Michael J. ROY, MD, MPH1, and Patricia L. KRAUS. Division of Military Internal Medicine, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
Abstract. Posttraumatic stress disorder (PTSD) is a frequent and debilitating consequence of exposure to war and other life-threatening events. PTSD often goes undiagnosed and even when it is diagnosed; treatment is all too often inadequate or ineffective. It is imperative to identify more effective diagnostic and therapeutic approaches. We discuss currently available screening and treatment measures, and present approaches we are planning to try to improve each of these modalities.
Keywords: Posttraumatic stress disorder, combat stress, depression, pharmacotherapy, virtual reality, behavioral therapy
Posttraumatic stress disorder (PTSD) became part of our lexicon in the aftermath of the Vietnam War, but the symptoms and associated functional impairment it represents have been known for centuries. Perhaps Cain was the first to suffer the torment of this disorder, and Homer certainly depicts its symptoms in his account of Achilles in The Iliad. More recently, the medical literature has featured hundreds of accounts from the American Civil War, both World Wars, and other national and international conflicts. Authors identify myriad physical and psychological symptoms that escape efforts to ascribe them to specific environmental factors, but are linked to the stress of war. PTSD is also well documented in many victims of terrorism, genocide and personal assaults such as rape. An estimated 10,000 Croatian Homeland War veterans (15% prevalence) have PTSD, with an alarmingly high suicide rate. The current conflict in Iraq, involving snipers and suicide bombings, as
Corresponding Author: LTC Michael Roy. Department of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, A3062, Bethesda, MD, 20814 USA. Telephone: (301) 295-9601; Fax: (301) 295-3557; Email: [email protected].
well as concerns about prisoner mistreatment, is a recipe for PTSD. This provides an opportunity to improve the care of combat veterans while defining optimal diagnostic and therapeutic approaches.
The first large study of American troops returning from duty in Iraq, conducted by Hoge et al., documented a rate of 12.9% meeting a strict case definition and 18% meeting a more broad definition of PTSD . Subsequent evaluations of injured soldiers receiving care at Walter Reed Army Medical Center have indicated that initial screens may miss as many as 70% of those who meet criteria within 6 months, indicating both high rates and the need for repeated screening. Early experience with veterans of the Iraq conflict also underscores the high prevalence of other psychiatric disorders after all are common after such experiences, with nearly 30% of those surveyed by Hoge et al. meeting criteria for some mood or anxiety disorder. In addition, rates of alcohol and substance abuse have been found to be higher in individuals diagnosed with PTSD. In patients with PTSD, one national study identified a lifetime history of at least one other psychiatric disorder in 88% of men and 79% of women with PTSD , underscoring the importance of screening for more than just PTSD. The PRIME-MD is a particularly useful validated instrument that screens for depression, panic and other anxiety disorders, eating disorders, somatoform disorders, and alcoholism .
PTSD is not solely associated with war, but has also been identified as a common reaction to traumatic events ranging from personal assaults such as rape or mugging to life-threatening acute medical conditions. Briefly, PTSD is characterized by symptoms that can be divided into three categories, which persist for at least one month, following a threatening event that initially elicited fear, helplessness, or horror. The first category covers symptoms of re-experiencing the event, including intrusive thoughts, recurrent dreams, flashbacks, and physiologic changes induced by stimuli reminiscent of the event. The second category includes manifestations of avoidance of stimuli associated with the trauma, such as avoiding activities, places, thoughts or feelings related in any way to the trauma, inability to recall an important aspect of the trauma, anhedonia, detachment from others, restricted range of affect, and a sense of a foreshortened future. The final category incorporates symptoms of increased arousal, such as insomnia, irritability, impaired concentration, hyper-vigilance, and an exaggerated startle response. In the general population, while a history of some traumatic exposure is more likely than not, PTSD has an estimated point prevalence of 2-5%, a lifetime prevalence of 8-12% and higher yet in combat veterans [2, 4-12]. The current environment in Iraq is likely to result in particularly high rates of PTSD. It often goes undiagnosed for months or years; consequently effective treatment is not provided. PTSD is associated with high rates of depression and other psychological conditions, poorer physical health, missing work, impaired function at work and at home, and significantly higher healthcare costs. Rapid diagnosis could enhance individual function and military readiness. PTSD is associated with increased somatic complaints, making it even more likely that someone with PTSD
will seek the help of their primary care physician, so that the prevalence of PTSD in primary care is undoubtedly significantly higher than in the general population. Recent studies in primary care found that 9-12% of patients met criteria for PTSD [7-8]. Samson et al. identified PTSD in 38.6% of patients who were referred by their primary care providers for mental health services based on suspicion of depression or anxiety . However, like most mental disorders, PTSD often goes undiagnosed in primary care, and such patients are frequently not referred to mental health. Several studies have examined the likelihood of developing PTSD after a traumatic event, and estimates that combine all stressors range from 9.2% to 25% [2, 8-10, 12]. Terrorist events have been shown to result in markedly elevated rates of PTSD. After terrorists released the nerve agent sarin in a Tokyo subway, 60% of those who presented for medical care after the incident had symptoms of PTSD that persisted at least 6 months, even though most did not have evidence of physical exposure to sarin . In fact, PTSD not uncommonly results in those not directly exposed to the event, as evidenced by the 7.5% of Manhattan residents (including 20% of those living near the World Trade Center) meeting criteria for PTSD 5-8 weeks after September 11, 2001. Moreover, 44% of adults outside of New York City reported substantial symptoms of distress 3-5 days after 9/11/01 . Wartime deployment is also associated with high rates of PTSD—we identified PTSD in 83 of 651 (12.7%) veterans of Operation Desert Shield/Desert Storm, upon completion of evaluation at Walter Reed Army Medical Center 4-6 years after their deployment, consistent with other reports [16-17]. PTSD is in turn associated with noticeably higher rates of depression and other psychological conditions, poorer physical health, missing work, impaired function at work and at home, and significantly higher healthcare costs [18-21]. Subthreshold PTSD, represented by the multiple symptoms but failure to meet strict criteria for the full disorder, has been reported to have at least an equal, if not greater, prevalence compared to full PTSD, and has also been shown to be associated with significant disability [6,11].
2. Screening Instruments
2.1 A model: The PHQ-9 for Depression
The under-diagnosis, comorbidities, somatic complaints, functional impairment, and health care utilization described for PTSD are also characteristic of depression. The PHQ-9 (Patient Health Questionnaire) is a 9-item screen for depression that has been validated in 3000 primary care and 3000 obstetrics and gynecology patients . The PHQ-9, included in Appendix B, consists of nine questions taken directly from the DSM-IV criteria for major depression. A score is given for each of the 9 responses, based upon whether the symptom bothered the individual not at all (0), for several days (1), more than half the days (2), or nearly every day (3), in recent weeks. A composite score can then be generated, with a range from 0 to 27; the scores have been shown to correlate with the severity of depression, as well as the frequency of physician visits, and measures of functional status. The PHQ-9 has been shown to identify about twice as many cases as primary care physicians were able to diagnose on their own. Using a cut-off score of 10 to diagnose depression, the PHQ-9 has a sensitivity and specificity of 88% each . The scores can be used not only to make an initial diagnosis of depression, but also, upon re-administration of the questionnaire, to monitor the response to therapy, to determine whether an individual patient is satisfactorily responding to treatment or not. In this way, the PHQ-9 provides an invaluable tool for the primary care physician, who has long had effective monitoring measures for other chronic diseases that are frequently encountered: hypertension (blood pressure cuff), diabetes mellitus (hemoglobin A1C), and hyperlipidemia (LDL). Prior to the PHQ-9, there was not such an instrument for depression, rendering diagnosis more difficult, with numerous studies indicating that depression was missed about half the time in a primary care setting.
The PHQ-9 fulfills ideal criteria for a screening instrument. It is quick, inexpensive, easy to administer, is well validated, with relatively high accuracy, can educate patients in providers with regard to criteria for the diagnosis, can be used to follow progress over time, and there is also some evidence that its use is associated with improved prognosis.
Numerous screens for PTSD have been previously developed. However, most are complex and time-consuming. A previous review of available instruments found that nearly all did not have well-established validity and reliability. Of those with some evidence of validity, it has generally not been demonstrated across both combat veteran and civilian populations. Since the time of that review, two instruments have become popular. The first is the Clinician-Administered PTSD Scale (CAPS), which is 17 pages long, must be administered by a professional, and features detailed instructions and complex scoring . The CAPS has become the gold standard instrument for the diagnosis of PTSD in the research setting, with a recent review confirming strong validity and documenting its use in more than 200 studies . However, it is not a practical instrument for use in a high-volume, rapid turnover setting, whether the primary care physician's office, or with combat veterans returning from deployment and eager to be reunited with their families. Efforts to use the CAPS to follow response to treatment have also proven more problematic . The other widely used instrument is the PTSD Checklist (PCL), a 17-item screen, which can be self-administered, having the advantages of rapid completion, little expenditure of professional time in administration, and relatively simple scoring. Although it compared favorably with the CAPS for initial diagnosis of PTSD in combat veterans, it was less effective in assessing response to treatment . Unfortunately, it also fared poorly in the only study to assess its utility in primary care, with a sensitivity of 32% , and while using a lower threshold score would improve the sensitivity, the PCL still may not be very useful to primary care physicians trying to diagnose this enigmatic condition. Since our experience with the PHQ-9 at Walter Reed has been overwhelmingly positive, as a site for its initial validation as well as a site where it is used on a regular basis to screen primary care patients, we chose to develop a PTSD screen patterned after the PHQ-9. Like the PHQ-9, it is comprised of questions taken directly from DSM-IV criteria for the disorder being screened for, and each is then scored on a scale from 0-3 based on the self-reported frequency of the feature. We seek to compare the efficacy of this instrument, as well as other available brief screens, in comparison to the more cumbersome, but gold-standard, CAPS. Since it has twelve questions, we have given our new instrument the appellation of PTSD-12.
Over the past decade, selective serotonin reuptake inhibitors (SSRIs) such as sertraline, fluoxetine and paroxetine have been shown to be superior to placebo in the treatment of PTSD [27-28], as well as in preventing relapse if they are continued after achieving a clinical response . SSRIs improve the quality of life of those with PTSD in multiple domains, improve functional status, decrease symptom severity, and reduce vulnerability to stress. In addition, non-pharmacologic therapies such as cognitive behavioral therapy (CBT) and exposure therapy have also shown efficacy, and probably have a greater duration of response in the absence of ongoing treatment [30-32]. CBT corrects irrational beliefs and thoughts and promotes rational behavioral changes, while exposure therapy helps individuals to confront stimuli associated with their traumatic experience through progressively more intense exposure, to identify and neutralize behavioral cues. Exposure therapy appears to be most useful when employed within the context of CBT. A recent Cochrane review demonstrated that CBT/exposure therapy had clear superiority over usual care and other psychological therapies such as supportive therapy and psychodynamic therapy . While the identification of effective therapies for PTSD is good news, the downside is that sizeable numbers of those with PTSD have an inadequate response. Overall, it appears that pharmacotherapy results have a response rate of 40-60%, and non-pharmacologic approaches are not appreciably better.
We postulate that a combination of pharmacologic and non-pharmacologic therapies should prove superior to either alone. This hypothesis has not yet been adequately tested, and it is important to do so, as the possibility that one form of therapy might interfere with the other can not be rejected out of hand. Functional magnetic resonance imaging (fMRI) or some other objective measure of the effect on neural pathways might be a particularly valuable measure to incorporate in such studies, to assess the interaction, if any, between the two different approaches.
Virtual reality (VR) is a form of exposure therapy with particularly high potential. In recent years, virtual reality technology has been utilized to help patients overcome phobias (e.g., claustrophobia , fear of flying , fear of heights , fear of spiders [37-38], and fear of driving after an automobile accident  ), as well as for anxiety disorders  and PTSD. In the latter case, small numbers of Vietnam War veterans  and World Trade Center survivors [42-43] have each been reported to improve through the use of progressively more realistic and intense virtual reality exposures. Imaginal exposure therapy has been found to be effective in multiple clinical trials, and expert consensus treatment guidelines published in 2000 characterized it as the non-pharmacologic treatment of choice , but it is only recently that technology has reached the point where virtual reality has reached sufficient quality to make it a realistic manner of administering this form of therapy.
While both exposure therapy and pharmacotherapy are effective treatment for PTSD, there are still significant numbers of patients who will not respond to one or the other. No study has previously examined both types of therapy combined, but given the diversity of the alternatives, it is reasonable to consider that combination therapy may result in a higher response rate than either therapy alone. On the other hand, the fact that each form of therapy has demonstrated superiority to placebo makes it unethical to include a pure placebo arm. Prior studies with both pharmacotherapy and desensitization therapy suggest that patients with PTSD are more sensitive than those with other psychiatric disorders, so that medication should be started at a low dose and gradually increased. Starting with too high a dose, even though such a starting dose might be appropriate for a condition such as depression, may exacerbate anxiety and lead to discontinuation of the therapy. Similarly, desensitization is most likely to be successful if started slowly, with most of the successful studies taking this approach; however, there is less experience with desensitization, and some believe efficacy may be greater with relatively intense exposure early in the course of treatment.
We have assembled an experienced team of experts on both sides of the Atlantic to conduct a randomized controlled trial assessing the efficacy of combined pharmacotherapy and CBT/VR exposure therapy vs. mono-therapy. The study will be carried out at both Uniformed Services University in the Washington, DC area, and the University of Zagreb in Croatia, in order to facilitate treatment of both recent American veterans from the Iraq and Afghanistan theaters, as well as veterans of the Croatian Homeland war with PTSD of longer duration. Inclusion of the diverse study populations will facilitate generalizability of results.
In a relatively short period of time, PTSD has been clearly identified and delineated, and effective treatment has been established. Simple approaches may improve diagnostic rates, and new technologies have the potential to significantly enhance the efficacy of treatment further. In an increasingly complex world, the likelihood of exposure to life-threatening disasters is greater than ever, and medical science must keep pace.
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