluating the scientific literature regarding an association between deployment-related stressors and health effects. Congress’s request regarding the possible association between illness and exposure to stressors in the Gulf War is similar to its approach after the Vietnam War to exposure to Agent Orange and after the 1991 Persian Gulf War to exposure to numerous biologic and chemical agents. Although seemingly straightforward conceptually, this task has proved to be much more difficult than previous studies. The committee discussed how to define deployment-related stress, the types of stressors encountered, and how they might be assessed or measured. In this report, the committee equated deployment-related stress with being deployed to a war zone, although it recognized that not everyone deployed to a war zone would respond to stressors in the same way and that not everyone would necessarily find a particular event stressful. The reaction to deployment-related stressors would depend on numerous factors that were present before, during, and after deployment. Stressors that people experienced in childhood, their interactions with friends and family, and whether they were wounded during deployment would all play a role in the nature of the response. The committee also understood that some military personnel would have minor reactions and transient health effects, some would have severe reactions and more chronic health effects, and some would go on to develop posttraumatic stress disorder (PTSD), which could be associated with additional health effects. That approach is detailed in the committee’s report. The committee deliberated for many months and met 14 times. It reviewed all the studies of health effects in veterans deployed to a war zone and found that most studies did not measure the stressors of war (although that was not required for inclusion in the committee’s analysis), and that the ones that did measure deployment-related stress were most often related to PTSD. The committee noted that although experimental data from studies in animals indicated xvii

xviii PREFACE numerous health effects associated with various types of stressors, the human literature is much more challenging to interpret. I am deeply appreciative of the hard work of our committee members: Kathryn Basham, Evelyn Bromet, Gregory Burke, Dennis Charney, Michael Davis, Douglas Drossman, Dwight Evans, Vincent Felitti, Janice Krupnick, William Malarkey, Bruce McEwen, Thomas Pickering, Jerrold Rosenbaum, and Timothy Walsh, and of our expert consultants Carol North, Kerry Knox, and Miriam Davis. The committee would like to thank Jack Gorman for his thoughtful input. Although the committee developed conclusions independently of input from IOM staff, we deeply appreciate their hard work and attention to detail and the extensive research that they conducted to ensure that we had all the information that we needed from the outset. It has been a privilege and a pleasure to work with the IOM staff directed by Roberta Wedge and Carolyn Fulco. Without them, this report would not have been possible. Most of all, our committee appreciates the veterans who have served in this country’s wars. It is for them that we do this work, and we hope that this report will inform those who have given so much to our nation. Richard Mayeux, MD, MSc (Chair) Sergievsky Professor of Neurology, Psychiatry, and Epidemiology Director, Sergievsky Center; Codirector, Taub Institute College of Physicians and Surgeons Columbia University

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The sixth in a series of congressionally mandated reports on Gulf War veterans' health, this volume evaluates the health effects associated with stress. Since the launch of Operation Desert Storm in 1991, there has been growing concern about the physical and psychological health of Gulf War and other veterans. In the late 1990s, Congress responded by asking the National Academy of Sciences (NAS) to review and evaluate the scientific and medical literature regarding associations between illness and exposure to toxic agents, environmental or wartime hazards, and preventive medicines or vaccines in members of the armed forces who were exposed to such agents.

Deployment to a war zone has a profound impact on the lives of troops and on their family members. There are a plethora of stressors associated with deployment, including constant vigilance against unexpected attack, difficulty distinguishing enemy combatants from civilians, concerns about survival, caring for the badly injured, and witnessing the death of a person. Less traumatic but more pervasive stressors include anxiety about home life, such as loss of a job and income, impacts on relationships, and absence from family.

The focus of this report, by the Institute of Medicine (IOM) Committee on Gulf War and Health: Physiologic, and Psychosocial Effects of Deployment-Related Stress, is the long-term effects of deployment-related stress. Gulf War and Health: Volume 6. Physiologic, and Psychosocial Effects of Development Related Stress evaluates the scientific literature regarding association between deployment-related stressors and health effects, and provides meaningful recommendations to remedy this problem.

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