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Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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9

Research on PTSD

Ahigh-performing system for posttraumatic stress disorder (PTSD) management identifies and effectively applies research findings on prevention, assessment, diagnosis, and treatment to provide optimal care. Other attributes of a high-performing system are fostering new research on innovative approaches for PTSD management; expediting translation of new research findings to people who have PTSD and to their health care settings; striving to anticipate future research directions to address knowledge gaps; and exploring new ways to reduce stigma and promote access to and dissemination of evidence-based treatment. In its phase 1 report, the committee presented an overview of the current knowledge base on PTSD prevention, assessment, diagnosis, and treatment, including comorbidities and rehabilitation. This chapter reviews the research portfolios of the Department of Defense (DoD), the Department of Veterans Affairs (VA), and the National Institutes of Health (NIH) to assess specifically how science is fostered and what research is being conducted. The chapter ends with a discussion of the challenges to translating research into practice and a discussion of leveraging technology to improve access to and delivery of PTSD care.

FOSTERING RESEARCH

Conducting basic science, clinical, and health-management research requires an environment that can provide knowledgeable investigators with sufficient resources, a collaborative organizational structure, and innovative and forward-thinking leadership. Some of the ways in which DoD

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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and VA (and to some extent NIH) have fostered PTSD-related research are establishing clear mission statements for research, investing in the research, establishing an action plan, learning how to translate research into practice, and supporting innovation in technology.

Research Missions in DoD, VA, and NIH

DoD, VA, and NIH all conduct or support PTSD research and they have distinct but complementary research missions (Castro et al., 2013). DoD relies to some extent on the expertise and infrastructure of VA and NIH for research in PTSD prevention and treatment interventions. Research in VA tends to be focused on the long-term health of veterans. Its infrastructure can support and leverage clinical trials and epidemiological studies, and it has the capability to translate research findings into clinical care. DoD and VA collaboration in research has increased in recent years; examples include the National Research Action Plan for Improving Access to Mental Health Services for Veterans, Service Members, and Military Families and a research collaboration guidebook, which was created to foster cooperation between DoD and VA investigators in human subjects health care research (VA and DoD, 2013). PTSD research in NIH includes basic and clinical research, funded primarily through the National Institute of Mental Health (NIMH). Results of such basic and clinical research can be used to inform PTSD prevention, diagnosis, and treatment.

Although this chapter focuses on PTSD research funded by DoD, VA, and NIH, the pharmaceutical industry invests in new medications to treat for PTSD, although that investment has declined in recent years (DoD et al., 2013). There are also private efforts by foundations and other organizations to improve care of people who have PTSD. Numerous large centers, consortia, and collaborations funded by DoD, VA, and others, such as the South Texas Research Organizational Network Guiding Studies on Trauma and Resilience, are working toward a better understanding of PTSD prevention, pathogenesis, and treatment. More detailed information on some of those centers, consortiums, and collaborations can be found in Appendix D.

National Research Action Plan for Improving Access to Mental Health Services for Veterans, Service Members, and Military Families

On August 31, 2012, President Obama issued Executive Order 13625, which directs DoD, VA, the Department of Health and Human Services, the Department of Education, and the Department of Homeland Security to “take steps to meet the current and future demand for mental health and substance abuse treatment services for veterans, service members, and their families.” In response, those departments developed a national research

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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action plan in August 2013, which was organized around an interagency research continuum framework. For each component of the continuum—foundational science, epidemiology, etiology, prevention and screening, treatment, follow-up care, and services research—the interagency group was to undertake a gap analysis and identify short-term, mid-term, and long-term research needs to improve the prevention and diagnosis of and treatment for PTSD in service members and veterans (Castro et al., 2013; DoD et al., 2013). The research plan also considers comorbid conditions as appropriate.

As part of the National Research Action Plan, DoD, VA, and NIH have identified several PTSD research goals (Castro et al., 2013). They also identified several cross-cutting actions to increase transparency and communication among the departments (DoD et al., 2013). For example, “a new commitment will be to move the DoD’s medical research into the NIH Research Portfolio Online Reporting Tools via Electronic Research Administration Commons” (DoD et al., 2013). The committee believes that such a move will increase the transparency of mental health and other research being funded by DoD. The committee commends DoD, VA, and NIH for the thorough review they are undertaking, and it agrees with the gaps and future research goals the departments have identified.

Recent Funding for Mental Health and PTSD Research

Since 2007, DoD has invested $771 million in more than 453 mental health research studies. Of that investment, 60% supports PTSD research, 12% resilience research, 9% family-related research, and the remainder other types of mental health research (Miller, 2014). Since 2009, VA has invested $556.6 million in mental health research1 (see Table 9-1), and its funding of PTSD research has remained steady at around $30 million per year over the past 5 years. However, as a percentage of VA’s mental health research budget, PTSD research funding has decreased from a peak of 32.4% in 2010 to 24.6% in 2013 (Gleason, 2012), despite marked increases in the prevalence and incidence of PTSD in veterans who seek care in VA, as described in Chapter 2.

In 2011, DoD had 162 active PTSD studies for a total investment of $297.4 million (Defense Health Program and VA, 2011). The greatest funding that year went to treatment (40.0%), basic science (27.6%), and

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1 This funding supports research, equipment (typically Year 1 investment), salaries for nonclinical primary investigators, and VA administrative overhead (Gleason, 2012). It does not support research administration at VA medical centers, clinician primary investigator salaries (which are supported by medical care appropriation), animal facility support, research supported by non–Office of Research funding, or research system infrastructure (Gleason, 2012).

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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TABLE 9-1 VA Funding Amounts for Mental Health Research and PTSD

Year Mental Health Research (million) PTSD Research (million)
2009 $92.0 $27.6 (30.0%)
2010 $105.6 $34.2 (32.4%)
2011 $121.7 $36.4 (29.9%)
2012 $115.3 $30.8 (26.7%)
2013 $122.0 $30.0 (24.6%)

SOURCE: Data are from Gleason, 2013.

resilience (17.9%). In 2011, VA had 130 active studies on PTSD for a total investment of $155.4 million (Defense Health Program and VA, 2011). The greatest funding went to treatment (42.3%), epidemiology (25.1%), and basic science (17.1%). Those research priorities reflect DoD and VA efforts to understand, prevent, and treat for PTSD in service members and veterans who are exposed to traumatic events.

COMMITTEE’S SUMMARY OF CURRENT RESEARCH ON PTSD

In the committee’s statement of task, it was asked to “consider the status of studies and clinical trials involving innovative treatments for PTSD that are conducted by DoD, VA, or the private sector,” particularly physiological markers, causation, alternative therapies, and the use of pharmaceutical agents to prevent and treat PTSD (see Chapter 1, Box 1-1). The committee was also asked to provide recommendations for future PTSD research. This section presents an overview of PTSD research that is funded by DoD, VA, NIH, and other organizations. The categories of research in this chapter are based on the structure of the committee’s phase 1 report (IOM, 2012).

To identify PTSD research projects, the committee looked at several publicly available research databases. The committee limited its review to studies in adult populations and those on mechanisms, screening, diagnosis, treatment, or barriers related to PTSD in service members and veterans. Studies were excluded if they were specific to traumatic brain injury (TBI), caregiver support, or insomnia, chronic pain, and unexplained illnesses in veterans. The remaining studies were categorized into broad topic areas (see Table 9-2). Studies in each category were enumerated by funding agency and summarized to identify gaps and overlaps in the research. The following databases provided most of the research information:

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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  • The NIH Research Portfolio Online Reporting Tools (RePORT) database (http://report.nih.gov) contains intramural and extramural research funded by NIH, the Centers for Disease Control and Prevention, the Agency for Healthcare Research and Quality, the Health Resources and Services Administration, the Substance Abuse and Mental Health Services Administration, and VA. The RePORT database was searched on June 6, 2012, using the term PTSD for all active projects. The committee recognizes that this database is not static and that new projects may have been funded since June 2012.
  • The VA Health Services Research and Development database “pursues research that underscores all aspects of VA healthcare: patient care, care delivery, health outcomes, cost, and quality” (VA, 2011). The database was searched for all studies that were active during 2007−2012, on November 15, 2012, using the term PTSD.
  • The ClinicalTrials.gov database includes information about interventional and observational medical studies in human volunteers. Although it does not include all clinical trials conducted in the United States, it does contain the majority of federally and privately funded studies conducted under investigational new drug applications. The database search was conducted on August 27, 2013, using the term PTSD. Studies were eliminated if they were completed or expected to be completed before 2011, or were withdrawn.

The committee also obtained from DoD a list of PTSD studies it funded2 because, unlike VA and NIH, it does not have a publicly available database of studies.

Table 9-2 gives an overview of the research categories used by the committee and the number of funded studies in each category. The committee then provides a broad description of why each research category in this chapter is important for understanding and treating for PTSD in DoD and VA. It also provides a general summary of the ongoing research from the NIH RePORT database, the VA Health Services Research and Development database, the ClinicalTrials.gov database, and the information provided by DoD. Because the research is ongoing and not yet published (in most cases), citations could not be provided for some of the summaries below. More detailed descriptions of the ongoing studies reviewed by the committee are given in Appendix E. The level of detail provided in each of the research categories below and in Appendix E are variable and reflect the number

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2 A list of these studies can be obtained by contacting the National Academies Public Access Records Office.

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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TABLE 9-2 Research Categories and Targets a

  Number of Studies Identified in Searches
Research Category DoD VA NIMH Other NIH Institutes Other Organizationsb
Physiology, Neurobiology, and Behavior 40 18 134 32 23
Understand the process from trauma to exposure to PTSD; identify early markers of the development of PTSD after trauma; understand genomic changes associated with PTSD; identify differential responses to treatment; and establish preclinical studies of new pharmacotherapies.
Prevention 21 9 18 4 8
Identify factors that promote or prevent the development of PTSD and interventions that may minimize PTSD after trauma.
Screening 4 5 3 0 0
Understand the effectiveness and accuracy of screening and whether screening is associated with better PTSD outcomes.
Diagnosis and Determining Symptom Severity 5 5 1 0 0
Identify accurate and effective methods to diagnose PTSD and to determine symptom severity.
Treatment 78 101 31 26 104
Identify and understand effective pharmacotherapies, somatic treatments, psychotherapies, and treatments that combine psychotherapies and pharmacotherapies; complementary and
Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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alternative medicine; models for the delivery of PTSD care; different modalities for treatment interventions; treatments tailored to specific gender or racial groups; and treatments for PTSD in parallel with comorbidities.
Barriers 10 37 5 2 0
Individual, family, provider, and institutional barriers to the delivery of high-quality, evidence-based care; barriers to integrating findings from basic research into new treatments and clinical practice; and barriers to research or administrative reviews on the particularities of military culture, operational tempo, and institutional processes.
Long-Term Outcomes Associated with PTSD 9 10 4 5 0
Understand long-term health outcomes and the development of comorbidities such as cardiovascular disease in people diagnosed with PTSD.
Intimate Partner Violence 0 4 2 2 1
Understand risks for intimate partner violence or interpersonal violence in people diagnosed with PTSD.
Training 6 3 17 8 3
Training providers to improve the diagnosis and treatment of PTSD and research or training grants for career development.

aThis table represents the committee’s search of NIH RePORT, HSR&D, ClinicalTrials.gov, and research studies provided by DoD. Some studies could have been considered under multiple categories but were counted only in the most relevant category to avoid an overestimation of studies. There were also numerous studies that were funded by more than one organization. The committee tried to identify the main funding source so that the study would only be counted once in the table, but this was not always possible and some studies, particularly studies funded jointly by DoD and VA, were counted twice. Because of these caveats, Table 9-2 may underestimate the number of studies under each category or funding source, especially for DoD-, VA-, and NIH-funded research.

bIncludes international organizations, U.S. universities, hospitals, nonprofits, and pharmaceutical companies.

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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of studies and the level of information the committee was able to obtain about those studies.

The database information was variable and there were limitations to the committee’s review of the research. For example, some of the research descriptions had details on the study population, methodology, and even preliminary results, whereas others had only a title and a brief description of the goals and objectives of the study. The databases also varied in how costs and funding information were presented, so the number of studies in each funding column in Table 9-2 may be underestimated. In some cases, it was difficult to determine who was funding a particular study. The table does not reflect ongoing collaborations. Thus, the table should be considered as a general representation of currently or recently funded PTSD research.

Physiology, Neurobiology, and Behavior

As detailed extensively in the committee’s phase 1 report (IOM, 2012), the neurobiology of emotion and defensive responses to fear, anxiety, avoidance, and reward has been extensively investigated for several decades (Charney, 2003; Garakani et al., 2006; Hammack et al., 2012; Hartley and Phelps, 2010; Lanius et al., 2011; Martin et al., 2009; McTeague and Lang, 2012; Quirk at al., 2006). One reason is a desire to understand the brain–behavior interactions from a basic neuroscience perspective. Another is a desire to advance knowledge of the psychopathology of anxiety and mood disorders in general and of PTSD in particular. DoD, VA, and NIMH have set priorities for funding in these topics to elucidate the mechanistic underpinnings of the pathophysiology of fear and anxiety that are commonly observed in people who have PTSD. Some of the research reviewed by the committee is summarized below with a discussion of its relevance to PTSD psychopathology and treatment. The committee notes that other emotions, such as shame and guilt, frequently accompany a diagnosis of PTSD (Lee et al., 2001; Urlic and Simunkovic, 2009; Wilson et al., 2006); these social emotions may play a role in PTSD etiology and persistence and are not necessarily modeled or captured in existing experimental models and paradigms that focus on fear and anxiety.

Mechanistic Research

Understanding the psychological and neurobiological mechanisms by which traumatic experiences result in maladaptive emotional and threat responses is fundamental to basic research and of the translation of research on PTSD (see the section “Translating Research into Practice”). That understanding has been approached from a number of perspectives, from

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
×

cellular to cognitive to cultural (Feodorova and Saragian, 2012; Martin et al., 2009; Quirk et al., 2006; Schafe et al., 2001; Zovkic and Sweatt, 2013). Given that PTSD is triggered by experience and is commonly viewed as a disorder that emerges with an inability to cope with or recover from the aftermath of the trauma (Shvil et al., 2013), the primary focus of basic research has been the neurobiology and psychology of emotional learning and memory (Cahill, 1997; Hartley and Phelps, 2010; Kim and Jung, 2006; Maren, 2001; Milad and Quirk, 2012; Pitman et al., 2012; Rudy et al., 2004; Zovkic and Sweatt, 2013). Some people diagnosed with PTSD overgeneralize their fears and exhibit substantial avoidance symptoms, so animal research on passive and active avoidance is helpful. Overgeneralization is another research area that is very active (Dunsmoor et al., 2011; Lissek, 2012). The mechanisms of action by which some experiences can change neural networks are of the utmost importance for understanding the development and persistence of PTSD.

On the cellular level, one approach to understanding mechanisms of action is to study how different types of receptors interact with their ligands to mediate memory formation under normal physiological conditions. That knowledge can inform how malfunction or modification of cellular mechanisms could lead to changes in memory formation that may be relevant to the pathophysiology of PTSD. Over the last several decades, research has generated a wealth of knowledge about the processes by which learning and memory lead to the activation of several types of receptors; this activation triggers intracellular cascades that result in the activation of gene transcription and translation and causes synthesis of new proteins and modification of synaptic connections between neurons (Andero and Ressler, 2012; Gunduz-Cinar et al., 2013; Hauger et al., 2012; Johansen et al., 2011; Lutz, 2007; Shekhar et al., 2005). That line of research has helped to identify some cellular targets that may play a role in the pathophysiology of PTSD, such as corticotrophin-releasing factor, brain-derived neurotrophic factor (BDNF), and N-methyl-D-aspartate receptors. A recent study by Pace et al. (2012) found increased activity of nuclear factor kappa-light-chain-enhancer of activated B cells in women who have PTSD arising from childhood abuse, suggests an enhanced inflammatory system and decreased immune cell glucocorticoid sensitivity. New and promising work in preclinical neuroscience reviewed by the committee includes research to understand BDNF and its receptors (tyrosine receptor kinase B and some potential new targets such as neuropeptide Y and neurosteroids.

Building on the foundation of the cellular and molecular mechanisms of memory requires an understanding of the diverse and interacting brain systems and psychological processes that support adaptive and maladaptive memory formation and expression. One fundamental principle is that several kinds of memory make up distinct brain circuits, each having unique

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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characteristics. For instance, different memory systems support the conscious retrieval of episodes, habitual actions, and physiological defensive reactions (Luethi et al., 2009). Preliminary research suggests that the impact of trauma and stress on learning and memory depends on the type of memory assessed. One important topic that has not been investigated extensively is how different types of memory systems interact. Given that PTSD is characterized by intrusive and habitual episodic memory retrieval accompanied by heightened learned threat responses and physiological arousal, this might be an important avenue for future research.

Cellular and brain systems that support learning and memory have the potential to elucidate mechanisms of memory storage (consolidation) and restorage (reconsolidation). Traumatic events that result in PTSD could be conceptualized as resulting in memories that are over-consolidated. Knowing how that works, whether and how memories are retained in the absence of retrieval, and how memories are reconsolidated after retrieval are critical for understanding PTSD and could lead to new interventions. Traditional research on learning and memory has focused on memory encoding and retrieval, not the storage process itself, which is a promising topic.

Current nonpharmacological approaches to treating PTSD are based largely on controlling fear through either cognitive regulation or through exposure and extinction (Bisson et al., 2013; Rachamin et al., 2009). Initial studies of fear conditioning and extinction focused on fear learning because patients who have PTSD may overconsolidate traumatic memories (Pitman et al., 1989). However, recent studies suggest that over consolidation of fear memories may not be evident in PTSD—at least using de novo fear conditioning and extinction paradigms—and the extinction of conditioned fear memories may be deficient in PTSD patients (Milad et al., 2008, 2009). Although exploring means to enhance those techniques is useful, the committee identified relatively few ongoing studies of the mechanisms of fear resilience or fear-control techniques beyond extinction or cognitive regulation. In addition, the committee found little research on the relationship between the stress–hypothalamic pituitary axis response and the mechanisms of emotion and fear control. Those mechanisms are inherently intertwined in PTSD, so understanding their interactions is important and research on this topic should be expanded. Although an understanding of basic general psychological and neurobiological principles underlying the development and persistence of PTSD is clinically important, this research cannot be adequately translated into treatment and prevention unless it is known how the mechanisms interact with individual characteristics. For example, an important variability factor for PTSD is sex differences. The incidence of some anxiety and mood disorders is twice as high in women (Kinrys and Wygant, 2005), who seem to have symptoms for longer periods and poorer prognoses compared with men (Breslau et al., 1998; Seedat et

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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al., 2005). Despite these epidemiological data, relatively little is known about how sex differences may impact the underlying neurobiology and psychology of PTSD. In healthy humans and in clinical populations, studies do not generally exclude women, even if the differences between males and females are not fully explored or characterized (Lebron-Milad and Milad, 2012). However, the vast majority of PTSD-related research is conducted only in male animals, which may potentially limit its relevance to half the human population. Basic research for such physical conditions as heart disease must include an appreciation of sex differences, and this same standard should be extended to basic and translational research for PTSD.

Genomics

The factors that lead to individual differences in the development of PTSD are both experiential and genetic (Admon et al., 2013; Kremen et al., 2012; Mehta and Binder, 2012). The genomic basis of PTSD is critically important for determining who might be at risk. That includes identifying genotypes implicated in vulnerability or resilience to PTSD, gene pathways that undergo epigenetic modification after trauma exposure, and differential expression of genes in people who have and do not have PTSD (Almli et al., 2014). Because PTSD is fundamentally a brain disorder, identifying epigenetic modifications that result in differential gene expression in brain regions known to be dysfunctional in PTSD patients has a high priority. However, because brain tissue from living people cannot be assayed, brain-focused studies to identify differentially expressed genes are generally conducted in animal models. The committee identified human studies that are investigating whether epigenetic and expression differences observed in peripheral tissues are associated with PTSD.

The genomics of PTSD is in its infancy compared with the genomics of other common psychiatric disorders such as schizophrenia (Koenen et al., 2013). There is a great deal of knowledge to be gained in this field, but whether it will translate into innovative interventions to prevent or ameliorate PTSD is unknown. The most promising research for translation appears to be prospective human studies that integrate multiple levels of biological data. The best method for such studies begins with identifying people before exposure, but studies of people in the acute aftermath of a traumatic event are also likely to produce important translational results. The translational impact of PTSD genomics could be improved by integrating genome-wide data (for example, genotype, epigenetic, and gene expression) into treatment studies of PTSD, as has been done with functional magnetic resonance imaging research. Such studies may provide information on genomic profiles of people who do and do not respond to treat-

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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ment and information on genomic correlates (for example, gene expression changes) of symptom remission.

A major concern about genomic research on PTSD is the narrow focus on candidate genes—whether for genotype, epigenetic, or gene expression studies—in light of the discrediting of this approach for other psychiatric disorders, such as schizophrenia and bipolar disorder (Pitman et al., 2012). A further concern is the relatively small number of human studies due to current funding constraints. PTSD genomics would benefit from the formation of a PTSD working group in the Psychiatric Genomics Consortium aimed at sharing genotype, epigenetic, and gene expression data among human studies (Koenen et al., 2013). Large consortia have produced robust genomic discoveries related to other psychiatric disorders, such as schizophrenia (Sullivan et al., 2012), and there is no reason to assume that it would be different for PTSD. The major barriers to such a consortium are VA and DoD restrictions on the sharing of genomic data. For example, unlike NIH, which effectively requires data sharing, VA does not allow sharing of individual-level genotype data from genome-wide association studies. Such barriers to data sharing have in effect excluded VA investigators from the large consortia that are necessary for genomic research. Addressing such barriers would help ensure progress in PTSD genomics research.

Prevention

Ideally the occurrence of PTSD should be prevented. Unlike other psychiatric disorders, PTSD results from a known event, and this allows for immediate intervention and possibly even the prevention of pathological symptoms. It remains unclear why some people are resilient to trauma whereas others develop PTSD. Clarifying the reasons for this difference might improve strategies for enhancing resilience and preventing the development of PTSD. Logistically, this research is challenging to conduct in humans, as it requires recruiting people into studies immediately after a traumatic event and following them longitudinally. Establishing best practices for recruiting people into studies immediately after trauma and improving basic research techniques for early behavioral or neural interventions could result in new methods to prevent PTSD symptoms.

The committee identified some research projects that explore methods for increasing resilience and reducing adverse effects after exposure, such as investigations of early interventions (for example, intervening in the emergency room or as soon as the event occurs), of early behavioral and pharmacological interventions and different delivery systems (for example, telephone or Web-based delivery), and of different populations at risk. An early-intervention study found that a course of three sessions of modified prolonged exposure (PE) therapy in an emergency department was associ-

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
×

ated with significantly less depression and PTSD at 1-month and 3-month follow-up than in those who received assessment alone, and the early intervention appeared to mitigate a genetic risk of PTSD (Rothbaum et al., 2014a).

Some research is being done on prevention, but it does not appear to be sufficient. DoD is implementing prevention and resilience training programs, but most of them have yet to be evaluated (IOM, 2014). The committee did not identify any service-specific research that assessed whether existing programs successfully minimize PTSD after trauma or prevent the reemergence of symptoms and other sequelae.

Advances in basic science and PTSD genetics could help to identify social, psychological, or biological markers that might indicate vulnerability to PTSD either before or after trauma exposure. Such research could help to identify modifiable risk factors that might be targets for prevention interventions and people who are at high risk for PTSD and might benefit from enhanced training or early interventions after trauma exposure. Equally important but less studied is the question of whether psychological, social, or environmental variables may increase or decrease the likelihood of PTSD.

Prevention research is examining risk and protective factors for the development of PTSD symptoms. There has been some progress since the committee’s phase 1 report (Biehn et al., 2013; Goldmann et al., 2012; Goodwin et al., 2013a,b; Kok et al., 2012; LeardMann et al., 2013; Marshall et al., 2012, 2013; Walsh et al., 2013; Wilk et al., 2012, 2013), and research continues (see Appendix E). A challenge for research in this field is that although there are some commonalities in methods, in each study that the committee reviewed investigators focused on “innovative” risk or resilience factors; as a result, there were many factors peculiar to each study that cannot easily be translated among studies. In addition, the application of results to other populations—such as service members, veterans, or women—is questionable. This challenge could provide an opportunity for NIH, VA, and DoD to collaborate to support research that may help to actively build consensus around a specific prevention program, biomarker, or other scientific advancement. A notable gap is the absence of research that pools analyses or meta-analyses of extant studies.

Screening

The committee reviewed many research projects that might lead to advances in screening for PTSD and comorbidities (see Appendix E). A few studies were identified that screen for PTSD in high-risk populations, such as those with chronic pain, burns, mild TBI, accidental injury, and functional somatoform syndromes. New technologies and outreach approaches, such as automated telephone screening and the Army’s Behavioral Health

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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Data Portal (described in Chapter 4), might increase the efficiency and reduce the cost of screening.

Screening serves different purposes and there is no “one-size-fits-all” formula for screening procedures. The type of screening to be conducted depends on the question of interest, for example, whether the intention is to compare those who have PTSD with those who are healthy or to distinguish those who have PTSD from those who have a related diagnosis, such as mild TBI. Research is needed to move beyond the traditional questionnaire-based screening methods to neurobiological and behavioral screening for PTSD. There is also a need for randomized controlled trials that prospectively assess whether large-scale screening results in greater benefits to the population than more traditional approaches.

Diagnosis

Much PTSD research has been directed toward improving the diagnostic precision of structured interviews or self-ratings. Those techniques not only assist in diagnosis but are valuable tools for promoting measurement-based care. Efforts that go beyond structured interviews and rating scales have been under way for many years and include the study of physiological measures, neuroimaging, genetic markers, and neurotransmitters; the goal is to enhance diagnostic processes by incorporating neurobiological measures.

The committee identified studies that apply biological measures to address PTSD diagnosis (see Appendix E). Examples are the differentiation between PTSD and mild TBI, identification of the new symptoms of PTSD as given in the Diagnostic and Statistical Manual of Mental Health Disorders-Fifth Edition (APA, 2013), and the characterization of speech patterns in people who have PTSD compared with those who do not have PTSD. The committee identified a research gap in the area of diagnosis—one potentially useful approach that is not being studied is the use of advanced statistical procedures, such as random forest classification and functional magnetic resonance imaging, to develop a neurobiologically based approach to diagnosis PTSD and to evaluate it against standard (that is, clinically based) diagnostic predictors.

Treatment

There are effective treatments for PTSD in civilians, as shown in the numerous meta-analyses and treatment guidelines that were described in the committee’s phase 1 report (IOM, 2012). However, although such treatments as PE, cognitive processing therapy (CPT), eye movement desensitization and reprocessing (EMDR), selective serotonin reuptake inhibitors, and

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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other pharmacotherapies are more effective than placebo or other controls in civilians, they do not work in all people with PTSD. Some patients show only a partial response, others show no response, and some relapse after an initially promising response. There are a limited number of studies that have investigated PTSD treatments in service member and veteran populations. Other treatment challenges include the delayed onset of therapeutic action and adverse effects. Better and safer treatments are needed, not just modifications of current ones.

Research targets for treatment (see Appendix E) include several that are innovative and promising. Some of the most promising research is the use of new technologies to improve the effectiveness and accessibility of treatment. The combination of various clinical approaches to address the complexity of PTSD issues (for example, concurrent treatment for PTSD and comorbidities or treatments that combine psychotherapies, pharmacotherapies, and complementary and alternative therapies) needs to be studied further in military and veteran populations. Overarching research considerations for PTSD treatment are discussed below.

Pharmacotherapies

Both preclinical pharmacotherapies (for example, pilot studies) and pharmacotherapies are being investigated in military and civilian populations (see Appendix E). New pharmacotherapies, such as endocannabinoids, are promising and important for research. The committee found research gaps in the study of preclinical pharmacotherapies, such as the use of oxytocin, to identify molecular markers of reconsolidation and of hippocampal adult neurogenesis as related to pattern separation and pattern completion.

A broad array of new and established pharmaceuticals are being studied; some are being given as monotherapy and some to augment other therapies. Some are believed to work through different neurotransmitter pathways and should add valuable information to the knowledge base on PTSD pharmacotherapy. Particularly promising are the clinical investigation of low doses of anesthetic drugs, such as ketamine, and the increasing evidence base on prazosin. For example, a study looking at treatment with prazosin in active-duty Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) soldiers found that prazosin was superior to placebo in measures of sleep and total PTSD symptoms (Raskind et al., 2013). This study is the first major placebo-controlled trial of pharmacotherapy in active-duty service members who had been exposed to combat.

On the basis of an extensive review of current studies and a brief review of research published since its phase 1 report (IOM, 2012), the committee identified several gaps in PTSD-treatment research. First, studies of drug

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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effects on brain structure and chemistry, such as effects of escitalopram on BDNF, are valuable, and more studies of this type are needed. Second, hydrocortisone holds promise both for the prevention of PTSD and the understanding of the neurobiology of PTSD; further studies of antipsychotics as a treatment for PTSD are needed. Third, pharmacotherapy for PTSD comorbid with bipolar disorder, attention deficit disorder, and mild TBI is not well studied but should be. Fourth, polypharmacy is a continuing concern; it may result in improvement in PTSD symptoms, but it can also result in more side effects and be a factor in noncompliance to treatment.

Psychotherapies

Research that compares the efficacy of new psychotherapies with that of established evidence-based treatments is essential for a high-performing system of PTSD management. It is important to continue to develop and evaluate new psychotherapy options because there is currently no evidence-based treatment that is effective for everyone who has PTSD and no treatment that is so appealing, engaging, and pragmatically deliverable to patients that it breaks down all barriers to care. Thus, the rigorous study of new psychotherapies is essential for maximizing the treatment options to address each patient’s unique needs and preferences. Once efficacy is established, primary treatments can be studied in combination with other treatments to determine the added value of combination treatments or how treatment-protocol modifications can improve benefits.

Various treatment methods are being evaluated, most often to compare them with CPT or PE (see Appendix E for more detail). Rather than research gaps, there appears to be considerable diversity in the approaches being tested, including both trauma-focused and non-trauma-focused approaches. Examples are controlled studies to assess the value of adding components to evidence-based treatments. Various new treatments are being tested in randomized controlled trials, such as acceptance and commitment therapy, adaptive disclosure therapy, behavioral activation therapy, interpersonal psychotherapy, trauma-management therapy, and relatively new and untested cognitive training approaches to enhance modulation of emotion. The committee did not identify any studies of the value of combining cognitive training methods with traditional cognitive behavioral therapy (CBT) or exposure therapies, such as CPT, PE, and EMDR. That may constitute a research gap inasmuch as psychotherapy approaches may be more effective when combined to address both cognitive control of emotional regulation and extinction-based cognitive and behavioral concerns. Overall, current psychotherapy research reflects a diverse mixture of efforts. Some experimental methods for studying PTSD treatments involve computer-delivered approaches, which are discussed later in this chapter.

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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Combining Psychotherapy and Pharmacotherapy

The combined use of pharmacotherapy and psychotherapy is an important approach in the management of PTSD. A combined approach might result in greater therapeutic gains in two ways. In the first, a single dose of a drug is administered immediately before or after a psychotherapy session either to hasten the onset of therapeutic action or to produce greater therapeutic gains than psychotherapy alone. This model uses drugs that are cognitive enhancers—such as D-cycloserine (DCS), yohimbine, methylene blue, and hydrocortisone—or drugs that disrupt memory (such as propranolol) or facilitate therapy, such as 3,4-methylenedioxy-N-methylamphetamine (MDMA or “ecstasy”). In the second, a drug is administered chronically with psychotherapy, and the combined treatment may result in a greater gain than either treatment alone. In this model, use of the drug might precede the introduction of psychotherapy, be started simultaneously, or be added after the start of psychotherapy. The antidepressant drug sertraline and the anticonvulsant drug zonisamide (see Appendix E) are being studied as enhancements of psychotherapy.

Several trials of medication-enhanced psychotherapy have been reported recently. For example, Oehen et al. (2013) investigated MDMA in association with psychotherapy in treatment-resistant noncombat PTSD patients; greater improvement was observed in the higher-dose group. The use of single-dose DCS in combination with PE therapy has also been studied; mixed results have been reported. Litz et al. (2012) compared DCS and placebo with behavior therapy in OEF veterans and found inferior results in the DCS groups. De Kleine et al. (2012) reported significantly greater improvements with DCS than with placebo in civilians but only in those who required more sessions; Difede et al. (2013) showed reduced anger and PTSD symptoms compared with placebo in civilians who were given DCS combined with virtual-reality exposure therapy. Rothbaum et al. (2014b) found no reduction in overall PTSD symptoms in OEF and OIF veterans who were given a combination of DCS and virtual-reality exposure therapy but did find a significant decrease in cortisol and psychophysiological startle response in general.

Somatic Treatments

Neurostimulatory treatments for depression and obsessive compulsive disorder have shown benefit in some people who are resistant to first-line treatments. The U.S. Food and Drug Administration has approved devices for the use of repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant depression. More recently, the literature has shown promise for rTMS in treating PTSD (Karsen et al., 2014; Nam et al., 2013; Oznur

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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et al., 2014; Watts et al., 2012). The committee identified several current studies that are funded by DoD, VA, and others to investigate rTMS, cranial electrotherapy stimulation, stellate ganglion block, trigeminal nerve stimulation, and bright-light therapy (see Appendix E). Those and other stimulatory and somatic interventions are promising treatments for PTSD and clearly warrant further study.

Couple Therapy

In the last several years, research projects have assessed the effectiveness of couple therapy for PTSD (Fredman et al., 2011; Meis et al., 2012; Monson and Fredman, 2012; Monson et al., 2009; Sautter et al., 2009; Taft et al., 2011). In a small randomized controlled trial of cognitive-behavioral conjoint therapy for PTSD, Monson et al. (2012) found that this couple therapy model reduced PTSD symptoms and enhanced relationship satisfaction. Schumm et al. (2013) reported similar findings in a small study of OEF and OIF veterans who had PTSD and their female partners. The veterans’ PTSD symptoms and their partners’ relationship distress were reduced. Meis et al. (2013) found that OEF and OIF veterans were more interested in couple therapy than veterans of Vietnam and Korea, although both groups wanted more partner involvement.

Complementary and Alternative Therapies

As part of its statement of task, the committee was asked to look at complementary and alternative therapies for PTSD, particularly animal-assisted therapy. Surveys have demonstrated that the use of complementary and alternative therapies is substantial in the U.S. population and in the military (see Chapter 7). The more frequently studied complementary and alternative therapies are meditation, acupuncture, yoga, and biofeedback. Less studied therapies include animal-assisted therapy, mantram repetition, and music therapy. The former studies are being conducted in a variety of PTSD populations, including veterans, and they are being evaluated in combination with treatment as usual. Their value as stand-alone treatments for PTSD is unknown.

The committee identified different types of meditation—including mindfulness-based, loving-kindness, self-compassion, and transcendental meditation—that are being studied for PTSD. Most such studies were being conducted as randomized controlled trials with either an active or an inactive control (see Appendix E). The committee found that there were as many mindfulness projects in the NIH RePORT database as there were projects for treating for PTSD with a combination of pharmacotherapy and psychotherapy approaches—an indication that research on mindfulness

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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is growing. There is a lack of well-controlled studies on animal-assisted therapy and on acupuncture for PTSD; more research is needed on both. The study of psychobiotics (for example, gut microbiota) is a new field of medicine that is relevant to stress and related psychological disorders. Some researchers have suggested that preclinical and clinical studies of psychobiotics could inform treatment for stress-related conditions (Burnet and Cowen, 2013; Dinan et al., 2013).

Models of Care Delivery

A high-performing PTSD management system should expedite the translation of positive research findings into practice. Optimally, the translation would take advantage of proven methods for the delivery of clinical services in a way that breaks down barriers to care. The best evidence-based treatments will have little value without a model for promoting their effective and widespread delivery.

New models for delivering evidence-based treatments that focus on improving access to care must take into account patients’ sociocultural context as well as available technology-based delivery options. Research is being conducted on the structure or context in which evidence-based treatment is delivered, such as in primary care and in deployment settings (see Appendix E for more details) and on the use of technology to expand the reach and appeal of evidence-based treatment to maximize its clinical efficacy (see the section “Technology” below).

The committee identified a research gap with regard to the use of mobile communication devices and their applications. There appears to be little research to determine how much applications such as VA’s PTSD Coach are used once installed and what effect they have on improving treatment outcomes and reducing barriers to care. However, considering the relatively recent availability and adoption of mobile devices and applications, it is perhaps understandable that they are the subject of little research.

Modality of Treatment Intervention

The committee identified several studies that focused on treatment modality—that is, whether a treatment is given in a group setting, a couple setting, or an individual setting. Varied treatment modalities are being tested, either by delivering treatment in groups or in conjoint therapy or by adjusting the pace at which treatment is administered (for example, moving from one session per week to two sessions per week). More research is needed to determine the characteristics of patients who can benefit from treatment delivered in a group or from combinations of individual and group or conjoint treatment. More research is needed to determine the

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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role of the family in different treatment settings and the benefits of family involvement. Research is also needed to determine whether providing more choices of treatment modalities for service members and veterans helps to reduce barriers to care. And research is necessary to understand whether a patient who has initial involvement in a group setting with a non-evidence-based treatment (such as yoga or psychoeducation) is more likely to engage in an evidence-based treatment later.

Treating Different Sex and Racial Groups

Sex, ethnicity, and culture can all affect the risk of PTSD, its presentation, a patient’s (and the patient’s family’s) attitudes to treatment, the type of treatment that is preferred and received, and possibly the response to treatment. The committee identified current research that is aimed at assessing the potentially different needs of men and women who have PTSD and alcohol or substance use disorders, or who have experienced military sexual trauma. Some studies are focused on making PTSD treatment more accessible to members of minority groups, on adapting manualized PE for Hispanic patients, and on developing culturally relevant treatment for American Indians.

Concurrent Treatment of Comorbidities

As noted in Chapter 2, people who have PTSD are often diagnosed with one or more comorbidities, including other anxiety disorders, depression, and alcohol and substance use disorders (Brown and Wolfe, 1994; IOM, 2012; Jacobsen et al., 2001; Kaufman and Charney, 2000; Pompili et al., 2013). To better understand the pathophysiology of PTSD, some studies have focused solely on it as the primary diagnosis and often excluded patients from studies if they present with comorbidities. Excluding certain patients may be important for studying the psychopathology of PTSD itself, but research examining the interactions between the pathophysiology of PTSD and other psychiatric conditions is as important as research that explores the psychological and neural processes underlying the interaction of drug addiction or TBI with the development and treatment of PTSD. Not only can understanding how alcohol, drugs, and brain injuries may interact to alter the brain circuitry implicated in PTSD provide information on why PTSD is linked to addiction and TBI, but these types of studies might also help identify new PTSD treatments (Brady et al., 2013; Kaplan et al., 2010). Some literature published since the phase 1 report shows an improvement in PTSD symptoms and a reduction in comorbid alcohol use when the disorders are treated together. Foa et al. (2013) compared PE, both with and without naltrexone, with supportive counseling in patients

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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who had PTSD and alcohol use disorder, and found that participants who received naltrexone had fewer drinking days (those who received both PE and naltrexone had the lowest rate of posttreatment relapse), that all patients had a reduction in PTSD symptoms, and that PE did not exacerbate alcohol use disorder. Kaysen et al. (2014) observed that CPT was well tolerated in veterans who had PTSD and comorbid alcohol use disorders and that CPT treatment was associated with decreased symptoms of PTSD and depression.

The committee found a variety of current studies of psychotherapy, most of which are CBT-based, for PTSD and comorbidities. There is an emphasis on promoting adherence to treatment and maintenance of long-term treatment gains by using motivational interviewing and relapse-prevention strategies. There is little redundancy in the research being conducted in this area. The committee noted one study designed to generate comorbidity clusters to predict outcomes. Other treatment approaches included physiological response-tailored exposure therapy, imagery rehearsal with or without CBT, and group CBT. The diversity of the study targets and clinical approaches suggests that DoD and VA recognize the importance and challenge of treating for PTSD and comorbid conditions.

Barriers

Most research on barriers is related to individual, provider, and institutional obstacles to the delivery of high-quality, evidence-based PTSD care. It includes barriers to awareness, accessibility, availability, and acceptability; the role of leaders in reducing stigma; adherence to evidence-based treatments, and the dissemination of the outcomes. Two studies are looking at military culture, operational tempo, and institutional processes that impede research (for example, variations in institutional review board functioning and recruitment challenges). Two studies are identifying barriers to the delivery of such new treatments as acupuncture. Some studies ask about family functioning and a service member or veteran’s relationships with his or her family, but only one study was identified in which the family is considered specifically as a barrier to or asset for PTSD treatment. There is no research on overcoming barriers to translation of basic research to treatment and clinical practice. The potential for new interventions (for example, Web-based approaches or after-care telephone monitoring) to break down access barriers is increasing (see the section “Technology”). The research portfolio is top-heavy with studies on OEF and OIF cohorts, including several studies of National Guard and reserve cohorts, but the committee identified very few studies that included Vietnam-era veterans.

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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Long-Term Outcomes

As noted in Chapter 2, PTSD can be a long-term, chronic, and even lifelong disorder. Longitudinal studies can advance the understanding of how aging affects PTSD and comorbidities and can help to elucidate whether some interventions are beneficial in altering the course of the disorder. Thus, long-term follow-up of large DoD and VA cohorts might shed light on the effectiveness of prevention programs, early screening, and a variety of treatment interventions for PTSD. See Appendixes D and E for examples of long-term studies.

Intimate Partner Violence

Intimate partner violence is an often overlooked research topic with regard to PTSD, but it can have substantial impact on families. Some service members or veterans who have PTSD may perpetrate intimate partner violence (Meis et al., 2010), but what distinguishes those who do from those who do not is not fully understood. There is a continuing need to conduct research that identifies effective ways to assess intimate partner violence and to determine what factors encourage potential or actual perpetrators (or their partners) to seek access to mental health care. Several recent research efforts are designed to validate intimate-partner violence treatment interventions (Taft et al., 2013), but there are still few empirically supported interventions.

The committee identified promising innovative studies that focused on racial and ethnic factors associated with PTSD and intimate partner violence; the intersections of TBI, intimate partner violence, and PTSD; and the effects of PTSD and intimate partner violence on children in military and veteran families. Continuing research is needed to develop and validate couple, family, and group interventions that address intimate partner violence in military and veteran families.

Training

Provider training is important for diagnosing and for disseminating and implementing evidence-based treatments. The committee divided research on training into training providers to improve the diagnosis of and treatment for PTSD and administering training grants for career development (see Appendix E). The committee considered efforts to train providers to be particularly important. One innovative study is under way on the use of virtual patients for training providers. Another study is attempting to develop and evaluate a Web-based CBT training system that expands on existing content and incorporates live online training. Considering the need

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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for well-trained providers of evidence-based treatments and the ubiquitous penetration of high-bandwidth Internet connectivity, the absence of more studies on online clinical training appears to be a gap in research and practice. If current or recently completed studies on developing Web-based or new training curricula or tools are effective, they could be used to reach a larger audience.

TRANSLATING RESEARCH INTO PRACTICE

Translating research into practice can be thought of in different ways, depending on the context. For example, a laboratory scientist may be interested in how the basic science of cell lines or animals can be translated to humans. A researcher conducting a clinical trial may be interested in how the results in a controlled experimental setting are translated to the general population in a real-world setting. A health care administrator may be interested in taking a body of evidence and translating it to clinical practice guidelines. To distinguish between types and contexts of translation, investigators sometimes think of translation as a continuum of activities (see Table 9-3). All research does not have to go through each stage of translation, nor does the translation have to be linear; some research may move directly from an early stage to direct application.

The committee recognizes the importance of conducting basic research that translates from animal models to healthy humans and to clinical and trauma-exposed populations. Basic research on physiological and biologi-

TABLE 9-3 The Continuum of Translation Research

Translational
Phase
Notation Types of Research
1 Discovery to candidate health applications Phases I and II clinical trials; observational studies
2 Health application to evidence-based practice guidelines Phase III clinical trials; observational studies; evidence synthesis and guidelines development
3 Practice guidelines to health practice Dissemination research; implementation research; diffusion research Phase IV clinical trials
4 Practice to population health impact Outcomes research (includes many disciplines); population monitoring of morbidity, mortality, benefits, and risks

SOURCE: Modified from Khoury et al., 2007, with permission.

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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cal mechanisms potentially relevant to PTSD has used primarily animal models (Almli et al., 2014; Neumann et al., 2011; Pitman et al., 2012) because this research could not be ethically conducted in humans. These models are vitally important to understanding many of the neurobiological principles governing learning, memory, trauma, and stress. However, this research has limited usefulness if its applicability to and modification by the complex cognitive, social, and emotional factors typical of human experiences cannot be explored. Animal models also cannot capture the impacts of social factors, including such emotions as shame and guilt; social structures; cultural attitudes; or the complex cognitive abilities in people that may change the expression and persistence of PTSD symptoms. Basic research that explores the psychological and biological mechanisms of learning, memory, trauma, and stress in people should be expanded to include psychological and neurobiological mechanisms in healthy people and in trauma-exposed military populations. Unless a broad range of researchers can access relevant populations to conduct studies on how trauma exposure and PTSD influence the brain or behavior, the applicability of basic research to treatments for PTSD will continue to be limited. New research models—for example, pragmatic trials, practical clinical trials, and hybrid effectiveness–implementation trials—may be useful for addressing the common translational gap between randomized controlled trials and clinical practice (Curran et al., 2012; Tunis et al., 2003). Translational research can provide feedback from population-based studies of new interventions that lead to their modification and eventual implementation as evidence-based interventions for a variety of populations (Glasgow et al., 2012; Zatzick and Galea, 2007).

NIH has made an effort to streamline the translation of mental health research to the clinic. The NIMH Research Domain Criteria Project is defining functional dimensions, such as fear circuitry or working memory, that will be studied in multiple dimensions, including genes, neural circuits, and behavior. The project’s goal is to translate progress in basic neurobiological and behavioral research to an improved and integrated understanding of psychopathology and the development of new and optimally matched treatment for mental disorders (NIMH, 2013a). In addition, NIH is revising its clinical trials process to make NIH-funded research more efficient, to encourage data sharing and publication, and to have a greater impact on the burden of illness. Emphasis is being placed on target validation and experimental therapeutic studies instead of traditional efficacy trials in an effort to identify new targets for treatment and to improve knowledge of the disease process (NIMH, 2013b). The committee commends NIH for these efforts, and it encourages DoD and VA to use best practices learned from NIH to improve the efficiency and transparency of their own mental

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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health research and to continue to use such collaborative mechanisms as the National Research Action Plan.

TECHNOLOGY

The last decade has seen a dramatic increase in the use of innovative digital technologies, such as mobile devices, high-speed network access, smart televisions, social media, hyperrealistic computer and video games, and new interaction and behavioral sensing devices. The power of these technologies to automate processes and create engaging user experiences has led to health care applications that leverage off-the-shelf technology and push the boundaries of new technological development.

An increased focus has been placed on the use of technology to enhance the management of and treatment for PTSD and comorbid health conditions. DoD and VA have driven advances in mental health care technology by supporting research to improve the delivery of evidence-based treatments for mental health conditions and to reduce barriers to care by investigating ways to improve the awareness of, availability of, access to, appeal of, acceptance of, and adherence to evidence-based treatments and services (IOM, 2012). Technology-based advances in mental health care include telehealth, informational and self-help websites, mobile smartphone applications, virtual reality and online virtual worlds, intelligent health care agents, and interactive clinical training systems.

Telehealth

One of the more widely studied applications of technology in mental health is the use of telehealth (sometimes referred to as teletherapy or telemental health) to expand the accessibility of and adherence to evidence-based treatments. Telehealth refers to an approach that uses technology (typically videoconferencing) for the delivery of clinical care by a provider who is geographically distant from the patient (Schopp et al., 2006). The number of published reports on telehealth outcomes has grown exponentially since 2000, and the number of trials continues to grow (Backhaus et al., 2012). Since the committee’s phase 1 report, new studies have shown encouraging results (Backhaus et al., 2012; Strachan et al., 2012), and a substantial number of projects have been funded by DoD, VA, and others to investigate the telehealth delivery of both evidence-based treatment and emerging non-evidence-based interventions that target the needs of service members and veterans who have PTSD and comorbid conditions. The research needs to be assessed to determine whether telehealth approaches for both screening and treatment offer a preferable and cost-effective approach to PTSD care (Jones et al., 2012).

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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Self-Help and Informational Websites

DoD and VA have supported the development of online self-help and informational websites. These efforts are intended to break down barriers to care by building user awareness of PTSD and treatment options, promoting accessibility to care with self-help content, encouraging acceptance of seeking treatment with persuasive information, and enhancing adherence by providing self-help treatment options or between-session support. Receiving PTSD-relevant content privately via the Internet may encourage those who are initially reluctant to seek help to reach out eventually to a mental health care professional.

Another new form of online deliverable treatment is the use of computerized training programs to build the cognitive skills that may help to modulate emotions. Often termed cognitive remediation therapy, this approach is a standardized intervention that involves performing cognitive exercises to improve attention, processing speed, executive function, and memory through practice by using various software packages. The committee identified six projects that evaluate cognitive remediation therapy programs as an alternative intervention for PTSD in combat veterans. One study compared a commercial program called CogPack with playing Tetris. Two projects evaluated similar computer-based systems to retrain negative attentional bias in people who have a diagnosis of PTSD and to address comorbid mild TBI. All the cognitive remediation therapy projects test the hypothesis that this form of care will promote home-based practice by using cognitive training programs that are available online.

Other DoD and VA websites intended for service members, veterans, and their families present less structured treatment activities and are generally information-rich, reviewed, and regularly updated, and present a wide array of PTSD resources, including some self-assessment materials and information on where to access treatment. Examples of the sites are the VA’s National Center for PTSD (http://www.ptsd.va.gov), the National Center for Telehealth and Technology (T2) (http://www.t2.health.mil), and T2’s flagship PTSD and comorbidity AfterDeployment (http://www.afterdeployment.org). T2 also hosts the Moving Forward site (http://startmovingforward.t2.health.mil), an online educational life-coaching program focused on resilience and prevention for service members and veterans who are experiencing challenges but are not yet engaged in mental health care. DoD supports the wider-ranging Military OneSource site (http://www.militaryonesource.mil), and there are numerous private foundation “gateway” sites, such as the Dart Foundation’s Gateway to Post Traumatic Stress Disorder Information (http://www.ptsdinfo.org). Screening for PTSD and other psychological disorders is available for all veterans through VA’s My Health eVet website (VA, 2013), which allows all registered users of VA

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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health care services to access their clinical records and provides a number of wellness and health-enhancement options.

Two novel online approaches leverage interactions with virtual human characters to engage users with PTSD-related content. One project is Kognito Interactive’s site Family of Heroes (http://www.familyofheroes.com), which offers an interactive role-playing game that teaches motivational interviewing skills to family members and helps them to recognize when their service member or veteran is exhibiting signs of PTSD, depression, or suicidal ideation. A small randomized controlled trial showed that 22% of the veterans who were approached by their family members during the study sought help for postdeployment stress. Another virtual human site is the DoD-funded SimCoach (www.simcoach.org), which engages users in an interactive discussion to provide information, advice, and conversationally delivered self-assessment.

Considering the expense and effort of creating those websites, there is a lack of knowledge about how they are used and what outcomes they produce. However, because anonymity may be a primary selling point for the sites, researchers studying the sites need to ensure that real-world users’ identities are protected. As the general population increasingly views the Internet as an acceptable and natural option for shopping, education, health care information, and social interaction and bonding, the committee believes that research will continue to focus on whether and how evidence-based mental health treatment can be delivered to service members and veterans via online tools and websites. Research needs to evaluate which treatments can be delivered to which patients who have which health conditions to maximize safe access to evidence-based treatment for service members, veterans, and their significant others.

Virtual Reality

DoD and VA have supported research to create and evaluate virtual-reality exposure therapy applications. Avoidance of trauma reminders is symptomatic of PTSD and some patients are unable or unwilling to visualize traumatic events and memories effectively (Difede and Hoffman, 2002). To address the avoidance issue, virtual reality delivery of PE is one way to immerse users in personalized simulations of trauma-relevant environments in which the emotional intensity of the scenes can be controlled by a clinician. Thus, virtual-reality exposure therapy offers a way to circumvent a natural avoidance tendency by directly delivering multisensory and context-relevant cues that aid in the confrontation and processing of traumatic memories.

Favorable outcomes have been reported in several PTSD populations treated with virtual reality therapy (Difede and Hoffman, 2002; Difede

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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et al., 2007; Gerardi et al., 2008; McLay et al., 2011; Miyahira et al., 2012; Reger and Gahm, 2008; Reger et al., 2011; Rizzo et al., 2010; Rothbaum et al., 2001, 2014b), and five randomized controlled trials of virtual-reality exposure therapy in active-duty service member and veteran populations are under way. Those studies are assessing virtual reality alone or in combination with other enhancing treatments, such as imaginal PE, DCS, and trauma management therapy (Beidel et al., 2011; Difede et al., 2013; Reger et al., 2011). In addition to providing more and better options for PTSD treatment, virtual-reality exposure therapy may be useful for overcoming barriers to care by improving treatment appeal, acceptability, and adherence. Young service members, many of whom have grown up with digital gaming technology, may be attracted to and comfortable with participation in virtual reality therapy (Reger et al., 2009; Wilson et al., 2008).

In spite of DoD and VA efforts to foster adoption of PE as a first-line treatment, its dissemination has been a challenge, in part owing to clinician hesitancy to adopt and use it (Becker et al., 2004; IOM, 2012). Virtual reality can also be used to help meet this challenge through the use of virtual reality systems that allow a mental health care provider to create customized simulated scenarios to support patient trauma narratives more easily with a computer control interface. DoD is supporting research on training social workers to work with military families using conversational interactions with life-size, voice-interactive, high-fidelity virtual military patients and is developing a toolkit for clinical educators so that they can create virtual patients for training others. Other virtual reality projects seek to train primary care providers to screen, treat, and refer patients who have PTSD using a series of challenging menu-driven, role-play conversations with virtual patients (Albright et al., 2012). However, the attraction and adoption of virtual-reality exposure therapy still requires controlled research to determine how and to what extent this approach may break down barriers to PTSD care and enhance treatment dissemination. It also requires research to determine best practices for training providers to use and to implement the technology in DoD and VA settings.

Mobile Applications

Mobile devices, including mobile telephones, tablets, computers, e-readers, and wearable body sensors that can record various physiological measurements, can be used to wirelessly deliver health care services. Mobile applications can potentially be used to motivate and inform people and to monitor and track health measures and activities. Many of the applications (such as fitness applications and calorie counters) focus on providing information to the end user, and others provide information to clinicians via a network connection. The availability of mobile health care applications

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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has grown at a dramatic pace, in large part owing to the massive adoption of smartphone and tablet technology and the ubiquitous access to network connections. DoD and VA have recognized that growth and produced several PTSD and other mental health–related applications, including PTSD Coach, PE Coach, Mood Tracker, Breathe2Relax, BioZen, LifeArmor, Positive Activity Jackpot, and Tactical Breather. All the applications attempt to extend the reach of currently used practices—such as self-monitoring, self-assessment, biofeedback, CBT tactics, and relaxation strategies—via mobile devices. T2 has worked with VA to develop, test, and conduct research on the PE Coach, a smartphone application. And the center is distributing the CBT-I Coach application as an adjunct treatment for the insomnia associated with PTSD (National Center for Telehealth and Technology, 2013) and the PTSD Coach application as an educational tool. Those programs require evaluation as they are further developed and disseminated.

VA is also investing substantial effort in its Mobile Health program to evolve its mobile application portfolio. It is piloting the use of iPads that have a suite of 10 applications to 1,000 seriously injured veterans (Miller, 2013). VA applications that are available or in development include CBT-I (insomnia-focused), Acceptance and Commitment Therapy Coach, Cognitive Processing Therapy Coach, Mindfulness Coach, and PTSD Family Coach. Although much of the content in the new mobile applications is similar to that on existing informational webpages, such as AfterDeployment and the VA’s National Center for PTSD, research on their use and effectiveness in a mobile format is still needed. There are practical challenges to studying the use of the technologies in DoD and VA with regard to development, dissemination, sustainability, and privacy protection, but current research efforts fit in well with the DoD and VA visions for using mobile health technologies to expand care options for service members and veterans. The creation of engaging and effective mobile health technologies will require an interdisciplinary effort by clinicians, device manufacturers, application developers, communication service providers, and patient and consumer end users, who appreciate the need to integrate portable computing devices, cloud infrastructures, network capabilities, data analytics, and human factors.

Online Clinical Training and Virtual Patients

Although human “actor” patients are the gold standard for training in medical schools, such live standardized patients are rarely available for clinical training with psychologists, social workers, and other mental health care providers. In most training, direct patient-interaction skills are acquired via role-playing with supervising clinicians, fellow graduate students, and closely supervised “on-the-job” training. Virtual patient

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
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systems offer a novel technological approach to address the training needs of health care providers, and these systems take many forms (Talbot et al., 2012). Basic applications can be as simple as providing trainees with static patient images and accompanying text-based case summaries and tests. Simple computer animations can also be used, with interactions driven by trainee menu choices. More recently, virtual human conversational agents have been created that can credibly fill the role of standardized patients by simulating diverse varieties of clinical presentations. These agents can be available for anytime–anywhere training via computer.

As mentioned in the section on training, DoD and VA are funding a few studies to assess the use of virtual reality for training (see also Appendix E). Such prototype systems, designed for interacting with highly realistic and natural-language-capable virtual patients, do not yet have an evidence base for their effectiveness for training. However, if found to be effective, virtual patient technology could have a considerable impact by supplementing existing in-person training approaches.

SUMMARY

Executive Order 13625 and The National Research Action Plan for Improving Access to Mental Health Services for Veterans, Service Members, and Military Families established PTSD as a high national research priority. The committee found the ongoing PTSD research portfolios of DoD and VA to be broad, diverse, and complementary. Over the last few decades, the departments have spent hundreds of millions of dollars on PTSD research. Much of DoD’s currently funded PTSD research centers on treatment, basic science, and prevention. VA’s PTSD research portfolio focuses on treatment, barriers, and basic science. Those research priorities reflect the mental health needs of the service member and veteran populations that each department serves and are reflected in the types and numbers of studies that are funded (see Table 9-2). In DoD, PTSD research represents approximately 60% of the mental health research portfolio (Miller, 2014). VA funding for PTSD has been stagnant over the past 5 years (Gleason, 2012), despite the growing prevalence of PTSD in veterans seeking care in VA.

The committee identified areas of research that are critical to improving PTSD management for service members and veterans—basic research, use of technology, PTSD treatment, and overcoming system-level barriers. Much work is being accomplished in basic research, but the scientific community still lacks an understanding of the biological mechanisms that lead to PTSD, factors that may prevent or promote its development, and biomarkers that could improve PTSD prevention, diagnosis, and treatment.

PTSD researchers are trying to identify more and better treatments, such as psychotherapies, pharmacotherapies, combinations of therapies,

Suggested Citation:"9 Research on PTSD." Institute of Medicine. 2014. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment. Washington, DC: The National Academies Press. doi: 10.17226/18724.
×

and complementary and alternative therapies. Identifying treatments for PTSD and any comorbidities is particularly important, considering the high prevalence of mental health disorders, such as depression and substance use disorder, and physical ailments, such as TBI and chronic pain, in many service members and veterans who have PTSD. Such comorbidities as cardiovascular disease, are likely to increase as the veteran population ages.

The use of technology to improve the management and treatment of PTSD has potential to improve treatment options, clinical practice, and real-time contact with service members and veterans. Technology is also expanding the use of system-wide approaches to better capture and monitor patient treatments and outcomes in a systematic and continuous manner, but questions remain as to whether such technological enhancements will achieve improved treatment delivery and outcomes.

Given the current and growing number of service members and veterans who have PTSD symptoms and the availability of effective treatments for PTSD, a topic of research that is often overlooked but would be beneficial in the short term is methods to overcome barriers that prevent the widespread use of effective treatments in DoD and VA health care systems. This may include research on health services, effective models for PTSD management, the establishment of evidence-based practice competencies, provider training, and the effective implementation and dissemination of evidence-based care. The committee encourages research on all those subjects and new efforts to be undertaken.

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Posttraumatic stress disorder (PTSD) is one of the signature injuries of the U.S. conflicts in Afghanistan and Iraq, but it affects veterans of all eras. It is estimated that 7-20% of service members and veterans who served in Operation Enduring Freedom and Operation Iraqi Freedom may have the disorder. PTSD is characterized by a combination of mental health symptoms - re-experiencing of a traumatic event, avoidance of trauma-associated stimuli, adverse alterations in thoughts and mood, and hyperarousal - that last at least 1 month and impair functioning. PTSD can be lifelong and pervade all aspects of a service member's or veteran's life, including mental and physical health, family and social relationships, and employment. It is often concurrent with other health problems, such as depression, traumatic brain injury, chronic pain, substance abuse disorder, and intimate partner violence.

The Department of Defense (DoD) and the Department of Veterans Affairs (VA) provide a spectrum of programs and services to screen for, diagnose, treat for, and rehabilitate service members and veterans who have or are at risk for PTSD. The 2010 National Defense Authorization Act asked the Institute of Medicine to assess those PTSD programs and services in two phases. The Phase 1 study, Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Initial Assessment, focused on data gathering. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations Final Assessment is the report of the second phase of the study. This report analyzes the data received in Phase 1 specifically to determine the rates of success for each program or method.

Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations Final Assessment considers what a successful PTSD management system is and whether and how such a system is being implemented by DoD and VA. This includes an assessment of what care is given and to whom, how effectiveness is measured, what types of mental health care providers are available, what influences whether a service member or veteran seeks care, and what are the costs associated with that care. This report focuses on the opportunities and challenges that DoD and VA face in developing, implementing, and evaluating services and programs in the context of achieving a high-performing system to care for service members and veterans who have PTSD. The report also identifies where gaps or new emphases might be addressed to improve prevention of, screening for, diagnosis of, and treatment and rehabilitation for the disorder. The findings and recommendations of Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment will encourage DoD and VA to increase their efforts in moving toward a high-performing, comprehensive, integrated PTSD management strategy that addresses the needs of current and future service members, veterans, and their families.

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