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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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Suggested Citation:"5 POSTTRAUMATIC STRESS DISORDER." 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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5 POSTTRAUMATIC STRESS DISORDER Posttraumatic stress disorder (PTSD) is an anxiety disorder that is defined as resulting from exposure to a traumatic event. War-related traumatic events have been detailed in numerous studies (see Chapter 3). However, not everyone exposed to a war-zone trauma will develop PTSD, nor is the course of the disorder the same for everyone that does develop it. There are many factors that affect a person’s response to a traumatic event and there is much research being done to elucidate the biological mechanisms of PTSD. It is widely recognized that soldiers suffer psychologic consequences of combat (Jones 2006). The constellation of symptoms that has come to be known as PTSD was given other names in earlier wars. During the Civil War, “irritable heart” or “effort syndrome” featured shortness of breath, disturbed sleep, palpitations, and other symptoms. During World War I, effort syndrome was again diagnosed, as was “shell shock,” which was first described in British soldiers evacuated from the trenches in France. Marked by blindness, muteness, and amnesia, shell shock was initially thought to be the result of brain concussion from nearby shell explosions, but over time it became clear that effort syndrome and shell shock had psychologic origins (Hyams et al. 1996; Shephard 2001). During World War II, physicians identified an acute psychologic syndrome commonly found in soldiers, which they referred to as battle fatigue or combat exhaustion, so named to avoid stigma and to imply that soldiers would recover naturally with food and rest. Although the sheer number of psychiatric casualties was high, many of the troops were returned to combat after treatment near the front line (Grob 1994; Shephard 2001). Nevertheless, in 1942-1945, 850,000 active-duty U.S. soldiers were admitted to military hospitals for neuropsychiatric care (Starr 1982). A persistent and chronic form of battle fatigue was described among those veterans (Friedman et al. 1994; Grob 1994; Southwick et al. 1994). In World War II, Grinker and Spiegel (1945) described cases of “war neurosis” in members of combat aircrews. The primary symptoms of war neurosis were restlessness, irritability, aggression, fatigue, sleep difficulties, anxiety, startle reaction, tension, depression, personality changes, memory disturbances, tremors, difficulty in concentrating, alcoholism, preoccupation with combat experiences, decrease in appetite, psychosomatic symptoms, irrational fears, and suspiciousness. The experiences of World War II military psychiatrists were instrumental in spurring the profession into the modern era of psychiatric diagnosis. Military psychiatrists believed that psychiatric disorders among veterans of military combat were more pervasive and serious than had been anticipated before the war. They also believed, contrary to prevailing views, that psychological maladjustment could be triggered by external stress (Grob 1994). Their influence 75

76 GULF WAR AND HEALTH was felt in the first edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM), published in 1952 by the American Psychiatric Association (APA). After the Vietnam War, research demonstrated that many veterans, particularly those exposed to severe war-related trauma, and other traumatized populations such as Holocaust survivors, suffered from chronic psychologic problems that often resulted in social and occupational dysfunction. The strength of the evidence led to the formal recognition of PTSD as a psychiatric diagnosis in the third edition of DSM (DSM-III), published in 1980. Because the DSM-III provided a formal operational definition of PTSD, it presented a platform for large-scale studies of PTSD in Vietnam veterans and veterans of later wars. In the sections below, the committee discusses the diagnosis and clinical features of PTSD; its prevalence in military populations; the course of the disorder; the comorbidity of PTSD with other psychiatric disorders and associated disability of people who have PTSD; risk and protective factors for PTSD; and finally the neurobiology of PTSD. DIAGNOSIS AND CLINICAL FEATURES People who are exposed to traumatic events react to them in different ways; some experience temporary distress, and others will go on to develop PTSD or other psychiatric disorders, such as major depression. The criteria for PTSD are listed in the fourth edition of the DSM (DSM-IV-TR) (Box 5-1) and require that the person have experienced, witnessed, or been confronted with an event that involves actual or threatened death, serious injury, or a threat to the physical integrity of self or others and that the person have responded with intense fear, helplessness, or horror. Symptoms must persist for a month or more and include three symptom clusters: • Re-experiencing—intrusive recollections of a traumatic event, such as flashbacks or nightmares. • Avoidance/numbing—efforts to avoid reminders of the event and numbing of emotions. • Hyperarousal—manifested by, for example, difficulty in sleeping or jumpiness. Finally, the person must have clinically significant distress or functional impairment resulting from the symptoms (APA 2000). Two terms are used to describe PTSD in this report: lifetime and current. In lifetime PTSD, the person has met the criteria for a diagnosis of PTSD at some point and may or may not be symptomatic at the time of the assessment. The meaning of current PTSD varies by study; it can mean that the person met the criteria for PTSD at the time of the assessment, within the preceding month, within the preceding 3 months, 6 months, even 12 months. The committee used the terminology and timeframe for PTSD as given in each study. Lifetime and current PTSD may or may not be related to combat or deployment experiences; when PTSD has been related to combat or deployment experiences, the committee has included this information in its discussion. PTSD should be assessed on the basis of a thorough diagnostic interview; structured or semistructured interviews, such as the Clinician-Administered PTSD Scale, the Structured Clinical Interview for DSM-IV (SCID), the Diagnostic Interview Schedule for DSM-IV (DIS-IV), and the Composite International Diagnostic Interview (CIDI) are examples of diagnostic

POSTTRAUMATIC STRESS DISORDER 77 interviews. However, many epidemiologic studies use screening instruments to assess the number and frequency of symptoms of PTSD, rather than a full diagnostic interview. Those screening instruments include the Department of Veterans Affairs (VA) Primary Care PTSD Screen, the PTSD Checklist (either military or civilian version), the Mississippi Scale for Combat-Related PTSD, and the Keane Scale of the Minnesota Multiphasic Personality Inventory (MMPI-PK). BOX 5-1 DSM-IV Diagnostic Criteria for Posttraumatic Stress Disorder A. The person has been exposed to a traumatic event in which both of the following were present: (1) The person experienced, witnessed, or was confronted with an event or events that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others. (2) The person’s response involved intense fear, helplessness, or horror. B. The traumatic event is persistently re-experienced in one (or more) of the following ways: (1) Recurrent and intrusive distressing recollections of the event, including images, thoughts, and/or perceptions; (2) Recurrent distressing dreams of the event; (3) Acting or feeling as if the traumatic event were recurring (includes a sense of reliving the experience, illusions, hallucinations, and/or dissociative flashback episodes, including those that occur on awakening or when intoxicated); (4) Intense psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event; (5) Physiological reactivity on exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event. C. Persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness (not present before the trauma), as indicated by at least three of the following: (1) efforts to avoid thoughts, feelings, and/or conversations associated with the trauma; (2) efforts to avoid activities, places, and/or people that arouse recollections of the trauma; (3) inability to recall an important aspect of the trauma; (4) markedly diminished interest or participation in significant activities; (5) feeling of detachment or estrangement from others; (6) restricted range of affect (e.g., inability to have loving feelings); (7) sense of a foreshortened future (e.g., does not expect to have a career, marriage, children, or a normal life span). D. Persistent symptoms of increased arousal (not present before the trauma), as indicated by at least two of the following: (1) difficulty falling or staying asleep; (2) irritability or outbursts of anger; (3) difficulty concentrating; (4) hypervigilance; (5) exaggerated startle response. E. Duration of the disturbance (symptoms in Criteria B, C, and D) is more than one (1) month. F. The disturbance causes clinically significant distress and/or impairment in social, occupational, and/or other important areas of functioning. SOURCE: Reprinted with permission from APA (2000).

78 GULF WAR AND HEALTH PREVALENCE The National Comorbidity Survey (NCS) conducted in 1990-1992 on a nationally representative sample of 5877 people, found the prevalence of lifetime PTSD to be 7.8% (5% in men and 10% in women) (Kessler et al. 1995). In the NCS replication conducted in 2001-2003 on 9282 people, Kessler et al. (2005b) found the prevalence of PTSD in the previous 12 months to be 3.5%. PTSD was assessed according to the World Health Organization World Mental Health Survey version of the CIDI. In a study of young adults in a health maintenance organization in an urban area, Breslau (2001a) estimated that about 8% of adults may experience lifetime PTSD, or about 15-24% of those who are exposed to traumatic events. Although women’s exposure to traumatic events is estimated to be somewhat less than that of men, twice as many women develop PTSD (Breslau 2001a). In a comparison group of 500 civilians in the National Vietnam Veterans Readjustment Study (NVVRS), Kulka et al. (1990) found that 1.2% of men and 0.3% of women had current (6-month) PTSD. Many people experience traumatic events. Some traumatic events are common and are associated with a relatively low prevalence of PTSD, such as the sudden death of a loved one; other, less common traumatic events, such as rape, are associated with a very high prevalence of PTSD (see Table 5-1). In the case of the 1995 Oklahoma City bombing, it was found that the postdisaster prevalence of PTSD was 34% among all cases identified in 4-8 months after the bombing (North et al. 1999). TABLE 5-1 Prevalence of Traumatic Events and PTSD in Men and Women Prevalence of Lifetime PTSD in Prevalence of Event (%) Response to Event (%) Traumatic Event Men Women Men Women Rape 0.7 9.2 65.0 45.9 Molestation 2.8 12.3 12.2 26.5 Physical assault 11.1 6.9 1.8 21.3 Accident 25.0 13.8 6.3 8.8 Natural disaster 18.9 15.2 3.7 5.4 Witnessed death or injury 40.1 18.6 9.1 2.8 Learned about a traumatic event 63.1 61.8 1.4 3.2 Sudden death of a loved one 61.1 59.0 12.6 16.2 SOURCE: Adapted with permission from Yehuda (2002). Combat is one of the most traumatic events a person can experience. Men who named combat as their “worst lifetime traumatic event” were found to be 7 times as likely to have PTSD than men naming other experiences (Prigerson et al. 2001). Nearly 30% of all cases of PTSD in the U.S. population are attributed to combat experience (Prigerson et al. 2002). Numerous studies in military populations have provided estimates of the prevalence of PTSD; some of those are discussed below.

POSTTRAUMATIC STRESS DISORDER 79 Operation Enduring Freedom and Operation Iraqi Freedom In U.S. combat troops deployed to Afghanistan and Iraq, the risk of having PTSD 3-4 months after their return was 6.2% for Army troops returning from Afghanistan (odds ratio [OR] 1.26, 95% confidence interval [CI] 0.97-1.64) and 12.9% for Army (OR 2.84, 95% CI 2.17-3.72) and 12.2% for Marines (OR 2.66, 95% CI 2.01-3.51) returning from Iraq. The risk of having PTSD before deployment was 5.0% for all the military personnel screened using the PTSD Checklist (Hoge et al. 2004). A year after their return from Iraq, 16.6% of the U.S. Army combat troops met the screening criteria for PTSD (Hoge et al. 2007). The Department of Defense conducted a mental-health survey of Army soldiers and Marines deployed in Iraq in 2003, 2004, and 2006. In 2003, 16% of the soldiers and Marines met the screening criteria for PTSD while deployed; in 2004, 14% met the criteria; and in 2006, 17% of soldiers and 14% of Marines met the criteria (MHAT 2006). Gulf War The effects of the 1991 Gulf War on Army active-duty, and reserve or National Guard units from Pennsylvania and Hawaii were studied about 2 years after the war (Stretch et al. 1996). Of the deployed active-duty and reserve or National Guard soldiers, 8% and 9.2%, respectively, had a symptom complex suggestive of PTSD; of the nondeployed active-duty and reserve or National Guard soldiers, only 1.3% and 2.1%, respectively, had such symptoms. In an earlier study of 11,000 active-duty Gulf War soldiers conducted 6-12 months after the war, current PTSD rates were 12.9-15.5% (Stretch et al. 1996). The lower rates in the Pennsylvania and Hawaiian troops were attributed to their military occupations—support activities—which may have resulted in less exposure to traumatic events than the active-duty Army soldiers who had engaged in combat. In a 1995-1997 survey of 9476 Gulf War-era veterans and 11,441 Gulf War-deployed veterans in all four services, Kang et al. (2003) found that 12.1% of deployed veterans and 4.3% of nondeployed veterans met the screening criteria for current PTSD using the PTSD Checklist (adjusted OR 3.1, 95% CI 2.7-3.4). The risk of PTSD increased with the severity of the stress, ranging from 3.3% in activated but nondeployed reserve personnel (minimal stress) to 22.6% in Gulf War-deployed veterans who had worn chemical protective gear, heard chemical alarms, been involved in direct combat duty, and witnessed deaths (maximal stress). In a followup to that study, Toomey et al. (2007) found that 6.2% of Gulf War-deployed veterans and 1.1% of nondeployed veterans had a diagnosis of war-related PTSD 10 years after the war (OR 5.78, 95% CI 2.62-12.74; adjusted for age, sex, ethnicity, duty type, service branch, and rank). Ikin et al. (2004) found that a decade after the Gulf War, 5.1% of Australian Gulf War veterans had PTSD (diagnosed with the CIDI), compared with 1.7% of nondeployed Australian veterans. Few of the Australian veterans experienced direct combat; rather, their stressors were associated with the threat of combat, anticipation of attack with biologic or chemical agents, and the discomfort and isolation of deployment. Similar risks for PTSD were seen in Canadian Gulf War-deployed and nondeployed veterans (Goss Gilroy Inc. 1998). A 1998-2001 mail survey of 23,358 UK Gulf War veterans also found increased self-reports of PTSD and associated symptoms compared with nondeployed military personnel (1.0% vs 0.4%, OR 2.4, 95% CI 1.8- 3.1) (Simmons et al. 2004).

80 GULF WAR AND HEALTH Vietnam War The NVVRS assessed the readjustment to civilian life and the prevalence of PTSD and other psychiatric disorders in 3016 Vietnam veterans 15-20 years after the war (Kulka et al. 1990). It was estimated that 15.2% of all male Vietnam-theater veterans had current (6-month) combat-related PTSD and 30.9% had lifetime combat-related PTSD (the former value is equivalent to about 479,000 of the 3.14 million men who served in the Vietnam theater). Of the 7200 female veterans, it was estimated that 8.5% had current PTSD and 26.9% had lifetime PTSD. The prevalence of current PTSD (35.8%) was 4 times as high in men (7 times as high as in women) exposed to high levels of war-zone stress as in men exposed to low or moderate war- zone stress (8.5%); 2-3 times as high as in those with service-connected physical disabilities (wounded in combat), and twice as high as in men (5 times as high in women) with lifetime substance-abuse disorders (Schlenger et al. 1992). Exposure to war-zone stress was more predictive of PTSD in the NVVRS study than were predisposing factors (Keane 1998). Dohrenwend et al. (2006) reanalyzed the military records of 1200 male Vietnam-theater veterans from the NVVRS with a records-based military-history measure of exposure to war- zone stressors. Over 86% of the veterans with war-related PTSD described events that were personally life-threatening or involved witnessing death of or physical harm to others. A diagnosis of PTSD was based on the SCID. A dose-response relationship was established: fewer than 1% of low-exposed veterans had a diagnosis of current (as of 1988) war-related PTSD vs 28.1% of those in the high-exposure category. When adjusted for impairment of functioning and documentation of exposure to war-related traumatic events, the prevalence of lifetime and current war-related PTSD was 18.7% and 9.1%, respectively. The Vietnam Experience Study (VES) was conducted by the Centers for Disease Control and Prevention in 1984 on a random sample of 2490 Vietnam theater and 1972 era Army veterans via telephone interview. A subsample of the respondents received a physical examination by a clinician and were interviewed with the DIS for assessment of psychiatric disorders (CDC 1988). Lifetime and current (1-month) PTSD rates were 14.7% and 2.2%, respectively, in the theater veterans 13 years after the end of the war. PTSD prevalence in the era veterans was not given. Using the same dataset, but including noncombat PTSD with combat- related PTSD, Boscarino (1995) found the prevalence of current PTSD in theater and era veterans to be 12% and 2%, respectively. PTSD was positively associated with reported combat exposure (OR 2.42, p < 0.001). In an effort to reconcile the different prevalences of combat-related PTSD in Vietnam veterans reported in the NVVRS and the VES, Thompson et al. (2006) noted that the discrepancies could be minimized if the same definition of PTSD were applied to both studies. Rates determined with particularly broad and sensitive criteria were about 5 times those determined with more restrictive criteria. The authors concluded that consistent methods of diagnosis are needed to compare rates of PTSD in different studies of veteran populations. O’Toole et al. (1996) found the prevalence of lifetime PTSD to be 21% in Australian Vietnam veterans (diagnosed with the SCID) and 12% for current PTSD, 20-25 years after the war. World War II and Korean War Veterans of World War II and the Korean War who are participating in the Normative Aging Study, a long-term study established by the VA in Boston that has screened and tracked

POSTTRAUMATIC STRESS DISORDER 81 over 6000 men for a variety of health conditions since its inception in 1961, were screened for PTSD in 1990 (Spiro et al. 1994). The Mississippi Scale for Combat-Related PTSD was used to assess 809 World War II veterans (54% of whom experienced combat) and 401 Korean War veterans (19% of whom experienced combat); the Combat Exposure Scale and two additional questions on length of time in combat and exposure to combat outcomes were used to assess combat-exposure severity. The estimated prevalence of PTSD was 0.74% in World War II veterans (whether combat-exposed or not) and 0.25% in Korean War veterans (whether combat- exposed or not). On the basis of combat exposure of the World War II veterans, the estimated prevalence of PTSD increased from 0.94% in those with light to moderate exposure to 3.45% in those with moderate to heavy exposure. None of the 76 combat-exposed Korean War veterans screened positively for PTSD, although 0.31% of the Korean War veterans who were not exposed to combat did. Kang et al. (2006) compared the health status of 19,442 U.S. World War II prisoners of war with a randomly selected control group of 9728 veterans who had served in the military during World War II but had not been prisoners of war. On the basis of computerized VA inpatient medical records for 1990-2000 and outpatient medical records for 1997-2000 or computerized medical records from the Health Care Financing Administration, they found that 113 of the control group (1.16%) had a diagnosis of PTSD. PTSD had been diagnosed in 3254 (16.7%) of the POWs, 71% of whom had been interned in Europe. The study did not indicate whether the control group had been engaged in combat or where they had served during the war. Table 5-2 summarizes the prevalence or risk of PTSD in numerous studies of U.S. military personnel. Some of the difference in rates might be attributed to the definition of PTSD being used (DSM-III-R or DSM-IV-TR) and the instruments used to screen for or diagnose it. COURSE DSM-IV recognizes that the onset of PTSD may be acute, beginning within 6 months of exposure to the traumatic event, or delayed, beginning more than 6 months after the traumatic event. Symptoms typically begin shortly after exposure—even on the first day (North et al. 1999). The lag time between exposure and development of enough symptoms to meet the diagnostic criteria is variable and may be years (Bremner et al. 1996; Bryant and Harvey 2002; Carty et al. 2006; Gray et al. 2004; Green et al. 1990a; Op den Velde et al. 1996; Port et al. 2001; Ruzich et al. 2005). It is considered to be chronic by DSM-IV-TR criteria if symptoms persist for 3 months or longer. PTSD can be chronic with no remission, or it can be recurrent with periods of remission and recurrence (Friedman 2003). Of the veterans with PTSD in the NVVRS, Schnurr et al. (2003) found that PTSD resulted from traumatic experiences before their Vietnam deployment in 8%; for those with PTSD related to Vietnam, it began in 31% in the same year that they went to Vietnam; it began in 31% in the following year, it began in 32% within 2-5 years of entry into Vietnam, and it began in 6% even later. More than 40% of the veterans had symptoms that had persisted for more than 2 decades. Symptoms began earlier in men than in women. Among men, members of ethnic minority groups were slower to develop symptoms.

82 GULF WAR AND HEALTH TABLE 5-2 Estimated Prevalence of PTSD in U.S. Military Populations Population PTSD Prevalence How Measured When Assessed Reference OEF combat Current: predeployment PTSD Checklist Army: 3-4 months after Hoge et al. 2004 troops 5%; 6% postdeployment return from combat duty (n = 1962) OIF combat Current: 5% PTSD Checklist Army: 1 week before Hoge et al. 2004 troops predeployment; deployment and 3-4 months 12-13% postdeployment after return from combat Iraq (n = 1709) duty Marines: 3-4 months after return from combat duty Current: 14-17% PTSD Checklist 9 months into deployment MHAT 2006 (n = 1767) Gulf War Current: 3.4% CIDI February 2000-October Fiedler et al. 2006 veterans (n = 967) 2001 Current: Ft. Devens 5%, CAPS for 75% of Ft. Devens cohort: initial Proctor et al. 1998 8% (n = 148) subjects survey within 5 days of New Orleans 7%, 8% (n return (spring 1991) and = 58) Mississippi Scale for winter 1992/spring 1993 (according to CAPS and Desert Storm War Mississippi Scale, Personnel for 99% of New Orleans cohort: initial respectively) subjects survey within 9 months of return in 1991 and summer 1994/fall 1995 Current: 12% PTSD Checklist November 1995-1997 Kang et al. 2003 (n = 11441) Lifetime: 6.2% CAPS 10 years after war Toomey et al. 2007 (n = 1061) Current: 8-9.2% 17-item 1.5-2 years after war Stretch et al. 1996 (n = 1524) questionnaire based on DSM-III-R criteria Impact of Event Scale Brief Symptom Inventory Vietnam Current: 15% men Mississippi Scale for 15 or more years after Kulka et al. 1990 veterans (n = 1200), 8.5% women Combat-Related service (n = 432) PTSD Lifetime: 30.6% men, DIS 26.9% women MMPI PTSD Scale SCID Current: 9.1% Military records 1988 for NVVRS Dohrenwend et al. Lifetime: 18.7% Historical accounts 2006 (n = 1200) Diagnostic histories of PTSD MMPI SCID Current: 2.2% DIS 11-12 years after Vietnam CDC 1988 Lifetime: 14.7% post MMPI War; 15-20 years after deployment Army service (n = 2490)

POSTTRAUMATIC STRESS DISORDER 83 TABLE 5-2 Continued Population PTSD Prevalence How Measured When Assessed Reference Korean War Current: 0.25% Mississippi Scale for Normative Aging Study Spiro et al. 1994 veterans (n = 401) Combat-Related cohort; questionnaires sent PTSD in 1990 Combat Exposure Scale World War II Current: 0.74% Mississippi Scale for Normative Aging Study Spiro et al. 1994 veterans (n = 809) Combat-Related cohort; questionnaires sent PTSD in 1990 Combat Exposure Scale NOTE: CAPS = Clinician-Administered PTSD Scale, CIDI = Composite International Diagnostic Interview, DIS = Diagnostic Interview Schedule, MMPI = Minnesota Multiphasic Personality Inventory, OEF = Operation Enduring Freedom, OIF = Operation Iraqi Freedom, SCID = Structured Clinical Interview for DSM-IV. In a small study, Bremner et al. (1996) found that of 61 Vietnam veterans with combat- related PTSD, 0 (15%) developed PTSD during their combat tour and 38 (62%) met the criteria for PTSD within 2 years of the end of their combat tour, and 8 patients (13%) did not meet the full criteria for PTSD until 10 or more years after their tours ended. The first symptoms reported were typically in the hyperarousal cluster. Symptoms typically increased during the first few years and then leveled off. Increasing PTSD symptoms and symptom severity were observed Wolfe et al. (1999) in a larger cohort of 2119 male and 194 female Gulf War veterans screened for PTSD. Five days after their return from the gulf, 3% of the veterans (8% of women and 3% of men) exceeded the PTSD screening cutoff; at 18-24 months, the percentage of veterans exceeding the cutoff had more than doubled to 8% (16% of women and 7% of men). Similar results were seen in 84 National Guard troops (medical and military police units) returning from the Gulf War (Southwick et al. 1993b, 1995). Most of the PTSD symptoms reported at 2 years after deployment were present by 6 months, but symptom severity continued to increase. The hyperarousal symptom cluster was more prevalent than the intrusive-memories cluster, which was more prevalent than the avoidance-numbing cluster. PTSD symptom severity did not differ between the units or between the sexes. Those who were highly symptomatic at 6 months continued to be symptomatic at 2 years. In many cases, PTSD will remit naturally (McFarlane 1997). Most (60%) PTSD remissions in the general population occur within 1 year. More than one-third of cases do not remit, however, regardless of whether the person receives treatment (Connor and Butterfield 2003; Kessler et al. 1995). In the NCS, the median time to remission among people who ever sought professional treatment was 36 months, but it was 64 months for those who did not (Kessler et al. 1995). Factors associated with PTSD chronicity in the general population are a greater number of symptoms (especially numbing and arousal symptoms), comorbid alcohol abuse or other psychiatric or medical illness, being female, having a family history of antisocial behavior, and having a history of childhood trauma (Breslau 2001b). Marshall et al. (2006) found that NVVRS veterans with chronic war-related PTSD had more numbing symptoms and, to a lesser extent, more hyperarousal symptoms than veterans with PTSD in remission; re-experiencing symptoms did not appear to be related to PTSD chronicity.

84 GULF WAR AND HEALTH The above studies indicate that the development and course of PTSD are variable. Some people may have no or few symptoms of PTSD initially but develop more symptoms over time and others may rapidly develop symptoms that meet the full diagnostic criteria for PTSD. Some recover or experience a reduction in symptoms, others suffer longstanding PTSD symptoms (Friedman et al. 1994; Kulka et al. 1990; Schnurr et al. 2003), and still others will follow an episodic course. Even those who appear to have recovered entirely from PTSD may experience a recurrence of symptoms years later, especially if exposed to additional trauma or other important life events, such as the death of a spouse (Friedman et al. 1994). COMORBIDITY AND DISABILITY People with PTSD tend to report poor health and impaired function in many life activities. Several studies indicate that veterans with PTSD report more symptoms of adverse health and disability than do veterans without PTSD (see Chapter 6 for more information on symptom reporting). On examination, many people with PTSD are found to have other psychiatric disorders that increase the complexity of diagnosing PTSD. The presence of those additional psychiatric disorders may also play a role in the adverse health effects seen with PTSD. In Chapter 6, studies are assessed for the strength of the association between deployment to a war zone and PTSD; those studies are found in the section on psychiatric disorders. The body of evidence that addresses specific health effects that may occur in veterans with PTSD is also reviewed in Chapter 6 for each relevant health effect. The psychosocial effects seen in veterans with PTSD, including effects on family and employment, are considered in Chapter 7. Comorbidity In veteran and general population samples, PTSD frequently co-occurs with other psychiatric or substance-use disorders. In the NVVRS, male and female theater veterans with PTSD were 10-15 times more likely to have depression and dysthymia and 20 times more likely to have an anxiety disorder than their counterparts without PTSD (Kulka et al. 1990). Zatzick et al. (1997a) found that the risk of having PTSD was significantly greater in male NVVRS veterans with major depression (OR 17.6, 95% CI 6.5-47.4), alcohol abuse or dependence (OR 3.2, 95% CI 1.9-5.4), drug abuse or dependence (OR 7.4, 95% CI 2.2-24.5), or panic disorder (OR 22.6, 95% CI 3.1-163.5) that in those with the disorders. Among female veterans, PTSD was seen in 51% of those with major depression, 40.7% of those with alcohol abuse or dependence, and 70.1% of those with panic disorder (Zatzick et al. 1997b). High rates of comorbidity are also seen in the general population. In the NCS, 88.3% of men and 79.0% of women with PTSD had a life history of mood, anxiety, or substance-use disorders (Kessler et al. 1995). The temporal relationship between PTSD and other psychiatric and substance-use disorders is complex. Psychiatric comorbidity increases the likelihood of PTSD, as found in the NCS. However, PTSD also increases the likelihood of developing the other disorders (Schnurr et al. 2000a, 2002; Shalev et al. 1998). Trauma can also lead to the simultaneous development of PTSD and other psychiatric disorders, such as major depression (Shalev et al. 1998). For example, in a study of 262 World War II and Korean War prisoners of war (Engdahl et al. 1998), half of whom developed war-related PTSD, 66% of those with PTSD but only 34% of those without PTSD had another anxiety, mood, or substance-use disorder. The

POSTTRAUMATIC STRESS DISORDER 85 majority of the other disorders began in the same year as PTSD. Although the high rate of psychiatric and substance-use comorbidity can be partly explained by symptom overlap in DSM- IV, it does not diminish the diagnostic integrity of PTSD; rather, it suggests the importance of complete clinical evaluations to elucidate the full clinical picture of each patient. Disability PTSD can result in profound and long-term impairment of functioning and quality of life. This section considers the functional outcomes and disability that may occur in veterans with PTSD. Psychosocial effects and the impact of PTSD on family, friends, and others are discussed in Chapter 7. DSM-IV requires that a diagnosis of PTSD include “clinically significant distress and/or impairment in social, occupational, and/or other important areas of functioning” (APA 2000). Therefore, it is important to understand the distress and disability that may be associated with it. Zatzick et al. evaluated 1190 male and 432 female Vietnam veterans by using data from the NVVRS (1997a,b). Of the men, 242 (15.3%) were diagnosed with PTSD and more than 90% of those men reported having one or more of 30 chronic nonpsychiatric medical conditions within the preceding 12 months. Of the veterans with no nonpsychiatric medical disorders, less than 10% had PTSD, whereas of the 141 veterans reporting four or more medical disorders, 31.9% had PTSD. Among the women, 8.9% had PTSD diagnosed, of whom 70% reported having one or more of 37 chronic medical conditions within the preceding 12 months. PTSD was present in only 4.2% of the female veterans with no chronic medical conditions but in 19.1% of those reporting four or more medical conditions. Veterans with PTSD reported significantly (p < 0.05) more functional impairment than veterans without PTSD, including inability to work, fair or poor health, diminished well-being, current limitation in physical functioning, and more days in bed in the preceding 3 months. Dohrenwend et al. (2006) also reanalyzed the NVVRS data, including the Global Assessment of Functioning (GAF) scale that is traditionally used by VA to assess a veteran’s functional impairment. Of the sample of 260 veterans who had no diagnosis of PTSD or a diagnosis of past PTSD, 47% and 44%, respectively, were rated as having good functioning, although none of the veterans who had a diagnosis of current PTSD had good functioning in all GAF areas. Of those with current PTSD, 15% had only slight impairment, 41% had some difficulty, and 37% had moderate or serious impairment. The GAF scores were related to the severity of the PTSD. A study of 70 UK active-duty military personnel referred to a PTSD clinic found that a diagnosis of PTSD, major depression, or alcohol dependence did not predict disability in work, relationships, or social activities, although symptoms of depression accounted for much of any total functional impairment, particularly in family life (Neal et al. 2004). Bleich and Solomon (2004) found that in Israeli veterans, PTSD symptoms resulted in more impairment in occupational functioning than in interpersonal functioning or activities of daily living. World War II veterans 70-74 years old, who had PTSD as a result of their participation in secret military tests of mustard gas during the war were assessed for health-related disability (Schnurr et al. 2000b). As of 1996, compared with similarly exposed veterans without PTSD, veterans with PTSD had decreased functioning and increased impairment on all measures: physical function, social function, physical role impairment, emotional role impairment, lifetime disability, and current unemployment.

86 GULF WAR AND HEALTH Men and women appear to suffer equal degrees of impairment from PTSD, although women are more likely to seek medical help and take medication. In a study of PTSD in the general population, Breslau (2001b) found that when symptoms were most severe, about 25% of both men and women in a population of young adults felt that they were unable to work during the entire 30-day period during which they experienced the symptoms. When inability to work was added to reports of reduced activity, almost 39% of the 20 men and 44% of 44 women reported that they were unable to do their jobs or had to reduce their activities. When young people with a diagnosis of PTSD, other psychiatric diagnoses, or no psychiatric diagnosis were compared, the limitation of activities from PTSD was twice that from the other diagnoses and 4 times that associated with no diagnosis. RISK AND PROTECTIVE FACTORS Risk and protective factors influence responses to stressors or traumatic events. In the case of veterans, those factors might determine the extent of the response to a deployment- related stressor and whether PTSD will develop. The following discussion is not exhaustive and is meant to provide the reader with an overview of the types of risk and protective factors that may influence each veteran. Some of the risk and protective factors that have been noted in the development of PTSD are: sex; age; race and ethnicity; developmental history and early-life stressors; personal psychiatric history; hardiness, a sense of control, and coping strategies; socioeconomic status and military status; social support; exposure to combat; and physical injury. None of those factors occurs in isolation; they may interact with one another before, during, and after deployment (Benotsch et al. 2000; Stein et al. 2005). Although many of the studies discussed below focus on PTSD, other health effects, primarily other psychiatric disorders, are also discussed when the results are applicable to them. Sex As in the general population (Kessler et al. 1995), female veterans of both the Vietnam War and the Gulf War are more likely than their male counterparts to suffer from PTSD (Fiedler et al. 2006; Kang et al. 2003; Kulka et al. 1990; Wolfe 1996; Wolfe et al. 1993b, 1999; Zatzick et al. 1997b). After the Gulf War, Fiedler et al. (2006) found that deployed women were more likely than deployed men to experience PTSD (4.0% of women and 3.4% of men), other anxiety disorders (25.3% of women and 15.3% of men), and major depression (25.3% of women and 14.2% of men), but they were less likely than men to have drug or alcohol disorders; these findings are mirrored in the general population (Kessler et al. 1995, 2005a). In a study assessing the prevalence of PTSD and chronic fatigue syndrome (CFS) in Gulf War veterans, women made up 18.6% of the 11,441 veterans in the study; 24.3% of the women met the screening criteria for PTSD, and 16.7% had CFS symptoms (Kang et al. 2003). Female Gulf War veterans were more likely than men to have PTSD symptoms when assessed 5 days after their return from the gulf (8% vs 3%, respectively, OR 3.2, 95% CI 1.9-5.5) and after controlling for the effects of combat and other risk factors; 18-24 months later, the prevalence was still higher for women than men (16% vs 7%, respectively, OR 2.3, 95% CI 1.5-3.5) (Wolfe et al. 1999). However, Sutker et al. (1995a) found that female Gulf War veterans (14% of sample) reported similar levels of psychologic distress and had no more PTSD symptoms than their male counterparts.

POSTTRAUMATIC STRESS DISORDER 87 As discussed in Chapter 3, sexual assault is one of the two leading risk factors (combat is the other) for PTSD (Breslau et al. 2002; Kessler et al. 1995). Sexual victimization in military women was found to have a dose-response relationship with PTSD, according to two studies (Murdoch et al. 2006; Wolfe et al. 1993a), and sexual assault is associated with poorer health outcomes in female veterans (Goldzweig et al. 2006). Kang et al. (2005) found that among 2131 female and 9310 male Gulf War veterans, PTSD was associated with in-theater sexual harassment and assault in women (OR 5.41, 95% CI 3.19-9.17) and men (OR 6.21, 95% CI 2.26- 17.04). The risk of having PTSD associated with combat was almost identical in men (OR 4.45, 95% CI 3.54-5.60) and women (OR 4.03, 95% CI 1.97-8.23) and showed a dose-response relationship with increasing combat. Sexual assault, however, was a greater risk factor for PTSD than was combat exposure in both men and women. Race and Ethnicity Research results on the role of race and ethnicity as risk factors for stress-related illness are mixed but in general support the conclusion that blacks and Hispanics are at greater risk for developing psychiatric disorders, particularly PTSD, as a result of deployment. In the VES, nonwhite veterans had a poorer psychologic status 15-20 years after the war than did white veterans (CDC 1988). Findings from the NVVRS indicate that black and Hispanic veterans had a higher prevalence of PTSD than whites (Kulka et al. 1990). Among theater veterans, the prevalence of current PTSD in the NVVRS was 27.9% in Hispanics, 20.6% in blacks, and 13.7% in whites and others (Kulka et al. 1990). Those proportions held even when racial differences in combat exposure were controlled for as minority groups had a greater number of war-zone exposures. The Hawaii Vietnam Veterans Project (HVVP), modeled on the NVVRS, determined that veterans of Japanese ancestry had a lower prevalence of PTSD than whites (Friedman et al. 2004). Schnurr et al. (2003) studied 530 veterans drawn from the NVVRS and the HVVP, and found that black, Hispanic, and native Hawaiian men were more likely and Americans of Japanese descent were less likely than white men to have a lifetime diagnosis of PTSD and that Hispanic male veterans were more likely to have current PTSD than males in other ethnic groups (Schnurr et al. 2004). In a study of 1377 American Legionnaires who had served in Vietnam and were followed for 14 years, minority race contributed to a more chronic course of PTSD; however, the minority sample was too small for further investigation (Koenen et al. 2003). It has been suggested that the racial gap in prevalence or course of PTSD in Vietnam veterans might stem from racism in the military, overidentification with a nonwhite enemy, exacerbation of existing stress by institutional racism, and lower financial or emotional resources after the war (Marsella et al. 1993). Several studies of Gulf War veterans have also found that minority-group veterans had a greater prevalence of PTSD. In a study by Kang et al. (2003), nonwhite veterans had a greater prevalence of PTSD than white veterans, but the category “nonwhites” was not divided into minority subgroups, and there was no adjustment for socioeconomic factors other than age and marital status. There was no difference between whites and nonwhites in prevalence of CFS. A study of 653 Gulf War veterans from Louisiana with relatively high minority-group participation (35%) found that minority-group troops, particularly men, tended to report greater psychologic distress and more PTSD symptoms than white men (Sutker et al. 1995a); however, as in the Kang study, there was no stratification beyond “nonwhite status” and no adjustment for other factors that may have contributed to the reporting differences. Adjusted for age, sex, race, rank,

88 GULF WAR AND HEALTH branch, and military status, Black et al. (2004) found that nonwhite Gulf War veterans were at almost twice the risk of an anxiety disorder as white veterans (OR 1.9, 95% CI 0.7-5.3). Hoge et al. (2002) assessed the incidence of first hospitalization for a mental disorder in active-duty military personnel in 1990-1999. The rates of hospitalization per 1000 person-years were 9.34 for whites, 9.25 for Hispanics, 8.30 for blacks, 5.97 for Asians and Pacific Islanders, and 18.27 for American Indians and Alaskan Natives. Fontana et al. (2000) found that among U.S. peacekeepers in Somalia, PTSD symptoms were more severe in blacks, although there was no adjustment for socioeconomic factors in the model. Age Research results on age as a risk factor for PTSD and other psychiatric disorders are mixed. Studies of Vietnam veterans (Bremner et al. 1993; CDC 1988; Green et al. 1990b; Kulka et al. 1990) and Gulf War veterans (Wolfe et al. 1999) generally found lower age to be a risk factor for PTSD. Kulka et al. (1990) in the NVVRS found that older men (born before 1945) had a lower prevalence of PTSD (4-10%) than those born later (18-19%). Ikin et al. (2004) found that although Australian Gulf War-deployed veterans were at increased risk for any postwar anxiety disorder compared with nondeployed veterans, the risk did not vary significantly among four age groups (less than 20 years old, 20-24, 25-34, and 35 and higher). Black et al. (2004) also found that being 25 years old or younger did not significantly increase the risk of having a current anxiety condition among Gulf War veterans (OR 1.3; 95% CI 0.8-2.0). During the 1990s, however, active-duty military personnel aged 18-24 were at greater risk for hospitalization for a mental disorder than older veterans (Hoge et al. 2002). Seal et al. (2007) found that active-duty Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) male veterans 18-24 years old were more likely to have a diagnosis of PTSD or any other mental health disorder than were older veterans. The risk of having a diagnosis of PTSD or any mental health diagnosis decreased with increasing age. Compared with veterans 40 years and older, the relative risk for PTSD was 8.88 (95% CI 7.49- 10.54) for the youngest veterans, 6.91 (95% CI 5.82-8.21) for those 25-29 years old, and 6.07 (95% CI 5.05-7.28) for those 30-39 years old. Developmental History and Early-Life Stress Numerous epidemiologic studies of Vietnam and Gulf War veterans and of civilians have found that childhood trauma from physical or sexual abuse is a risk factor for PTSD, regardless of later combat exposure. The strongest evidence of the impact of early-life stress comes from large studies of Vietnam veterans (Fontana and Rosenheck 1994a; Kulka et al. 1990) and Gulf War veterans (Sutker et al. 1995b). Fontana et al. (1994a) analyzed data from the NVVRS, assigning weights to the major contributors to PTSD in female veterans. A history of child abuse contributed nearly as much to the risk of having PTSD as did military sexual trauma although combat exposure was twice as likely to contribute to the risk of PTSD (Fontana and Rosenheck 1994a). King et al. (1999) also found that a history of early-life trauma was linked to the development of PTSD in male and female Vietnam veterans; it also predicted the likelihood of stressful life events after the war. Childhood sexual and physical abuse is common in Gulf War and Vietnam veterans seeking treatment for psychiatric disorders including PTSD, with studies that assessed this endpoint

POSTTRAUMATIC STRESS DISORDER 89 finding that 25-60% of veterans with a psychiatric disorder had been abused (Bremner et al. 1993; Engel et al. 1993; Lapp et al. 2005). Psychiatric History Having been diagnosed previously with a psychiatric disorder increases the likelihood of PTSD after exposure to a traumatic event. People with a history of a psychiatric disorder may have an increased likelihood of engaging in risky behavior which increases the likelihood of their exposure to traumatic events and their potential for PTSD or other stress-related disorders. Someone with a pre-existing psychiatric disorder who is exposed to wartime trauma may respond ineffectively to the traumatic event because of pre-existing symptoms, inadequate coping styles, low social support, and poor self-esteem, all of which increase the likelihood of PTSD or related disorders. A study of Gulf War veterans by Black et al. (2004) found that the greatest risk of postwar anxiety disorder resulted from the presence of pre-existing anxiety disorders of any kind (OR 10.4, 95% CI 2.9-37.0), and pre-existing depressive disorders (OR 4.1, 95% CI 1.9-8.9). The overall likelihood of postwar anxiety disorders was increased by a factor of 4 (range, 2.2- 8.9) by a previous history of any psychiatric disorder. A study of Australian Gulf War veterans by Ikin et al. (2004) found that similar percentages of Gulf War-deployed veterans (31%) and a comparison group of era veterans (33.7%) reported having had a psychiatric disorder before deployment. Most frequently, the pre-existing disorders were substance-use disorders (25-28%) and anxiety disorders (6-8%). Hoge et al. (2004) screened 2530 U.S. infantry soldiers for mental health disorders before their deployment to Iraq in 2003. They found that 14.3% reported a moderate or severe mental health problem, 5.3% met the patient health questionnaire definition of depression, 6.4% met the definition of anxiety, 5.0% met the definition for PTSD, 17.3% reported using more alcohol than they meant to, and 12.5% had felt they wanted to cut down on their drinking. Those findings highlights that a substantial portion of military personnel may enter combat at increased risk for a psychiatric disorder on the basis of psychiatric history alone. Hardiness, Coping Strategies, and Sense of Control The occurrence and severity of stress-related health effects are not solely the result of interaction of physiologic processes with a threatening environment. Studies of Vietnam and Gulf War veterans indicate that particular personality or psychologic characteristics can affect a person’s reactions to deployment-related stress. Personality includes inherent tendencies toward optimism or pessimism, coping styles, resilience, and hardiness that would be expected to affect one’s ability to manage stressful events. Those characteristics are determined or modulated by the action of life experiences on genetic makeup. One personality trait, hardiness, has been defined as a combination of commitment (feeling deeply involved in life activities), feeling in control of one’s experiences, and maintaining a sense of challenge (a positive anticipation of change). Dolan and Adler (2006) adapted the definition of hardiness in a military population to mean the degree to which military personnel are committed to and feel a sense of control over their work experiences. They surveyed U.S. Army soldiers during and after a 6-month peacekeeping mission in Kosovo. Military hardiness was correlated with psychologic but not physical health during and after deployment. Among soldiers who experienced high levels of deployment stressors, those with

90 GULF WAR AND HEALTH greater levels of hardiness had less postdeployment depression. Studies of deployed Gulf War veterans have found that hardiness was protective against the adverse effects of combat stress and stressful life events and that the level of hardiness was a significant predictor of health outcomes (Bartone 1999). Those with greater hardiness reported fewer physical symptoms than those with lower hardiness regardless of the intensity of the combat exposure or the reported level of stressful life events. For military personnel with long exposure to war-zone stressors, hardiness and perceived social support may gradually diminish, and the diminution can result in deterioration of physical health (Taft et al. 1999). The types of physiologic changes seen in animals after exposure to uncontrollable stressors have also been observed in humans (see Chapter 4 for a discussion of the animal studies). In a prospective study of 348 Gulf War veterans (all military reservists), Benotsch et al. (2000) measured sense of control with the 45-item Dispositional Resilience Scale 14 months after the conflict (time 1) and 13 months after that (time 2). Veterans’ perceptions of their personal resources, particularly the hardiness components of control and (to a lesser degree) commitment, and problem-focused coping decreased significantly between time 1 and time 2. Conversely, coping with stress through avoidance increased significantly between the two times. Storzbach et al. (2000) found that veterans with unexplained illness reported feeling less control over stressful events that they had recently experienced than did veterans without such illness. Coping strategies are also associated with ability to respond to stressors. In a study of Vietnam combat veterans, positive coping strategies were found to protect against the development of PTSD symptoms (Wolfe et al. 1993c). When assessed 15 years after their deployment, veterans who used negative coping strategies—such as mental escapism, externalization, and behavioral avoidance—had poorer psychological functioning and more PTSD symptoms than veterans who used nonavoidant coping styles, regardless of the level of combat exposure in each group. Vaillant (1977) found that avoidant behavior was also a major predictor of a downward trajectory in life in a civilian population. It has been shown in other stressful circumstances that ineffective coping strategies, especially avoidant or passive coping as opposed to active problem-solving strategies, predict adverse mental-health outcomes (Arata et al. 2000; Gibbs 1989; North 1995; North et al. 1994, 2001). In addition to a positive coping style, a perception that some benefit derives from military experience is associated with reduced potential for adverse health effects after combat exposure. Lee et al. (1995), in a 50-year prospective study of World War II combat veterans, found premorbid characteristics to be significantly associated with postcombat psychopathology. Aldwin et al. (1994) conducted a study of 1287 male veterans 44-91 years old, 40% of whom had been engaged in combat. The majority of veterans responded with positive comments about their military service (for example, a sense of mastery, enhanced self-esteem, and effective coping), and there was a linear relationship between perceived benefits and combat exposure. Similar results were seen by Jennings et al. (2006), who found that veterans in the Normative Aging Study (mean age, 74 years) with moderate combat exposure had higher levels of wisdom later in life than veterans with no or high combat exposure; wisdom was assessed with the Adult Self-Transcendence Inventory. Wisdom also correlated positively with perception of benefits of military experience and with positive coping strategies. The studies suggest that a favorable appraisal of one’s combat experience or personal attributes associated with it may mitigate long- term adverse health consequences, such as PTSD.

POSTTRAUMATIC STRESS DISORDER 91 Socioeconomic Status and Military Status In civilian studies, socioeconomically disadvantaged populations are at greater risk for psychiatric and somatic disorders (Neeleman et al. 2001); those in the lowest social and economic strata have 2-3 times the risk of psychiatric disorders, especially depression and anxiety disorders, of those in the highest strata (U.S. Department of Health and Human Services 1999). Not surprisingly, similar relationships are apparent in veteran populations. Low income and lack of education are associated with chronic stress-related disorders—for example, anxiety disorders, major depression, and substance-use disorders—in Gulf War and Vietnam veterans (Black et al. 2004; Boscarino 1995; Brewin et al. 2000; Fiedler et al. 2006). Low military rank (enlisted personnel vs officers) is also associated with greater risk of a stress-related disorder (Black et al. 2004; Fiedler et al. 2006; Kang et al. 2003; Kulka et al. 1990). Two studies found that being an officer or being college-educated reduced the risk of developing anxiety or depressive disorders after deployment by at least half (Black et al. 2004; Fiedler et al. 2006). Slusarcick et al. (2001) found that aboard a U.S. Navy hospital ship during the Gulf War, junior enlisted health-care providers had the highest levels of depression followed by junior officers, senior enlisted, and senior officers, in that order. By occupation, corpsmen were the most depressed, and physicians the least. However, Ikin et al. (2004) found that although Australian Gulf War-deployed veterans were at higher risk for any postwar anxiety disorder than were nondeployed veterans, the risk did not vary significantly by rank, whether officer or enlisted. Social Support Social support has been linked to favorable mental-health outcomes (Bland et al. 1997; Regehr et al. 2001) especially among men (Solomon et al. 1987). Studies have shown that good social support is a protective factor against the onset of PTSD (Benotsch et al. 2000; Fontana and Rosenheck 1994b; Fontana et al. 1997). Two meta-analyses found that lack of social support was the factor most strongly associated with the development of PTSD after a traumatic event for veterans of the Vietnam War and the Gulf War (Benotsch et al. 2000; Brewin et al. 2000; Fontana et al. 1997; Koenen et al. 2003; Ozer et al. 2003). Vietnam veterans with low levels of social support 10 years after the war had more symptoms of PTSD than those with high levels of social support; and when combined with high levels of combat exposure, those with low social support had far more symptoms of PTSD (Barrett and Mizes 1988). The role of social-support networks in the Vietnam-Era Adjustment Survey was explored in nursing and combat personnel (Stretch 1985, 1986; Stretch et al. 1985). The rates of PTSD were highest in men and women who had lacked positive social supports from family, friends, and society in general. Hispanic Vietnam veterans who were highly symptomatic for PTSD expressed fewer social contacts, more adverse social encounters, and smaller family and social networks (Escobar et al. 1983). One study, conducted in 1978, explored the burden of war and social bonding in 149 veterans of World War II and the Korean War. Painful memories of war and symptoms of stress in later life were diminished through involvement with a supportive community of service mates and partners (Elder and Clipp 1988). Prospective studies reveal a downward spiral: as PTSD symptoms worsen, veterans lose more social support, the lack of which in turn exacerbates their PTSD symptoms (Benotsch et al. 2000).

92 GULF WAR AND HEALTH Although most studies of social support deal with PTSD, particularly in Vietnam veterans, the same findings are applicable to major depression and other stress-related illnesses (Boscarino 1995; Fontana et al. 1997; Green et al. 1990b). Those studies all showed that low social support increased the risk of depression and other psychiatric disorders, such as generalized anxiety disorder. Most findings regarding social support come from studies of homecoming support, whether given by family, friends, or community. A perceived lack of family cohesion has also been associated with PTSD in Gulf War veterans (Sutker et al. 1995b). Few studies have specifically investigated social support during the period of deployment to a war zone. In one such study of Vietnam-theater and Vietnam-era veterans (Stretch 1985), social support during and after deployment was found to be a major factor in development of PTSD symptoms (social support accounted for 12% of explained variance). The lack of studies of the role of social support during deployment is an important gap because U.S. military personnel consistently report “being away from family” as a leading deployment stressor, according to several periodic DoD surveys of more than 12,000 active-duty military personnel serving in Iraq (MHAT 2006). The committee notes that it is difficult to determine whether low social support leads to mental-health sequelae, psychiatric problems reduce social support, or the relationship is indirect with other variables, such as the association of personality with both social support and other psychopathology. Combat Exposure One of the major risk factors for PTSD is exposure to combat. Combat as a deployment- related stressor was discussed in Chapter 3. PTSD appears to be associated with intensity and length of combat exposure. Studies of veterans from the Vietnam War and the Gulf War have confirmed a dose-response relationship between level of combat exposure and likelihood of PTSD. A study of 641 Australian Vietnam veterans conducted 20-25 years after the war found a dose-response relationship between exposure to combat and PTSD (O’Toole et al. 1996). The prevalence of lifetime combat-related PTSD was 20.9% with the Australian version of the SCID and 11.7% with the DIS; the prevalence of current (1-month) PTSD was 11.6% with the SCID. When the prevalence of lifetime or current PTSD (based on the SCID) was compared with responses to a 21-item combat index, there was a linear dose-response relationship with increasing combat exposure. The OR for each combat-score quartile for lifetime PTSD was 1.00, 3.03, 5.36, and 9.18; for current PTSD, the OR was 1.00, 2.11, 6.97, and 10.33 for each quartile increase in combat exposure. Dohrenwend et al. (2006) used NVVRS data on 1200 Vietnam-theater veterans to assess exposure to war-zone stressors. A diagnosis of PTSD was based on the SCID. A dose-response relationship between PTSD and exposure to war-zone stressors was established. Current (as of 1988) war-related PTSD was diagnosed in 0.3% of low-exposure veterans, 14.4% of moderate- exposure, 27.0% of high-exposure, and 28.1% of very-high-exposure. Longer and more intense combat exposure is associated with a greater prevalence of current PTSD. One study of male twins discordant for serving in Vietnam found more PTSD symptoms in the Vietnam veterans than in their twins who did not serve in Vietnam, even 15 years after the war (Goldberg et al. 1990). Roy-Byrne et al. (2004) also compared PTSD in twins, of whom one had substantial combat exposure in Vietnam and the other had low or no combat exposure or did not serve in Vietnam. Over the 10-year followup, the number of PTSD

POSTTRAUMATIC STRESS DISORDER 93 symptoms in veterans with greater combat exposure gradually decreased, but it was never reduced to the number seen in veterans with low or no combat exposure. One study of 1709 Marines and soldiers deployed to OIF found that the number of veterans who screened positively for PTSD 3-4 months after their return increased linearly with the number of reported firefights with the enemy: 4.5% for no firefights, 9.3% for 1-2 firefights, 12.7% for 3-5 firefights, and 19.3% for more than 5 firefights. PTSD rates for 1962 Army soldiers deployed to Afghanistan were 4.5%, 8.2%, 8.3%, and 18.9%, respectively (Hoge et al. 2004). Other combat-related factors influence the risk of PTSD and its course. Vietnam veterans (n = 1377) were questioned about possible PTSD symptoms in 1984 and again in 1998 (Koenen et al. 2003). The estimated prevalence of current (1 month) PTSD decreased from 11.8% in 1984 to 10.5% in 1998; 5.3% of those surveyed had symptoms of PTSD at both times, 6.5% met the criteria only in 1984, and 5.2% met the criteria only in 1998. Veterans who experienced high or medium combat exposure, perceived adverse community attitudes, or had discomfort in disclosing their war experience were more likely to have PTSD at either time. Discomfort in disclosing their Vietnam experience was associated with increased risk for developing PTSD but not with its course. For veterans with PTSD in 1984, high combat exposure increased the likelihood of having PTSD in 1998 and was the most important predictor of the course of PTSD. A veteran was also more likely to have PTSD in 1998 if he had symptoms of depression or anger in 1984, regardless of whether he had PTSD (Koenen et al. 2003). Combat-related lifetime PTSD is associated with increased current PTSD symptoms and a lower rate of remission among a group of 255 Hispanic and American Indian Vietnam veterans with PTSD. PTSD severity was greater in the 106 veterans who reported having had a traumatic experience associated with combat, 90% of whom were in combat units and the remaining veteran had served in roles related to combat such as medic or helicopter crews. The other 149 veterans had PTSD that was not related to combat experiences (Brinker et al. 2007). In 1996, Schnurr et al. (2000b) assessed 363 World War II veterans for PTSD. The veterans had participated in secret military tests during the war that exposed them to mustard gas (and lewisite). Even 50 years after the war, 32% of the veterans had mustard-gas-related PTSD. Risk factors that had the greatest impact on the development of PTSD were having physical symptoms during the test, seeing others in distress during the test, and being prohibited from disclosing participation in the test; having volunteered for the test lowered the risk of PTSD. Different combat-related traumas may result in different prominence of particular PTSD symptoms as manifestations of the disorder. For example, participation in atrocities might result in more avoidant symptoms, whereas heavy combat might result in more intrusive rather than avoidant symptoms (Yehuda et al. 1992b). Physical Injury Being wounded in combat significantly increases the risk of having current PTSD, regardless of the severity of the injury or the severity of the traumatic event that caused the injury (Koren et al. 2005). Veterans with injuries are at far greater the risk of PTSD than their noninjured counterparts (Gill et al. 2005; Koren et al. 2005; Kulka et al. 1990; Pitman et al. 1989). In a study of 13 Vietnam combat veterans who had been wounded and 21 who had not, of those who were wounded, only 1 had never had PTSD, 2 had PTSD that was in remission, and 10 (77%) had current PTSD, compared with 8, 7, and 6, respectively, of the nonwounded. Although the sample was small, the study suggests a strong association between being wounded

94 GULF WAR AND HEALTH and developing PTSD (Buydens-Branchey et al. 1990). Hoge et al. (2007) found that of 2863 OIF combat veterans surveyed a year after their return from Iraq, those who had been wounded or injured at least once were more than twice as likely to have PTSD as veterans who had never been wounded (31.8% vs 13.6%). Being wounded is also associated with increased risk of suicide in veterans. Bullman and Kang (1996) found a dose-response relationship between the number of times a Vietnam veteran was wounded in combat and the likelihood of suicide (see the Chapter 6 section on suicide for more details). Grieger et al. (2006) found that the prevalence of PTSD in combat-wounded soldiers increased with time. A month after their injury, 4.2% of the OEF and OIF soldiers screened positive for likelihood of PTSD, but PTSD likelihood increased to 12% at 7 months after injury. Lee et al. (1995) found that all the World War II men who were wounded in the war reported later symptoms of PTSD regardless of the level of combat to which they were exposed. It has been suggested that veterans with chronic physical disabilities as a result of war-related injuries have higher rates of PTSD, particularly chronic PTSD. The disability may serve as a constant reminder of the traumatic incident, possibly contributing to the likelihood of PTSD and its persistence (Friedman et al. 1994). NEUROBIOLOGY Most neurobiologic research in PTSD has concentrated on two systems critical for survival: the sympathetic nervous system and the hypothalamus-pituitary-adrenal (HPA) axis (as discussed in Chapter 4). This discussion of PTSD focuses on the noradrenergic system and the HPA axis, but it is important to emphasize that numerous neurobiologic systems—such as the serotonin system, the opiate system, and sex steroidal systems—are also involved in pathologic and protective responses to stress, although less is known about their involvement in the genesis of PTSD. Sympathetic Nervous System Alterations Findings from clinical physiologic, receptor-binding, and pharmacologic-challenge studies have provided evidence of noradrenergic hyperreactivity in traumatized people who have PTSD (Bremner et al. 1999; Pitman and Orr 1990; Southwick and Friedman 2001). The exaggerated activity is generally not present under baseline or resting conditions but is evident during stress, especially stress associated with traumatic reminders. Numerous psychophysiologic studies have documented heightened sympathetic nervous system arousal in combat veterans who suffer from PTSD (Orr et al. 1990; Prins et al. 1995). Trauma victims with PTSD respond with greater psychophysiologic reactivity (particularly heart rate) to trauma- relevant stimuli than do comparison groups, such as trauma victims without PTSD and nontraumatized controls. Some studies have reported a higher baseline resting heart rate in those with PTSD than in control groups, but most studies have found no differences (Pitman and Orr 1990; Prins et al. 1995). In addition, response to generic stressors has typically been the same in groups with and without PTSD (Pitman and Orr 1990). Thus, trauma survivors with PTSD appear to have normal resting sympathetic nervous system activity as reflected in heart rate and blood pressure that become abnormally reactive in response to specific reminders of a personally experienced trauma but not in response to generic stressors (Murburg et al. 1994; Prins et al. 1995).

POSTTRAUMATIC STRESS DISORDER 95 Biochemical correlates of the heightened sympathetic nervous system activation in veterans and civilians with PTSD include increased excretion of epinephrine and norepinephrine (Davidson and Baum 1986; Kosten et al. 1987; Yehuda et al. 1992a) and decreased numbers of alpha-2 adrenergic receptors on the surface of platelets (Perry 1994; Perry et al. 1987). As noted in Chapter 4, chronic increases in circulating epinephrine and norepinephrine may lead to a decrease in the number of adrenergic receptors. These increases in epinephrine and norepinephrine may not be present during resting states. However, it appears that PTSD subjects respond to a variety of stressors with greater increases in catecholamines than do healthy controls (McFall et al. 1990; Murburg et al. 1994; Southwick et al. 1995). Greater increases in epinephrine have been observed in veterans with war-related PTSD than in controls during and after viewing of a combat film but not in response to a film of an automobile accident (McFall et al. 1990). Auditory reminders of trauma have also been used as in vivo probes of noradrenergic responsivity in combat veterans with PTSD. In a study of 15 combat veterans with PTSD and 6 combat veterans without a mental disorder, Blanchard et al. (1991) sampled plasma norepinephrine before and after exposure to combat- related auditory stimuli. The PTSD group showed a 30% increase in plasma norepinephrine and heart rate in contrast with no change in the combat control group. Pharmacologic provocation studies have also revealed exaggerated catecholamine responses in patients with PTSD. To assess adrenergic responsivity of the peripheral and central nervous system more directly, yohimbine was administered to 20 Vietnam combat veterans with PTSD and 18 healthy controls (Southwick et al. 1993a). Yohimbine is an alpha-2 adrenergic receptor antagonist that activates noradrenergic neurons by blocking the alpha-2 adrenergic auto receptor, thereby increasing the release of endogenous norepinephrine. Yohimbine caused a marked increase in anxiety and PTSD-specific symptoms: 70% of combat veterans with PTSD experienced yohimbine-induced panic attacks, and 40% had flashbacks, but there were no panic attacks and only one flashback in the placebo group. Subjects with PTSD also had significantly greater increases in heart rate and more than twice the plasma 3-methoxy-4-hydroxy phenylglycol, which is a breakdown product of norepinephrine. In the Southwick et al. (1993a) study, the yohimbine-induced increase in catecholamine activity may have produced a biologic response that resembled the biologic state at the time when the traumatic memory was encoded, which then facilitated the retrieval of traumatic memories, a phenomenon known as “state- dependent recall.” Those findings suggest a dysfunction of the locus coeruleus-norepinephrine function in patients with PTSD. Interventions designed to suppress noradrenergic hyperreactivity directly in trauma survivors with PTSD have been limited to trials with the antiadrenergic agents clonidine (Kinzie and Leung 1989), guanfacine (Horrigan 1996), prazosin (Raskind et al. 2002), and propranolol (Pitman et al. 2002). Pitman et al. (2002), in a pilot study, administered propranolol to survivors of car accidents within 6 hours of the accidents. Although PTSD symptom scores 1 and 3 months after the trauma did not differ significantly between the two groups, the propranolol group at 3 months demonstrated significantly less psychophysiologic reactivity (in heart rate, skin conductance, and corrugator electromyography) to mental imagery that symbolized or resembled the index trauma. Positive results with propanolol have also been reported in accident victims who presented at an emergency room with tachycardia (Vaiva et al. 2003). Those preliminary studies with propranolol need replication, however, to determine whether it will be an effective treatment after trauma exposure to prevent PTSD. The propranolol results are consistent with data on healthy people. Southwick et al. (1993a) found a positive association between enhanced

96 GULF WAR AND HEALTH noradrenergic activity and enhanced long-term memory, and Cahill et al. (1994) reported that propranolol blocked enhanced memory of an arousing story. However, it is important to note that evidence has shown that propranolol can block extinction of fear-related memories (Cain et al. 2004). Taken together, the above evidence suggests that at least a subgroup of people with PTSD has increased responsivity of the sympathetic nervous system that is most clearly evident when people are restressed (Southwick et al. 1995). HPA-Axis Alterations That cortisol concentrations are increased during stress and that the magnitude of stress response is associated with the magnitude of increases in cortisol led to the hypothesis that cortisol would be increased in PTSD. However, the first report, 20 years ago, of cortisol in PTSD yielded counterintuitive results: the mean 24-hour urinary excretion of cortisol was lower in patients with PTSD than in other psychiatric patients (Mason et al. 1986). Ambiguity has persisted in the literature regarding the direction of any PTSD, associated change in cortisol concentrations as some investigators have reported increased urinary cortisol excretion in PTSD. Yehuda et al. (2002) noted that PTSD is associated with a dysregulation of the cortisol response rather than with a clear-cut directional response (cortisol that is “too low” or “too high”). Present evidence supports the hypothesis that pre-existing low cortisol is associated with increased risk of PTSD. Several recent studies have found that trauma victims who develop PTSD have lower initial cortisol responses to a traumatic event than do trauma victims who do not develop PTSD (McFarlane 1997; Resnick et al. 1997). In combat veterans with chronic PTSD, low plasma cortisol has been recorded throughout the day and night, especially in the early morning and late evening (Yehuda et al. 2002). Finally, in a randomized double-blind placebo-controlled study, Schelling et al. (2001, 2006) assessed the effect of hydrocortisone administered during septic shock. Physiologically stressful doses of hydrocortisone did have a moderately protective effect against PTSD. Receptor-binding studies have found higher numbers of glucocorticoid receptors in subjects with PTSD than in controls without PTSD (Yehuda 1997; Yehuda et al. 1995). As discussed in Chapter 4, an increased number of receptors would enhance sensitivity by providing more binding sites for cortisol. It is consistent with increased receptor number and sensitivity that subjects with PTSD hyperrrespond to administration of dexamethasone, a synthetic glucocorticoid that acts like cortisol (Yehuda 1997; Yehuda et al. 2004). Usually, when dexamethasone is administered to healthy people, it engages glucocorticoid receptors that serve as part of a negative feedback mechanism. When engaged, the receptors signal the hypothalamus and pituitary to decrease the release of corticotropin-releasing hormone (CRH) and corticotropin; this results in decreased stimulation of the adrenal gland and diminished release of endogenous cortisol. In several different populations of trauma survivors with PTSD, dexamethasone has had an exaggerated effect and endogenous cortisol release has been reduced to a greater degree than in healthy controls. The HPA-axis findings in PTSD differ markedly from findings in studies of major depressive disorder, in which cortisol tends to be increased, and the cortisol response to dexamethasone reduced. Additional findings in subjects with PTSD include increased CRH in cerebrospinal fluid (Baker et al. 1997; Bremner et al. 1997), blunted corticotropin response to CRH infusion (Smith et al. 1989), and increased corticotropin response to metyrapone (Yehuda et al. 2004). Those findings are consistent with studies in primates that have experienced early-life stress (Coplan et al. 1996). Animal data on the effects of a nonpeptide CRH receptor-1 antagonist (antalarmin)

POSTTRAUMATIC STRESS DISORDER 97 that penetrates the blood-brain barrier have shown that it blocks the development, consolidation, and expression of conditioned fear (Deak et al. 1999). Recent studies in rhesus monkeys showed that oral administration of antalarmin significantly inhibited stress-induced increases in plasma norepinephrine, cortisol, and anxiety-related behaviors (Habib et al. 2000). If applicable to humans, those data suggest that a CRH antagonist could be helpful after an acute traumatic event or in preventing harmful central nervous system changes that occur during chronic stress (Gold et al. 2005). In summary, most PTSD studies demonstrate alterations consistent with increased feedback inhibition of the HPA axis and increased CRH activity. The degree to which those abnormalities represent predisposing neurobiologic risk factors for PTSD rather than consequences of trauma or of living with PTSD is not clear (Yehuda et al. 2002). Fear Conditioning Several investigators have noted that the behavioral and physiologic responses of veterans with PTSD are similar to the effects of fear conditioning in animals (Kardiner and Spiegel 1947; Kolb 1987). Fear conditioning can be adaptive. A person who can anticipate a threat by responding to conditioned contextual cues can rapidly engage in appropriate defensive behaviors. Clinically, specific environmental stimuli may be linked to a traumatic event, a spontaneous panic attack, or an embarrassing social situation in such a way that exposure to a similar cue produces a recurrence of symptoms of anxiety and fear. For example, a Vietnam veteran may associate the smell of stir-fried pork with unpleasant memories of Vietnam or the sound of thunder with being in combat. Fear conditioning occurs outside conscious awareness (LeDoux 1996). For the Vietnam veteran, a formerly neutral stimulus has become frightening because it has been transformed into a fear-conditioned stimulus. Clinically, that means that a traumatized person, when exposed to a fear-conditioned cue, may become frightened, anxious, or irritable for reasons that he or she does not understand. Fear-conditioned responses, once they are established, can persist for long periods. Theoretically, once a conditioned fear stimulus is no longer associated with an aversive outcome, the conditioned fear response should extinguish. However, evidence in animals suggests that extinction is an active process that may involve new learning and that the old fear-conditioned association may persist indefinitely and under the right circumstances become reactivated (Bouton and Nelson 1994). In addition to the formation of vivid memories, patients with PTSD may fail to recover because fear is not extinguished after trauma. Most trauma survivors appear to respond with the re-experiencing, avoidance, and arousal symptoms of PTSD in the immediate aftermath of trauma. However, most of those fear reactions extinguish over time, and people do not develop chronic PTSD. Prospective studies indicate that those who recover from PTSD show a decrease in PTSD symptoms beginning soon after the trauma, but those who do not recover show a different pattern: their PTSD symptoms decrease in the first month after trauma but then remain fairly steady (Rothbaum et al. 1992); they do not worsen, but their original fear reactions are not extinguished to the extent found in non-PTSD people. People with PTSD do not seem to benefit from safety signals, such as the presence of a spouse, that potentially could help them to cope with painful fear memories (Herman 1992). An example might be a female rape victim who, before the rape, had a close, intimate relationship with her husband (a safety signal) but now feels unsafe with him and with other men. Similarly, despite the passage of many years and being in an environment very different from Vietnam, a war veteran’s fear can persist despite the presence of many potential safety signals, such as being

98 GULF WAR AND HEALTH in the United States instead of Vietnam, being in regular clothes instead of battle fatigues, and being back with loved ones. Thus, although a great deal is known about brain systems involved in fear generation, much less is known about brain systems involved in fear inhibition (extinction and safety signals). The need to understand the biologic mechanisms of fear inhibition is just beginning to be appreciated (Myers and Davis 2007). Startle Reflex Exaggerated startle reflex is commonly associated with PTSD. Metzger et al. (1999) in a meta-analysis of the eye-blink component of the startle reflex in PTSD, concluded that the weighted effect sizes across all 11 studies provide support for exaggerated startle as a symptom of PTSD. Eight of 11 of the studies found medium to large-sized effects for eye-blink electromyogram startle-response magnitude to acoustic stimuli. Studies included Vietnam and Gulf War combat veterans and victims of sexual assault and mixed trauma. In a comprehensive review of the startle reflex in PTSD, Grillon and Baas (2003) concluded that abnormalities of both a tonic and a phasic nature may exist in PTSD. They suggest that exposure to a traumatic event probably prompts a sensitization process that leads to an initial exaggerated startle. As the trauma becomes more distant in time, the enhanced startle response may gradually subside. The exaggerated startle response in patients with chronic PTSD may be a phasic symptom that is elicited by later trauma-related stimuli or by stressful environments and may involve different brain circuits over time. The amygdala may be involved in the early sensitization and in conditioned emotional responses (Hitchcock and Davis 1986; Hitchcock et al. 1989), whereas in chronic PTSD sufferers the exaggeration of startle in stressful contexts suggests that excessive release of CRH leads to involvement of the bed nucleus of the stria terminal (see Chapter 4). The most robust findings of exaggerated startle in PTSD are seen in patients with recent onset (within the preceding 5 years). The results in patients with chronic PTSD (onset more than 10 years earlier) are less clear. Vietnam veterans with chronic PTSD showed exaggerated startle response when assessed under stressful experimental conditions, but only one of the five studies that assessed the veterans with PTSD under nonstressful conditions found exaggerated startle response (Grillon and Baas 2003). Sleep Disturbances PTSD is characterized by trauma-related nightmares and sleep disturbance, which are often refractory to treatment (Friedman 2002; Ross et al. 1989; Taylor et al. 2007; Van Liempt et al. 2006). It has been hypothesized that increased noradrenergic function in the brain might contribute to PTSD-associated sleep symptoms (Mellman et al. 1995a). For example, increased noradrenergic activity could account for the abnormalities in rapid-eye-movement (REM) sleep in people with PTSD. The abnormalities include increased phasic motor activity, stage shifts, and arousal (Ross et al. 1994; Breslau et al. 2004), and REM fragmentation during early PTSD development (Mellman et al. 1995b). Furthermore, disruption in REM sleep could be related to nightmares (Mellman et al. 1995b, 2002) and the cognitive processing of traumatic events (Stickgold 2007). It is consistent with those findings that prazosin, an alpha-1 adrenergic antagonist, has been demonstrated to be an effective treatment for trauma nightmares and sleep disturbance in PTSD (Raskind et al. 2003, 2007; Taylor and Raskind 2002) by increasing total

POSTTRAUMATIC STRESS DISORDER 99 sleep time, REM sleep time, and REM-period duration (Taylor et al. 2007). See Chapter 6 for more discussion of PTSD and sleep disturbance. Neuroimaging Studies Neuroimaging studies have been used to identify the neural circuits that may be involved in the development of PTSD. Neuroimaging studies, using magnetic resonance imaging (MRI), of people with PTSD have focused primarily on the amygdala, the hippocampus, the medial prefrontal cortex, and the anterior cingulate cortex. Reduced hippocampal volume has been reported in a diverse population of adults with PTSD, both those with a history of childhood trauma and those who suffered trauma as adults. A recent neuroimaging study of identical twin children of veterans who had PTSD and reduced hippocampal volume found that the twin children also had reduced hippocampal volume despite having had no exposure to combat and no history of PTSD (Gilbertson et al. 2002). In some people, smaller hippocampal volumes may predate their trauma exposure and PTSD and be a risk factor for PTSD rather than a consequence of it. However, not all studies report smaller hippocampal findings in subjects with PTSD (Bonne et al. 2001), and the literature is ambiguous about whether PTSD is associated with reduced hippocampal volume in children (De Bellis et al. 2001). Recent studies suggest that traumatic stress in early development may have diffuse effects on total brain volume rather than only effects on hippocampal volume (De Bellis et al. 2002a,b). Possible explanations for discrepant findings on hippocampal volume in PTSD include variability in intensity and duration of trauma exposure, the presence of comorbid psychiatric disorders, differences in imaging methods (Vythilingam et al. 2005), and the lack of an effect of PTSD on hippocampal volume. Functional MRI studies that measure regional cerebral blood flow (rCBF) using cognitive activation models, script-driven imagery, or other methods that provoke PTSD re-experiencing symptoms have generally found exaggerated activation of the amygdala or reduced activation of the prefrontal cortex. The overactive amygdala may be receiving insufficient negative feedback from the anterior cingulate gyrus and the medial prefrontal cortex. Although most functional imaging studies have examined responses to threat- or trauma- relevant stimuli, it is also important to sort out how neural networks function in PTSD in the absence of threat-related stimuli. One study explored PTSD responses to a selective attention task that engages anterior cingulate cortex networks but in response to a nonthreatening stimulus. Bryant and Guthrie (2005) investigated whether anterior cingulate-amygdala dysregulation in PTSD was specific to processing threat-related stimuli or generalized to more generic, nonthreatening stimuli. They believe that their findings of enhanced anterior cingulate responses, and activation in the left amygdala and posterior parietal networks in response to nonthreatening stimuli, may reflect generalized hypervigilance. The nature and anatomic bases of attention and working-memory deficits in PTSD are also being studied with functional neuroimaging. With proton-emission tomography, working-memory deficits in PTSD have been found to be associated with reduced left dorsolateral prefrontal cortical activity (Clark et al. 2003). In summary, many structural MRI studies have found that decreased hippocampal volume is associated with PTSD in adults. In general, functional neuroimaging studies in trauma survivors with PTSD have reported exaggerated rCBF in the amygdala and other paralimbic regions and relative decreases in prefrontal cortical rCBF. Increased stress-induced activation of the amygdala in combination with reduced inhibition by the prefrontal cortex might leave a

100 GULF WAR AND HEALTH trauma survivor with an exaggerated and relatively unchecked amygdala-driven fight-or-flight stress response. CONCLUSIONS Characterized by symptoms of hyperarousal, numbing or avoidance, and re-experiencing of a traumatic event, PTSD may be evident shortly after exposure to the traumatic event or take years to produce symptoms sufficient to meet the diagnostic criteria; once developed, the symptoms may persist for many years. PTSD (or symptoms associated with it) has been reported in veterans from World War II, the Korean War, the Vietnam War, the Gulf War, and OEF and OIF. The prevalence of PTSD in the Vietnam War, Gulf War, and OEF and OIF have been estimated to be 14-19% (lifetime), 5-9% (lifetime), and 12-16% (current), respectively. Across a variety of precipitating events, women have twice the PTSD prevalence as men both in veteran populations and in the general population. In the general population, the prevalence of lifetime PTSD is estimated to be about 5% for men and 10% for women. The prevalence of PTSD in veterans increases as combat exposure increases, in some cases showing a linear dose-response relationship. PTSD is also highly comorbid with other psychiatric disorders, particularly major depression, general anxiety disorder, and substance-use disorders. PTSD is also associated with more disability and impaired functioning in veterans. Although military personnel may be exposed to identical stressors during their deployment to a war zone, their short-term and long-term responses to those stressors vary. The variation is due to a host of individual risk and protective factors that influence the likelihood of long-term health effects after exposure. The committee found that among the most significant risk factors for PTSD or other psychiatric disorders are being in combat and being physically wounded. Other important risk factors include childhood maltreatment, the presence of a pre- existing psychiatric disorder, poor social support on homecoming, negative coping styles, being a minority, and a lack of hardiness. Protective factors include better education, higher military rank, having a stable family life, and having a sense of control. Research has shown heightened sympathetic nervous system activation in people with PTSD, which includes increased excretion of epinephrine and norepinephrine. PTSD subjects respond to a variety of stressors with greater increases in catecholamines than do healthy controls. Pre-existing low cortisol is associated with increased risk of PTSD, and most PTSD studies demonstrate physiologic alterations consistent with enhanced feedback inhibition of the HPA axis and increased HPA reactivity. PTSD has also been associated with a lack of fear extinction after trauma. REFERENCES Aldwin CM, Levenson MR, Spiro A 3rd. 1994. Vulnerability and resilience to combat exposure: Can stress have lifelong effects? Psychology and Aging 9(1):34-44. APA (American Psychiatric Association). 2000. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric Publishing Association.

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Gulf War and Health: Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress Get This Book
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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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