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Objectives: Major Depressive Disorder (MDD) is a complex neuropsychiatric disease with known genetic associations, but without known links to rare variation in the human genome. Here we aim to identify rare genetic variants associated with MDD using deep whole-genome sequencing data in an independent population., Methods: We report the sequencing of 1,688 whole genomes in a large sample of male-male Veteran twins. Depression status was classified based on a structured diagnostic interview according to DSM-III-R diagnostic criteria. Searching only rare variants in genomic regions from recent GWAS on MDD, we used the optimised sequence kernel association test and Fisher's Exact test to fine map loci associated with severe depression., Results: Our analysis identified one gene associated with severe depression, basic helix loop helix e22 ( P Adjusted = 0.03) via SKAT-O test between unrelated severely depressed cases compared to unrelated non-depressed controls. The same gene BHLHE22 had a non-silent variant rs13279074 ( P Adjusted = 0.032) based on a single variant Fisher's Exact test between unrelated severely depressed cases compared to unrelated non-depressed controls., Conclusion: The gene BHLHE22 shows compelling genetic evidence of directly impacting the severe depression phenotype. Together these results advance understanding of the genetic contribution to major depressive disorder in a new cohort and link a rare variant to severe forms of the disorder.

Symptom endorsement after traumatic brain injury (TBI) is common acutely post-injury and is associated with other adverse outcomes. Prevalence of persistent symptoms has been debated, especially in mild TBI (mTBI). A cohort of participants ≥17 years with TBI ( n  = 2039), 257 orthopedic trauma controls (OTCs), and 300 friend controls (FCs) were enrolled in the TRACK-TBI study and evaluated at 2 weeks and 3, 6, and 12 months post-injury using the Rivermead Post-Concussion Symptoms Questionnaire (RPQ). TBI participants had significantly higher symptom burden than OTCs or FCs at all times, with average scores more than double. TBI cases showed significant decreases in RPQ score between each evaluation ( p  < 0.001), decreasing ∼1.7 points per month between 2 weeks and 3 months and 0.2 points per month after that. More than 50% of the TBI sample, including >50% of each of the mild and moderate/severe TBI subsamples, continued to endorse three or more symptoms as worse than pre-injury through 12 months post-injury. A majority of TBI participants who endorsed a symptom at 3 months or later did so at the next evaluation as well. Contrary to reviews that report symptom resolution by 3 months post-injury among those with mTBI, this study of participants treated at level 1 trauma centers and having a computed tomography ordered found that persistent symptoms are common to at least a year after TBI. Additionally, although symptom endorsement was not specific to TBI given that they were also reported by OTC and FC participants, TBI participants endorsed over twice the symptom burden compared with the other groups.

Traumatic brain injury (TBI) is associated with a host of psychiatric and neurobehavioral problems. As mortality rates have declined for severe TBI, attention has turned to the cognitive, affective, and behavioral sequelae of injuries across the severity spectrum, which are often more disabling than residual physical effects. Moderate and severe TBI can cause personality changes including impulsivity, severe irritability, affective instability, and apathy. Mild TBI, once considered a largely benign phenomenon, is now known to be associated with a range of affective symptoms, with suicidality, and with worsening or new onset of several psychiatric disorders including posttraumatic stress disorder and major depressive disorder. Repetitive head impacts, often in athletic contexts, are now believed to be associated with a number of emotional and behavioral sequelae. The nature and etiology of mental health manifestations of TBI (including a combination of brain dysfunction and psychological trauma and interrelationships between cognitive, affective, and physical symptoms) are complex and have been a focus of recent epidemiological and mechanistic studies. This paper will review the epidemiology of psychiatric and neurobehavioral problems after TBI in military, civilian, and athletic contexts., (Published by Elsevier Inc.)

The practice of therapeutic skills outside of sessions in which they are learned is one presumed key component of cognitive behavioral therapy (CBT). Yet, our understanding of how skills practice relates to clinical outcomes remains limited. Here, we explored patients' emotional responses to CBT skills practice in a pilot study pairing smartphone-app-delivered skills reminders and guided practice (ecological momentary intervention [EMI]) using ecological momentary assessment (EMA). Participants (n = 25) were adults recently hospitalized for a suicide attempt or severe suicidal thinking. They received brief inpatient CBT (1 to 3 sessions covering core CBT skills from the Unified Protocol), followed by 1 month of EMI and EMA after discharge. On average, participants reported modest reductions in negative affect after skills use (i.e., immediate responses; median time elapsed = 4.30 minutes). Additionally, participants tended to report less negative affect when the timepoint preceding the current assessment included EMI skills practice, rather than EMA alone (i.e., delayed responses; median time elapsed between prompts = 2.17 hours). Immediate effects were unrelated to longer-term clinical outcomes, whereas greater delayed effects were associated with lower symptom severity at follow-up. Future studies should further examine how CBT skills use in daily life may alleviate symptoms., (Copyright © 2021. Published by Elsevier Ltd.)

Epigenetic factors modify the effects of environmental factors on biological outcomes. Identification of epigenetic changes that associate with PTSD is therefore a crucial step in deciphering mechanisms of risk and resilience. In this study, our goal is to identify epigenetic signatures associated with PTSD symptom severity (PTSS) and changes in PTSS over time, using whole blood DNA methylation (DNAm) data (MethylationEPIC BeadChip) of military personnel prior to and following combat deployment. A total of 429 subjects (858 samples across 2 time points) from three male military cohorts were included in the analyses. We conducted two different meta-analyses to answer two different scientific questions: one to identify a DNAm profile of PTSS using a random effects model including both time points for each subject, and the other to identify a DNAm profile of change in PTSS conditioned on pre-deployment DNAm. Four CpGs near four genes (F2R, CNPY2, BAIAP2L1, and TBXAS1) and 88 differentially methylated regions (DMRs) were associated with PTSS. Change in PTSS after deployment was associated with 15 DMRs, of those 2 DMRs near OTUD5 and ELF4 were also associated with PTSS. Notably, three PTSS-associated CpGs near F2R, BAIAP2L1 and TBXAS1 also showed nominal evidence of association with change in PTSS. This study, which identifies PTSD-associated changes in genes involved in oxidative stress and immune system, provides novel evidence that epigenetic differences are associated with PTSS., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Factors such as age, pre-injury health, and injury severity, account for less than 35% of outcome variability in traumatic brain injury (TBI). While some residual outcome variability may be attributable to genetic factors, published candidate gene association studies have often been underpowered and subject to publication bias., Methods: We performed the first genome- and transcriptome-wide association studies (GWAS, TWAS) of genetic effects on outcome in TBI. The study population consisted of 5268 patients from prospective European and US studies, who attended hospital within 24 h of TBI, and satisfied local protocols for computed tomography., Findings: The estimated heritability of TBI outcome was 0·26. GWAS revealed no genetic variants with genome-wide significance (p < 5 × 10 -8 ), but identified 83 variants in 13 independent loci which met a lower pre-specified sub-genomic statistical threshold (p < 10 -5 ). Similarly, none of the genes tested in TWAS met tissue-wide significance. An exploratory analysis of 75 published candidate variants associated with 28 genes revealed one replicable variant (rs1800450 in the MBL2 gene) which retained significance after correction for multiple comparison (p = 5·24 × 10 -4 )., Interpretation: While multiple novel loci reached less stringent thresholds, none achieved genome-wide significance. The overall heritability estimate, however, is consistent with the hypothesis that common genetic variation substantially contributes to inter-individual variability in TBI outcome. The meta-analytic approach to the GWAS and the availability of summary data allows for a continuous extension with additional cohorts as data becomes available., Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section., Competing Interests: Declaration of interests K.K. is now an employee of Boehringer Ingelheim. S.I. declares royalties or licenses with McGraw Hill education. L.W. reports receiving consultancy fees from Vasopharm and Novartis outside the submitted work. C.D.A. declares sponsored research support from Bayer AG and consulting fees from ApoPharma. R.DA. declares consultation for MesoScale Discoveries and Ischemix, Inc.; stocks/stock options in BrainBox Solutions, Inc. and NovaSignal, Inc.; and has received equipment, materials, drugs, medical writing, gifts or other services from MesoScale Discoveries. M.B.S. declares advisory work and stock options with Oxeia Biopharmaceuticals. A.I.R.M. serves as an advisory board member for PressuraNeuro. D.K.M. declares the following conflicts of interest outside the scope of the submitted work: collaborative grant funding, consultancy fees, or educational grants from Lantmannen AB, GlaxoSmithKline Ltd., PressuraNeuro Ltd., Calico LLC, NeuroTrauma Sciences LLC, and Integra Neurosciences. He acts as a Trustee for Queens’ College (Cambridge, UK), the Intensive Care National Audit and Research Centre (London, UK), and is Chair and Trustee of the European Brain Injury Consortium. J.R. declares participation on advisory boards for Takeda Pharmaceuticals, Pfizer and Boehringer Ingelheim, outside the scope of the submitted work. The remaining authors declare no competing interests., (Copyright © 2022. Published by Elsevier B.V.)

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that may arise in response to severe traumatic event and is diagnosed based on three main symptom clusters (reexperiencing, avoidance, and hyperarousal) per the Diagnostic Manual of Mental Disorders (version DSM-IV-TR). In this study, we characterized the biological heterogeneity of PTSD symptom clusters by performing a multi-omics investigation integrating genetically regulated gene, splicing, and protein expression in dorsolateral prefrontal cortex tissue within a sample of US veterans enrolled in the Million Veteran Program (N total  = 186,689). We identified 30 genes in 19 regions across the three PTSD symptom clusters. We found nine genes to have cell-type specific expression, and over-representation of miRNA-families - miR-148, 30, and 8. Gene-drug target prioritization approach highlighted cyclooxygenase and acetylcholine compounds. Next, we tested molecular-profile based phenome-wide impact of identified genes with respect to 1678 phenotypes derived from the Electronic Health Records of the Vanderbilt University biorepository (N = 70,439). Lastly, we tested for local genetic correlation across PTSD symptom clusters which highlighted metabolic (e.g., obesity, diabetes, vascular health) and laboratory traits (e.g., neutrophil, eosinophil, tau protein, creatinine kinase). Overall, this study finds comprehensive genomic evidence including clinical and regulatory profiles between PTSD, hematologic and cardiometabolic traits, that support comorbidities observed in epidemiologic studies of PTSD., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Posttraumatic stress disorder (PTSD) is triggered by environmental stressors. Empathy may predispose an individual to respond to life events differently if high empathizers are emotionally more sensitive to trauma. For the first time, we test this hypothesis using genetic information., Methods: We applied polygenic scoring (PGS) to investigate the shared genetics linking empathy (measured using the Empathy Quotient (EQ), a self-report measure of empathy; N = 46,861) and PTSD symptom severity (measured using the 6-item PTSD Checklist 6-item (PCL-6)) in the UK Biobank (N = 126,219). Follow-up analyses were performed in the context of (1) experiencing any of 16 potential traumas, (2) the total number of traumas endorsed, and (3) the context of trauma. Autism, depression, generalized anxiety, and PCL-17 PGS were included as covariates to verify the specificity of the effect., Results: EQ PGS associated with PCL-6 ( R 2  = 0.012%, P  = 9.35 × 10 -5 ). This effect remained significant after accounting for autism, depression, PTSD, and anxiety PGS but was observed only in those who endorsed experiencing at least one traumatic event. EQ PGS showed the strongest effect on PCL-6 ( β  = 2.32, s.e. = 0.762, P  = 0.002) among those who endorsed childhood neglect/abuse (felt hated as a child ). With respect to case status, the highest probability of PTSD was 17.93% and 10.04% for those who endorsed " feeling hated as a child " and those who did not, respectively ( P diff  = 0.011; Cohen's d  = 1.951, 95%CI 1.70-2.20)., Conclusions: A genetic predisposition to higher empathy, which may index greater emotional sensitivity, predisposes an individual to more severe PTSD symptoms, especially after early-life adversity., Competing Interests: Dr. Gelernter is named as an inventor on PCT patent application #15/878,640 entitled: “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. Dr. Stein is paid for his editorial work on the journals Biological Psychiatry and Depression and Anxiety, and the health professional reference Up-To-Date; he has also 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. Drs. Polimanti and Gelernter are paid for their editorial work on the journal Complex Psychiatry. Dr. Krystal reports compensation as the Editor of Biological Psychiatry. He also serves on the Scientific Advisory Boards for Bioasis Technologies, Inc., Biohaven Pharmaceuticals, BioXcel Therapeutics, Inc. (Clinical Advisory Board), Cadent Therapeutics (Clinical Advisory Board), PsychoGenics, Inc, Stanley Center for Psychiatric research at the Broad Institute of MIT and Harvard and the Lohocla Research Corporation. He owns stock in ArRETT Neuroscience, Inc., Biohaven Pharmaceuticals, Sage Pharmaceuticals, and Spring Care, Inc. and stock options in Biohaven Pharmaceuticals Medical Sciences, BlackThorn Therapeutics, Inc. and Storm Biosciences, Inc. He is a co-inventor on multiple patents as listed below: (1) Seibyl JP, Krystal JH, Charney DS. Dopamine and noradrenergic reuptake inhibitors in treatment of schizophrenia. US Patent #:5,447,948.September 5, 1995, (2) Vladimir, Coric, Krystal, John H, Sanacora, Gerard—Glutamate Modulating Agents in the Treatment of Mental Disorders US Patent No. 8,778,979 B2 Patent Issue Date: July 15, 2014. US Patent Application No. 15/695,164: Filing Date: 09/05/2017, (3) Charney D, Krystal JH, Manji H, Matthew S, Zarate C.—Intranasal Administration of Ketamine to Treat Depression United States Application No. 14/197,767 filed on March 5, 2014; United States application or Patent Cooperation Treaty (PCT) International application No. 14/306,382 filed on June 17, 2014, (4): Zarate, C, Charney, DS, Manji, HK, Mathew, Sanjay J, Krystal, JH, Department of Veterans Affairs “Methods for Treating Suicidal Ideation”, Patent Application No. 14/197.767 filed on March 5, 2014 by Yale University Office of Cooperative Research, (5) Arias A, Petrakis I, Krystal JH.—Composition and methods to treat addiction. Provisional Use Patent Application no.61/973/961. April 2, 2014. Filed by Yale University Office of Cooperative Research, (6) Chekroud, A., Gueorguieva, R., & Krystal, JH. “Treatment Selection for Major Depressive Disorder” [filing date 3rd June 2016, USPTO docket number Y0087.70116US00]. Provisional patent submission by Yale University, (7) Gihyun, Yoon, Petrakis I, Krystal JH—Compounds, Compositions and Methods for Treating or Preventing Depression and Other Diseases. U. S. Provisional Patent Application No. 62/444,552, filed on January 10, 2017 by Yale University Office of Cooperative Research OCR 7088 US01, (8) Abdallah, C, Krystal, JH, Duman, R, Sanacora, G. Combination Therapy for Treating or Preventing Depression or Other Mood Diseases. U.S. Provisional Patent Application No. 047162–7177P1 (00754) filed on August 20, 2018 by Yale University Office of Cooperative Research OCR 7451 US01. The other authors have no competing interests to disclose., (© 2022 The Authors.)

Objective: Suicide and suicide attempts among U.S. Army soldiers are a significant concern for public health. This study examined the association of parental suicide attempt prior to age 13 of the soldier with subsequent risk of pre-enlistment suicide attempt., Method: We conducted secondary analyses of survey data from new soldiers who participated in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) (N = 38,396). A series of logistic regression analyses were conducted., Results: Of all new soldiers, 1.4% reported that they attempted suicide between age 13 and entering the Army, and 2.3% reported a parental suicide attempt prior to age 13. Parental suicide attempt was associated with increased odds of subsequent suicide attempt; however, this association was moderated by gender and was significant only among male soldiers. The association between parental suicide attempt and pre-enlistment suicide attempt among male soldiers was still significant after controlling for socio-demographic characteristics, soldier/parental psychopathology, and childhood adversities., Conclusions: These results highlight parental suicide attempt as a unique pre-enlistment risk factor for suicide attempt, especially among male new soldiers. Further studies are needed to separate the genetic and environmental contributions to intra-familial risk for suicidal behavior., (© 2021 American Association of Suicidology. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Introduction: Little is known about the degree to which U.S. Army soldiers in the Reserve Components (Army National Guard and Army Reserve) and Active Component (Regular Army) differ with respect suicide attempt (SA) risk during high-stress times, such as deployment., Method: Using administrative person-month records of enlisted soldiers on active duty during 2004-2009, we identified 1170 soldiers with a medically documented SA during deployment and an equal-probability control sample of other deployed soldiers (n = 52,828 person-months). Logistic regression analyses examined the association of Army component (Guard/Reserve vs. Regular) with SA before and after adjusting for socio-demographic and service-related predictors., Results: Guard/Reserve comprised 32.1% of enlisted soldiers and 19.7% of suicide attempters in-theater, with a SA rate of 81/100,000 person-years (vs. 157/100,000 person-years among Regular; rate ratio = 0.5 [95% CI = 0.5-0.6]). Risk peaked near mid-deployment for both groups but was consistently lower for Guard/Reserve throughout deployment. Guard/Reserve had lower odds of SA after adjusting for covariates (OR = 0.7 [95%CI = 0.6-0.8]). Predictors of SA were similar between components., Conclusions: Guard/Reserve and Regular soldiers had similar patterns and predictors of SA during deployment, but Guard/Reserve had lower risk even after controlling for important risk factors. Additional research is needed to understand the lower SA risk among Guard/Reserve in-theater., (© 2021 American Association of Suicidology. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Background: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders., Methods: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors., Results: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged., Conclusions: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)

Background: Suicide is a serious public health problem, including among U.S. Army personnel. There is great interest in discovering objective predictors of suicide and non-fatal suicidal behaviors. The current study examined the association between neurocognitive functioning and pre-military history of suicide attempts (SA) and post-enlistment onset of SA., Methods: New Soldiers reporting for Basic Combat Training (N = 38,507) completed a comprehensive computerized neurocognitive assessment battery and self-report questionnaires. A subset of Soldiers (n = 6216) completed a follow-up survey, including assessment of lifetime SA, 3-7 years later., Results: Six hundred eighty-nine Soldiers indicated lifetime SA at baseline and 210 Soldiers indicated new-onset SA at follow-up. Regression analyses, adjusted for demographic variables, revealed significant bivariate associations between neurocognitive performance on measures of sustained attention, impulsivity, working memory, and emotion recognition and lifetime SA at baseline. In a multivariable model including each of these measures as predictors, poorer impulse control and quicker response times on an emotion recognition measure were significantly and independently associated with increased odds of lifetime SA. A second model predicted new-onset SA at follow-up for Soldiers who did not indicate a history of SA at baseline. Poorer impulse control on a measure of sustained attention was predictive of new-onset SA., Limitations: Effect sizes are small and of unlikely clinical predictive utility., Conclusions: We simultaneously examined multiple neurocognitive domains as predictors of SA in a large, representative sample of new Army Soldiers. Impulsivity most strongly predicted past and future SA over and beyond other implicated cognitive-emotional domains., (Published by Elsevier Ltd.)

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Unit cohesion may protect service member mental health by mitigating effects of combat exposure; however, questions remain about the origins of potential stress-buffering effects. We examined buffering effects associated with two forms of unit cohesion (peer-oriented horizontal cohesion and subordinate-leader vertical cohesion) defined as either individual-level or aggregated unit-level variables., Methods: Longitudinal survey data from US Army soldiers who deployed to Afghanistan in 2012 were analyzed using mixed-effects regression. Models evaluated individual- and unit-level interaction effects of combat exposure and cohesion during deployment on symptoms of post-traumatic stress disorder (PTSD), depression, and suicidal ideation reported at 3 months post-deployment (model n 's = 6684 to 6826). Given the small effective sample size ( k = 89), the significance of unit-level interactions was evaluated at a 90% confidence level., Results: At the individual-level, buffering effects of horizontal cohesion were found for PTSD symptoms [ B = -0.11, 95% CI (-0.18 to -0.04), p < 0.01] and depressive symptoms [ B = -0.06, 95% CI (-0.10 to -0.01), p < 0.05]; while a buffering effect of vertical cohesion was observed for PTSD symptoms only [ B = -0.03, 95% CI (-0.06 to -0.0001), p < 0.05]. At the unit-level, buffering effects of horizontal (but not vertical) cohesion were observed for PTSD symptoms [ B = -0.91, 90% CI (-1.70 to -0.11), p = 0.06], depressive symptoms [ B = -0.83, 90% CI (-1.24 to -0.41), p < 0.01], and suicidal ideation [ B = -0.32, 90% CI (-0.62 to -0.01), p = 0.08]., Conclusions: Policies and interventions that enhance horizontal cohesion may protect combat-exposed units against post-deployment mental health problems. Efforts to support individual soldiers who report low levels of horizontal or vertical cohesion may also yield mental health benefits.

Purpose: The interplay between critical illness and mental disorders is poorly understood. The purpose of this study is to measure both the treated prevalence of mental disorders and psychotropic medication use before and after hospitalization and the impact of intensive care unit (ICU) admission on these outcomes., Methods: Using a population-based administrative database in Manitoba, Canada, 49,439 ICU patients admitted between 2000 and 2012 were compared to two matched comparison groups (hospitalized; n = 146,968 and general population; n = 141,937). Treated prevalence of mental disorders and psychotropic medication prescriptions were measured in the 5-year periods before and after the hospitalization. Multivariable models compared adjusted prevalence ratios (APRs) between populations., Results: The 5-year treated mental disorder prevalence in the ICU population increased from 41.5% pre-hospitalization to 55.6% post-hospitalization. Compared to non-ICU hospitalized patients, the adjusted treated mental disorder prevalence in ICU patients was lower prior to hospitalization (1-year APR 0.94, 95% CI 0.92-0.97, p < 0.0001; 5-year APR 0.99, 95% CI 0.98-1.00, p = 0.1), but higher following discharge (1-year APR 1.08, 95% CI 1.05-1.11, p < 0.0001, 5-year APR 1.03, 95% CI 1.01-1.05, p < 0.0001). A high proportion of ICU patients received antidepressant, anxiolytic and sedative-hypnotic prescriptions before and after their hospitalization. In multivariable analyses, ICU exposure was associated with an increase in mood, anxiety and psychotic disorders, and sedative-hypnotics use (p < 0.0001 for all Time × Group interactions)., Conclusions: During the 5 years after admission to ICU, there is a significant increase in treated prevalence of mental disorders and psychotropic medication use compared to the 5 years prior to ICU and compared to general population and hospital cohorts. Prevention and intervention programs that identify and treat mental disorders among survivors of critical illness warrant further study., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Objectives: Reduction of trauma related negative cognitions, such as guilt, is thought to be a mechanism of change within PTSD treatments like prolonged exposure (PE). Research suggests PE can directly address guilt cognitions. However, whether pharmacotherapies for PTSD can remains unclear., Methods: Data from a randomized controlled trial of PE plus placebo (PE + PLB), sertraline plus enhanced medication management (SERT + EMM), and their combination (PE + SERT) in 195 Veterans from recent wars was analyzed., Results: The unadjusted means and mixed-effects model showed guilt decreased significantly over the follow-up time as expected; however, contrary to our hypothesis, PE conditions were not associated with greater reductions in guilt than the SERT + EMM condition. As hypothesized, week 12 reduction in guilt predicted post-treatment (weeks 24-52) reduction in PTSD and depression, but not impairments in function., Limitations: Generalizability of findings is limited by the sample being comprised of combat Veterans who were predominantly male, not on SSRI at study entry, willing to be randomized to therapy or medication, and reporting low levels of guilt. To reduce differences in provider attention, SERT + EMM was administered over 30 min to include psychoeducation and active listening; it is unknown if this contributed to effects on guilt., Conclusions: PE + PLB, SERT + EMM, and PE + SERT were equally associated with reduction in trauma related guilt. Reducing trauma related guilt may be a pathway to reducing PTSD and posttraumatic depression symptoms. Further study is needed to determine how best to treat trauma related guilt and to understand the mechanisms by which guilt improves across different treatments for PTSD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Suicide is a major public health problem. The contribution of common genetic variants for major depressive disorder (MDD) independent of personal and parental history of MDD has not been established. Polygenic risk score (using PRS-CS) for MDD was calculated for US Army soldiers of European ancestry. Associations between polygenic risk for MDD and lifetime suicide attempt (SA) were tested in models that also included parental or personal history of MDD. Models were adjusted for age, sex, tranche (where applicable), and 10 principal components reflecting ancestry. In the first cohort, 417 (6.3%) of 6,573 soldiers reported a lifetime history of SA. In a multivariable model that included personal [OR = 3.83, 95% CI:3.09-4.75] and parental history of MDD [OR = 1.43, 95% CI:1.13-1.82 for one parent and OR = 1.64, 95% CI:1.20-2.26 for both parents), MDD PRS was significantly associated with SA (OR = 1.22 [95% CI:1.10-1.36]). In the second cohort, 204 (4.2%) of 4,900 soldiers reported a lifetime history of SA. In a multivariable model that included personal [OR = 3.82, 95% CI:2.77-5.26] and parental history of MDD [OR = 1.42, 95% CI:0.996-2.03 for one parent and OR = 2.21, 95% CI:1.33-3.69 for both parents) MDD PRS continued to be associated (at p = .0601) with SA (OR = 1.15 [95% CI:0.994-1.33]). A soldier's PRS for MDD conveys information about likelihood of a lifetime SA beyond that conveyed by two predictors readily obtainable by interview: personal or parental history of MDD. Results remain to be extended to prospective prediction of incident SA. These findings portend a role for PRS in risk stratification for suicide attempts., (© 2021 Wiley Periodicals LLC.)

We still have little understanding of short-term predictors of suicidal thoughts and behaviors (STBs). Prior research links increased negative affect to STBs, but the vast majority of earlier work is limited by measuring negative affect at one time point and aiming to predict STBs months or years in the future. Recently, intensive longitudinal studies have shown that negative affect is associated with suicidal thoughts over relatively short, clinically useful time periods; however, the specific patterns and types of negative affect that predict STBs remain unclear. Using ecological momentary assessment (EMA) data from psychiatric inpatients hospitalized for suicide risk ( N = 83), this study sought to test whether the patterns (means and variability) of two types of negative affect (anxiety/agitation and shame/self-hatred, which were derived from a larger EMA battery) during hospitalization predict STBs in the four weeks after discharge: an extremely high-risk time for suicidal behavior. The mean - but not the variability - of both anxiety/agitation and shame/self-hatred during hospitalization predicted the number of days with suicidal thoughts after discharge. The mean and the variability of shame/self-hatred - but not anxiety/agitation - predicted post-discharge suicide attempt. We discuss implications for assessment and treatment of suicidal individuals and propose key directions for future research.

Importance: Posttraumatic epilepsy (PTE) is a recognized sequela of traumatic brain injury (TBI), but the long-term outcomes associated with PTE independent of injury severity are not precisely known., Objective: To determine the incidence, risk factors, and association with functional outcomes and self-reported somatic, cognitive, and psychological concerns of self-reported PTE in a large, prospectively collected TBI cohort., Design, Setting, and Participants: This multicenter, prospective cohort study was conducted as part of the Transforming Research and Clinical Knowledge in Traumatic Brain Injury study and identified patients presenting with TBI to 1 of 18 participating level 1 US trauma centers from February 2014 to July 2018. Patients with TBI, extracranial orthopedic injuries (orthopedic controls), and individuals without reported injuries (eg, friends and family of participants; hereafter friend controls) were prospectively followed for 12 months. Data were analyzed from January 2020 to April 2021., Exposure: Demographic, imaging, and clinical information was collected according to TBI Common Data Elements. Incidence of self-reported PTE was assessed using the National Institute of Neurological Disorders and Stroke Epilepsy Screening Questionnaire (NINDS-ESQ)., Main Outcomes and Measures: Primary outcomes included Glasgow Outcome Scale Extended, Rivermead Cognitive Metric (RCM; derived from the Rivermead Post Concussion Symptoms Questionnaire), and the Brief Symptom Inventory-18 (BSI)., Results: Of 3296 participants identified as part of the study, 3044 met inclusion criteria, and 1885 participants (mean [SD] age, 41.3 [17.1] years; 1241 [65.8%] men and 644 [34.2%] women) had follow-up information at 12 months, including 1493 patients with TBI; 182 orthopedic controls, 210 uninjured friend controls; 41 patients with TBI (2.8%) and no controls had positive screening results for PTE. Compared with a negative screening result for PTE, having a positive screening result for PTE was associated with presenting Glasgow Coma Scale score (8.1 [4.8] vs.13.5 [3.3]; P < .001) as well as with anomalous acute head imaging findings (risk ratio, 6.42 [95% CI, 2.71-15.22]). After controlling for age, initial Glasgow Coma Scale score, and imaging findings, compared with patients with TBI and without PTE, patients with TBI and with positive PTE screening results had significantly lower Glasgow Outcome Scale Extended scores (mean [SD], 6.1 [1.7] vs 4.7 [1.5]; P < .001), higher BSI scores (mean [SD], 50.2 [10.7] vs 58.6 [10.8]; P = .02), and higher RCM scores (mean [SD], 3.1 [2.6] vs 5.3 [1.9]; P = .002) at 12 months., Conclusions and Relevance: In this cohort study, the incidence of self-reported PTE after TBI was found to be 2.8% and was independently associated with unfavorable outcomes. These findings highlight the need for effective antiepileptogenic therapies after TBI.

It is important to measure quality of life (QoL) after traumatic brain injury (TBI), yet limited studies have compared QoL inventories. In 2579 TBI patients, orthopedic trauma controls, and healthy friend control participants, we compared the Quality of Life After Brain Injury-Overall Scale (QOLIBRI-OS), developed for TBI patients, to the Satisfaction with Life Scale (SWLS), an index of generic life satisfaction. We tested the hypothesis that group differences (TBI and orthopedic trauma vs. healthy friend controls) would be larger for the QOLIBRI-OS than the SWLS and that the QOLIBRI-OS would manifest more substantial changes over time in the injured groups, demonstrating more relevance of the QOLIBRI-OS to traumatic injury recovery. (1) We compared the group differences (TBI vs. orthopedic trauma control vs. friend control) in QoL as indexed by the SWLS versus the QOLIBRI-OS and (2) characterized changes across time in these two inventories across 1 year in these three groups. Our secondary objective was to characterize the relationship between TBI severity and QoL. As compared with healthy friend controls, the QOLIBRI reflected greater reductions in QoL than the SWLS for both the TBI group (all time points) and the orthopedic trauma control group (2 weeks and 3 months). The QOLIBRI-OS better captured expected improvements in QoL during the injury recovery course in injured groups than the SWLS, which demonstrated smaller changes over time. TBI severity was not consistently or robustly associated with self-reported QoL. The findings imply that, as compared with the SWLS, the QOLIBRI-OS appears to identify QoL issues more specifically relevant to traumatically injured patients and may be a more appropriate primary QoL outcome measure for research focused on the sequelae of traumatic injuries.

Importance: Rates of suicidal thoughts and behaviors (STBs) in US soldiers have increased sharply since the terrorist attacks on September 11, 2001, and postdeployment posttraumatic stress disorder (PTSD) remains a concern. Studies show that soldiers with greater combat exposure are at an increased risk for adverse mental health outcomes, but little research has been conducted on the specific exposure of responsibility for the death of others., Objective: To examine the association between responsibility for the death of others in combat and mental health outcomes among active-duty US Army personnel at 2 to 3 months and 8 to 9 months postdeployment., Design, Setting, and Participants: This cohort study obtained data from a prospective 4-wave survey study of 3 US Army brigade combat teams that deployed to Afghanistan in 2012. The sample was restricted to soldiers with data at all 4 waves (1-2 months predeployment, and 2-3 weeks, 2-3 months, and 8-9 months postdeployment). Data analysis was performed from December 12, 2020, to April 23, 2021., Main Outcomes and Measures: Primary outcomes were past-30-day PTSD, major depressive episode, STBs, and functional impairment at 2 to 3 vs 8 to 9 months postdeployment. Combat exposures were assessed using a combat stress scale. The association of responsibility for the death of others during combat was tested using separate multivariable logistic regression models per outcome adjusted for age, sex, race and ethnicity, marital status, brigade combat team, predeployment lifetime internalizing and externalizing disorders, and combat stress severity., Results: A total of 4645 US soldiers (mean [SD] age, 26.27 [6.07] years; 4358 men [94.0%]) were included in this study. After returning from Afghanistan, 22.8% of soldiers (n = 1057) reported responsibility for the death of others in combat. This responsibility was not associated with any outcome at 2 to 3 months postdeployment (PTSD odds ratio [OR]: 1.23 [95% CI, 0.93-1.63]; P = .14; STB OR: 1.19 [95% CI, 0.84-1.68]; P = .33; major depressive episode OR: 1.03 [95% CI, 0.73-1.45]; P = .87; and functional impairment OR: 1.12 [95% CI, 0.94-1.34]; P = .19). However, responsibility was associated with increased risk for PTSD (OR, 1.42; 95% CI, 1.09-1.86; P = .01) and STBs (OR, 1.55; 95% CI, 1.03-2.33; P = .04) at 8 to 9 months postdeployment. Responsibility was not associated with major depressive episode (OR, 1.30; 95% CI, 0.93-1.81; P = .13) or functional impairment (OR, 1.13; 95% CI, 0.94-1.36; P = .19). When examining enemy combatant death only, the pattern of results was unchanged for PTSD (OR, 1.44; 95 CI%, 1.10-1.90; P = .009) and attenuated for STBs (OR, 1.46; 95 CI%, 0.97- 2.20; P = .07)., Conclusions and Relevance: This cohort study found an association between being responsible for the death of others in combat and PTSD and STB at 8 to 9 months, but not 2 to 3 months, postdeployment in active-duty soldiers. The results suggest that delivering early intervention to those who report such responsibility may mitigate the subsequent occurrence of PTSD and STBs.

Social impairments are common across many psychiatric conditions. Standardized dyadic assessments intended to elicit social affiliation between unacquainted partners are used to elucidate mechanisms that disrupt relationship formation and inform possible treatment targets; however, the psychometric properties of such paradigms remain poorly understood. This study evaluated the psychometric properties of a controlled social affiliation paradigm intended to induce connectedness between a target participant and trained confederate. Individuals with an anxiety or depressive disorder diagnosis (clinical group; n = 132) and those without (control group; n = 35) interacted face-to-face with a trained confederate; partners took turns answering a series of increasingly intimate questions about themselves. Social connectedness, affect, and affiliative behavior measures were collected during the interaction. Participant symptom and social functioning measures were collected to examine validity. The paradigm elicited escalating social connectedness throughout the task for both participants and confederates. Parallel forms (i.e., different question sets) elicited similar affiliation outcomes. Self-reported (but not behavioral) affiliation differed across some demographic variables (e.g., participant gender, Hispanic ethnicity). Within-task affiliation measures were associated with one another and with global social connectedness and social anxiety symptom measures, but not with somatic anxiety measures. Clinical participants reported lower social affiliation and positive affect reactivity and higher negative affect reactivity than healthy participants. These findings provide initial psychometric support for a standardized and controlled dyadic affiliation paradigm that could be used to reliably probe social disconnection mechanisms across psychopathology., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: The authors sought to identify predictors of imminent suicide attempt (within 30 days) among U.S. Army soldiers following their first documented suicidal ideation., Methods: Using administrative data from the Army Study to Assess Risk and Resilience in Servicemembers, the authors identified 11,178 active-duty Regular Army enlisted soldiers (2006-2009) with medically documented suicidal ideation and no prior medically documented suicide attempts. The authors examined risk factors for suicide attempt within 30 days of first suicidal ideation using logistic regression analyses, including sociodemographic and service-related characteristics, psychiatric diagnoses, physical health care visits, injuries, and history of family violence or crime perpetration or victimization., Results: Among soldiers with first documented suicidal ideation, 830 (7.4%) attempted suicide, 46.3% of whom (N=387) attempted suicide within 30 days (rate, 35.4 per 1,000 soldiers). Following a series of multivariate analyses, the final model identified females (odds ratio=1.3, 95% CI=1.0, 1.8), combat medics (odds ratio=1.6, 95% CI=1.1, 2.2), individuals with an anxiety disorder diagnosis prior to suicidal ideation (odds ratio=1.3, 95% CI=1.0, 1.6), and those who received a sleep disorder diagnosis on the same day as the recorded suicidal ideation (odds ratio=2.3, 95% CI=1.1, 4.6) as being more likely to attempt suicide within 30 days. Black soldiers (odds ratio=0.6, 95% CI=0.4, 0.9) and those who received an anxiety disorder diagnosis on the same day as suicidal ideation (odds ratio=0.7, 95% CI=0.5, 0.9) were less likely., Conclusions: Suicide attempt risk is highest in the first 30 days following ideation diagnosis and is more likely among women, combat medics, and soldiers with an anxiety disorder diagnosis before suicidal ideation and a same-day sleep disorder diagnosis. Black soldiers and those with a same-day anxiety disorder diagnosis were at decreased risk. These factors may help identify soldiers at imminent risk of suicide attempt.

This study examines the construct validity of the Social Cognition and Object Relations Scale-Global Rating Method (SCORS-G; Westen, 1995; see also Stein & Mulford, 2018) by exploring the degree of convergence across different narrative sources (i.e., early memories [EM] and psychotherapy narratives [PT]) in relation to patient- and therapist-rated psychotherapy process measures. Using a university-based outpatient sample (n = 81), we found limited convergence for SCORS-G ratings across narrative type. First, paired t tests showed that the means for six of the eight SCORS-G dimensions differed significantly between the EM and PT narratives with the majority having a large magnitude of effect. Moreover, despite 29 significant correlations between a SCORS-G dimension and either an alliance or session quality variable, only two of the eight SCORS-G dimensions significantly correlated with the same process variable across narrative type (e.g., patient-rated session depth with SCORS-G Self Esteem [SE] and Identity and Coherence of Self [ICS]). Importantly, the high degree of theoretical coherence in the associations that emerged between the SCORS-G dimensions and the process variables suggest that the lack of convergence was not due to limited validity of the SCORS-G. Instead, the results underscore the importance of multi-method assessment techniques by highlighting that the manner in which a narrative is elicited will impact the object relational content patients provide. Future research and clinical implications related to the SCORS-G, alliance and psychotherapy process are discussed., (© 2021 John Wiley & Sons, Ltd.)

Objective: Knowledge is limited regarding the longitudinal course and predictors of mental health problems, suicide, and physical health outcomes among military and veterans. Statistics Canada, in collaboration with researchers at the University of Manitoba and an international team, conducted the Canadian Armed Forces Members and Veterans Mental Health Follow-Up Survey (CAFVMHS). Herein, we describe the rationale and methods of this important survey., Method: The CAFVMHS is a longitudinal survey design with 2 time points (2002 and 2018). Regular Force military personnel who participated in the first Canadian Community Health Survey Cycle 1.2-Mental Health and Well-Being, Canadian Forces Supplement (CCHS-CFS) in 2002 ( N = 5,155) were reinterviewed in 2018 ( n = 2,941). The World Mental Health Survey-Composite International Diagnostic Interview was used with the Diagnostic and Statistical Manual of Mental Disorders , fourth edition ( DSM -IV) criteria., Results: The CAFVMHS includes 2,941 respondents (66% veterans; 34% active duty) and includes data on mental disorder diagnoses, physical health conditions, substance use, medication use, general health, mental health services, perceived need for care, social support, moral injury, deployment experiences, stress, physical activity, military-related sexual assault, childhood experiences, and military and sociodemographic information., Conclusions: The CAFVMHS provides a unique opportunity to further understand the health and well-being of military personnel in Canada over time to inform intervention and prevention strategies and improve outcomes. The data are available through the Statistics Canada Research Data Centres across Canada and can be used cross-sectionally or be longitudinally linked to the 2002 CCHS-CFS data.

Objective: The current study used the Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey (CAFVMHS) to (1) examine the incidence and prevalence of mental disorders and (2) estimate the comorbidity of mental disorders over the follow-up period., Method: The CAFVMHS (2018) is a longitudinal study with two time points of assessment. The sample is comprised of 2,941 Canadian Forces members and veterans who participated in the 2002 Canadian Community Health Survey: Canadian Forces Supplement. The World Health Organization Composite International Diagnostic Interview (WHO-CIDI) was utilized to diagnose Diagnostic and Statistical Manual -IV post-traumatic stress disorder (PTSD), major depressive episode (MDE), generalized anxiety disorder, social anxiety disorder (SAD), and alcohol abuse and dependence. Self-report health professional diagnoses were assessed for attention deficit hyperactivity disorder (ADHD), mania, obsessive compulsive disorder (OCD), and personality disorder. We established weighted prevalence of mental disorders and examined the association between mental disorders using logistic regression., Results: In 2018, lifetime prevalence of any WHO-CIDI-based or self-reported mental disorder was 58.1%. Lifetime prevalence of any mood or anxiety disorder or PTSD was 54.0% in 2018. MDE (39.9%), SAD (25.7%), and PTSD (21.4%) were the most common mental disorders. There was a substantial increase in new onset or recurrence/persistence of mental disorders between the two measurement points (16-year assessment gap); 2002-2018 period prevalences were 43.5% for mood and anxiety disorder and 16.8% for alcohol abuse or dependence. The prevalence of self-reported ADHD, OCD, any personality disorder, and mania were 3.3%, 3.0%, 0.8%, and 0.8%, respectively. Comorbidity between mental disorders increased over the follow-up., Conclusions: This study demonstrates a high burden of mental disorders among a large Canadian military and veteran cohort. These findings underscore the importance of prevention and intervention strategies to reduce the burden of mental disorders and alcohol use disorders in these populations.

Importance: Most previous genome-wide association studies (GWAS) of depression have used data from individuals of European descent. This limits the understanding of the underlying biology of depression and raises questions about the transferability of findings between populations., Objective: To investigate the genetics of depression among individuals of East Asian and European descent living in different geographic locations, and with different outcome definitions for depression., Design, Setting, and Participants: Genome-wide association analyses followed by meta-analysis, which included data from 9 cohort and case-control data sets comprising individuals with depression and control individuals of East Asian descent. This study was conducted between January 2019 and May 2021., Exposures: Associations of genetic variants with depression risk were assessed using generalized linear mixed models and logistic regression. The results were combined across studies using fixed-effects meta-analyses. These were subsequently also meta-analyzed with the largest published GWAS for depression among individuals of European descent. Additional meta-analyses were carried out separately by outcome definition (clinical depression vs symptom-based depression) and region (East Asian countries vs Western countries) for East Asian ancestry cohorts., Main Outcomes and Measures: Depression status was defined based on health records and self-report questionnaires., Results: There were a total of 194 548 study participants (approximate mean age, 51.3 years; 62.8% women). Participants included 15 771 individuals with depression and 178 777 control individuals of East Asian descent. Five novel associations were identified, including 1 in the meta-analysis for broad depression among those of East Asian descent: rs4656484 (β = -0.018, SE = 0.003, P = 4.43x10-8) at 1q24.1. Another locus at 7p21.2 was associated in a meta-analysis restricted to geographically East Asian studies (β = 0.028, SE = 0.005, P = 6.48x10-9 for rs10240457). The lead variants of these 2 novel loci were not associated with depression risk in European ancestry cohorts (β = -0.003, SE = 0.005, P = .53 for rs4656484 and β = -0.005, SE = 0.004, P = .28 for rs10240457). Only 11% of depression loci previously identified in individuals of European descent reached nominal significance levels in the individuals of East Asian descent. The transancestry genetic correlation between cohorts of East Asian and European descent for clinical depression was r = 0.413 (SE = 0.159). Clinical depression risk was negatively genetically correlated with body mass index in individuals of East Asian descent (r = -0.212, SE = 0.084), contrary to findings for individuals of European descent., Conclusions and Relevance: These results support caution against generalizing findings about depression risk factors across populations and highlight the need to increase the ancestral and geographic diversity of samples with consistent phenotyping.

Objective: This study examined baseline risk and protective predictors and interim correlates of the persistence/recurrence, remission, and onset of posttraumatic stress disorder (PTSD) in a 16-year prospective, nationally representative sample of Canadian Forces members and veterans., Methods: The 2018 Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey is a prospective study of 2,941 regular force service members and veterans who participated in the 2002 Canadian Community Health Survey on Mental Health and Wellbeing: Canadian Forces Supplement ( n = 5,155; ages 15 to 64 years; response rate 68%). PTSD diagnoses in 2002 and 2018 were used to create 4 groups: (1) no lifetime , (2) remitted , (3) new onset , and (4) persistent/recurrent PTSD. Multinomial regressions were conducted to identify predictors of PTSD courses., Results: Female sex, being a junior noncommissioned member (vs. officer), and land (vs. air) operations in 2002 were associated with all PTSD courses relative to no lifetime PTSD (relative risk ratio [RRR] range: 1.28 to 3.65). After adjusting for sociodemographic variables, baseline predictors of all PTSD courses included lifetime mental disorder, history of mental health care utilization, all trauma type categories (deployment-associated, sexual, "other"), and the number of lifetime traumatic events (RRR range: 1.14 to 8.95). New ("since 2002") traumas, transitioning to veteran status, and alcohol dependence were mostly associated with the new onset and persistent/recurrent PTSD courses (RRR range: 1.79 to 4.31), while mental health care utilization and greater avoidance coping were associated with all PTSD courses (RRR range: 1.10 to 17.87). Protective factors for several PTSD courses at one or both time points included social support, social network size, and problem-focused coping (RRR range: 0.71 to 0.98)., Conclusions: This is the first population-based survey to examine the longitudinal course of PTSD in Canadian Forces members. Prevention and intervention programs focused on bolstering social support and active coping strategies as possible protective factors/correlates may help mitigate the development and persistence of PTSD.

There are currently no validated pharmacotherapies for posttraumatic stress disorder (PTSD)-related insomnia. The purpose of the National Adaptive Trial for PTSD-Related Insomnia (NAP Study) is to efficiently compare to placebo the effects of three insomnia medications with different mechanisms of action that are already prescribed widely to veterans diagnosed with PTSD within U.S. Department of Veterans Affairs (VA) Medical Centers. This study plans to enroll 1224 patients from 34 VA Medical Centers into a 12- week prospective, randomized placebo-controlled clinical trial comparing trazodone, eszopiclone, and gabapentin. The primary outcome measure is insomnia, assessed with the Insomnia Severity Index. A novel aspect of this study is its adaptive design. At the recruitment midpoint, an interim analysis will be conducted to inform a decision to close recruitment to any "futile" arms (i.e. arms where further recruitment is very unlikely to yield a significant result) while maintaining the overall study recruitment target. This step could result in the enrichment of the remaining study arms, enhancing statistical power for the remaining comparisons to placebo. This study will also explore clinical, actigraphic, and biochemical predictors of treatment response that may guide future biomarker development. Lastly, due to the COVID-19 pandemic, this study will allow the consenting process and follow-up visits to be conducted via video or phone contact if in-person meetings are not possible. Overall, this study aims to identify at least one effective pharmacotherapy for PTSD-related insomnia, and, perhaps, to generate definitive negative data to reduce the use of ineffective insomnia medications. NATIONAL CLINICAL TRIAL (NCT) IDENTIFIED NUMBER: NCT03668041., (Published by Elsevier Inc.)

Posttraumatic stress disorder (PTSD) is characterized by a persistent maladaptive reaction after exposure to severe psychological trauma. Traumatic events that may precipitate PTSD include violent personal assaults, natural and human-made disasters, and exposure to military combat or warfare. There is a growing body of evidence for associations of PTSD with major risk factors for cardiovascular disease (CVD), such as hypertension and diabetes, as well as with major CVD outcomes, such as myocardial infarction and heart failure. However, it is unclear whether these associations are causal or confounded. Furthermore, the biological and behavioral mechanisms underlying these associations are poorly understood. Here, the available evidence on the association of PTSD with CVD from population, basic, and genomic research as well as from clinical and translational research are reviewed, seeking to identify major research gaps, barriers, and opportunities in knowledge acquisition and technology as well as research tools to support and accelerate critical research for near-term and longer-term translational research directions. Large-scale, well-designed prospective studies, capturing diverse and high-risk populations, are warranted that include uniform phenotyping of PTSD as well as broad assessment of biological and behavioral risk factors and CVD outcomes. Available evidence from functional brain imaging studies demonstrates that PTSD pathophysiology includes changes in specific anatomical brain regions and circuits, and studies of immune system function in individuals with PTSD suggest its association with enhanced immune inflammatory activity. However, establishment of animal models and human tissue biobanks is also warranted to elucidate the potential causal connection of PTSD-induced brain changes and/or inflammation with CVD pathophysiology. Emerging large-scale genome-wide association studies of PTSD will provide an opportunity to conduct mendelian randomization studies that test hypotheses regarding the presence, magnitude, and direction of causal associations between PTSD and CVD outcomes. By identifying research gaps in epidemiology and genomics, animal, and human translational research, opportunities to better justify and design future interventional trials are highlighted that may test whether treatment of PTSD or underlying neurobiological or immune dysregulation may improve or prevent CVD risk or outcomes.

Background: Evidence-based pharmacological treatments for posttraumatic stress disorder (PTSD) are few and of limited efficacy. Previous work suggests that angiotensin type 1 receptor inhibition facilitates fear inhibition and extinction, important for recovery from PTSD. This study tests the efficacy of the angiotensin type 1 receptor antagonist losartan, an antihypertensive drug, repurposed for the treatment of PTSD., Methods: A randomized controlled trial was conducted for 10 weeks in 149 men and women meeting DSM-5 PTSD criteria. Losartan (vs. placebo) was flexibly titrated from 25 to 100 mg/day by week 6 and held at highest tolerated dose until week 10. Primary outcome was the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) change score at 10 weeks from baseline. A key secondary outcome was change in CAPS-5 associated with a single nucleotide polymorphism of the ACE gene. Additional secondary outcomes included changes in the PTSD Checklist for DSM-5 and the Patient Health Questionnaire-9, and proportion of responders with a Clinical Global Impressions-Improvement scale of "much improved" or "very much improved.", Results: Both groups had robust improvement in PTSD symptoms, but there was no significant difference on the primary end point, CAPS-5 measured as week 10 change from baseline, between losartan and placebo (mean change difference, 0.9, 95% confidence interval, -3.2 to 5.0). There was no significant difference in the proportion of Clinical Global Impressions-Improvement scale responders for losartan (58.6%) versus placebo (57.9%), no significant differences in changes in PTSD Checklist for DSM-5 or Patient Health Questionnaire-9, and no association between ACE genotype and CAPS-5 improvement on losartan., Conclusions: At these doses and durations, there was no significant benefit of losartan compared with placebo for the treatment of PTSD. We discuss implications for failure to determine the benefit of a repurposed drug with strong a priori expectations of success based on preclinical and epidemiological data., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)

Objective: We tested the aspects of social support, unit cohesion, and religiosity hypothesized to be protective factors for suicide among U.S. service members., Methods: This case-control study compared U.S. Army soldiers who died by suicide while on active duty (n = 135) to controls of two types: those propensity score-matched on known sociodemographic risk factors (n = 128); and those controls who had thought about, but not died by, suicide in the past year (n = 108). Data included structured interviews of next of kin (NOK) and Army supervisors (SUP) for each case and control soldier. Logistic regression analyses were used to examine predictors of suicide., Results: Perceived social closeness and seeking help from others were associated with decreased odds of suicide, as reported by SUP (OR = 0.2 [95% CI = 0.1, 0.5]) and NOK (OR = 0.4 [95% CI = 0.2, 0.8]). Novel reports by SUP informants of high levels of unit cohesion/morale decreased odds of suicide (OR = 0.1 [95% CI = 0.0, 0.2]). Contrary to study hypotheses, no religious affiliation was associated with lower odds of suicide (OR = 0.3 [95% CI = 0.2, 0.6])., Conclusions: Perceived social closeness and unit/group cohesion are associated with lower odds of suicide. These results point toward social intervention strategies as testable components of suicide prevention programs., (© 2021 American Association of Suicidology. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Objectives. To examine associations of current mental and substance use disorders with self-reported gun ownership and carrying among recently separated US Army soldiers. Veterans have high rates of both gun ownership and mental disorders, the conjunction of which might contribute to the high suicide rate in this group. Methods. Cross-sectional survey data were collected in 2018-2019 from 5682 recently separated personnel who took part in the Army Study to Assess Risk and Resilience in Servicemembers. Validated measures assessed recent mood, anxiety, substance use, and externalizing disorders. Logistic regression models examined associations of sociodemographic characteristics, service characteristics, and mental disorders with gun ownership and carrying. Results. Of the participants, 50% reported gun ownership. About half of owners reported carrying some or most of the time. Mental disorders were not associated significantly with gun ownership. However, among gun owners, major depressive disorder, panic disorder, posttraumatic stress disorder, and intermittent explosive disorder were associated with significantly elevated odds of carrying at least some of the time. Conclusions. Mental disorders are not associated with gun ownership among recently separated Army personnel, but some mental disorders are associated with carrying among gun owners. ( Am J Public Health . 2021;111(10):1855-1864. https://doi.org/10.2105/AJPH.2021.306420).

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5-90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Objectives: Individuals with major depressive disorder (MDD) have problems with engaging in approach behaviour to potentially rewarding encounters, which contributes to the maintenance of depressive symptoms. Approach-avoidance training (AAT) retrains implicit approach tendencies, and behavioural activation (BA) promotes explicit approach behaviour in MDD. As a novel MDD treatment strategy, this study aimed to implement a brief, computerized version of BA integrated with implicit AAT., Design: Adults with a principal diagnosis of MDD (N = 25) were randomly assigned to complete one of two versions of AAT - approach-positive faces (n = 12) or balanced approach of positive and neutral faces (n = 13) - concurrently with self-guided BA twice weekly for 2 weeks., Methods: Outcomes included treatment completion rates; bias scores for automatic approach towards positive social cues; and symptom scales for depression, positive affect, social relationship functioning, anhedonia, and anxiety., Results: Feasibility and acceptability of computerized BA + AAT were supported by moderate pre-treatment credibility and expectancy ratings and 80% treatment completion. Participants across both conditions displayed significant and large sized reductions in depression from pre- to post-assessment (Cohen's d = -1.23) that maintained three months later, as well as decreased anxiety and anhedonia and increased positive affect and social relationship functioning (medium to large effects)., Conclusion: Results support the feasibility and potential efficacy of brief, computerized BA + AAT. Research is needed to determine whether AAT is additive to BA, and what AAT parameters best enhance treatment outcomes., Practitioner Points: Brief, computerized behavioral activation plus approach/avoidance training (BA + AAT) may be acceptable and beneficial for some patients with moderate-to-severe major depression. Computer-delivered BA + AAT can be implemented as a largely self-guided program for MDD and could be administered remotely and/or with minimal clinician interaction. As this was a small proof of concept study, it cannot be determined which treatment components - AAT, BA, or both - contributed to positive clinical outcomes. Because BA + AAT was implemented in a research clinic, it remains unknown what treatment engagement and response would look like in community settings., (© 2021 The British Psychological Society.)

This study aimed to elucidate the structure of the Rivermead Postconcussion Symptoms Questionnaire (RPQ) and evaluate its longitudinal and group variance. Factor structures were developed and compared in 1,011 patients with mild traumatic brain injury (mTBI; i.e., Glasgow Coma Scale score 13-15) from the Transforming Research and Clinical Knowledge in TBI study, using RPQ data collected at 2 weeks, and 3, 6, and 12 months postinjury. A bifactor model specifying a general factor and emotional, cognitive, and visual symptom factors best represented the latent structure of the RPQ. The model evinced strict measurement invariance over time and across sex, age, race, psychiatric history, and mTBI severity groups, indicating that differences in symptom endorsement were completely accounted for by these latent dimensions. While highly unidimensional, the RPQ has multidimensional features observable through a bifactor model, which may help differentiate symptom expression patterns in the future.

In recent years, there has been growing interest in examining the stimulus pull effects on respondent narratives to the Thematic Apperception Test (Murray, 1943) using standardized coding methods such as the Social Cognition and Object Relations Scale-Global Rating Method (SCORS-G; Stein, Hilsenroth, Slavin-Mulford, & Pinsker, 2011; Westen, 1995). The present study expands on prior work by examining sources of variance in SCORS-G dimensions and card pull effect patterns in an adult clinical sample characterized by high psychiatric comorbidity and clinical severity. A sample of 158 adult psychiatric patients in long-term residential treatment provided narratives to 10 TAT cards (five of which have not previously been studied for pull effects). Cards 2 and 7BM pulled for significantly more adaptive narratives (positive pull), whereas Card 13MF pulled for more pathological stories (negative pull). Like prior studies, variance in cognitive dimensions of the SCORS-G was most explained by person effects, whereas the largest source of variance for all other dimensions was best explained by a combination of the card and the person effects on the narrative. Finally, exploratory analyses of card pull effects within different gender groups were conducted. The implications of these findings for performance-based future studies and possible clinical applications of card pull findings are discussed., (© 2021 John Wiley & Sons, Ltd.)

Importance: Anger is linked to adverse outcomes in military populations; however, whether pre-enlistment anger attacks are associated with postenlistment mental disorders and suicidality is unknown., Objective: To explore the associations of pre-enlistment anger attacks with postenlistment mental health., Design, Setting, and Participants: In this observational cohort study, the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) New Soldier Study (NSS) surveyed soldiers entering basic training from April 2011 to November 2012, with a subsample recruited for wave 1 of the STARRS Longitudinal Study (STARRS-LS) (conducted September 2016 to April 2018). Participants were recruited from 3 US Army installations for the NSS survey. Those who were subsequently contacted for STARRS-LS completed the follow-up survey via web or telephone. Prospective analyses were based on a weighted NSS subsample included in wave 1 of STARRS-LS. Data were analyzed from May 22, 2020, to March 17, 2021., Exposures: History of anger attacks at baseline (NSS). Survey responses were used to classify new soldiers as having nonimpairing anger attacks (>2 attacks without interference in work or personal life), impairing anger attacks (>2 attacks with interference in work or personal life), or no significant history of anger attacks., Main Outcomes and Measures: Baseline analyses examined sociodemographic and clinical correlates of a history of anger attacks. Prospective logistic regression models estimated associations of baseline history of anger attacks with new onset and persistence of posttraumatic stress disorder, major depressive disorder (MDD), generalized anxiety disorder (GAD), panic disorder, mania/hypomania, substance use disorder, suicidal ideation, and suicide attempt at wave 1 of STARRS-LS., Results: Of the 38 507 baseline participants (83.0% male and 17.0% female; mean [SD] age, 20.97 [3.57] years), 6216 were selected for and completed wave 1 of the STARRS-LS. Baseline prevalence (SE) of nonimpairing and impairing anger attacks was 8.83% (0.16%) and 5.75% (0.15%), respectively. Prospective models showed that impairing anger attacks were associated with new onset of MDD (adjusted odds ratio [AOR], 1.98; 95% CI, 1.31-2.99), GAD (AOR, 2.39; 95% CI, 1.66-3.45), panic disorder (AOR, 2.02; 95% CI, 1.34-3.05), and suicidal ideation (AOR, 2.11; 95% CI, 1.45-3.07). When baseline psychiatric comorbidity was controlled for, impairing attacks remained associated with onset of GAD (AOR, 1.75; 95% CI, 1.19-2.58) and suicidal ideation (AOR, 1.62; 95% CI, 1.09-2.42). Anger attacks were not significantly associated with persistence of pre-enlistment mental disorders., Conclusions and Relevance: The findings of this study suggest that a pre-enlistment history of impairing anger attacks may be associated with elevated risk of developing GAD, MDD, and suicidality after enlistment. Detection of impairing anger attacks could aid in assessing psychiatric risk in new soldiers.

Importance: A head computed tomography (CT) with positive results for acute intracranial hemorrhage is the gold-standard diagnostic biomarker for acute traumatic brain injury (TBI). In moderate to severe TBI (Glasgow Coma Scale [GCS] scores 3-12), some CT features have been shown to be associated with outcomes. In mild TBI (mTBI; GCS scores 13-15), distribution and co-occurrence of pathological CT features and their prognostic importance are not well understood., Objective: To identify pathological CT features associated with adverse outcomes after mTBI., Design, Setting, and Participants: The longitudinal, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study enrolled patients with TBI, including those 17 years and older with GCS scores of 13 to 15 who presented to emergency departments at 18 US level 1 trauma centers between February 26, 2014, and August 8, 2018, and underwent head CT imaging within 24 hours of TBI. Evaluations of CT imaging used TBI Common Data Elements. Glasgow Outcome Scale-Extended (GOSE) scores were assessed at 2 weeks and 3, 6, and 12 months postinjury. External validation of results was performed via the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Data analyses were completed from February 2020 to February 2021., Exposures: Acute nonpenetrating head trauma., Main Outcomes and Measures: Frequency, co-occurrence, and clustering of CT features; incomplete recovery (GOSE scores <8 vs 8); and an unfavorable outcome (GOSE scores <5 vs ≥5) at 2 weeks and 3, 6, and 12 months., Results: In 1935 patients with mTBI (mean [SD] age, 41.5 [17.6] years; 1286 men [66.5%]) in the TRACK-TBI cohort and 2594 patients with mTBI (mean [SD] age, 51.8 [20.3] years; 1658 men [63.9%]) in an external validation cohort, hierarchical cluster analysis identified 3 major clusters of CT features: contusion, subarachnoid hemorrhage, and/or subdural hematoma; intraventricular and/or petechial hemorrhage; and epidural hematoma. Contusion, subarachnoid hemorrhage, and/or subdural hematoma features were associated with incomplete recovery (odds ratios [ORs] for GOSE scores <8 at 1 year: TRACK-TBI, 1.80 [95% CI, 1.39-2.33]; CENTER-TBI, 2.73 [95% CI, 2.18-3.41]) and greater degrees of unfavorable outcomes (ORs for GOSE scores <5 at 1 year: TRACK-TBI, 3.23 [95% CI, 1.59-6.58]; CENTER-TBI, 1.68 [95% CI, 1.13-2.49]) out to 12 months after injury, but epidural hematoma was not. Intraventricular and/or petechial hemorrhage was associated with greater degrees of unfavorable outcomes up to 12 months after injury (eg, OR for GOSE scores <5 at 1 year in TRACK-TBI: 3.47 [95% CI, 1.66-7.26]). Some CT features were more strongly associated with outcomes than previously validated variables (eg, ORs for GOSE scores <5 at 1 year in TRACK-TBI: neuropsychiatric history, 1.43 [95% CI .98-2.10] vs contusion, subarachnoid hemorrhage, and/or subdural hematoma, 3.23 [95% CI 1.59-6.58]). Findings were externally validated in 2594 patients with mTBI enrolled in the CENTER-TBI study., Conclusions and Relevance: In this study, pathological CT features carried different prognostic implications after mTBI to 1 year postinjury. Some patterns of injury were associated with worse outcomes than others. These results support that patients with mTBI and these CT features need TBI-specific education and systematic follow-up.

The Glasgow Outcome Scale (GOS) in its original or extended (GOSE) form is the most widely used assessment of global disability in traumatic brain injury (TBI) research. Several publications have reported concerns about assessor scoring inconsistencies, but without documentation of contributing factors. We reviewed 6801 GOSE assessments collected longitudinally, across 18 sites in the 5-year, observational T ransforming R esearch and C linical K nowledge in TBI (TRACK-TBI) study. We recorded error rates (i.e., corrections to a section or an overall rating) based on site assessor documentation and categorized scoring issues, which then informed further training. In cohort 1 ( n  = 1261; February 2014 to May 2016), 24% of GOSEs had errors identified by central review. In cohort 2 ( n  = 1130; June 2016 to July 2018), acquired after curation of cohort 1 data, feedback, and further training of site assessors, the error rate was reduced to 10%. GOSE sections associated with the most frequent interpretation and scoring difficulties included whether current functioning represented a change from pre-injury (466 corrected ratings in cohort 1; 62 in cohort 2), defining dependency in the home and community (163 corrections in cohort 1; three in cohort 2) and return to work/school (72 corrections in cohort 1; 35 in cohort 2). These results highlight the importance of central review in improving consistency across sites and over time. Establishing clear scoring criteria, coupled with ongoing guidance and feedback to data collectors, is essential to avoid scoring errors and resultant misclassification, which carry potential to result in "failure" of clinical trials that rely on the GOSE as their primary outcome measure.

This article focuses on neuropsychiatric clinical expression and neuropathology associated with chronic traumatic encephalopathy (CTE), which is thought to develop years after traumatic brain injury. The incidence, prevalence, additional risk factors, and pathophysiology remain largely unknown. CTE is considered a tauopathy because the endogenous brain protein tau, in its hyperphosphorylated state (p-tau), defines the predominant neuropathological findings and may underlie aspects of cell toxicity, synapse and circuit dysfunction, and clinical signs and symptoms. We discuss pathophysiological mechanisms possibly affecting p-tau accumulation. Finally, we interweave how clinical features and neuroanatomical sites associated with CTE potentially intersect with posttraumatic stress disorder., Competing Interests: Disclosure The opinions expressed herein are those of the authors and are not necessarily representative of those of the Uniformed Services University of the Health Sciences, the Department of Defense, or the US Army, Navy, or Air Force., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: US military veterans have high rates of suicide relative to civilians. However, little is known about the prevalence and correlates of suicidal behaviors in the general US veteran population., Methods: Data were from the National Health and Resilience in Veterans Study, a representative survey of US veterans conducted in 2019-2020 (n = 4,069). Analyses (1) estimated the prevalence of current suicidal ideation, lifetime suicide plans, and lifetime suicide attempts; (2) identified associated sociodemographic, military, DSM-5 psychiatric, and other risk correlates; and (3) examined mental health treatment utilization among veterans with suicidal ideation, suicide plans, or suicide attempts., Results: The prevalence of current suicidal ideation, lifetime suicide plans, and lifetime suicide attempts was 9.0%, 7.3%, and 3.9%, respectively. Suicidal behaviors were most prevalent among veterans aged 18-44 years, with 18.2%, 19.3%, and 11.1%, respectively, endorsing suicidal ideation, suicide plans, and suicide attempts. Major depressive disorder (MDD), age, posttraumatic stress disorder, and adverse childhood experiences (ACEs) emerged as the strongest correlates of suicidal ideation and suicide plans, while MDD, age, alcohol use disorder, and ACEs were the strongest correlates of suicide attempts. Only 35.5% of veterans with current suicidal ideation were engaged in mental health treatment, with veterans who used the US Veterans Administration (VA) as their primary source of health care more than twice as likely as VA non-users to be engaged in such treatment (54.7% vs 23.8%)., Conclusions: Suicidal behaviors are highly prevalent among US veterans, particularly among young veterans. Results suggest that nearly two-thirds of veterans with current suicidal ideation are not engaged in mental health treatment, signaling the need for enhanced suicide prevention and outreach efforts., (© Copyright 2021 Physicians Postgraduate Press, Inc.)

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1426 individuals with PTSD and 1621 controls (2174 males/873 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen's d = -0.11, p = 0.0055). The tapetum connects the left and right hippocampus, for which structure and function have been consistently implicated in PTSD. Results were consistent even after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network., (© 2019. The Author(s), under exclusive licence to Springer Nature Limited.)

Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = -0.111 to -0.068, FDR corrected P values < 0.039) and were significantly negatively correlated with PTSS severity. After adjusting for depression symptoms, the PTSD findings in left and right LOFG remained significant. These findings indicate that cortical volumes in PTSD patients are smaller in prefrontal regulatory regions, as well as in broader emotion and sensory processing cortical regions., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Posttraumatic stress disorder (PTSD) is a complex psychiatric disorder that can develop following exposure to traumatic events. The Psychiatric Genomics Consortium PTSD group (PGC-PTSD) has collected over 20,000 multi-ethnic PTSD cases and controls and has identified both genetic and epigenetic factors associated with PTSD risk. To further investigate biological correlates of PTSD risk, we examined three PGC-PTSD cohorts comprising 977 subjects to identify differentially expressed genes among PTSD cases and controls. Whole blood gene expression was quantified with the HumanHT-12 v4 Expression BeadChip for 726 OEF/OIF veterans from the Veterans Affairs (VA) Mental Illness Research Education and Clinical Center (MIRECC), 155 samples from the Injury and Traumatic Stress (INTRuST) Clinical Consortium, and 96 Australian Vietnam War veterans. Differential gene expression analysis was performed in each cohort separately followed by meta-analysis. In the largest cohort, we performed co-expression analysis to identify modules of genes that are associated with PTSD and MDD. We then conducted expression quantitative trait loci (eQTL) analysis and assessed the presence of eQTL interactions involving PTSD and major depressive disorder (MDD). Finally, we utilized PTSD and MDD GWAS summary statistics to identify regions that colocalize with eQTLs. Although not surpassing correction for multiple testing, the most differentially expressed genes in meta-analysis were interleukin-1 beta ( IL1B ), a pro-inflammatory cytokine previously associated with PTSD, and integrin-linked kinase ( ILK ), which is highly expressed in brain and can rescue dysregulated hippocampal neurogenesis and memory deficits. Pathway analysis revealed enrichment of toll-like receptor (TLR) and interleukin-1 receptor genes, which are integral to cellular innate immune response. Co-expression analysis identified four modules of genes associated with PTSD, two of which are also associated with MDD, demonstrating common biological pathways underlying the two conditions. Lastly, we identified four genes ( UBA7 , HLA-F , HSPA1B , and RERE ) with high probability of a shared causal eQTL variant with PTSD and/or MDD GWAS variants, thereby providing a potential mechanism by which the GWAS variant contributes to disease risk. In summary, we provide additional evidence for genes and pathways previously reported and identified plausible novel candidates for PTSD. These data provide further insight into genetic factors and pathways involved in PTSD, as well as potential regions of pleiotropy between PTSD and MDD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Garrett, Qin, Mehta, Dennis, Marx, Grant, VA Mid-Atlantic MIRECC Workgroup, PTSD Initiative, Injury and Traumatic Stress (INTRuST) Clinical Consortium, Psychiatric Genomics Consortium PTSD Group, Stein, Kimbrel, Beckham, Hauser and Ashley-Koch.)

Major depressive disorder is the most common neuropsychiatric disorder, affecting 11% of veterans. Here we report results of a large meta-analysis of depression using data from the Million Veteran Program, 23andMe, UK Biobank and FinnGen, including individuals of European ancestry (n = 1,154,267; 340,591 cases) and African ancestry (n = 59,600; 25,843 cases). Transcriptome-wide association study analyses revealed significant associations with expression of NEGR1 in the hypothalamus and DRD2 in the nucleus accumbens, among others. We fine-mapped 178 genomic risk loci, and we identified likely pathogenicity in these variants and overlapping gene expression for 17 genes from our transcriptome-wide association study, including TRAF3. Finally, we were able to show substantial replications of our findings in a large independent cohort (n = 1,342,778) provided by 23andMe. This study sheds light on the genetic architecture of depression and provides new insight into the interrelatedness of complex psychiatric traits.

The SPECTRA: Indices of Psychopathology is a broadband assessment inventory compatible with contemporary hierarchical models of psychopathology (internalizing, externalizing, reality impairing dimensions and global psychopathology factor). This study explored the SPECTRA's construct validity using a wide range of life event (extra-test) variables in a clinical sample. The life event variables included the following: education level, school failure, childhood adversity, suicide attempts, psychiatric hospitalizations, depression, psychotic symptoms, self-injury, substance abuse, arrests, physical violence, marital status, employment status and current medications. Results showed that all SPECTRA clinical scales had significant life event correlations. For the higher-order Spectra scales, the global index of psychopathology had the greatest number and range of life event correlations. Correlations for the externalizing and reality impairing Spectra scales provided solid validity evidence, while correlations for the internalizing Spectra scale were more diffuse. These findings provide the first non-test-based evidence of construct validity for the SPECTRA., (© 2021 John Wiley & Sons, Ltd.)

Positive valence system (PVS) deficits are increasingly recognized as important treatment targets for depression and anxiety. Emerging behavioral treatments designed to upregulate the PVS show initial promise; however, neural mechanisms underlying these approaches remain unknown. This study investigated neural reward-processing-related changes following Amplification of Positivity (AMP)-a treatment designed to enhance positive thinking, emotions and behaviors through positive activity interventions (Clinicaltrials.gov: NCT02330627). Individuals with depression and/or anxiety (N = 29) were randomized to 10 sessions of AMP (n = 16) or waitlist (WL; n = 13). Participants completed a monetary incentive delay task during fMRI at baseline and post-assessment. Hypothesis-driven region of interest (ventral striatum, insula, anterior cingulate) and exploratory whole-brain activation and connectivity analyses evaluated pre-to-post changes for AMP vs. WL when anticipating potential monetary gain or loss. No between-group brain activation changes emerged in regions of interest or whole-brain analyses. Increased neural connectivity from pre-to-post-treatment was observed in AMP vs. WL, including ventral striatum, anterior insula, and anterior cingulate connectivity with prefrontal, limbic, occipital and parietal regions-predominantly during loss anticipation. This preliminary study is the first to examine neural mechanisms of positive activity interventions in depression and anxiety and suggests that AMP may strengthen brain connectivity in reward processing, attention, and emotion regulation networks., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Neuropsychiatric symptoms are common, comorbid, and often disabling for patients with traumatic brain injury (TBI). Identifying transdiagnostic symptom dimensions post-TBI may help overcome limitations of traditional psychiatric diagnoses and advance treatment development. We characterized the dimensional structure of neuropsychiatric symptoms at 2-weeks postinjury in n = 1,732 TBI patients and n = 238 orthopedic-injured trauma controls (OTC) from the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. Symptoms were reported on the Brief Symptom Inventory-18, Patient Health Questionnaire-9 Depression checklist, PTSD Checklist for DSM-5, PROMIS Pain Intensity scale, and Insomnia Severity Index. We established a novel factor model of neuropsychiatric symptoms and evaluated how 3 TBI severity strata and OTC patients differed in symptom severity. The final factor model had 6 first-order factors subsumed by 2 second-order factors: Internalizing (encompassing Depression, Anxiety, and Fear) and Somatic symptoms (Sleep, Physical, Pain). Somatic symptoms fit better as a correlated factor of (vs. a lower-order factor within) Internalizing. All symptom dimensions except for Pain were more severe in 1 or more TBI subgroups, as compared to the OTC group. Milder brain injury was generally associated with more severe symptoms, whereas more general injury severity (higher level of care, e.g., emergency department, intensive care unit) was associated with more pain. The findings indicate a broad factor resembling the internalizing factor of general psychopathology in traumatically injured patients, alongside a distinct somatic symptom factor. Brain injury, especially milder brain injury, may exacerbate liabilities toward these symptoms. These neuropsychiatric dimensions may help advance more precision medicine research for TBI. (PsycInfo Database Record (c) 2021 APA, all rights reserved).