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Background and Objective Posttraumatic stress disorder (PTSD) is a serious and frequently debilitating psychiatric condition that can occur in people who have experienced traumatic stressors, such as war, violence, sexual assault and other life‐threatening events. Treatment of PTSD and traumatic brain injury (TBI) in veterans is challenged by diagnostic complexity, partially due to PTSD and TBI symptoms overlap and to the fact that subjective self‐report assessments may be influenced by a patient's willingness to share their traumatic experiences and resulting symptoms. Corticotropin‐releasing factor (CRF) is one of the main mediators of hypothalamic pituitary adrenal (HPA)‐axis responses in stress and anxiety. Methods and Results We analyzed serum CRF levels in 230 participants including heathy controls (64), and individuals with PTSD (53), TBI (70) or PTSD + TBI (43) by enzyme immunoassay (EIA). Significantly lower CRF levels were found in both the PTSD and PTSD + TBI groups compared to healthy control (PTSD vs. Controls: P = 0.0014, PTSD + TBI vs. Controls: P = 0.0011) and chronic TBI participants (PTSD vs. TBI: P

Fear extinction underlies prolonged exposure, one of the most well-studied treatments for posttraumatic stress disorder (PTSD). There has been increased interest in exploring pharmacological agents to enhance fear extinction learning in humans and their potential as adjuncts to PE. The objective of such adjuncts is to augment the clinical impact of PE on the durability and magnitude of symptom reduction. In this study, we examined whether hydrocortisone (HC), a corticosteroid, and D-Cycloserine (DCS), an N-methyl-D-aspartate receptor partial agonist, enhance fear extinction learning and consolidation in individuals with PTSD. In a double-blind placebo-controlled 3-group experimental design, 90 individuals with full or subsyndromal PTSD underwent fear conditioning with stimuli that were paired (CS+) or unpaired (CS−) with shock. Extinction learning occurred 72 h later and extinction retention was tested one week after extinction. HC 25 mg, DCS 50 mg or placebo was administered one hour prior to extinction learning. During extinction learning, the DCS and HC groups showed a reduced differential CS+/CS− skin conductance response (SCR) compared to placebo (b = −0.19, CI = −0.01 to −37, p = 0.042 and b = −0.25, CI = −08 to −0.43, p = 0.005, respectively). A nonsignificant trend for a lower differential CS+/CS− SCR in the DCS group, compared to placebo, (b = −0.25, CI = 0.04 to −0.55, p = 0.089) was observed at retention testing, one week later. A single dose of HC and DCS facilitated fear extinction learning in participants with PTSD symptoms. While clinical implications have yet to be determined, our findings suggest that glucocorticoids and NMDA agonists hold promise for facilitating extinction learning in PTSD.

Anger is a common and debilitating symptom of post-traumatic stress disorder (PTSD). Although studies have identified brain circuits underlying anger experience and expression in healthy individuals, how these circuits interact with trauma remains unclear. Here, we performed the first study examining the neural correlates of anger in patients with PTSD. Using a data-driven approach with resting-state fMRI, we identified two prefrontal regions whose overall functional connectivity was inversely associated with anger: the left anterior middle frontal gyrus (aMFG) and the right orbitofrontal cortex (OFC). We then used concurrent TMS-EEG to target the left aMFG parcel previously identified through fMRI, measuring its cortical excitability and causal connectivity to downstream areas. We found that low-anger PTSD patients exhibited enhanced excitability in the left aMFG and enhanced causal connectivity between this region and visual areas. Together, our results suggest that left aMFG activity may confer protection against the development of anger, and therefore may be an intriguing target for circuit-based interventions for anger in PTSD.

Funding Information: This work was supported by the National Institute of Mental Health / U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium ), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience . Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. Funding Information: MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc., RallyPoint Networks, Inc., Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work was supported by the National Institute of Mental Health/ U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience. Statistical analyses were carried out on the LISA/Genetic Cluster Computer (https://userinfo.surfsara.nl/systems/lisa) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. This material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting true views of the U.S. Department of the Army or the Department of Defense. We thank the investigators who comprise the PGC-PTSD working group and especially the more than 206,000 research participants worldwide who shared their life experiences and biological samples with PGC-PTSD investigators. We thank Mark Zervas for his critical input. Full acknowledgments are in Supplement 1. MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc. RallyPoint Networks, Inc. Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled ?Genotype-guided dosing of opioid agonists,? filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2021 Society of Biological Psychiatry Background: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods. publishersversion published

In January 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, was identified as the causative agent for pneumonia cases in the Hubei Province of China. By March 11, 2020, coronavirus disease 2019 (COVID-19) reached pandemic levels and had spread to nearly every continent. Due to an exponential growth of cases and high rate of hospital admission, patient volume rapidly exceeded capacity. To meet demand, physicians in Asia, Europe, and the United States, regardless of their specialty, were redeployed to COVID-19 units. Redeployment of physicians involves complex decisions, such as whom to reassign, where to reassign, and how to balance needs of frontline services with those of other critical services. Guidelines for these challenging decisions are scarce. To address this critical gap in policy, we present general recommendations for redeploying psychiatrists to the medical front lines. We address levels of preparedness, complexity of the medical settings, use of house staff, medical supervision, emotional support, risk management, back-filling psychiatric services, provider diversity, and ethical, legal, and regulatory challenges. Our guidelines are general and not intended to be “one size fits all,” as we recognize that local conditions will necessitate adaptation. [ Psychiatr Ann . 2020;50(7):301–305.]

Annually, approximately 30 million patients are discharged from the emergency department (ED) after a traumatic event1. These patients are at substantial psychiatric risk, with approximately 10-20% developing one or more disorders, including anxiety, depression or post-traumatic stress disorder (PTSD)2-4. At present, no accurate method exists to predict the development of PTSD symptoms upon ED admission after trauma5. Accurate risk identification at the point of treatment by ED services is necessary to inform the targeted deployment of existing treatment6-9 to mitigate subsequent psychopathology in high-risk populations10,11. This work reports the development and validation of an algorithm for prediction of post-traumatic stress course over 12 months using two independently collected prospective cohorts of trauma survivors from two level 1 emergency trauma centers, which uses routinely collectible data from electronic medical records, along with brief clinical assessments of the patient's immediate stress reaction. Results demonstrate externally validated accuracy to discriminate PTSD risk with high precision. While the predictive algorithm yields useful reproducible results on two independent prospective cohorts of ED patients, future research should extend the generalizability to the broad, clinically heterogeneous ED population under conditions of routine medical care.

Although glucocorticoid resistance contributes to increased inflammation, individuals with posttraumatic stress disorder (PTSD) exhibit increased glucocorticoid receptor (GR) sensitivity along with increased inflammation. It is not clear how inflammation coexists with a hyperresponsive hypothalamic-pituitary-adrenal (HPA) axis. To understand this better, we developed and analyzed an integrated mathematical model for the HPA axis and the immune system. We performed mathematical simulations for a dexamethasone (DEX) suppression test and IC50-dexamethasone for cytokine suppression by varying model parameters. The model analysis suggests that increasing the steepness of the dose-response curve for GR activity may reduce anti-inflammatory effects of GRs at the ambient glucocorticoid levels, thereby increasing proinflammatory response. The adaptive response of proinflammatory cytokine-mediated stimulatory effects on the HPA axis is reduced due to dominance of the GR-mediated negative feedback on the HPA axis. To verify these hypotheses, we analyzed the clinical data on neuroendocrine variables and cytokines obtained from war-zone veterans with and without PTSD. We observed significant group differences for cortisol and ACTH suppression tests, proinflammatory cytokines TNFα and IL6, high-sensitivity C-reactive protein, promoter methylation of GR gene, and IC50-DEX for lysozyme suppression. Causal inference modeling revealed significant associations between cortisol suppression and post-DEX cortisol decline, promoter methylation of human GR gene exon 1F ( NR3C1-1F), IC50-DEX, and proinflammatory cytokines. We noted significant mediation effects of NR3C1-1F promoter methylation on inflammatory cytokines through changes in GR sensitivity. Our findings suggest that increased GR sensitivity may contribute to increased inflammation; therefore, interventions to restore GR sensitivity may normalize inflammation in PTSD.

Active-duty Army personnel can be exposed to traumatic warzone events and are at increased risk for developing post-traumatic stress disorder (PTSD) compared with the general population. PTSD is associated with high individual and societal costs, but identification of predictive markers to determine deployment readiness and risk mitigation strategies is not well understood. This prospective longitudinal naturalistic cohort study—the Fort Campbell Cohort study—examined the value of using a large multidimensional dataset collected from soldiers prior to deployment to Afghanistan for predicting post-deployment PTSD status. The dataset consisted of polygenic, epigenetic, metabolomic, endocrine, inflammatory and routine clinical lab markers, computerized neurocognitive testing, and symptom self-reports. The analysis was computed on active-duty Army personnel (N = 473) of the 101st Airborne at Fort Campbell, Kentucky. Machine-learning models predicted provisional PTSD diagnosis 90–180 days post deployment (random forest: AUC = 0.78, 95% CI = 0.67–0.89, sensitivity = 0.78, specificity = 0.71; SVM: AUC = 0.88, 95% CI = 0.78–0.98, sensitivity = 0.89, specificity = 0.79) and longitudinal PTSD symptom trajectories identified with latent growth mixture modeling (random forest: AUC = 0.85, 95% CI = 0.75–0.96, sensitivity = 0.88, specificity = 0.69; SVM: AUC = 0.87, 95% CI = 0.79–0.96, sensitivity = 0.80, specificity = 0.85). Among the highest-ranked predictive features were pre-deployment sleep quality, anxiety, depression, sustained attention, and cognitive flexibility. Blood-based biomarkers including metabolites, epigenomic, immune, inflammatory, and liver function markers complemented the most important predictors. The clinical prediction of post-deployment symptom trajectories and provisional PTSD diagnosis based on pre-deployment data achieved high discriminatory power. The predictive models may be used to determine deployment readiness and to determine novel pre-deployment interventions to mitigate the risk for deployment-related PTSD.

DNA methylation patterns at specific cytosine-phosphate-guanine (CpG) sites predictably change with age and can be used to derive “epigenetic age”, an indicator of biological age, as opposed to merely chronological age. A relatively new estimator, called “DNAm GrimAge”, is notable for its superior predictive ability in older populations regarding numerous age-related metrics like time-to-death, time-to-coronary heart disease, and time-to-cancer. PTSD is associated with premature mortality and frequently has comorbid physical illnesses suggestive of accelerated biological aging. This is the first study to assess DNAm GrimAge in PTSD patients. We investigated the acceleration of GrimAge relative to chronological age, denoted “AgeAccelGrim” in combat trauma-exposed male veterans with and without PTSD using cross-sectional and longitudinal data from two independent well-characterized veteran cohorts. In both cohorts, AgeAccelGrim was significantly higher in the PTSD group compared to the control group (N = 162, 1.26 vs −0.57, p = 0.001 and N = 53, 0.93 vs −1.60 Years, p = 0.008), suggesting accelerated biological aging in both cohorts with PTSD. In 3-year follow-up study of individuals initially diagnosed with PTSD (N = 26), changes in PTSD symptom severity were correlated with AgeAccelGrim changes (r = 0.39, p = 0.049). In addition, the loss of CD28 cell surface markers on CD8 + T cells, an indicator of T-cell senescence/exhaustion that is associated with biological aging, was positively correlated with AgeAccelGrim, suggesting an immunological contribution to the accelerated biological aging. Overall, our findings delineate cellular correlates of biological aging in combat-related PTSD, which may help explain the increased medical morbidity and mortality seen in this disease.

Veterans Health Administration (VA) Medical Centers provide excellent care for many veterans. However, there are a number of veterans who are ineligible or choose not to access mental health treatment at the VA. To meet the needs of those veterans and of military family members, private centers have emerged to fill in gaps where care is unavailable or scarce. This paper describes how one such center, the Steven A. Cohen Military Family Center at NYU Langone Health, partnered with the local VA hospital to give one veteran ineligible for free mental health services the care he desperately needed. The case demonstrates the transformative work that can take place when public-private partnerships are forged and evidence-based treatments can be provided in a flexible way. It also illustrates the complexity of many veterans' presentations, which in this case required the therapist to continually challenge her conceptualization as she and the patient navigated different phases of his treatment.

Military families face specific challenges related to military service, deployments, separations, and coming together. The process of reintegration back to civilian life can be challenged by posttraumatic stress and other readjustment difficulties that can affect not only the veteran but the family as a whole. Strengthening bonds and relationships is an important step in recovery. In this paper, the authors review the application of emotionally focused therapy to couples therapy with military couples and identify factors that can facilitate the therapeutic process with this unique population.

The authors sought to identify brain regions whose frequency-specific, orthogonalized resting-state EEG power envelope connectivity differs between combat veterans with posttraumatic stress disorder (PTSD) and healthy combat-exposed veterans, and to determine the behavioral correlates of connectomic differences.The authors first conducted a connectivity method validation study in healthy control subjects (N=36). They then conducted a two-site case-control study of veterans with and without PTSD who were deployed to Iraq and/or Afghanistan. Healthy individuals (N=95) and those meeting full or subthreshold criteria for PTSD (N=106) underwent 64-channel resting EEG (eyes open and closed), which was then source-localized and orthogonalized to mitigate effects of volume conduction. Correlation coefficients between band-limited source-space power envelopes of different regions of interest were then calculated and corrected for multiple comparisons. Post hoc correlations of connectomic abnormalities with clinical features and performance on cognitive tasks were conducted to investigate the relevance of the dysconnectivity findings.Seventy-four brain region connections were significantly reduced in PTSD (all in the eyes-open condition and predominantly using the theta carrier frequency). Underconnectivity of the orbital and anterior middle frontal gyri were most prominent. Performance differences in the digit span task mapped onto connectivity between 25 of the 74 brain region pairs, including within-network connections in the dorsal attention, frontoparietal control, and ventral attention networks.Robust PTSD-related abnormalities were evident in theta-band source-space orthogonalized power envelope connectivity, which furthermore related to cognitive deficits in these patients. These findings establish a clinically relevant connectomic profile of PTSD using a tool that facilitates the lower-cost clinical translation of network connectivity research.

Fear extinction underlies prolonged exposure, one of the most well-studied treatments for posttraumatic stress disorder (PTSD). There has been increased interest in exploring pharmacological agents to enhance fear extinction learning in humans and their potential as adjuncts to PE. The objective of such adjuncts is to augment the clinical impact of PE on the durability and magnitude of symptom reduction. In this study, we examined whether hydrocortisone (HC), a corticosteroid, and D-Cycloserine (DCS), an N-methyl-D-aspartate receptor partial agonist, enhance fear extinction learning and consolidation in individuals with PTSD. In a double-blind placebo-controlled 3-group experimental design, 90 individuals with full or subsyndromal PTSD underwent fear conditioning with stimuli that were paired (CS+) or unpaired (CS-) with shock. Extinction learning occurred 72 h later and extinction retention was tested one week after extinction. HC 25 mg, DCS 50 mg or placebo was administered one hour prior to extinction learning. During extinction learning, the DCS and HC groups showed a reduced differential CS+/CS- skin conductance response (SCR) compared to placebo (b = -0.19, CI = -0.01 to -37, p = 0.042 and b = -0.25, CI = -08 to -0.43, p = 0.005, respectively). A nonsignificant trend for a lower differential CS+/CS- SCR in the DCS group, compared to placebo, (b = -0.25, CI = 0.04 to -0.55, p = 0.089) was observed at retention testing, one week later. A single dose of HC and DCS facilitated fear extinction learning in participants with PTSD symptoms. While clinical implications have yet to be determined, our findings suggest that glucocorticoids and NMDA agonists hold promise for facilitating extinction learning in PTSD.

Posttraumatic stress disorder (PTSD) is associated with neuroendocrine alterations and metabolic abnormalities; however, how metabolism is affected by neuroendocrine disturbances is unclear. The data from combat-exposed veterans with PTSD show increased glycolysis to lactate flux, reduced TCA cycle flux, impaired amino acid and lipid metabolism, insulin resistance, inflammation, and hypersensitive hypothalamic-pituitary-adrenal (HPA) axis. To analyze whether the co-occurrence of multiple metabolic abnormalities is independent or arises from an underlying regulatory defect, we employed a systems biological approach using an integrated mathematical model and multiomic analysis. The models for hepatic metabolism, HPA axis, inflammation, and regulatory signaling were integrated to perform metabolic control analysis (MCA) with respect to the observations from our clinical data. We combined the metabolomics, neuroendocrine, clinical laboratory, and cytokine data from combat-exposed veterans with and without PTSD to characterize the differences in regulatory effects. MCA revealed mechanistic association of the HPA axis and inflammation with metabolic dysfunction consistent with PTSD. This was supported by the data using correlational and causal analysis that revealed significant associations between cortisol suppression, high-sensitivity C-reactive protein, homeostatic model assessment of insulin resistance, γ-glutamyltransferase, hypoxanthine, and several metabolites. Causal mediation analysis indicates that the effects of enhanced glucocorticoid receptor sensitivity (GRS) on glycolytic pathway, gluconeogenic and branched-chain amino acids, triglycerides, and hepatic function are jointly mediated by inflammation, insulin resistance, oxidative stress, and energy deficit. Our analysis suggests that the interventions to normalize GRS and inflammation may help to manage features of metabolic dysfunction in PTSD.

OBJECTIVE This study aimed to identify modifiable factors associated with perceived functioning among veterans with high symptoms of posttraumatic stress disorder (PTSD). METHOD Two hundred fifty-one post-9/11 veterans completed a survey of psychosocial symptoms and functioning; a subset participated in a follow-up survey (n = 109). Latent profile analysis (LPA) at baseline identified groups that differed by level of functioning (high/low). Items utilized in the LPA analysis were derived from the World Health Organization Quality of Life-Bref self-report measure. Veterans with high PTSD symptoms in both groups were compared and logistic regression was utilized to predict group membership. RESULTS Veterans with high functioning/high symptoms (n = 45) had significantly lower alcohol use and sleep problems, and higher postdeployment social support, posttraumatic growth, and optimism than veterans with low functioning/high symptoms (n = 100). Fewer sleep difficulties and higher postdeployment social support and optimism were associated with membership in the high functioning/high symptom group. CONCLUSIONS These findings support the importance of identifying factors that can facilitate higher social, occupational, and general functional capacity for those with high levels of PTSD symptomatology. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Attempts to correlate blood levels of brain-derived neurotrophic factor (BDNF) with post-traumatic stress disorder (PTSD) have provided conflicting results. Some studies found a positive association between BDNF and PTSD diagnosis and symptom severity, while others found the association to be negative. The present study investigated whether serum levels of BDNF are different cross-sectionally between combat trauma-exposed veterans with and without PTSD, as well as whether longitudinal changes in serum BDNF differ as a function of PTSD diagnosis over time. We analyzed data of 270 combat trauma-exposed veterans (230 males, 40 females, average age: 33.29 ± 8.28 years) and found that, at the initial cross-sectional assessment (T0), which averaged 6 years after the initial exposure to combat trauma (SD=2.83 years), the PTSD positive group had significantly higher serum BDNF levels than the PTSD negative controls [31.03 vs. 26.95 ng/mL, t(268) = 3.921, p

We sought to find clinical subtypes of posttraumatic stress disorder (PTSD) in veterans 6–10 years post-trauma exposure based on current symptom assessments and to examine whether blood biomarkers could differentiate them. Samples were males deployed to Iraq and Afghanistan studied by the PTSD Systems Biology Consortium: a discovery sample of 74 PTSD cases and 71 healthy controls (HC), and a validation sample of 26 PTSD cases and 36 HC. A machine learning method, random forests (RF), in conjunction with a clustering method, partitioning around medoids, were used to identify subtypes derived from 16 self-report and clinician assessment scales, including the clinician-administered PTSD scale for DSM-IV (CAPS). Two subtypes were identified, designated S1 and S2, differing on mean current CAPS total scores: S2 = 75.6 (sd 14.6) and S1 = 54.3 (sd 6.6). S2 had greater symptom severity scores than both S1 and HC on all scale items. The mean first principal component score derived from clinical summary scales was three times higher in S2 than in S1. Distinct RFs were grown to classify S1 and S2 vs. HCs and vs. each other on multi-omic blood markers feature classes of current medical comorbidities, neurocognitive functioning, demographics, pre-military trauma, and psychiatric history. Among these classes, in each RF intergroup comparison of S1, S2, and HC, multi-omic biomarkers yielded the highest AUC-ROCs (0.819–0.922); other classes added little to further discrimination of the subtypes. Among the top five biomarkers in each of these RFs were methylation, micro RNA, and lactate markers, suggesting their biological role in symptom severity.

The understanding and treatment of psychiatric disorders with neurobiological and clinical heterogeneity could benefit from the identification of disease subtypes on the basis of data acquired with established neuroimaging technologies. Here, we report the identification of two clinically relevant subtypes of post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) on the basis of robust and distinct functional-connectivity patterns, prominently within the frontoparietal-control and default-mode networks. We identified the disease subtypes by analysing, via unsupervised and supervised machine learning, the power-envelope-based connectivity of signals reconstructed from high-density resting-state electroencephalography in four datasets from patients with PTSD and MDD, and show that the subtypes are transferable across independent datasets recorded under different conditions. The subtype whose functional connectivity differed most from those of healthy controls was less responsive to psychotherapy treatment for PTSD and failed to respond to an antidepressant medication for MDD. By contrast, both subtypes responded equally well to two different forms of repetitive transcranial magnetic stimulation therapy for MDD. Our data-driven approach may constitute a generalizable solution for connectome-based diagnosis., One-sentence editorial summary The analysis of functional-connectivity patterns in resting-state electroencephalography data via machine learning led to the identification of two clinically relevant subtypes of post-traumatic stress disorder and major depressive disorder.

This article reports on a study aimed to elucidate the complex etiology of post-traumatic stress (PTS) in a longitudinal cohort of police officers, by applying rigorous computational causal discovery (CCD) methods with observational data. An existing observational data set was used, which comprised a sample of 207 police officers who were recruited upon entry to police academy training. Participants were evaluated on a comprehensive set of clinical, self-report, genetic, neuroendocrine and physiological measures at baseline during academy training and then were re-evaluated at 12 months after training was completed. A data-processing pipeline—the Protocol for Computational Causal Discovery in Psychiatry (PCCDP)—was applied to this data set to determine a causal model for PTS severity. A causal model of 146 variables and 345 bivariate relations was discovered. This model revealed 5 direct causes and 83 causal pathways (of four steps or less) to PTS at 12 months of police service. Direct causes included single-nucleotide polymorphisms (SNPs) for the Histidine Decarboxylase (HDC) and Mineralocorticoid Receptor (MR) genes, acoustic startle in the context of low perceived threat during training, peritraumatic distress to incident exposure during first year of service, and general symptom severity during training at 1 year of service. The application of CCD methods can determine variables and pathways related to the complex etiology of PTS in a cohort of police officers. This knowledge may inform new approaches to treatment and prevention of critical incident related PTS.

Background We reanalyzed a multisite 26‐week randomized double‐blind placebo‐controlled clinical trial of 600 mg twice‐a‐day Gabapentin Enacarbil Extended‐Release (GE‐XR), a gabapentin prodrug, designed to evaluate safety and efficacy for treating alcohol use disorder. In the original analysis (n = 338), published in 2019, GE‐XR did not differ from placebo. Our aim is to advance precision medicine by identifying likely responders to GE‐XR from the trial data and to determine for likely responders if GE‐XR is causally superior to placebo. Methods The primary outcome measure in the reanalysis is the reduction from baseline of the number of heavy drinking days (ΔHDD). Baseline features including measures of alcohol use, anxiety, depression, mood states, sleep, and impulsivity were used in a random forest (RF) model to predict ΔHDD to treatment with GE‐XR based on those assigned to GE‐XR. The resulting RF model was used to obtain predicted outcomes for those randomized to GE‐XR and counterfactually to those randomized to placebo. Likely responders to GE‐XR were defined as those predicted to have a reduction of 14 days or more. Tests of causal superiority of GE‐XR to placebo were obtained for likely responders and for the whole sample. Results For likely responders, GE‐XR was causally superior to placebo (p, Individuals with AUD likely to respond to Gabapentin XR were identified based on predictive baseline clinical features. Their responses were causally superior to a matched group assigned to placebo. At baseline, likely responders had more heavy drinking days, lower levels of depression and anxiety and higher levels of cognitive and motor impulsivity. In the whole sample, there were no between treatment differences. The likely responder statistical paradigm as a valuable approach to analyzing RCTs and for advancing precision medicine.

DNA methylation patterns at specific cytosine-phosphate-guanine (CpG) sites predictably change with age and can be used to derive "epigenetic age", an indicator of biological age, as opposed to merely chronological age. A relatively new estimator, called "DNAm GrimAge", is notable for its superior predictive ability in older populations regarding numerous age-related metrics like time-to-death, time-to-coronary heart disease, and time-to-cancer. PTSD is associated with premature mortality and frequently has comorbid physical illnesses suggestive of accelerated biological aging. This is the first study to assess DNAm GrimAge in PTSD patients. We investigated the acceleration of GrimAge relative to chronological age, denoted "AgeAccelGrim" in combat trauma-exposed male veterans with and without PTSD using cross-sectional and longitudinal data from two independent well-characterized veteran cohorts. In both cohorts, AgeAccelGrim was significantly higher in the PTSD group compared to the control group (N = 162, 1.26 vs -0.57, p = 0.001 and N = 53, 0.93 vs -1.60 Years, p = 0.008), suggesting accelerated biological aging in both cohorts with PTSD. In 3-year follow-up study of individuals initially diagnosed with PTSD (N = 26), changes in PTSD symptom severity were correlated with AgeAccelGrim changes (r = 0.39, p = 0.049). In addition, the loss of CD28 cell surface markers on CD8 + T cells, an indicator of T-cell senescence/exhaustion that is associated with biological aging, was positively correlated with AgeAccelGrim, suggesting an immunological contribution to the accelerated biological aging. Overall, our findings delineate cellular correlates of biological aging in combat-related PTSD, which may help explain the increased medical morbidity and mortality seen in this disease.

Background Traumatic stress can adversely affect physical and mental health through neurobiological stress response systems. We examined the effects of trauma exposure and posttraumatic stress disorder (PTSD) on telomere length, a biomarker of cellular aging, and volume of the amygdala, a key structure of stress regulation, in combat-exposed veterans. In addition, the relationships of psychopathological symptoms and autonomic function with telomere length and amygdala volume were examined. Methods Male combat veterans were categorized as having PTSD diagnosis (n = 102) or no lifetime PTSD diagnosis (n = 111) based on the Clinician-Administered PTSD Scale. Subjects were assessed for stress-related psychopathology, trauma severity, autonomic function, and amygdala volumes by magnetic resonance imaging. Results A significant interaction was found between trauma severity and PTSD status for telomere length and amygdala volume after adjusting for multiple confounders. Subjects with PTSD showed shorter telomere length and larger amygdala volume than those without PTSD among veterans exposed to high trauma, while there was no significant group difference in these parameters among those exposed to low trauma. Among veterans exposed to high trauma, greater telomere shortening was significantly correlated with greater norepinephrine, and larger amygdala volume was correlated with more severe psychological symptoms and higher heart rates. Conclusions These data suggest that the intensity of the index trauma event plays an important role in interacting with PTSD symptomatology and autonomic activity in predicting telomere length and amygdala volume. These results highlight the importance of trauma severity and PTSD status in predicting certain biological outcomes.

Introduction Current pharmacological treatments of post-traumatic stress disorder (PTSD) have limited efficacy. Although the diagnosis is based on psychopathological criteria, it is frequently accompanied by somatic comorbidities and perhaps “accelerated biological aging,” suggesting widespread physical concomitants. Such physiological comorbidities may affect core PTSD symptoms but are rarely the focus of therapeutic trials. Methods To elucidate the potential involvement of metabolism, inflammation, and mitochondrial function in PTSD, we integrate findings and mechanistic models from the DOD-sponsored “Systems Biology of PTSD Study” with previous data on these topics. Results Data implicate inter-linked dysregulations in metabolism, inflammation, mitochondrial function, and perhaps the gut microbiome in PTSD. Several inadequately tested targets of pharmacological intervention are proposed, including insulin sensitizers, lipid regulators, anti-inflammatories, and mitochondrial biogenesis modulators. Conclusions Systemic pathologies that are intricately involved in brain functioning and behavior may not only contribute to somatic comorbidities in PTSD, but may represent novel targets for treating core psychiatric symptoms.

Background United Nations (UN) personnel address a diverse range of political, social, and cultural crises throughout the world. Compared with other occupations routinely exposed to traumatic stress, there remains a paucity of research on mental health disorders and access to mental healthcare in this population. To fill this gap, personnel from UN agencies were surveyed for mental health disorders and mental healthcare utilization. Methods UN personnel (N = 17 363) from 11 UN entities completed online measures of generalized anxiety disorder (GAD), major depressive disorder (MDD), posttraumatic stress disorder (PTSD), trauma exposure, mental healthcare usage, and socio-demographic information. Results Exposure to one or more traumatic events was reported by 36.2% of survey responders. Additionally, 17.9% screened positive for GAD, 22.8% for MDD, and 19.9% for PTSD. Employing multivariable logistic regressions, low job satisfaction, younger age ( Conclusions UN personnel appear to be at high risk for trauma exposure and screening positive for a mental health disorder, yet a small percentage screening positive for mental health disorders sought treatment. Despite the mental health gaps observed in this study, additional research is needed, as these data reflect a large sample of convenience and it cannot be determined if the findings are representative of the UN.

Post-traumatic stress disorder (PTSD) is a heterogeneous condition evidenced by the absence of objective physiological measurements applicable to all who meet the criteria for the disorder as well as divergent responses to treatments. This study capitalized on biological diversity observed within the PTSD group observed following epigenome-wide analysis of a well-characterized Discovery cohort (N = 166) consisting of 83 male combat exposed veterans with PTSD, and 83 combat veterans without PTSD in order to identify patterns that might distinguish subtypes. Computational analysis of DNA methylation (DNAm) profiles identified two PTSD biotypes within the PTSD+ group, G1 and G2, associated with 34 clinical features that are associated with PTSD and PTSD comorbidities. The G2 biotype was associated with an increased PTSD risk and had higher polygenic risk scores and a greater methylation compared to the G1 biotype and healthy controls. The findings were validated at a 3-year follow-up (N = 59) of the same individuals as well as in two independent, veteran cohorts (N = 54 and N = 38), and an active duty cohort (N = 133). In some cases, for example Dopamine-PKA-CREB and GABA-PKC-CREB signaling pathways, the biotypes were oppositely dysregulated, suggesting that the biotypes were not simply a function of a dimensional relationship with symptom severity, but may represent distinct biological risk profiles underpinning PTSD. The identification of two novel distinct epigenetic biotypes for PTSD may have future utility in understanding biological and clinical heterogeneity in PTSD and potential applications in risk assessment for active duty military personnel under non-clinician-administered settings, and improvement of PTSD diagnostic markers.

Objective The Fort Campbell Cohort study was designed to assess predeployment biological and behavioral markers and build predictive models to identify risk and resilience for posttraumatic stress disorder (PTSD) following deployment. This article addresses neurocognitive functioning variables as potential prospective predictors. Method In a sample of 403 soldiers, we examined whether PTSD symptom severity (using the PTSD Checklist) as well as posttraumatic stress trajectories could be prospectively predicted by measures of executive functioning (using two web-based tasks from WebNeuro) assessed predeployment. Results Controlling for age, gender, education, prior number of deployments, childhood trauma exposure, and PTSD symptom severity at Phase 1, linear regression models revealed that predeployment sustained attention and inhibitory control performance were significantly associated with postdeployment PTSD symptom severity. We also identified two posttraumatic stress trajectories utilizing latent growth mixture models. The "resilient" group consisted of 90.9% of the soldiers who exhibited stable low levels of PTSD symptoms from pre- to postdeployment. The "increasing" group consisted of 9.1% of the soldiers, who exhibited an increase in PTSD symptoms following deployment, crossing a threshold for diagnosis based on PTSD Checklist scores. Logistic regression models predicting trajectory revealed a similar pattern of findings as the linear regression models, in which predeployment sustained attention (95% CI of odds ratio: 1.0109, 1.0558) and inhibitory control (95% CI: 1.0011, 1.0074) performance were significantly associated with postdeployment PTSD trajectory. Conclusions These findings have clinical implications for understanding the pathogenesis of PTSD and building preventative programs for military personnel. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

BACKGROUND AND PURPOSE: Cerebral microhemorrhages are a known marker of mild traumatic brain injury. Blast-related mild traumatic brain injury relates to a propagating pressure wave, and there is evidence that the mechanism of injury in blast-related mild traumatic brain injury may be different from that in blunt head trauma. Two recent reports in mixed cohorts of blunt and blast-related traumatic brain injury in military personnel suggest that the prevalence of cerebral microhemorrhages is lower than in civilian head injury. In this study, we aimed to characterize the prevalence of cerebral microhemorrhages in military service members specifically with chronic blast-related mild traumatic brain injury. MATERIALS AND METHODS: Participants were prospectively recruited and underwent 3T MR imaging. Susceptibility-weighted images were assessed by 2 neuroradiologists independently for the presence of cerebral microhemorrhages. RESULTS: Our cohort included 146 veterans (132 men) who experienced remote blast-related mild traumatic brain injury (mean, 9.4 years; median, 9 years after injury). Twenty-one (14.4%) reported loss of consciousness for 2 episodes. No cerebral microhemorrhages were identified in any subject, as opposed to the frequency of SWI-detectable cerebral microhemorrhages following blunt-related mild traumatic brain injury in the civilian population, which has been reported to be as high as 28% in the acute and subacute stages. CONCLUSIONS: Our results may reflect differences in pathophysiology and the mechanism of injury between blast- and blunt-related mild traumatic brain injury. Additionally, the chronicity of injury may play a role in the detection of cerebral microhemorrhages.

Background Approximately half of US service members are married, equating to 1.1 million military spouses, yet the prevalence of psychiatric morbidity among military spouses remains understudied. We assessed the prevalence and correlates of eight mental health conditions in spouses of service members with 2-5 years of service. Method We employed baseline data from the Millennium Cohort Family Study, a 21-year longitudinal survey following 9,872 military-affiliated married couples representing all US service branches and active duty, Reserve, and National Guard components. Couples were surveyed between 2011 and 2013, a period of high military operational activity associated with Operation Iraqi Freedom and Operation Enduring Freedom. Primary outcomes included depression, anxiety, posttraumatic stress disorder (PTSD), panic, alcohol misuse, insomnia, somatization, and binge eating, all assessed with validated self-report questionnaires. Results A total of 35.90% of military spouses met criteria for at least one psychiatric condition. The most commonly endorsed conditions were moderate-to-severe somatization symptoms (17.63%) and moderate-to-severe insomnia (15.65%). PTSD, anxiety, depression, panic, alcohol misuse, and binge eating were endorsed by 9.20%, 6.65%, 6.05%, 7.07%, 8.16%, and 5.23% of spouses, respectively. Having a partner who deployed with combat resulted in higher prevalence of anxiety, insomnia, and somatization. Spouses had lower prevalence of PTSD, alcohol misuse, and insomnia but higher rates of panic and binge eating than service members. Both members of a couple rarely endorsed having the same psychiatric problem. Conclusions One third of junior military spouses screened positive for one or more psychiatric conditions, underscoring the need for high-quality prevention and treatment services.

Traumatic brain injury (TBI) and Alzheimer's disease (AD) are devastating neurological disorders, whose complex relationship is not completely understood. Cerebrovascular pathology, a key element in both conditions, could represent a mechanistic link between Aβ/tau deposition after TBI and the development of post concussive syndrome, dementia and chronic traumatic encephalopathy (CTE). In addition to debilitating acute effects, TBI-induced neurovascular injuries accelerate amyloid β (Aβ) production and perivascular accumulation, arterial stiffness, tau hyperphosphorylation and tau/Aβ-induced blood brain barrier damage, giving rise to a deleterious feed-forward loop. We postulate that TBI can initiate cerebrovascular pathology, which is causally involved in the development of multiple forms of neurodegeneration including AD-like dementias. In this review, we will explore how novel biomarkers, animal and human studies with a focus on cerebrovascular dysfunction are contributing to the understanding of the consequences of TBI on the development of AD-like pathology., Highlights • Cerebrovascular dysfunction (CVD) is emerging as a key element in the development of neurodegeneration after TBI. • We propose that TBI initiates CVD, accelerating Aβ/tau deposition and leading to neurodegeneration and dementias. • Clarifying this connection will support the development of novel biomarkers and therapeutic approaches for both TBI and AD.

Chronic sleep deficiency is prevalent in modern society and is associated with increased risk of metabolic and other diseases. While the mechanisms by which chronic sleep deficiency induces pathophysiological changes are yet to be elucidated, the hypothalamic–pituitary–adrenal (HPA) axis may be an important mediator of these effects. Cortisol, the primary hormone of the HPA axis, exhibits robust circadian rhythmicity and is moderately influenced by sleep and wake states and other physiology. Several studies have explored the effects of acute or chronic sleep deficiency (i.e., usually from self-selected chronic sleep restriction, CSR) on the HPA axis. Quantifying long-term changes in the circadian rhythm of cortisol under CSR in controlled conditions is inadequately studied due to practical limitations. We use a semi-mechanistic mathematical model of the HPA axis and the sleep/wake cycle to explore the influence of CSR on cortisol circadian rhythmicity. In qualitative agreement with experimental findings, model simulations predict that CSR results in physiologically relevant disruptions in the phase and amplitude of the cortisol rhythm. The mathematical model presented in this work provides a mechanistic framework to further explore how CSR might lead to HPA axis disruption and subsequent development of chronic metabolic complications.

Objective Acute leukemia (AL) is associated with an immediate threat to life, an unpredictable clinical course, and substantial physical suffering. Traumatic stress symptoms that may meet criteria for acute stress disorder (ASD) may be common and disabling in this context, but have received little clinical attention. We investigated the incidence over time and risk factors for traumatic stress symptoms and ASD in the 3 months following diagnosis or relapse of AL. Methods Individuals with AL were recruited at a tertiary cancer center in Canada within one month of diagnosis or relapse. Participants (N = 230) completed self-report measures, including the Stanford Acute Stress Reaction Questionnaire, at baseline and monthly over 3 months. The incidence of traumatic stress symptoms over time was examined, and a generalized logistic model was used to identify factors associated with ASD. Results Participants were 60% male, with a mean age of 48.9 ± 15.2 years. Symptoms of ASD were identified on ≥1 assessment over the study period in 24.4% of participants at baseline and in an additional 12.6% at a subsequent follow-up. Of these, 55.3% reported symptoms on ≥2 assessments. ASD was associated with having young children, being unmarried, acute lymphocytic leukemia, and greater physical symptom burden. Persistent or recurrent ASD was associated with female sex, acute lymphocytic leukemia, greater attachment anxiety, less spiritual well-being, and less satisfactory patient-clinician communication. Conclusions Symptoms of ASD are common and often persist or recur following diagnosis or relapse of AL. Research is urgently needed to determine the impact of interventions to prevent and treat psychological distress in this population.

Background Few studies have longitudinally examined predictors of posttraumatic stress disorder (PTSD) in a nationally representative sample of US veterans. We examined predictors of warzone-related PTSD over a 25-year span using data from the National Vietnam Veterans Longitudinal Study (NVVLS). Methods The NVVLS is a follow-up study of Vietnam theater veterans (N = 699) previously assessed in the National Vietnam Veterans Readjustment Study (NVVRS), a large national-probability study conducted in the late 1980s. We examined the ability of 22 premilitary, warzone, and postmilitary variables to predict current warzone-related PTSD symptom severity and PTSD symptom change in male theater veterans participating in the NVVLS. Data included a self-report Health Questionnaire survey and a computer-assisted telephone Health Interview Survey. Primary outcomes were self-reported PTSD symptoms assessed by the PTSD Checklist for DSM-5 (PCL 5) and Mississippi PTSD Scale (M-PTSD). Results Predictors of current PTSD symptoms most robust in hierarchical multivariable models were African-American race, lower education level, negative homecoming reception, lower current social support, and greater past-year stress. PTSD symptoms remained largely stable over time, and symptom exacerbation was predicted by African-American race, lower education level, younger age at entry into Vietnam, greater combat exposure, lower current social support, and greater past-year stressors. Conclusions Findings confirm the robustness of a select set of risk factors for warzone-related PTSD, establishing that these factors can predict PTSD symptom severity and symptom change up to 40 years postdeployment.

Introduction Several lines of evidence indicate that increased inflammation is associated with Post-Traumatic Stress Disorder (PTSD). We have previously reported that peripheral inflammatory markers are significantly higher in combat-exposed veterans with than without PTSD. This study was designed to replicate these findings in a new study cohort using the same population and recruitment strategies. Methods Sixty-one male war veterans (31 PTSD and 30 control subjects) were included in this replication study. Levels of Interleukin-6, Tumor Necrosis Factor-alpha, Gamma interferon, and high-sensitivity C-reactive protein were quantified in blood samples. A standardized “total pro-inflammatory score” was calculated to limit the number of statistical comparisons. The Clinician Administered PTSD Scale (CAPS) rating scale was used to assess PTSD symptom severity. Results PTSD subjects had significantly higher total pro-inflammatory scores compared to non-PTSD subjects in unadjusted analysis (Cohen’s d = 0.75, p = 0.005) as well as after adjusting for potentially confounding effects of age, BMI, smoking, and potentially interfering medications and somatic co-morbidities (p = 0.023). There were no significant correlations between inflammatory markers and severity of symptoms within the PTSD group. Conclusions We replicated, in a new sample, our previous finding of increased inflammatory markers in combat-exposed PTSD subjects compared to combat-exposed non-PTSD controls. These findings strongly add to the growing literature suggesting that immune activation may be an important aspect of PTSD pathophysiology, although not directly correlated with current PTSD symptom levels in the PTSD group.

Background A growing body of evidence suggests that the ability to flexibly express and suppress emotions (“expressive flexibility”) supports successful adaptation to trauma and loss. However, studies have yet to examine whether individuals that meet criteria for posttraumatic stress disorder (PTSD) or depression exhibit alterations in expressive flexibility. The present study aims to test whether lower levels of expressive flexibility are associated with PTSD and depression in combat-exposed veterans. Methods Fifty-nine combat veterans with and without PTSD completed self-report measures assessing symptoms of depression, PTSD, and combat exposure. Participants also completed an expressive flexibility task in which they were asked to either enhance or suppress their expressions of emotion while viewing affective images on a computer screen. Expressive flexibility was assessed by both expressive enhancement ability and expressive suppression ability. Results Repeated measures ANOVA's showed that both PTSD and depression were associated with lower levels of emotional enhancement ability. In addition, a series of linear regressions demonstrated that lower levels of emotional enhancement ability were associated with greater symptom severity of PTSD and depression. The ability to suppress emotional responses did not differ among individuals with and without PTSD or depression. Limitations of the study include a cross-sectional design, precluding causality; the lack of a non-trauma exposed group and predominantly male participants limit the generalizability to other populations. Conclusions Alterations in expressive flexibility is a previously unrecognized affective mechanism associated with PTSD and depression. Clinical strategies aimed at enhancing emotional expression may aid in the treatment of these disorders.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5–20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations., Post-traumatic stress disorder (PTSD) is a common mental health problem. Here, the authors report a GWAS from the Psychiatric Genomics Consortium in which they identify two risk loci in European ancestry and one locus in African ancestry individuals and find that PTSD is genetically correlated with several other psychiatric traits.

Childhood maltreatment is highly prevalent and serves as a risk factor for mental and physical disorders. Self-reported childhood maltreatment appears heritable, but the specific genetic influences on this phenotype are largely unknown. The aims of this study were to 1) identify genetic variation associated with reported childhood maltreatment, 2) calculate the relevant SNP-based heritability estimates, and 3) quantify the genetic overlap of reported childhood maltreatment with mental and physical health-related phenotypes. Genome-wide association analysis for childhood maltreatment was undertaken, using a discovery sample from the UK Biobank (UKBB) (n=124,000) and a replication sample from the Psychiatric Genomics Consortium–posttraumatic stress disorder working group (PGC-PTSD) (n=26,290). Heritability estimations for childhood maltreatment and genetic correlations with mental/physical health traits were calculated using linkage disequilibrium score regression (LDSR). Two genome-wide significant loci associated with childhood maltreatment, located on chromosomes 3p13 (rs142346759, beta=0.015, p=4.35×10−8,FOXP1) and 7q31.1 (rs10262462, beta=-0.016, p=3.24×10−8,FOXP2), were identified in the discovery dataset but were not replicated in the PGC-PTSD sample. SNP-based heritability for childhood maltreatment was estimated to be ∼6%. Childhood maltreatment was most significantly genetically correlated with depressive symptoms (rg=0.70, p=4.65×10−40). This is the first large-scale genetic study to identify specific variants associated with self-reported childhood maltreatment.FOXPgenes could influence traits such as depression and thereby be relevant to childhood maltreatment. Alternatively, these variants may be associated with a greater likelihood of reporting maltreatment. A clearer understanding of the genetic relationships of childhood maltreatment, including particular abuse subtypes, with various psychiatric disorders, may ultimately be useful in in developing targeted treatment and prevention strategies.

Dysregulation of circulating microRNAs (miRNAs) in body fluids has been reported in psychiatric disorders such as schizophrenia, bipolar disorder, major depressive disorder, and post-traumatic stress disorder (PTSD). Recent studies of various diseases showed that extracellular vesicles (EV) in body fluids can provide different spectra of circulating miRNAs and disease-associated signatures from whole fluid or EV-depleted fraction. However, the association of miRNAs in EVs to PTSD has not been studied. In this study, we performed a comprehensive profiling of miRNAs in whole plasma, extracellular vesicles (EV) and EV-depleted plasma (EVD) samples collected from combat veterans with PTSD and matched controls by utilizing a next-generation sequencing (NGS) platform. In total, 520 circulating miRNAs were quantified from 24 male Iraq and Afghanistan combat veterans with (n = 12) and without (n = 12) PTSD. The overall miRNA profiles in whole plasma, EV and EVD fractions were different and miRNAs affected by PTSD were also distinct in each sample type. The concentration changes of miR-203a-3p in EV and miR-339-5p in EVD were confirmed in an independent validation cohort that consisted of 20 veterans (10 with and 10 without PTSD) using qPCR. The target genes of these two miRNAs were involved in signaling pathways and comorbid conditions associated with PTSD (e.g., neurotransmitter systems such as dopaminergic and serotonergic signaling, inflammatory response, and cardiovascular diseases). Our findings suggest that PTSD may have different impacts on miRNAs encapsulated in vesicles and outside of vesicles. Further studies using larger samples are needed to evaluate the utility of these miRNAs as diagnostic biomarkers for PTSD.