Appendix E

Detailed Descriptions of PTSD Research in the Department of Defense, the Department of Veterans Affairs, and the National Institutes of Health

In the sections that follow, the committee provides a detailed summary of the studies it reviewed using the following
Sources of information: the VA Health Services Research and Development database, the National Institutes of Health (NIH) Research Portfolio Online Reporting Tools (RePORT) database, ClinicalTrials.gov, and information provided from the Department of Defense (DoD).¹ After identification of relevant research projects, it categorized those projects based on 10 research categories that parallel the major topics of the committee’s phase 1 report and Table 9-2 in this report. The committee tried to qualitatively describe the kind of posttraumatic stress disorder (PTSD) research currently being funded and who is funding that research. For each research target in the categories below, the committee presents the percentage of studies undertaken (and in some instances funded) by DoD, the Department of Veterans Affairs (VA), the National Institute of Mental Health (NIMH), other NIH institutes, or other
Sources (Other). The studies are described to the extent possible, given the available information in each database. 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 be counted only once, but this was not always possible and some studies, particularly studies funded jointly by DoD and VA, were counted twice. A

________________

¹ A list of these studies can be obtained by contacting the National Academies Public Access Records Office.

detailed discussion of the committee’s approach and search strategy can be found in Chapter 9.

PHYSIOLOGY, NEUROBIOLOGY, AND BEHAVIOR

Target A: Mechanistic Research on the Process
from Trauma Exposure to PTSD

Target A.1: Neural Circuitry, Neural Connectivity, Brain Regions

Involved in PTSD Pathogenesis, and Neuronal Plasticity

DoD = 9; VA = 0; NIMH = 28; Other NIH Institutes = 6; Other = 10

The committee identified numerous studies that were a mix of research across species and methodologic designs including:

• Studies investigating neural correlates associated with basic mechanisms of fear learning and extinction, including in PTSD patients, and some efforts to computationally characterize that circuitry.
• Studies examining details of components of the fear learning circuitry (for example, subdivisions of the basolateral regions of the amygdala) or examined circuitry that overlaps with other behavioral paradigms (for example, responding to ambiguous faces).
• Studies related to cognitive techniques for controlling emotion and several studies that examined details of the circuitry that may be involved in the control of emotion.
• A few projects comparing other anxiety disorders such as social anxiety disorder with PTSD to understand the similarities and differences in the mechanisms underlying the pathophysiology across the different disorders.
• Projects investigating the mechanisms of the stress response and the hypothalamic pituitary axis, its neural circuitry, and factors that modify that circuitry.
• Relatively few studies on techniques linked to the development of resilience.
• A few projects examining circuitry in patients with PTSD.
• A few studies on sleep abnormalities and the interactions between sleep deprivation and PTSD pathophysiology.

Target A.2: Neuropeptides, Neurotransmitters, Cytokines, and Specific Receptors that Play a Role in PTSD Pathology and Symptoms

DoD = 4; VA = 1; NIMH = 38; Other NIH Institutes = 4; Other = 3

A large number of the studies funded under this category and target area were focused on basic mechanisms by which stress interacts with fear memories and resilience. A range of tools were used, including standard molecular tools, lesions and electrophysiology, and optogenetics. The experimental procedures used most often were fear conditioning and extinction, exposure to predators, and other stress models.

• Most of the studies were focused on the amygdala circuit and its interaction with the hippocampus and medial prefrontal cortex.
• Several studies focused on the hypothalamic pituitary axis, specifically the corticotrophin-releasing factors and corticotrophin-releasing hormone, associated receptors, and how those enhance fear memory consolidation.
• A few studies focused on the selective serotonin reuptake inhibitors (SSRIs) and interactions with brain-derived neurotrophic factors and their receptors.
• A few studies focused on neurosteroids, such as allopregnanolone and progesterone.
• A few studies that investigated the bed nucleus of the stria terminalis or the locus coeruleus.

Target A.3: Pathways to Understand Comorbidities and Overlapping Pathways Between PTSD and Comorbidities

DoD = 7; VA = 4; NIMH = 4; Other NIH Institutes = 11; Other = 1

A quarter of the studies in this section examined the mechanisms that underlie alcoholism and PTSD, and one examined cocaine. A few examined the relationship between stress, PTSD, and depression. Others examined the relationship between the neural circuitry or traumatic brain injury (TBI) and fear control techniques in PTSD. Additional projects examined overlap in the circuitry between stress and chronic fatigue syndrome and stress and sleep impairments. Most of the projects funded by DoD under this category were focused on the interactions between TBI and blast injuries, with few exceptions (one on depression and PTSD and another on epilepsy and PTSD). Individual studies in this area included the following:

• A project to explore the relationship between combat history, stress-induced drinking, and PTSD. The first aim was to explore the effect of combat trauma history on stress reactivity using subjective, neuroendocrine, and physiologic measures of stress. The second aim examined the effect of combat trauma history and subsequent drinking behavior and subjective response to alcohol.
• A project to evaluate if a dose response relationship existed between level of exposure to stressors and functioning over time; to understand the role of resilience and psychopathology in level of functioning; and to understand the role of healthy coping strategies and social supports as associated with functioning.
• A project to examine the relationship between combat-related PTSD and alcohol use over time; to test theorized (self-medication and social learning theory) PTSD and alcohol use associations; to examine the effect of length of time postdeployment on PTSD and alcohol use associations; and to examine associations between self-medication and concurrent functioning.
• A project to examine the prospective influences of pre-trauma adolescent and family risk factors and alcohol and drug problems, and to disentangle the directions of influence among traumatic stress, PTSD, and problematic alcohol and drug use. A goal was to determine the extent to which PTSD and alcohol share common developmental antecedents.
• A project to explore whether ecologic stressors influence the risk of PTSD and drug abuse and dependence among residents of Detroit, Michigan.

Target A.4: Memory, Fear Memory, and Memory Processing

DoD = 4; VA = 1; NIMH = 33; Other NIH Institutes = 5; Other = 1

Some of the projects in this section overlap with those captured under Target A.1 because some fear control techniques are essentially manipulating learning and memory. For instance, projects on reconsolidation were included under this target area because they involved memory manipulation, whereas projects on extinction were included under both this target area and target area A.1. Both the extinction and reconsolidation studies mostly examined models of conditioned fear as the learning task. Other studies under this category with no overlap included the following:

• Studies on conditioned fear generalization, trace fear conditioning, safety learning, and the impact of sleep. These projects spanned

• techniques from studies of cellular and molecular mechanisms to animal models of neural circuits to human systems.

• A few studies examined other types of memories as they are influenced by trauma or stress and a few examined sleep, traumatic memories and emotion, and episodic memory.
• A few studies were focused on the effects of sleep deprivation on fear learning and fear extinction, and others focused on appraisal and neurocognition in relation to PTSD.

Several projects that examined basic memory processes that were not specifically related to fear, emotion, trauma, or stress were identified. However, many of them investigated topics such as mechanisms of memory plasticity or altering memory consolidation that could be relevant to PTSD, including creating and understanding new interventions.

Target A.5: Neurobiology Underlying Gender Differences

DoD = 0; VA = 1; NIMH = 5; Other NIH Institutes = 1; Other = 0

There were a few studies that could be categorized under this target research area. The studies that did fall into this area focused on the influence of stress and norepinephrine on fear responses; sex differences in corticotrophin releasing factor in the prefrontal cortex; adenylate cyclase-activity polypeptide, its antagonists, and its interaction with the bed nucleus of the stria terminalis during fear learning; and morphological differences (gross differences or at the synaptic levels in the prefrontal cortex) between males and females.

Target B: Genomics of PTSD

DoD = 6; VA = 6; NIMH = 20; Other NIH Institutes = 3; Other = 1

Examples of studies under this target included those to identify genes or epigenetic modifications or changes in gene expression after trauma that are associated with an increased or decreased risk for developing PTSD. Studies were carried out in vitro, in rodent models, and in humans.

In vitro studies included the following:

• Studies that focused on understanding genetic changes and mechanisms related to stress, such as a sequencing study to examine the effects of early stress on histone and DNA modifications and a study on GluR2 gene transcription and consequent alterations in learning-induced synaptic plasticity.

• Studies to determine the role of epigenetic markers in the regulation of corticotrophin-releasing hormone, to identify peripheral markers of PACAP/PAC1 pathway activity to act as a biomarker for PTSD, and to identify epigenetic mechanisms that control the differentiation of Th1/Th2/TH17/Trey cells of the adaptive immune response.
• One study to determine how variations in acute tryptophan deletions affect emotional processing as a function of serotonin transporter genotype and one study to identify rare coding and noncoding serotonin transporter sequences.

Most of the rodent animal models under this research target were concerned with identifying and understanding mechanisms of resilience, memory formation, fear responses, and learned fear.

• Two rodent models were used to identify genetic and biologic factors that may influence risk for PTSD and comorbid alcohol use disorders.
• One study to advance the ability to manipulate gene expression within subsets of neurons, specifically the adrenergic, dopaminergic, serotonergic, and orexinergic systems.
• One study used a mouse model to examine whether the GIT2 gene is involved in susceptibility to PTSD.
• One study used a rat model to validate peripheral biomarkers of PTSD.
• One study used a rat model to identify genes in the brain that are differentially expressed in relation to a rat model of PTSD. This study was extended to examine how these genes are differentially expressed after cortisol administration in the posttrauma period. It has translational implications, as acute cortisol administration is viewed as having potential for PTSD prevention.

The studies in adult humans include both civilian and military populations. One goal of many of those studies was to understand the way in which candidate genes may or may not be associated with the development of PTSD. A futher goal was to gain a better understanding of the relationship between genetics and the environment and how that relationship could be influenced by the development of PTSD. Many of the studies integrated information from a variety of
Sources such as brain imaging, human genotyping, neuropsychological measurements, and clinical assessments. Three genome-wide association studies of PTSD were identified, one of which was used primarily in a veteran population. Some additional studies included the following:

• Studies to examine the way in which patterns of DNA methylation vary by TBI diagnosis and severity of the disease.
• Studies to identify genetic pathways implicated in PTSD.
• Studies to identify genetic and epigenetic changes associated with the disorder.
• A feasibility study to determine whether a sample of 1,000 veterans could be obtained for the purpose of examining the relationship between genes and PTSD.
• One study to examine epigenetic patterns associated with PTSD and other disorders and to examine whether epigenetic patterns change during psychotherapy.
• One study to examine the role of SLC6A3/SLC6A4 in PTSD symptoms, comorbidity, and treatment outcome.

Target C: Differential Responses to Treatment

DoD = 6; VA = 2; NIMH = 1; Other NIH Institutions = 0; Other = 6

The goal of the studies that were categorized under this category was to examine how people respond to PTSD treatment.

• One study used functional magnetic resonance imaging (fMRI) before and after cognitive processing therapy (CPT).
• One study used fMRI to compare psychiatric patients (including those with PTSD) to people without a psychiatric diagnosis to examine trust and interpersonal dysfunction before and after treatment.
• One study used pictures from the International Affective Picture System and investigated mildly painful skin sensations to predict response to treatment with quetiapine.
• One study looked at assessments across all of the South Texas Research Organizational Network Guiding Studies on Trauma and Resilience trials to examine predictors (that is, moderators and mediators) of response to treatment.
• One study examined if paroxetine changed fMRI responses in veterans with PTSD.
• One study aimed to develop psychophysiological, neuropsychological, and self-report models to predict PTSD symptom response to pharmacotherapy, psychotherapy, and combined pharmacotherapy and psychotherapy in veterans with PTSD.
• One study used a fear learning-extinction paradigm with fMRI and skin conductance response among civilian patients with PTSD.

• One study used fMRI to predict response to prolonged exposure (PE) therapy in a mixed group sample with PTSD.
• One study looked at neurobiology and neuropsychology as predictors of intervention efficacy in veterans with both TBI and PTSD.
• One study investigated how brain activations in PTSD predicted therapeutic responses to seroquel XR pharmacotherapy using pictures from the International Affective Picture System.
• One study looked at changes in psychological symptoms and gene expression in war veterans after emotionally focused therapy.

Target D: Preclinical Studies of New Pharmacotherapies

DoD = 4; VA = 3; NIMH = 5; Other NIH Institutes = 2; Other = 1

In its search of upcoming PTSD research, the committee found several novel and promising preclinical studies of new pharmacotherapies.

• One study examined brain pH and acid sensing in depression-related behaviors (for example, fear conditioning and acid-sensing ion channel 1a/ASIC1a). The investigators were trying to determine how this molecular model may be related to and may modulate fear and anxiety.
• One study examined the role of the immune system and T-cells in anxiety and stress.
• Several projects aimed to understand new molecules and targets, including arginine vasopressin, 1a receptor antagonists, an α-amino3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor modulator called CDPPB, cannabinoids, corticotropin-releasing factor, and transcranial direct current stimulation.

PREVENTION

DoD = 21; VA = 9; NIMH = 18; Other NIH Institutions = 4; Other = 8

The committee identified several studies that investigated the prevention of PTSD through stress-management interventions and pharmacological interventions. Some of those studies included the following:

• Several studies investigated the development of or severity of PTSD symptoms when substances such as hydrocortisone, oxytocin, diazepam, and polyunsaturated fatty acid were administered around the time of the trauma.

• Several studies examined research protocols and other interventions that aim to reduce anxiety in first responders after experiencing a traumatic event.
• One study delivered depression and anxiety reduction treatment in military personnel at Bagram Air Base, Afghanistan.
• One study investigating physiologic reactivity to virtual reality environments that depict common Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) combat scenarios.
• One cognitive-bias assessment used a recognition memory paradigm in Army National Guardsmen prior to deployment.
• Two predeployment resiliency interventions were tested: heart rate variability biofeedback and cognitive bias modification training.
• One study investigated the effectiveness of the stress resilience training system program at reducing perceived stress, PTSD symptoms, depression, anxiety, sleep quality, coping, attrition, and class and operational performance among U.S. Navy service members.
• One study examined preventive narrative exposure therapy (PreNET) in members of the Burundian Army and the joint African Union and United Nations peacekeeping mission in Somalia.

In addition to the above studies that focused on preventing PTSD by administering interventions before trauma exposure or immediately following trauma exposure, the committee identified several studies that focused on identifying early markers of the development of PTSD after trauma. Those studies examined general biomarkers for stress (sweat and saliva) and epigenetic markers for PTSD. Two studies explored potential genetic, neuroanatomical, and behavioral markers of resilience and one looked at neuroimaging and cerebrospinal fluid markers to distinguish PTSD from TBI and neurodegeneration following TBI. Others studies described the development of tools using single-photon emission computed tomography imaging and novel positron emission tomography tracers that may be used in the future to explore biomarkers for PTSD. Of those studies, there was one study that was focused on developing biomarkers that are specific to women. The committee also identified several studies that investigated modifiable factors that promote or prevent the development of PTSD. Some of the specific studies in this area include the following:

• One study focused on predicting mental health and substance abuse service needs in OEF and OIF military personnel within the first 12 months of returning from deployment.
• One study focused on the associations among military sexual trauma, PTSD symptoms, health behaviors, and physical health problems in male and female marine recruits.

• Two studies were components of the Marine Resiliency Study which aims to understand risk and resilience in a cohort of about 2,500 marines through an integrated series of three prospective, longitudinal, and interrelated projects. One of the projects aimed to identify individual and contextual factors that predict trajectories of PTSD and other mental health problems postdeployment. A second study was in the pilot phase and aimed to identify biomarkers of PTSD risk and chronicity among marines using genomic and other biologic and cognitive data collected predeployment.
• Two epidemiologic studies of National Guard and reserve personnel. One study focused on the Ohio National Guard and on identifying risk and protective factors for the development and course of psychopathology over a decade of follow-up. The other was a national sample of National Guard and reservists to identify factors associated with health service utilization.
• One study followed marines to identify predeployment and postdeployment factors that predict the development of psychopathology.
• Several studies investigated the role of early-life stress using a rat model.
• Several studies investigated brain indices that predict the development of acute or delayed-onset PTSD.
• Several studies investigated factors that predict risk of and response to military sexual trauma in active-duty personnel.
• One study used a population-based registry of combat veterans with PTSD and followed the cohort longitudinally to examine the role of risk factors and the progression, remission, and outcomes of veterans who have PTSD.
• One study examined the time of day of a trauma exposure in relation to risk of developing PTSD, with a specific interest in the role of cortisol diurnal variation.
• One study examined psychological mechanisms of resilience in combat veterans.

SCREENING

DoD = 4; VA = 5; NIMH = 3; Other NIH Institutes = 0; Other = 0

The studies in this target area were mostly focused on screening for PTSD, mild TBI, PTSD comorbid with substance abuse, cognitive symptoms of PTSD, interpersonal violence, or exposure to military sexual trauma. Most of the studies were conducted in veterans of OEF and OIF, with a small number in Gulf War veterans. A few were gender specific

(that is, restricted to women or men). Methods of screening included computer-assisted testing, health information technology, automated telephone screening, use of administrative data to develop algorithms, and use of compensation and pension reports to develop concept-based indexing. Four studies specifically examined the following:

• A new observer-rated screening interview for embedded professionals in the Marine Corps.
• A procedure to detect neurological impairment following combat.
• A questionnaire to screen for PTSD following road traffic accidents.
• Assessment of whether screening was associated with better PTSD outcomes.

DIAGNOSIS AND DETERMINING SYMPTOM SEVERITY

DoD = 5; VA = 5; NIMH = 1; Other NIH Institutes = 0; Other = 0

In this target area, several studies were identified that investigated tools for diagnosing PTSD and determining PTSD symptom severity.

• Two studies used positive emission tomography to investigate objective biologic markers, one used positive emission tomography for a limited aspect of PTSD, negative expectancies, and another used it to study region-specific metabolic changes to identify differences between mild TBI and PTSD.
• One study used text-mining to distinguish PTSD with TBI from PTSD without TBI.
• Several studies used prosodic and acoustic speech analysis to compare PTSD and non-PTSD groups and the use of electroencephalography, advanced brain imaging, and magnetoencephalography to differentiate those with mild TBI, PTSD, or acute stress disorder, or those with TBI and orthopedic controls.
• One study examined longitudinal PTSD Checklist scores in the VA to enhance its use.
• One study used the neurobehavioral symptom inventory to predict delayed-onset PTSD in those with subsyndromal PTSD and evaluate postconcussive symptoms in those with mild TBI and PTSD, mild TBI alone, PTSD alone, and subjects without mild TBI or PTSD.
• One study focused on quality of life and the development of a better instrument for assessing functional daily life activities of people who have PTSD.

TREATMENT

Target A.1: Pharmacotherapy

DoD = 11; VA = 13; NIMH = 2; Other NIH Institutes = 1; Other = 33

The pharmaceutical studies identified by the committee involved a broad spectrum of drugs with different mechanisms of action and novel methods of administration. The following types of studies were categorized under this target area:

• Three studies formed part of the Injury and Traumatic Stress consortium (a PTSD and TBI clinical consortium). These studies considered the relationship between pharmaceutical agents and PTSD or pharmaceuticals and variables that may effect PTSD (including rapid eye movement sleep, amygdala metabolism, medial prefrontal response to stress with positron emission tomography, pain, and memory).
• Several studies investigated specific pharmaceutical agents in OEF and OIF veterans, including the use of a single intravenous dose of ketamine versus midazolamanalgesic, tramodol, ganaxolone (a neurosteroid), galantamine, methylphenidate, nepicastat (an inhibitor of dopamine-beta-hydroxylase), riluzole (a glutamate modulator), fluoxetine (an SSRI), paroxetine, sertraline, mirtazapine, escitalopram (a neurokinin-1 antagonist) GSK561679, PRX-03140, carvedilol, oytocin, mifepristone, pregnenolone, intransal neuropetide-Y, and tetrahydrocannabinol.
• Several studies investigated antipsychotic drugs, including risperidone augmentation versus placebo in partial responders to SSRIs, risperidone augmentation of sertraline, iloperidone versus placebo, and asenapine open-label augmentation of SSRIs. Other drugs under study included lithium augmentation of SSRIs for its effects on hyperarousal and modafinil versus placebo augmentation.
• Several studies investigated propranolol to block memory consolidation and physiological hyperresponsivity and reduce symptoms of PTSD.
• Some studies investigated at over-the-counter natural products such as omega-3 fatty acids, N-acetylcysteine, and dehydroepiandrosterone.
• Two studies focused on 3,4 methylenedioxy-N-methyl amphetamine (MDMA) as an augmenter of psychotherapy, either to evaluate a single dose or to compare low- versus high-dose effects of the drug.

• Hydrocortisone is under study in four trials to evaluate different aspects of its action, such as effects on PTSD and physiological response after memory activation, brain imaging effects (hippocampus, amygdala, medial prefrontal cortex), and effects on fear extinction and memory.
• Two studies assessed aspects of sleep in PTSD. In one study, a single education session followed immediately by the option to use lorazepam was compared with an educational session with instructions to avoid sleep the first night after exposure to trauma. Another study of continuous positive airways pressure was investigated in patients with PTSD and sleep-disordered breathing as determined by polysomnography.
• Two studies examined prescribing patterns to treat PTSD. One study used a VA data set to examine prescribing patterns for new antipsychotic medications. A second aimed to intervene with care providers to improve evidence-based practices by reducing the number of benzodiazepine prescriptions to PTSD patients.

Target A.2: Somatic Treatments

DoD = 2; VA = 2; NIMH = 0; Other NIH Institutes = 0; Other = 6

The committee identified several studies that explored surgical treatment approaches or the use of stimulatory devices. Examples include the following:

• Two open-label pilot studies evaluated stellate ganglion block, a surgical procedure, for PTSD.
• Six studies used transcranial magnetic stimulation (TMS), including the evaluation of laterality (left versus right), dose (low or high frequency), “deep” TMS, the use of TMS for flashbacks, and the use of TMS to reduce relapse rates compared to treatment as usual.
• Bright light and trigeminal nerve stimulation were two other novel treatments under exploration, each in randomized controlled trials.

Target A.3: Psychotherapies

DoD = 4; VA = 12; NIMH = 6; Other NIH Institutes = 2; Other = 20

The committee found numerous treatment studies that were psychotherapy-specific. The following types of studies were identified in this target area:

• Two studies related to variations and extensions of cognitive behavioral therapy (CBT)-focused treatment. One examined cognitive training in working memory and executive function to strengthen the frontal areas of the brain that might serve to modulate limbicdriven emotional responding.
• One study compared interpersonal therapy (adapted for PTSD) with PE therapy and an active control receiving relaxation therapy.
• One study investigated an evidenced-based combination trauma intervention for veterans with depression, substance use disorder, and trauma exposure with and without PTSD.
• One study focused on an approach called expressive writing that appeared to have a writing component that is similar to CPT. The approach was delivered in an online format.
• One randomized controlled trial compared the impact of trauma management therapy on PTSD and social and emotional function compared with PE and psychoeducation. The study also investigated resource and cost outcomes.
• One study compared adaptive disclosure with CPT.
• Three studies examined the value of manipulating elements of PE to improve efficacy.
• One study investigated the potential to augment any evidence-based treatment with an additive CBT module designed to specifically address issues related to killing in a war zone.
• One study compared PE with a non-trauma-focused present-centered psychotherapy approach called Trauma Affect Regulation: Guide for Education and Therapy (TARGET). In a separate project CBT was compared with present-centered therapy for PTSD caused by military sexual trauma.
• One study investigated the enhancement of eye movement approaches with interactive personal guidance, referred to as accelerated resolution therapy. Non-trauma-focused approaches were also directly tested in three trials (behavioral activation, interpersonal psychotherapy, and an early intervention for sexual trauma using a psychoeducation video).
• Two trials specifically focused on military sexual trauma. One was open to male or female veterans of any war era (CPT versus present-centered therapy) and the other (psychoeducational video approach) was open to both civilian and female service members.
• One study compared attention bias modification treatment to a control scenario.
• One study conducted a feasibility trial of cognitive remediation therapy using a computer-based program that delivered cognitive exercises to improve attention, processing speed, and memory

• through practice as a way to reduce PTSD via better cognitive modulation of emotion.

• More than 10 studies were identified that were conducted outside of the United States and primarily in civilian populations. Treatments were varied and included attention bias modification treatment, rescripting and reprocessing therapy, CPT, gestalt therapy, narrative exposure therapy, eye movement desensitization and reprocessing, skills training in affective and emotional regulation, trauma-focused CBT, imagery rehearsal, supported employment, and interpersonal therapy.

Target A.4: Combining Psychotherapy and Pharmacotherapy

DoD = 4; VA = 4; NIMH = 8; Other NIH Institutes = 0; Other = 6

A few studies were identified that investigated the effectiveness of combining psychotherapy and pharmacotherapy treatments for PTSD.

• One study tested methylene blue to enhance PE therapy.
• Several studies combined a pharmaceutical agent (D-cycloserine, sertraline, or hydrocortisone) with PE therapy (one with virtual reality exposure therapy and two with standard PE therapy) to enhance or accelerate treatment response.
• Several studies investigated MDMA-assisted psychotherapy and augmentation of psychotherapy with D-cycloserine, hydrocortisone, yohimbine, or zonisamide.
• Two studies investigated patient-centered collaborative care with drug and psychotherapy versus treatment as usual.

Target A.5: Complementary and Alternative Treatments

DoD = 15; VA = 14; NIMH = 0; Other NIH Institutes = 4; Other = 12

The committee identified a range of complementary and alternative medicine studies, including those that focused on mindfulness, relaxation, yoga, mantram repetition, acupuncture, acupressure, biofeedback, and guitar music therapy. Specific studies in this category included

• Different forms of meditation, such as mindfulness-based, loving-kindness, self-compassion and transcendental meditation, were found most often in randomized controlled trials with either an active or inactive control. These studies are distributed across a wide range of populations with PTSD, including some in veterans.

• A randomized controlled trial to compare a 12-week acupuncture treatment program with a treatment-as-usual for both PTSD and TBI.
• A randomized controlled trial of thought field therapy in Rwandan subjects.
• Animal-assisted therapy was studied in two trials with veterans.
• A randomized controlled trial of the relaxation response using hyperbaric oxygen.
• The use of narrative writing to reduce PTSD symptoms.
• An open-label protocol using Sentra—a complex of various amino acids and herbal substances—for PTSD and comorbid fibromyalgia.

Target A.6: Different Models for the Delivery of PTSD Care

DoD = 24; VA = 19; NIMH = 4; Other NIH Institutions = 2; Other = 10

The committee identified several projects that tested new technologies to deliver telehealth using a remotely located clinician, to provide supplementary self-help material via websites, to monitor patient reactions using patient-worn sensors connected to mobile devices between sessions, and to use interactive voice response telephone monitoring systems to maintain patient engagement. Some of the studies in this area included the following:

• Three projects that focused on primary care settings, including ways that the primary care model could maximize accessibility of care and the added value of an array of technologies to improve the stepped care model.
• Four projects examined the relative efficacy of telehealth approaches for delivering care compared with in-person approaches. Two directly compared PE delivered in each format, and a third project explored the delivery of CPT conducted in an online group format. One telehealth approach examined early intervention for PTSD and comorbid insomnia in a group format.
• Two projects tested the use of virtual reality to deliver exposure-based treatments.
• Two studies focused on the use of technology (telephone-based pre-CBT treatment and Internet-based virtual reality) to deliver treatment to civilians who have PTSD.
• Several studies evaluated the use of computerized cognitive training programs for building cognitive skills that could be helpful in modulating emotion. One study tested cognitive remediation therapy as an alternative intervention for PTSD. Two other projects used similar computer-based systems to retrain attentional bias in

• individuals with PTSD and to specifically address comorbid mild TBI. All of these cognitive remediation therapy projects test the rationale that computer-delivered cognitive training programs will promote access via home-based practice.

• Several studies tested the use of computer-based and web or mobile technology to deliver psychosocial self-care and symptom management, and to engage significant others in the care process.
• Three studies investigated evidence-based treatments (two CPT and one PE) delivered online via video teleconference, and one examined outcomes from the delivery of expressive writing online.
• Two studies that did not use technology-based approaches examined the use of patient and provider collaborative-care models to enhance clinical service in primary care.
• One study compared DESTRESS-T (telephone therapy plus intensive telephone care management) to optimize usual care.
• Nine telehealth studies were identified: One focused on PE, three tested CPT, one tested an Internet writing intervention, two tested a behavioral activation approach, and two tested general CBT approaches.
• Five virtual reality exposure therapy projects were identified: One studied the development of a virtual reality exposure therapy system, one dismantled the virtual reality component of the therapy to see if showing only still images would be sufficient for reducing PTSD symptoms, and the other three compared virtual reality exposure therapy with traditional PE (one of which also tested the interaction with D-cycloserine).
• The largest project ($14.8 million) was on enhancing non-technology-related care. The study compared the stepped enhancement of PTSD and depression services using a primary care (STEPS UP) intervention.

Target A.7: Modality of the Treatment Intervention

DoD = 4; VA = 6; NIMH = 2; Other NIH Institutions = 0; Other = 3

The committee identified a few studies that investigated the modality of the treatment intervention—that is, treatments that are given in group, couple, or individual settings.

• One study examined the way in which family involvement could enhance PTSD treatment.
• Three projects examined conjoint couple therapy for PTSD, three

• of which were with veterans. A mix of treatment approaches was used, including mindfulness training

• Four studies investigated ways to enhance the efficiency of established evidence-based treatments, specifically PE and CPT. One focused on comparing efficacy of massed versus spaced trials for PE therapy delivery in recently returned active-duty service members. Another PE study compared delivery in a traditional PE one-on-one format versus cognitive behavioral conjoint therapy for PTSD, which is a trauma-focused approach designed to be delivered in a couples format to produce greater improvement in intimate relationship functioning. Two CPT projects were funded—one tested the efficacy of CPT delivered in groups to determine if it could be delivered more efficiently than one-on-one treatment, and the other was a randomized controlled trial that compared traditional delivery in an office with face-to-face delivery in the home.
• Four studies focused on testing group therapy as a mechanism for delivering treatment. Three used veteran samples and one was open to both active-duty service members and veterans. One compared group exposure therapy with treatment as usual in veterans. Another compared group CBT with emotional freedom techniques in veterans. An open trial tested the efficacy of group CBT in veterans. One investigated structured group therapy compared with unstructured group therapy in both service members and veterans.
• Three projects focused on couple therapy for veterans. Two tested a newer approach called structured approach therapy, which is specifically designed for PTSD treatment. A third project tested the efficacy of a CBT couples approach.

Target A.8: Treating Different Gender and Racial Groups

DoD = 2; VA = 3; NIMH = 4; Other NIH Institutions = 3; Other = 1

The committee identified a few research studies that were focused on women and minority populations.

• In the studies on women, the focus was primarily on alcohol, depression, early sexual assault, and interpersonal violence. A number of studies had large sample sizes and most combined treatments that are usually implemented in isolation (for example, relapse prevention with PE, and skills training in affective and interpersonal regulation plus modified PE); one study tested online treatment formats for rape victims and survivors.

• In the studies of minority populations, one addressed ways to improve medication prescribing, and the other focused on the tailored delivery of standard CBT.
• A few studies investigated the value of combining treatments and tested ways to make current treatments more accessible in female and minority populations.
• Two projects relied on secondary analyses of existing databases to compare differences in male and female PTSD mental health care service needs and to examine differences in comorbid substance abuse in male and female veterans. The aim of these studies was to determine if there were differences in the mental health needs across gender in veterans with PTSD and substance use.
• One study focused on the translation and cultural adaptation of the PE manual to better meet the needs of Hispanic veterans with PTSD.
• One project focused on testing a manualized approach that combines three treatment approaches in a group format for women.
• One study focused on American Indians and investigated a culturally relevant form of therapy, which involved indigenous healers compared with standard treatment.

Target A.9: Concurrent Treatment of Comorbidities

DoD = 12; VA = 28; NIMH = 5; Other NIH Institutes = 14; Other = 13

Most of the studies in this target area focused on PTSD and alcohol or substance use. Other areas of research were PTSD and depression, suicide, other mental health disorders, interpersonal violence, sleep disturbances, pain, and irritable bowel syndrome. Some of the treatment approaches in this research category were tailored exposure, imagery rehearsal with or without CBT, and cognitive behavior social rhythm therapy in groups. There were also a few studies related to pharmaceutical agents, technological applications, and yoga. Examples of specific studies included the following:

• A study examined prescribing patterns for PTSD and bipolar disorder to better characterize and understand prescribers’ decision making.
• A study secondarily analyzed data gathered from the STRONG STAR cohort to investigate pain and sleep with an existing sample of PE or CPT participants.

• One study examined thermal imaging as a way to measure the central nervous system to aid in the assessment of PTSD and to support therapy.
• Several studies evaluated the treatment of PTSD and smoking. These included the use of a nicotine patch versus placebo patch along with CBT and bupropion; integration of smoking cessation treatment with CBT for PTSD versus smoking cessation treatment alone; vareniclane and smoking cessation versus vareniclane; smoking cessation versus PE; use of supplemental nicotine administration prior to quitting; use of CBT for insomnia in subjects with PTSD, smoking, and insomnia; and the use of mobile text messaging for integrating CPT and smoking cessation treatments.
• A group of studies assessed the treatment of PTSD and severe insomnia or comorbid primary or secondary insomnia disorder. These included a comparison of prazosin, placebo, and CBT as augmentation to SSRI drug therapy; mindfulness-based mind-body bridging versus zolpidem treatment for primary and secondary insomnia; evaluation of short-term CBT for chronic insomnia; CBT for insomnia in survivors of interpersonal violence who have PTSD, depression, and insomnia; CBT for sleep in subjects who have PTSD and insomnia; and cognitive behavioral group therapy for sleep and nightmare problems in veterans who have PTSD and insomnia. One study assessed the effects of treating sleeplessness with CBT versus wait list on blood pressure and other cardiovascular indices.
• Other studies of comorbidity include narrative exposure therapy versus treatment-as-usual for PTSD with borderline personality disorder; tailored CBT treatment of PTSD in conjunction with serious mental illness such as psychosis and bipolar disorder; treatment of PTSD with panic attacks or panic disorder with multiple channel exposure therapy; and the use of repetitive transcranial magnetic stimulation for suicidality in those who have PTSD, depression, and mild TBI.
• Several studies investigated treatments for patients who have PTSD and depression using quetiapine, aripiprazole, vilazodone, and prazosin. One study compared metacognitive therapy with regular CBT for PTSD with depression or other anxiety disorders.

BARRIERS

DoD = 10; VA = 37; NIMH = 5, Other NIH Institutes = 2; Other = 0

Fifty-four projects refer to barriers to care. Several studies focused on barriers as the main purpose of the project and others included them as subsidiary goals (for example, in studies of treatment or the design of a new procedure to enhance care).

With respect to target populations, the largest group was of OEF and OIF veterans. There were also two studies of predominantly Vietnam-era veterans, nine that either did not specify the population of interest or studied veterans of all eras, and six that were limited to National Guard and reserve service members. Some examples of studies categorized in this area included the following:

• Studies that evaluated outcomes such as dropping out of treatment, acceptance of treatment, adherence to antidepressants in older patients, and adherence to PE or CBT.
• Studies on overcoming a barrier to treatment, such as the use of Web-based interventions, supportive education, buddy-to-buddy contact, telephone monitoring aftercare, and attitude-modifying interventions.
• Studies on barriers related to geographic determinants and ambulatory care.
• Studies focused on identifying barriers to care such as stigma and knowledge of types of treatment in active-duty and veteran populations.

Nearly all studies appropriately pertained to research on individual, family, provider, and institutional barriers to the delivery of evidence-based care. However, there were two studies that investigated variations in institutional review board functioning, one study that focused on transitioning care from DoD to VA, and two studies that were focused on identifying barriers for delivering novel treatments, such as acupuncture.

LONG-TERM OUTCOMES ASSOCIATED WITH PTSD

DoD = 9; VA = 10; NIMH = 4; Other NIH Institutes = 5; Other = 0

The committee identified several studies that investigated long-term health outcomes in people who had a diagnosis of PTSD. The studies varied widely and some considered such topics as the following:

• PTSD as a risk factor for cardiovascular disease and metabolic syndrome.
• A lifespan model looking at health outcomes with increasing age.
• Early detection and intervention in relation to later substance abuse and attrition from the military.
• Exposure to trauma cues and later risk taking.
• Factors determining long-term outcome following sexual trauma.
• A 6-year follow-up study to investigate how new stress impacts the trajectory of those who have PTSD and a comorbidity.
• One study to investigate reactions to extreme stress and biomarkers (for example, heart rate variability and endothelial function) in a Danish population.
• A long-term follow-up cohort of OEF and OIF National Guard personnel who are over 50 years old.
• Two studies to evaluate aspects of fibromyalgia, specifically its prevalence and impact on PTSD in active-duty service members.
• One study was a long-term follow-up of male and female veterans that assessed risk factors for missed diagnoses.
• As part of the RESTORE project, there were five protocols related to long-term outcomes. Three of the protocols were Web-based interventions (two randomized controlled trials of acceptance and commitment therapy and accelerated resolution therapy and an assessment of rates of high-risk behavior), one was a study of health outcomes in female veterans, and one was a randomized controlled trial of telemedicine for mild TBI.

INTIMATE PARTNER VIOLENCE

DoD = 0; VA = 4; NIMH = 2; Other NIH Institutes = 2; Other = 1

The committee identified a few studies that included reference to associations between PTSD and intimate partner violence.

• One study focused on mental health and physical health of men who sustain partner violence and their children.
• One study focused on racial and ethnic differences in the daily dynamics of PTSD, sexual risk, and substance abuse. It explored the mechanisms by which intimate partner violence may increase the risk of substance abuse and risky sexual behavior.
• One study assessed the longitudinal course of women who differed in intimate partner violence exposure and the emotional and behavioral problems of their children, to assess the additive and interactive effects of recent intimate partner violence and non-

• intimate partner violence on PTSD and depression; and to assess the additive or interactive effects of maternal attachment on PTSD and depression symptoms and biomarkers of allostatic load.

• One study in OEF and OIF veterans tested the hypothesis that TBI and executive functioning deficits moderate the impacts of PTSD symptoms and cognitive deficits and biases on the intimate partner violence outcomes.
• One study aimed to provide data to support the associations between PTSD and heightened rates of intimate partner violence in a veteran population. The primary objective was twofold: to describe the differences and examine factors that facilitate the detection by providers of intimate partner violence perpetrated by veterans and to describe and examine what variables might promote accurate detection.
• One study was a pilot program to treat 15 cases using a model for PTSD-focused CBT for partner violence.

TRAINING

Target A: Training Providers

DoD = 6; VA = 2; NIMH = 4; Other NIH Institutes = 0; Other = 3

The research in this target area included of primary care providers; mental health clinicians and trainees; clinical psychology graduate students; military, VA, and community mental health care providers; and primary care physicians. Some of the studies in this area included the following:

• Development and testing of a computer-based simulation training program.
• Development of a virtual patient for the identification and treatment of trauma-related mental health and health disorders in primary care of traumatized, low-income, culturally diverse patients with low English proficiency.
• Develop and test a Web-based system for training in CBT for social anxiety disorder and PTSD.
• Develop and mentor trainees in screening and intervention procedures to target PTSD and related conditions after injury.
• Create a PE computer-assisted therapy program to assist clinicians in implementing PE in real time.
• Development of a curriculum that provides clinical psychology graduate students with a broad training in exposure-based therapy for anxiety disorders.

• Teach a Seeking Safety program to 36 clinicians and a randomized controlled trial to randomly assign 100 clinicians to a Web-based PE refresher course for clinicians trained in PE versus clinicians not trained in PE.
• Whether supervision is required for PE.
• Use of a virtual patient and online course to train graduate students in motivational interviewing.
• Teach military primary care physicians how to interview following a postdeployment health reassessment.
• Web-centered supervision with internet training in VA and for community clinicians.
• Web-based training to help primary care physicians detect and treat PTSD.
• Development of a continuing medical education course based on PTSD treatment guidelines.
• Examining 120 Canadian clinicians and their PTSD patients and the importance of post-workshop support (6-month duration) on clinicians’ competence in CPT and patient symptoms.
• Document outcomes of CBT interventions delivered by credentialed, but not licensed, trainees treating a range of disorders.

Target B: Research or Training Grants for Career Development

DoD = 0; VA = 1; NIMH = 13; Other NIH Institutions = 8; Other = 0

The committee identified several k-awards or training grants in the NIH RePORT database. Some of the major topic areas of these awards and grants included the impact of PTSD on older veterans; laboratory methods for PTSD; the molecular basis of emotional learning; the use of fMRI for emotional memory research in PTSD; olfaction and PTSD; the neural basis of safety learning and fear inhibition by safety; and the genetic and environmental etiology of depression, anxiety disorders; s and PTSD. The impact of individual career development awards cannot be determined from the committee’s review of the databases. However, the committee acknowledges that grants aimed at training the next generation of researchers and clinicians in empirically supported methods are of utmost importance.