Faculty Bibliography

Posttraumatic stress disorder (PTSD) is characterized by atrophy within the prefrontal-limbic network. Graph analysis was used to investigate to what degree atrophy in PTSD is associated with impaired structural connectivity within prefrontal limbic network (restricted) and how this affects the integration of the prefrontal limbic network with the rest of the brain (whole-brain). 85 male veterans (45 PTSD neg, 40 PTSD pos) underwent volumetric MRI on a 3T MR. Subfield volumes were obtained using a manual labeling scheme and cortical thickness measurements and subcortical volumes from FreeSurfer. Regression analysis was used to identify regions with volume loss. Graph analytical Toolbox (GAT) was used for graph-analysis. PTSD pos had a thinner rostral anterior cingulate and insular cortex but no hippocampal volume loss. PTSD was characterized by decreased nodal degree (orbitofrontal, anterior cingulate) and clustering coefficients (thalamus) but increased nodal betweenness (insula, orbitofrontal) and a reduced small world index in the whole brain analysis and by orbitofrontal and insular nodes with increased nodal degree, clustering coefficient and nodal betweenness in the restricted analysis. PTSD associated atrophy in the prefrontal-limbic network results in an increased structural connectivity within that network that negatively affected its integration with the rest of the brain.

Cannabidiol (CBD), a Cannabis sativa constituent, is a pharmacologically broad-spectrum drug that in recent years has drawn increasing interest as a treatment for a range of neuropsychiatric disorders. The purpose of the current review is to determine CBD's potential as a treatment for anxiety-related disorders, by assessing evidence from preclinical, human experimental, clinical, and epidemiological studies. We found that existing preclinical evidence strongly supports CBD as a treatment for generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, and post-traumatic stress disorder when administered acutely; however, few studies have investigated chronic CBD dosing. Likewise, evidence from human studies supports an anxiolytic role of CBD, but is currently limited to acute dosing, also with few studies in clinical populations. Overall, current evidence indicates CBD has considerable potential as a treatment for multiple anxiety disorders, with need for further study of chronic and therapeutic effects in relevant clinical populations.

IMPORTANCE: Posttraumatic stress disorder (PTSD) is a disabling psychiatric disorder common among military personnel and veterans. First-line psychotherapies most often recommended for PTSD consist mainly of "trauma-focused" psychotherapies that involve focusing on details of the trauma or associated cognitive and emotional effects. OBJECTIVE: To examine the effectiveness of psychotherapies for PTSD in military and veteran populations. EVIDENCE REVIEW: PubMed, PsycINFO, and PILOTS were searched for randomized clinical trials (RCTs) of individual and group psychotherapies for PTSD in military personnel and veterans, published from January 1980 to March 1, 2015. We also searched reference lists of articles, selected reviews, and meta-analyses. Of 891 publications initially identified, 36 were included. FINDINGS: Two trauma-focused therapies, cognitive processing therapy (CPT) and prolonged exposure, have been the most frequently studied psychotherapies for military-related PTSD. Five RCTs of CPT (that included 481 patients) and 4 RCTs of prolonged exposure (that included 402 patients) met inclusion criteria. Focusing on intent-to-treat outcomes, within-group posttreatment effect sizes for CPT and prolonged exposure were large (Cohen d range, 0.78-1.10). CPT and prolonged exposure also outperformed waitlist and treatment-as-usual control conditions. Forty-nine percent to 70% of participants receiving CPT and prolonged exposure attained clinically meaningful symptom improvement (defined as a 10- to 12-point decrease in interviewer-assessed or self-reported symptoms). However, mean posttreatment scores for CPT and prolonged exposure remained at or above clinical criteria for PTSD, and approximately two-thirds of patients receiving CPT or prolonged exposure retained their PTSD diagnosis after treatment (range, 60%-72%). CPT and prolonged exposure were marginally superior compared with non-trauma-focused psychotherapy comparison conditions. CONCLUSIONS AND RELEVANCE: In military and veteran populations, trials of the first-line trauma-focused interventions CPT and prolonged exposure have shown clinically meaningful improvements for many patients with PTSD. However, nonresponse rates have been high, many patients continue to have symptoms, and trauma-focused interventions show marginally superior results compared with active control conditions. There is a need for improvement in existing PTSD treatments and for development and testing of novel evidence-based treatments, both trauma-focused and non-trauma-focused.

Importance: The long-term course of readjustment problems in military personnel has not been evaluated in a nationally representative sample. The National Vietnam Veterans Longitudinal Study (NVVLS) is a congressionally mandated assessment of Vietnam veterans who underwent previous assessment in the National Vietnam Veterans Readjustment Study (NVVRS). Objective: To determine the prevalence, course, and comorbidities of war-zone posttraumatic stress disorder (PTSD) across a 25-year interval. Design, Setting, and Participants: The NVVLS survey consisted of a self-report health questionnaire (n = 1409), a computer-assisted telephone survey health interview (n = 1279), and a telephone clinical interview (n = 400) in a representative national sample of veterans who served in the Vietnam theater of operations (theater veterans) from July 3, 2012, through May 17, 2013. Of 2348 NVVRS participants, 1920 were alive at the outset of the NVVLS, and 81 died during recruitment; 1450 of the remaining 1839 (78.8%) participated in at least 1 NVVLS study phase. Data analysis was performed from May 18, 2013, through January 9, 2015, with further analyses continued through April 13, 2015. Main Outcomes and Measures: Study instruments included the Mississippi Scale for Combat-Related PTSD, PTSD Checklist for DSM-IV supplemented with PTSD Checklist for DSM-5 items (PCL-5+), Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), and Structured Clinical Interview for DSM-IV, Nonpatient Version. Results: Among male theater veterans, we estimated a prevalence (95% CI) of 4.5% (1.7%-7.3%) based on CAPS-5 criteria for a current PTSD diagnosis; 10.8% (6.5%-15.1%) based on CAPS-5 full plus subthreshold PTSD; and 11.2% (8.3%-14.2%) based on PCL-5+ criteria for current war-zone PTSD. Among female veterans, estimates were 6.1% (1.8%-10.3%), 8.7% (3.8%-13.6%), and 6.6% (3.5%-9.6%), respectively. The PCL-5+ prevalence (95% CI) of current non-war-zone PTSD was 4.6% (2.6%-6.6%) in male and 5.1% (2.3%-8.0%) in female theater veterans. Comorbid major depression occurred in 36.7% (95% CI, 6.2%-67.2%) of veterans with current war-zone PTSD. With regard to the course of PTSD, 16.0% of theater veterans reported an increase and 7.6% reported a decrease of greater than 20 points in Mississippi Scale for Combat-Related PTSD symptoms. The prevalence (95% CI) of current PCL-5+-derived PTSD in study respondents was 1.2% (0.0%-3.0%) for male and 3.9% (0.0%-8.1%) for female Vietnam veterans. Conclusions and Relevance: Approximately 271000 Vietnam theater veterans have current full PTSD plus subthreshold war-zone PTSD, one-third of whom have current major depressive disorder, 40 or more years after the war. These findings underscore the need for mental health services for many decades for veterans with PTSD symptoms.

The National Vietnam Veterans Longitudinal Study (NVVLS) is the second assessment of a representative cohort of US veterans who served during the Vietnam War era, either in Vietnam or elsewhere. The cohort was initially surveyed in the National Vietnam Veterans Readjustment Study (NVVRS) from 1984 to 1988 to assess the prevalence, incidence, and effects of post-traumatic stress disorder (PTSD) and other post-war problems. The NVVLS sought to re-interview the cohort to assess the long-term course of PTSD. NVVLS data collection began July 3, 2012 and ended May 17, 2013, comprising three components: a mailed health questionnaire, a telephone health survey interview, and, for a probability sample of theater Veterans, a clinical diagnostic telephone interview administered by licensed psychologists. Excluding decedents, 78.8% completed the questionnaire and/or telephone survey, and 55.0% of selected living veterans participated in the clinical interview. This report provides a description of the NVVLS design and methods. Together, the NVVRS and NVVLS constitute a nationally representative longitudinal study of Vietnam veterans, and extend the NVVRS as a critical resource for scientific and policy analyses for Vietnam veterans, with policy relevance for Iraq and Afghanistan veterans

Genetic factors appear to be highly relevant to predicting differential risk for the development of post-traumatic stress disorder (PTSD). In a discovery sample, we conducted a genome-wide association study (GWAS) for PTSD using a small military cohort (Systems Biology PTSD Biomarkers Consortium; SBPBC, N = 147) that was designed as a case-controlled sample of highly exposed, recently returning veterans with and without combat-related PTSD. A genome-wide significant single nucleotide polymorphism (SNP), rs717947, at chromosome 4p15 (N = 147, beta = 31.34, P = 1.28 x 10-8 ) was found to associate with the gold-standard diagnostic measure for PTSD (the Clinician Administered PTSD Scale). We conducted replication and follow-up studies in an external sample, a larger urban community cohort (Grady Trauma Project, GTP, N = 2006), to determine the robustness and putative functionality of this risk variant. In the GTP replication sample, SNP rs717947 associated with PTSD diagnosis in females (N = 2006, P = 0.005), but not males. SNP rs717947 was also found to be a methylation quantitative trait locus (meQTL) in the GTP replication sample (N = 157, P = 0.002). Further, the risk allele of rs717947 was associated with decreased medial and dorsolateral cortical activation to fearful faces (N = 53, P < 0.05) in the GTP replication sample. These data identify a genome-wide significant polymorphism conferring risk for PTSD, which was associated with differential epigenetic regulation and with differential cortical responses to fear in a replication sample. These results may provide new insight into understanding genetic and epigenetic regulation of PTSD and intermediate phenotypes that contribute to this disorder. (c) 2015 Wiley Periodicals, Inc.

BACKGROUND: Enhanced glucocorticoid receptor (GR) sensitivity is present in people with posttraumatic stress disorder (PTSD), but the molecular mechanisms of GR sensitivity are not understood. Epigenetic factors have emerged as one potential mechanism that account for how trauma exposure leads to sustained PTSD symptoms given that PTSD develops in only a subset of trauma survivors. METHODS: Cytosine methylation of a relevant promoter of the GR gene (NR3C1-1F promoter) and three functional neuroendocrine markers of hypothalamic-pituitary-adrenal axis function were examined in a sample of 122 combat veterans. RESULTS: Lower NR3C1-1F promoter methylation in peripheral blood mononuclear cells (PBMCs) was observed in combat veterans with PTSD compared with combat-exposed veterans who did not develop PTSD. NR3C1-1F promoter methylation was also associated with three functional measures of glucocorticoid activity that have been associated with PTSD in combat veterans: PBMCs' lysozyme inhibition on the lysozyme suppression test, plasma cortisol decline on the low-dose (.50 mg) dexamethasone suppression test, and 24-hour urinary cortisol excretion. Finally, NR3C1-1F promoter methylation was inversely correlated with clinical markers and symptoms associated with PTSD. CONCLUSIONS: Alterations in NR3C1-1F promoter methylation may reflect enduring changes resulting from combat exposure that lead to functional neuroendocrine alterations. Because epigenetic measures are thought to reflect enduring effects of environmental exposures, they may be useful in distinguishing combat-exposed veterans who do or do not develop PTSD.

The need to understand the impact of war on military families has never been greater than during the past decade, with more than three million military spouses and children affected by deployments to Operations Iraqi Freedom and Enduring Freedom. Understanding the impact of the recent conflicts on families is a national priority, however, most studies have examined spouses and children individually, rather than concurrently as families. The Department of Defense (DoD) has recently initiated the largest study of military families in US military history (the Millennium Cohort Family Study), which includes dyads of military service members and their spouses (n > 10,000). This study includes US military families across the globe with planned follow-up for 21+ years to evaluate the impact of military experiences on families, including both during and after military service time. This review provides a comprehensive description of this landmark study including details on the research objectives, methodology, survey instrument, ancillary data sets, and analytic plans. The Millennium Cohort Family Study offers a unique opportunity to define the challenges that military families experience, and to advance the understanding of protective and vulnerability factors for designing training and treatment programs that will benefit military families today and into the future.