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Background: Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated, but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction of this relationship. Methods: Linkage disequilibrium score regression and 2-sample Mendelian randomization were used to test for genetic correlation (r g) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and 6 PTSD definitions (up to 320,369 individuals). Several additional variables were included in the analysis to verify the independence of the ADHD-PTSD relationship. In a population-based sibling comparison (N = 2,082,118 individuals), Cox regression models were fitted to account for time at risk, a range of sociodemographic factors, and unmeasured familial confounders (via sibling comparisons). Results: ADHD and PTSD had consistent r g (r g range, 0.43–0.52; p < .001). ADHD genetic liability was causally linked with increased risk for PTSD (β = 0.367; 95% CI, 0.186–0.552; p = 7.68 × 10 −5). This result was not affected by heterogeneity, horizontal pleiotropy (Mendelian randomization Egger intercept = 4.34 × 10 −4, p = .961), or other phenotypes and was consistent across PTSD datasets. However, we found no consistent associations between PTSD genetic liability and ADHD risk. Individuals diagnosed with ADHD were at a higher risk for developing PTSD than their undiagnosed sibling (hazard ratio = 2.37; 95% CI, 1.98–3.53). Conclusions: Our findings add novel evidence supporting the need for early and effective treatment of ADHD, as patients with this diagnosis are at significantly higher risk to develop PTSD later in life.

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

Traumatic experiences and genetic heritability are among the most widely acknowledged risk factors leading to the development of psychopathology; including posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). The purpose of this study was to investigate if polygenic risk scores (PRS) among Veterans interacted with traumatic stress to predict PTSD and MDD. 1,389 Iraq-Afghanistan military service Veterans from the Mental Illness Research Education and Clinical Center dataset were analyzed. Genome-wide association study (GWAS) statistics were utilized to generate PRS for PTSD (PRS

Statistical analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu), which is supported by the Office of Research Infrastructure of the National Institutes of Health (Grant Nos. S10OD018522 and S10OD026880). This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. This work was funded by the National Institutes of Health (Grant Nos. R01MH116269 and R01MH121455 [to DMR]), NIGMS of the National Institutes of Health (Grant No. T32GM007347 [to JK]), and the Brain & Behavior Research Foundation (NARSAD Young Investigator Award No. 29551 [to NM])., 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., Office of Research Infrastructure of the National Institutes of Health S10OD018522 S10OD026880, United States Department of Health & Human Services, National Institutes of Health (NIH) - USA R01MH116269 R01MH121455, NIH National Institute of General Medical Sciences (NIGMS) T32GM007347 NARSAD 29551

ImportanceSuicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown.ObjectiveTo identify novel, replicable genomic risk loci for SITB.Design, Setting, and ParticipantsThis genome-wide association study included 633 778 US military veterans with and without SITB, as identified through electronic health records. GWAS was performed separately by ancestry, controlling for sex, age, and genetic substructure. Cross-ancestry risk loci were identified through meta-analysis. Study enrollment began in 2011 and is ongoing. Data were analyzed from November 2021 to August 2022.Main Outcome and MeasuresSITB.ResultsA total of 633 778 US military veterans were included in the analysis (57 152 [9%] female; 121 118 [19.1%] African ancestry, 8285 [1.3%] Asian ancestry, 452 767 [71.4%] European ancestry, and 51 608 [8.1%] Hispanic ancestry), including 121 211 individuals with SITB (19.1%). Meta-analysis identified more than 200 GWS (P −8) cross-ancestry risk single-nucleotide variants for SITB concentrated in 7 regions on chromosomes 2, 6, 9, 11, 14, 16, and 18. Top single-nucleotide variants were largely intronic in nature; 5 were independently replicated in ISGC, including rs6557168 in ESR1, rs12808482 in DRD2, rs77641763 in EXD3, rs10671545 in DCC, and rs36006172 in TRAF3. Associations for FBXL19 and AC018880.2 were not replicated. Gene-based analyses implicated 24 additional GWS cross-ancestry risk genes, including FURIN, TSNARE1, and the NCAM1-TTC12-ANKK1-DRD2 gene cluster. Cross-ancestry enrichment analyses revealed significant enrichment for expression in brain and pituitary tissue, synapse and ubiquitination processes, amphetamine addiction, parathyroid hormone synthesis, axon guidance, and dopaminergic pathways. Seven other unique European ancestry–specific GWS loci were identified, 2 of which (POM121L2 and METTL15/LINC02758) were replicated. Two additional GWS ancestry-specific loci were identified within the African ancestry (PET112/GATB) and Hispanic ancestry (intergenic locus on chromosome 4) subsets, both of which were replicated. No GWS loci were identified within the Asian ancestry subset; however, significant enrichment was observed for axon guidance, cyclic adenosine monophosphate signaling, focal adhesion, glutamatergic synapse, and oxytocin signaling pathways across all ancestries. Within the European ancestry subset, genetic correlations (r > 0.75) were observed between the SITB phenotype and a suicide attempt-only phenotype, depression, and posttraumatic stress disorder. Additionally, polygenic risk score analyses revealed that the Million Veteran Program polygenic risk score had nominally significant main effects in 2 independent samples of veterans of European and African ancestry.Conclusions and RelevanceThe findings of this analysis may advance understanding of the molecular genetic basis of SITB and provide evidence for ESR1, DRD2, TRAF3, and DCC as cross-ancestry candidate risk genes. More work is needed to replicate these findings and to determine if and how these genes might impact clinical care.

To identify pan-ancestry and ancestry-specific loci associated with attempting suicide among veterans, we conducted a genome-wide association study (GWAS) of suicide attempts within a large, multi-ancestry cohort of U.S. veterans enrolled in the Million Veterans Program (MVP). Cases were defined as veterans with a documented history of suicide attempts in the electronic health record (EHR; N = 14,089) and controls were defined as veterans with no documented history of suicidal thoughts or behaviors in the EHR (N = 395,064). GWAS was performed separately in each ancestry group, controlling for sex, age and genetic substructure. Pan-ancestry risk loci were identified through meta-analysis and included two genome-wide significant loci on chromosomes 20 (p = 3.64 × 10

Abstract. Autonomic dysfunction, in particular under-regulation of heart rate (HR) by the baroreflex, is implicated in development of insulin resistance (IR). According to reactivity hypothesis, sympathetic response to stressors may be more sensitive at predicting IR than baroreceptor sensitivity (BRS), a baseline measure of baroreflex functioning. Using ecological momentary assessment (EMA) of negative affect coupled with minute-to-minute HR and heart-rate variability (HRV) monitoring, we examined whether negative affect (NA)-related autonomic arousal mediates the association of BRS with IR. At baseline, BRS was measured, and fasting serum glucose and insulin levels were collected from 178 young adults (18–39 years old), from which homeostasis model assessment of IR (HOMA-IR) and beta-cell functioning (HOMA %B) were derived. Participants subsequently underwent one day of Holter HR and HRV monitoring while reporting NA levels via EMA. Multilevel modeling was used to assess the associations of momentary NA with HR and low- (LF) and high-frequency (HF) HRV during the 5-minute intervals following each EMA reading. Structural equation modeling was then used to determine whether individual differences in these associations mediated the association of BRS with IR, measured by HOMA-IR, HOMA %B, and insulin levels. As predicted, BRS was negatively associated with the IR (β = −.17, p = .024). However, NA-related autonomic arousal mediated their association, accounting for 56% of the covariance between BRS and IR. Not only do these results provide support for reactivity hypothesis, they reveal a potential point of intervention in the treatment of affective dysregulation.

Behavioural, structural, and functional neuroimaging have implicated the hippocampus as a critical brain region in posttraumatic stress disorder (PTSD) pathogenesis. Recent work in a normative, primarily European, sample identified 15 unique genetic loci contributing to structural variability in six hippocampal subfield volumes. We explored the relevance of these loci in two samples (Mental Illness Research Education and Clinical Centre [MIRECC] and Grady; n = 290) of trauma-exposed individuals enriched for PTSD and of diverse ancestry. Four of the previous loci demonstrated nominal evidence of replication in the MIRECC dataset, primarily within non-Hispanic whites (NHW). One locus replicated in the Grady cohort, which was composed exclusively of non-Hispanic blacks (NHB). Our data supported genetic interactions with diagnosis of lifetime PTSD and genetic interactions with childhood trauma in the MIRECC sample, but not the Grady sample. Given the racial, diagnostic, and trauma-exposure differences with the original genome-wide association study (GWAS) report, we conducted a full GWAS in the MIRECC and Grady datasets. Interactions between genetic variants and lifetime PTSD or childhood trauma were interrogated for single nucleotide polymorphisms (SNPs) with evidence of main effects. Genetic associations surpassed false discovery rate (FDR)-correction within hippocampal subfields in fimbria, subiculum, cornu ammonis-1 (CA1), and hippocampal amygdala transition area (HATA). One association was replicated in the Grady cohort (rs12880795 in TUNAR with left (L)-HATA volume). The most significant association in the MIRECC dataset was between rs6906714 in LINC02571 and right (R)-fimbria volume (p = 5.99×10−8, q = 0.0056). Interestingly, the effect of rs6906714 on R-fimbria volume increased with exposure to childhood trauma (gene*environment [G*E] interaction p = 0.022). These preliminary results argue for G*E interactions between genetic loci with PTSD and childhood trauma on hippocampal phenotypes. Our results underscore the need for larger neuroimaging-genetic studies in PTSD, trauma, and ancestrally diverse populations.

OBJECTIVE: The objective of the present study was to use retrospective data to test the hypothesis that cannabis dependence would be associated with an increased rate of post-deployment suicide attempts. METHODS: Participants included 319 veterans who had deployed to either Iraq or Afghanistan. Study procedures involved completion of a structured clinical interview and a battery of self-report questionnaires. RESULTS: As expected, lifetime cannabis dependence was significantly associated with post-deployment suicide attempts, AOR = 7.963, p = .014, even after controlling for the effects of pre-deployment suicide attempts, posttraumatic stress disorder, depression, pain, non-cannabis substance use disorder, and gender. CONCLUSIONS: While preliminary, our findings provide the first evidence to date that heavy cannabis use may be a unique risk factor for post-deployment suicide attempts among veterans.

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

Pediatric HIV infection remains a large global health concern despite the widespread use of antiretroviral therapy (ART). Thus, global elimination of pediatric HIV infections will require the development of novel immune-based approaches, and understanding infant immunity to HIV is critical to guide the rational design of these intervention strategies. Despite their immunological immaturity, HIV-infected children develop broadly neutralizing antibodies (bnAbs) more frequently and earlier than adults do. Furthermore, T-follicular helper (Tfh) cells have been associated with bnAb development in HIV-infected children and adults. To further our understanding of age-related differences in the development of HIV-specific immunity, we evaluated the generation of virus-specific humoral immune responses in infant (n=6) and adult (n=12) rhesus macaques (RMs) infected with a transmitted/founder (T/F) simian-human immunodeficiency virus (SHIV.C.CH505). The plasma HIV envelope-specific IgG antibody kinetics were similar in SHIV-infected infant and adult RMs, with no significant differences in the magnitude or breadth of these responses. Interestingly, autologous tier 2 virus neutralization responses also developed with similar frequency and kinetics in infant and adult RMs, despite infants exhibiting significantly higher Tfh and germinal center B cell frequencies compared to adults. Our results indicate that the humoral immune response to SHIV infection develops with similar kinetics among infant and adult RMs, suggesting that the early life immune system is equipped to respond to HIV-1 and promote the production of neutralizing HIV antibodies.ImportanceThere is a lack of understanding on how the maturation of the infant immune system influences immunity to HIV infection, or how these responses differ from those of adults. Improving our knowledge of infant HIV immunity will help guide antiviral intervention strategies that take advantage of the unique infant immune environment to successfully elicit protective immune responses. We utilized a rhesus macaque model of SHIV infection as a tool to distinguish the differences in HIV humoral immunity in infants versus adults. Here, we demonstrate that the kinetics and quality of the infant humoral immune response to HIV are highly comparable to that of adults during the early phase of infection, despite distinct differences in their Tfh responses, indicating that slightly different mechanisms may drive infant and adult humoral immunity.

Global elimination of pediatric human immunodeficiency virus (HIV) infections will require the development of novel immune-based approaches, and understanding infant immunity to HIV is critical to guide the rational design of these intervention strategies. Despite their immunological immaturity, chronically HIV-infected children develop broadly neutralizing antibodies (bnAbs) more frequently and earlier than adults do. However, the ontogeny of humoral responses during acute HIV infection is poorly defined in infants and challenging to study in human cohorts due to the presence of maternal antibodies. To further our understanding of age-related differences in the development of HIV-specific immunity during acute infection, we evaluated the generation of virus-specific humoral immune responses in infant (n = 6) and adult (n = 12) rhesus macaques (RMs) infected with a transmitted/founder (T/F) simian-human immunodeficiency virus (SHIV) (SHIV.C.CH505 [CH505]). The plasma HIV envelope-specific IgG antibody kinetics were similar in SHIV-infected infant and adult RMs, with no significant differences in the magnitude or breadth of these responses. Interestingly, autologous tier 2 virus neutralization responses also developed with similar frequencies and kinetics in infant and adult RMs, despite infants exhibiting significantly higher follicular T helper cell (Tfh) and germinal center B cell frequencies than adults. Finally, we show that plasma viral load was the strongest predictor of the development of autologous virus neutralization in both age groups. Our results indicate that the humoral immune response to SHIV infection develops with similar kinetics among infant and adult RMs, suggesting that the early-life immune system is equipped to respond to HIV-1 and promote the production of neutralizing HIV antibodies. IMPORTANCE There is a lack of understanding of how the maturation of the infant immune system influences immunity to HIV infection or how these responses differ from those of adults. Improving our knowledge of infant HIV immunity will help guide antiviral intervention strategies that take advantage of the unique infant immune environment to successfully elicit protective immune responses. We utilized a rhesus macaque model of SHIV infection as a tool to distinguish the differences in HIV humoral immunity in infants versus adults. Here, we demonstrate that the kinetics and quality of the infant humoral immune response to HIV are highly comparable to those of adults during the early phase of infection, despite distinct differences in their Tfh responses, indicating that slightly different mechanisms may drive infant and adult humoral immunity.

Posttraumatic stress disorder (PTSD) has been associated with accelerated progression of coronary heart disease (CHD). However, the underlying pathophysiological pathway has remained elusive and it is unclear whether there is a direct link between PTSD and CHD risk. This paper describes the methods of a randomized controlled trial developed to examine how changes in PTSD symptoms affect CHD disease pathways. One hundred twenty participants with current PTSD and who are free of known CHD will be randomized to receive either an evidence-based treatment for PTSD (Cognitive Processing Therapy; CPT) or a waitlist control (WL). Before and after CPT/WL, participants undergo assessment of CHD risk biomarkers reflecting autonomic nervous system dysregulation, systemic inflammation, and vascular endothelial dysfunction. The primary hypothesis is that individuals who show improvement in PTSD symptoms will show improvement in CHD risk biomarkers, whereas individuals who fail to improve or show worsening PTSD symptoms will have no change or worsening in CHD biomarkers. This study is expected to provide knowledge of the role of both the direct impact of PTSD symptoms on CHD risk pathways and the role of these systems as candidate mechanisms underlying the relationship between PTSD and CHD risk. Further, results will provide guidance on the utility of cognitive therapy as a tool to mitigate the accelerated progression of CHD in PTSD. Clinical Trials Registration: https://clinicaltrials.gov/ct2/show/NCT02736929; Unique identifier: NCT02736929.

Introduction The primary objective of this project was to examine the effectiveness of an Internet-based smoking cessation intervention combined with a tele-health medication clinic for nicotine replacement therapy (NRT) compared to referral to clinic-based smoking cessation care. Methods A total of 413 patients were proactively recruited from the Durham VA Medical Center and followed for 12 months. Patients were randomized to receive either a referral to VA specialty smoking cessation care (control) or to the Internet intervention and tele-health medication clinic. Primary outcomes included (1) intervention reach, (2) self-reported 7-day point prevalence abstinence rates at 3 months and 12 months, and 3) relative cost-effectiveness. Results Reach of the Internet intervention and use of smoking cessation aids were significantly greater compared to the control. At 3 months-post randomization, however, there were no significant differences in quit rates: 17% (95% CI: 12%–23%) in the Internet-based intervention compared to 12% (95% CI: 8%–17%) in the control arm. Similarly, there were no differences in quit rates at 12 months (13% vs. 16%). While costs associated with the Internet arm were higher due to increased penetration and intensity of NRT use, there were no statistically significant differences in the relative cost effectiveness (e.g., life years gained, quality adjusted life years) between the two arms. Conclusions Current results suggest that using an electronic medical record to identify smokers and proactively offering smoking cessation services that are consistent with US Public Health Guidelines can significantly reduce smoking in veterans. Novel interventions that increase the reach of intensive treatment are needed to maximize quit rates in this population.

Involvement in wartime combat often conveys a number of deleterious outcomes, including posttraumatic stress disorder (PTSD), depression, hostility, aggression, and suicidal ideation. Less studied is the effect of engagement in wartime atrocities, including witnessing and perpetrating abusive violence.This study employed path analysis to examine the direct effects of involvement in wartime atrocities on hostility, aggression, depression, and suicidal ideation independent of combat exposure, as well as the indirect effects via guilt and PTSD symptom severity among 603 help-seeking male Vietnam War veterans.Involvement in wartime atrocities was predictive of increased guilt, PTSD severity, hostility, aggression, depressive symptoms, and suicidal ideation after controlling for overall combat exposure. Combat-related guilt played a minor role in mediating the effect of atrocity involvement on depression and suicidal ideation. PTSD severity had a larger mediational effect. However, it still accounted for less than half of the total effect of involvement in wartime atrocities on hostility, aggression, and suicidal ideation.These findings highlight the heightened risk conveyed by involvement in wartime atrocities and suggest that the psychological sequelae experienced following atrocity involvement may extend well beyond guilt and PTSD.

Prior research has demonstrated that individuals exposed to trauma have shown impaired autonomic function. We sought to determine if heart rate variability (HRV), a marker of impaired autonomic function, differed across periods of wake, rest, and sleep as a function of the level of symptoms of posttraumatic stress disorder (PTSD). A sample of young adults (N = 209), 95 of whom met full criteria for current PTSD based on the Clinician Administered PTSD Scale (CAPS; Blake et al., 1995), were evaluated for ≈ 24 hr using actigraphy and electrocardiogram. Actigraphy data were categorized as active, rest, or sleep. Multilevel modeling analyses showed that individuals with high PTSD symptom severity had lower high-frequency HRV than individuals with low PTSD symptom severity during periods of sleep, t(1083) = 2.20, p = .028, Cohen's d = 0.12. No differences were found during periods of activity, t(1083) = 1.34, p = .499, d = 0.05, or rest, t(1083) = 1.34, p = .180, d = 0.09. Our findings extended the import of prior studies to suggest that those with elevated PTSD symptoms may have decreased parasympathetic control during sleep. Moreover, relative to periods of wake and rest, sleep may represent a state of increased vulnerability for decreased parasympathetic cardiac control. Individuals with elevated PTSD symptoms may benefit from early screening for detection of cardiovascular disease.

OBJECTIVE Posttraumatic stress disorder (PTSD) has been linked to elevated heart rate (HR) and reduced heart rate variability (HRV) in cross-sectional research. Using ecological momentary assessment and minute-to-minute HRV/HR monitoring, we examined whether cross-sectional associations between PTSD symptom severity and HRV/HR were due to overall elevations in distress levels or to attenuated autonomic regulation during episodes of acute distress. METHODS Two hundred nineteen young adults (18-39 years old), 99 with PTSD, underwent 1 day of Holter monitoring and concurrently reported distress levels via ecological momentary assessment. Using multilevel modeling, we examined the associations between momentary distress and the 5-minute means for low-frequency (LF) and high-frequency (HF) HRV and HR immediately following distress ratings, and whether PTSD symptom severity moderated these associations. RESULTS Compared with the controls, participants with PTSD recorded higher ambulatory distress (mean [standard deviation] = 1.7 [0.5] versus 1.2 [0.3], p .27). However, baseline PTSD symptom severity was associated with elevated HR (t(1257) = 2.76, p = .006) and attenuated LF (t(1257) = -3.86, p < .001) and HF (t(1257) = -2.62, p = .009) in response to acute momentary distress. CONCLUSIONS Results suggest that PTSD is associated with heightened arousal after situational distress and could explain prior findings associating PTSD with HR/HRV. Implications for treatment and cardiovascular risk are discussed.

Objective Posttraumatic stress disorder (PTSD) has been linked to chronic inflammation, a condition that poses a risk for cardiovascular disease. Attenuated vagal activity has been proposed as a potential mediator of PTSD and inflammation, although associated behavioral health risks—namely cigarette smoking and alcohol dependence—might also account for that link. Methods Inflammation was quantified by fasting serum concentrations of C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukin (IL)-10, and thymus- and activation-regulated chemokine (TARC)/CCL17 collected from 85 participants with PTSD and 82 without PTSD. Latent variable modeling was used to assess the relationship between PTSD symptom severity and inflammation along with potential mediators vagal activity (respiratory sinus arrhythmia; RSA), smoking status, and lifetime alcohol dependence. Results PTSD symptom severity was associated with increased inflammation ( β = .18, p = .02). However, this association was reduced in models that adjusted for RSA, smoking status, and lifetime alcohol dependence. Independent mediation effects were deemed significant via bootstrapping analyses. Together, RSA, smoking status, and lifetime alcohol dependence accounted for 95% of the effect of PTSD symptom severity on inflammation. Conclusion Although RSA accounted for a modest proportion of the association between posttraumatic stress and pro-inflammatory responses, behavioral factors—specifically cigarette smoking and alcohol dependence—proved to be larger mediators. The benefits of PTSD treatment may be enhanced by additional interventions aimed at modifying these health behaviors.

Recent research has documented high rates of comorbidity between cannabis use disorders and posttraumatic stress disorder (PTSD) in veterans. However, despite possible links between PTSD and cannabis use, relatively little is known about cannabis use in veterans who present for PTSD treatment, particularly among samples not diagnosed with a substance use disorder. This study examined the prevalence of cannabis use and the psychological and functional correlates of cannabis use among a large sample of veterans seeking treatment at a Veterans Affairs (VA) PTSD specialty clinic. Male veterans (N = 719) who presented at a VA specialty outpatient PTSD clinic completed measures of demographic variables, combat exposure, alcohol, cannabis and other drug use, and PTSD and depressive symptoms. The associations among demographic, psychological, and functional variables were estimated using logistic regressions. Overall, 14.6% of participants reported using cannabis in the past 6 months. After controlling for age, race, service era, and combat exposure, past 6-month cannabis use was associated with unmarried status, use of tobacco products, other drug use, hazardous alcohol use, PTSD severity, depressive symptom severity, and suicidality. The present findings show that cannabis use is quite prevalent among veterans seeking PTSD specialty treatment and is associated with poorer mental health and use of other substances. It may be possible to identify and treat individuals who use cannabis in specialty clinics (e.g., PTSD clinics) where they are likely to present for treatment of associated mental health issues. (PsycINFO Database Record

Post-traumatic stress disorder (PTSD) is a common and debilitating disorder. The risk of PTSD following trauma is heritable, but robust common variants have yet to be identified by genome-wide association studies (GWAS). We have collected a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls. We first demonstrate significant genetic correlations across 60 PTSD cohorts to evaluate the comparability of these phenotypically heterogeneous studies. In this largest GWAS meta-analysis of PTSD to date we identify a total of 6 genome-wide significant loci, 4 in European and 2 in African-ancestry analyses. Follow-up analyses incorporated local ancestry and sex-specific effects, and functional studies. Along with other novel genes, a non-coding RNA (ncRNA) and a Parkinson’s Disease gene,PARK2, were associated with PTSD. Consistent with previous reports, SNP-based heritability estimates for PTSD range between 10-20%. Despite a significant shared liability between PTSD and major depressive disorder, we show evidence that some of our loci may be specific to PTSD. These results demonstrate the role of genetic variation contributing to the biology of differential risk for PTSD and the necessity of expanding GWAS beyond European ancestry.

Death by suicide and suicidal behavior are major concerns among U.S. military veterans; however, no genome-wide association studies (GWAS) studies of suicidal behavior have been conducted among U.S. military veterans to date, despite the elevated rate of suicidal behavior observed within this population. Accordingly, the primary objective of the present research was to conduct the first GWAS of suicide attempts and suicidal ideation in a large and well-characterized sample of U.S. military veterans. The gene most significantly associated (p = 9.28 × 10−7) with suicide attempts was the Potassium Calcium-Activated Channel Subfamily M Regulatory Beta Subunit 2 (KCNMB2) gene, which plays a key role in neuronal excitability. In addition, replication analyses provided additional support for the potential role of the ABI Family Member 3 Binding Protein (ABI3BP) gene in the pathogenesis of suicidal behavior, as numerous nominal associations were found between this gene and both suicide attempts and suicidal ideation. Additional work aimed at replicating and extending these findings is needed.

OBJECTIVE: To determine whether augmenting standard smoking cessation treatment by wearing an active nicotine patch before the smoking quit date improves rates of smoking cessation in individuals with posttraumatic stress disorder (PTSD), and to explore mechanisms of treatment response such as decreased cigarette craving and symptom relief from smoking. METHODS: Double-blind parallel randomized controlled trial in 81 people with PTSD who smoked cigarettes. Participants were recruited from Veterans Affairs outpatient clinics and flyers in the community. Participants provided ecological momentary assessments (EMA) of PTSD symptoms, smoking withdrawal symptoms, and cravings before and after smoking a cigarette during one week of ad lib smoking, then three weeks of either a nicotine patch (n = 37) or placebo patch (n = 44) preceding the quit date. All participants received standard pharmacotherapy and behavioral treatment for smoking cessation after the quit date. To test the efficacy of nicotine patch preloading for engaging proposed treatment targets during the pre-quit phases, we used multilevel models to compare post-smoking changes in symptoms and cravings during the preloading phases to post-smoking changes reported during the ad lib smoking phase. RESULTS: There was no significant difference in quit rates across the two conditions on the primary outcome of 7-day point prevalence smoking abstinence bioverified with breath carbon monoxide (CO) at six weeks post-quit date. In a multivariable multilevel model pre- to post-cigarette changes in PTSD symptom clusters, smoking withdrawal symptoms, and cravings, there was a significant interaction between treatment phase and condition. Relative to participants in the placebo condition, participants in the nicotine patch condition experienced diminished relief from PTSD re-experiencing symptoms, smoking withdrawal symptoms, and cigarette craving after smoking a cigarette. CONCLUSIONS: Relative to placebo patch preloading, nicotine patch preloading diminished the reinforcing effects of smoking cigarettes. However, the low quit rates in both conditions suggest that nicotine patch preloading is not a sufficiently intensive treatment for achieving smoking cessation in people with PTSD. TRIAL REGISTRATION: Clinical Trials NCT00625131

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that can develop after experiencing traumatic events. A genome-wide association study (GWAS) design was used to identify genetic risk factors for PTSD within a multi-racial sample primarily composed of U.S. veterans.Participants were recruited at multiple medical centers, and structured interviews were used to establish diagnoses. Genotypes were generated using three Illumina platforms and imputed with global reference data to create a common set of SNPs. SNPs that increased risk for PTSD were identified with logistic regression, while controlling for gender, trauma severity, and population substructure. Analyses were run separately in non-Hispanic black (NHB; n = 949) and non-Hispanic white (NHW; n = 759) participants. Meta-analysis was used to combine results from the two subsets.SNPs within several interesting candidate genes were nominally significant. Within the NHB subset, the most significant genes were UNC13C and DSCAM. Within the NHW subset, the most significant genes were TBC1D2, SDC2 and PCDH7. In addition, PRKG1 and DDX60L were identified through meta-analysis. The top genes for the three analyses have been previously implicated in neurologic processes consistent with a role in PTSD. Pathway analysis of the top genes identified alternative splicing as the top GO term in all three analyses (FDR q3.5 × 10(-5)).No individual SNPs met genome-wide significance in the analyses.This multi-racial PTSD GWAS identified biologically plausible candidate genes and suggests that post-transcriptional regulation may be important to the pathology of PTSD; however, replication of these findings is needed.

Most smokers who attempt to quit lapse within the first week and are ultimately unsuccessful in their quit attempt. Nicotine withdrawal exacerbates cognitive and attentional problems and may be one factor in smoking relapse. The startle reflex response and prepulse inhibition (PPI) of the response are sensitive to arousal and early attentional dysregulation. The current study examined whether startle response and PPI are related to early smoking lapse, and if this differs in people with and without posttraumatic stress disorder (PTSD). Participants with ( N = 34) and without ( N = 57) PTSD completed a startle reflex and PPI assessment during (1) ad lib smoking (2) on the first day of abstinence during a quit attempt. Most (88%) participants lapsed within the first week of the quit attempt. PTSD status predicted shorter time to lapse. Larger startle magnitude and greater PPI predicted a longer duration before smoking lapse. When diagnostic groups were examined separately, greater PPI predicted a longer successful quit attempt only in participants with a PTSD diagnosis. The startle reflex response and PPI may provide an objective, neurophysiological evaluation of regulation of arousal and early attentional processes by nicotine, which are important factors in smoking cessation success.

Iraq/Afghanistan-era veterans are at increased risk for anxiety, mood, and substance-use disorders.1–3 One obvious explanation for the high rates of psychiatric problems and psychiatric comorbidity observed among returning veterans is combat exposure, which has been associated with a variety of problems, including PTSD, depression, and substance use.1, 4–6 While the impact of combat exposure on post-deployment psychiatric adjustment is evident, genetic factors are also likely to play a role.7–13 Indeed, it is estimated that approximately 30% of susceptibility to PTSD among Vietnam Veterans is due to genetic factors.7 Behavioral genetics studies further suggest that genetic factors may partially explain the co-occurrence of other disorders observed among veterans, such as the comorbidity observed between PTSD and depression.8 Much of the psychiatric genetics research conducted with veterans to date has involved candidate gene studies aimed at identifying the genetic basis of PTSD;9–12 however, the molecular genetic basis of PTSD has remained elusive, leading some researchers to propose the need for more gene x environment (GxE) investigations of PTSD.13 For example, while it is clear that trauma severity—particularly combat exposure severity—is associated with the development of PTSD,1, 4–6 there is also substantial variability in response to traumatic events,14 which suggests the possibility of GxE interactions.15 Moreover, a number of studies have already found evidence for GxE effects on PTSD.13, 16–20 There is also evidence for GxE effects on other closely-related disorders, such as other anxiety disorders, depression, and alcohol use-disorders.21–24 To date, however, there has been only limited research on whether the apolipoprotein E (APOE) gene might moderate the effect of trauma exposure on PTSD and other closely-related disorders.20, 25 The human APOE gene contains three polymorphic alleles, e2, e3, and e4, that are estimated to have worldwide frequencies of, 8.4%, 77.9% and 13.7%, respectively.26 Apolipoprotein E (apoE) supports injury repair in the brain by transporting cholesterol and other lipids to neurons; however, the e4 allele of the APOE gene is associated with a wide range of neurological problems, including apoptosis, cortical atrophy, abnormalities in the hippocampus, inflammation, increased amyloid-β (Aβ) peptide aggregation, decreased lipid and glucose metabolism, and decreased neurogenesis.26–27 The e4 allele is also associated with cardiovascular disease, difficulty recovering from traumatic brain injuries (TBI), and Alzheimer disease (AD).26–31 Most notable are the additive genetic effects observed for the APOE e4 allele on risk for AD. For example, among non-Hispanic Whites (NHW), the odds ratio (OR) of developing AD is 2.6 for e2/e4, 3.2 for e3/e4, and 14.9 among e4/e4 homozygotes relative to e3/e3 homozygotes.26 Age of onset for AD is also affected by APOE e4 in a dose-dependent manner.26 These findings, in conjunction with prior research suggesting an increased risk for dementia among veterans with PTSD,32 recently lead Lyons and colleagues to examine whether the e4 allele of the APOE gene might moderate susceptibility to PTSD in a sample of predominantly NHW male Vietnam-era veterans (N = 172).20 Consistent with their hypothesis, they found that e4 carriers who scored highly on a self-report measure of combat exposure were significantly more likely to have PTSD symptoms and to meet criteria for PTSD.20 While promising, the conclusions that can be drawn from this study are limited by its relatively small sample size, which prevented the authors from examining the potential additive effects of e4 on PTSD. An additional concern relates to disparate findings between this study and other studies on APOE and PTSD. The first such study examined the relationship between APOE genotype and PTSD symptoms among 54 male NHW combat veterans, all of whom met criteria for combat-related PTSD. 33 Carriers of the e2 allele—which is associated with decreased risk for AD26—reported more re-experiencing symptoms and worse memory functioning than the rest of the sample; however, the findings from this study are also limited by the small sample size and the fact that all of the participants met criteria for PTSD. A more recent study examined the relationship between APOE, PTSD, and alcohol use in Korean veterans of the Vietnam War.25 Absence of the e2 allele was associated with decreased risk for PTSD in this study after accounting for combat exposure. In addition, a significant interaction between APOE e2 and harmful drinking was observed, such that the e2 non-carriers with harmful drinking were more likely to have PTSD compared with e2 non-carriers without harmful drinking. While novel, this study was also limited by its small sample size (N = 256) and the small number of e4 homozygotes present (n = 3). Hypotheses Based on the recent findings from Lyons et al.20 as well as prior research demonstrating additive effects for e4 on AD,26 we hypothesized that the e4 allele would moderate the effect of combat exposure on PTSD in an additive fashion, such that e4 homozygotes exposed to high levels of combat would exhibit the highest rate of PTSD and have the worst symptom severity. In addition, given previous findings suggesting that much of the comorbidity observed between PTSD and other psychiatric disorders is due to genetic factors8 as well as evidence for GxE effects on other closely-related disorders, such as other anxiety disorders, depression, and alcohol use-disorders,21–24 we further hypothesized that the APOE e4 x combat interaction would be associated with psychiatric comorbidity in general, such that e4 homozygotes exposed to high levels of combat would also exhibit the highest overall rates of psychiatric comorbidity.

Introduction Smoking rates are 80% among persons who are homeless, and these smokers have decreased odds of quitting smoking. Little is known about relapse rates among homeless smokers. More information is needed regarding both quit rates and innovative methods to treat smoking cessation among homeless smokers. Web-based contingency management (CM) approaches have been found helpful in reducing smoking among other difficult-to-treat smoker populations but have been generally limited by the need for computers or frequent clinic-based carbon monoxide (CO) monitoring. This open pilot study builds on a web-based CM approach by evaluating a smartphone-based application for CM named mobile CM (mCM). The study was conducted from January 1, 2013-April 15, 2014. Method Following a 1-week training period, 20 homeless veteran smokers (≥ 10 cigarettes daily for 1 year or more and a CO baseline level ≥ 10 ppm) participated in a multicomponent smoking cessation intervention including 4 weeks of mCM. All smokers received 4 smoking cessation counseling sessions, nicotine replacement, and bupropion (if medically eligible). Participants could earn up to $815 ($480 for mCM, $100 for CO readings showing abstinence [ie, 6 ppm or less] at posttreatment and follow-up, and $35 for equipment return). Results Mean compensation for the mCM component was $286 of a possible $480. Video transmission compliance was high during the 1-week training (97%) and the 4-week treatment period (87%). Bioverified 7-day point prevalence abstinence was 50% at 4 weeks. Follow-up bioverified single assessment point prevalence abstinence was 55% at 3 months and 45% at 6 months. Conclusions Results of this open pilot study suggest that mCM may be a useful adjunctive smoking cessation treatment component for reducing smoking among homeless veterans. Trial registration ClinicalTrials.gov identifier: NCT01789710.

Compelling evidence suggests that epigenetic mechanisms such as DNA methylation play a role in stress regulation and in the etiologic basis of stress related disorders such as Post traumatic Stress Disorder (PTSD). Here we describe the purpose and methods of an international consortium that was developed to study the role of epigenetics in PTSD. Inspired by the approach used in the Psychiatric Genomics Consortium, we brought together investigators representing seven cohorts with a collective sample size of N=1147 that included detailed information on trauma exposure, PTSD symptoms, and genome-wide DNA methylation data. The objective of this consortium is to increase the analytical sample size by pooling data and combining expertise so that DNA methylation patterns associated with PTSD can be identified. Several quality control and analytical pipelines were evaluated for their control of genomic inflation and technical artifacts with a joint analysis procedure established to derive comparable data over the cohorts for meta-analysis. We propose methods to deal with ancestry population stratification and type I error inflation and discuss the advantages and disadvantages of applying robust error estimates. To evaluate our pipeline, we report results from an epigenome-wide association study (EWAS) of age, which is a well-characterized phenotype with known epigenetic associations. Overall, while EWAS are highly complex and subject to similar challenges as genome-wide association studies (GWAS), we demonstrate that an epigenetic meta-analysis with a relatively modest sample size can be well-powered to identify epigenetic associations. Our pipeline can be used as a framework for consortium efforts for EWAS.

OBJECTIVE Posttraumatic stress disorder (PTSD) has been linked to elevated heart rate (HR) and reduced heart rate variability (HRV) in cross-sectional research. Recent evidence suggests that this link may be driven by individual differences in autonomic arousal associated with momentary negative affect (NA). Using ecological momentary assessment (EMA) of NA and minute-to-minute HR/HRV monitoring, we examined whether NA-related HR/HRV mediated the association of PTSD symptom severity with 24-hour HRV and endothelial functioning. METHODS One hundred ninety-seven young adults (18-39 years), 93 with PTSD, underwent 1 day of Holter monitoring while concurrently reporting NA levels via EMA. Two noninvasive measures of endothelial functioning-flow-mediated dilation and hyperemic flow-were also collected. Multilevel modeling was used to assess the associations of momentary NA with HR and low- and high-frequency HRV during the 5-minute intervals after each EMA reading. Latent variable modeling was then used to determine whether individual differences in these associations mediated the association of PTSD symptom severity with 24-hour HRV, flow-mediated dilation, and hyperemic flow. RESULTS PTSD symptom severity was positively associated with NA-related autonomic arousal (β = .21, p < .001), which significantly mediated the association of PTSD symptom severity with 24-hour HRV and hyperemic flow, accounting for 62% and 34% of their associations, respectively, while overshadowing the influence of smoking, lifetime alcohol dependence, sleep duration, mean NA, and episodes of acute NA. CONCLUSIONS Results suggest that NA-related autonomic arousal is both a primary factor driving cardiovascular risk in PTSD and a potential point of intervention.

Acute stress has long been connected to cardiovascular risk (1). For individuals with posttraumatic stress disorder (PTSD), a disorder characterized by hyperarousal and frequent physiological symptoms related to anxiety and stress, dysregulation of the autonomic nervous system has been identified as an important precursor to cardiovascular disease, diabetes, and other health risks (2, 3). Indeed, a key indicator of autonomic functioning and cardiovascular health, heart-rate variability (HRV), is often depressed amongst individuals with PTSD (4). Although the link between PTSD and HRV is generally discussed as a purely psychosomatic phenomenon (5), a number of behavioral risk factors—namely smoking, alcohol misuse, obesity, and sleep disturbance—may account for this link. In this study, HRV was assessed amongst younger adults (18- to 39-years-old) with and without PTSD to determine whether autonomic dysfunction in individuals with PTSD is in part attributable to the higher rates of smoking, drinking, obesity, and sleep disturbance that often coincide with PTSD (6-9). Heart-Rate Variability Under normal circumstances, heart rate varies on a beat-to-beat basis due to the dynamic interplay of the sympathetic (SNS) and parasympathetic nervous system (PNS). The SNS stimulates excitation (e.g., increased heart rate and blood pressure) in response to unexpected changes in the body and/or environment through the release of catecholamines (10). The PNS restores cardiovascular activity to baseline levels via vagal innervation. When these two systems are in disequilibrium—either because the SNS is hyperactive or the PNS is hypoactive—HRV attenuates (3). Low HRV is both an indicator and a precursor of disease. It may signal some underlying irregularity, such as immune dysfunction resulting from diabetes, osteoporosis, arthritis, Alzheimer's disease, and some cancers (11). Reduced HRV may also stimulate deleterious effects on cardiovascular health. Lower HRV is a risk factor for arrhythmia and in turn is predictive of heart disease and cardiac arrest (12-14). Reduced HRV may also accelerate atherosclerosis (2) and result in increased variability in blood pressure, which is itself an independent risk factor for coronary artery disease (15). Psychophysiology of PTSD Exposure to psychological trauma increases the risk of developing PTSD, a disorder characterized by persistent re-experiencing of the traumatic event, avoidance of stimuli associated with the event, and increased arousal (16). These symptoms have long been known to convey autonomic dysregulation, such as elevated heart rate and increased blood pressure both at baseline (17) and in response to stressors (18). Even though the SNS is instrumental in the etiology of anxiety disorders, experimental evidence suggests that the PNS may be responsible for the maintenance of elevated physiology in psychopathology (15). For instance, the administration of catecholamine (SNS) antagonists prior to induced panic attacks does little to reduce heart rate, suggesting that the SNS plays a minor role in such attacks (19). However, lactate, which is a known suppressor of vagal (PNS) activity, accumulates during panic attacks (20), and is even administered in laboratory studies to induce panic attacks (21) and stimulate PTSD symptoms (22). Thus, suppressed PNS activity and consequently reduced HRV are implied in individuals with anxiety or trauma-related disorders such as PTSD. Indeed, individuals with PTSD exhibit reduced HRV in both short-term laboratory-based measurements of HRV (5, 23-26) and 24-hour ambulatory measures (4, 27). In turn, individuals with PTSD are more likely than those without PTSD to develop cardiovascular disease (28) and face an increased risk of cardiac death (29). Although reduced HRV in PTSD is primarily attributed to the direct impact of psychological hyperarousal and anxiety on the autonomic nervous system (5), behavioral risk factors could partially account for that association. Individuals with PTSD are more likely than individuals without PTSD to smoke and do so heavily (6), abuse alcohol (7), be obese (8), and suffer from sleep disturbance stemming from flashbacks and nightmares (9). Each of these risk factors are independently associated with reduced HRV (30-33), suggesting that the relationship between PTSD and HRV may in part be due to the behavioral health risks that frequently accompany PTSD. Current Study In the present study, the prediction that the link between PTSD and HRV is partially mediated by smoking, lifetime alcohol dependency, abdominal obesity, and sleep disturbance was tested amongst a sample of younger adults (i.e., under 40 years of age) with and without PTSD. Younger adults were targeted to quantify the early health risks posed by PTSD and associated psychopathology. Latent variable modeling was used to model HRV via a combination of long- and short-term measures of autonomic functioning to minimize the impact of measurement error on that construct. Three sets of hypotheses were tested: 1) PTSD symptoms would be associated with lower HRV; 2) PTSD symptoms would be associated with greater smoking, higher rates of lifetime alcohol dependence, higher rates of abdominal obesity, and more sleep disturbance; and 3) each of these behavioral risk factors would partially mediate the association between PTSD symptoms and HRV. That is, accounting for each of these behavioral health risks would attenuate the association of PTSD symptoms with HRV.

The objectives of the present research were to examine the prevalence of deliberate self-harm (DSH) among 214 U.S. male Iraq/Afghanistan-era veterans seeking treatment for posttraumatic stress disorder (PTSD) and to evaluate the relationship between DSH and suicidal ideation within this population. Approximately 56.5% (n = 121) reported engaging in DSH during their lifetime; 45.3% (n = 97) reported engaging in DSH during the previous 2 weeks. As hypothesized, DSH was a significant correlate of suicidal ideation among male Iraq/Afghanistan-era veterans, OR = 3.88, p < .001, along with PTSD symptom severity, OR = 1.03, p < .001, and combat exposure, OR = 0.96, p = .040. A follow-up analysis identified burning oneself, OR = 17.14, p = .017, and hitting oneself, OR = 7.93, p < .001, as the specific DSH behaviors most strongly associated with suicidal ideation. Taken together, these findings suggest that DSH is quite prevalent among male Iraq/Afghanistan-era veterans seeking treatment for PTSD and is associated with increased risk for suicidal ideation within this population. Routine assessment of DSH is recommended when working with male Iraq/Afghanistan veterans seeking treatment for PTSD.

Objectives Posttraumatic stress disorder (PTSD) has been linked to dyslipidemia, which is a major risk factor for coronary artery disease. Although this link is thought to reflect response to heightened stress, behavioral health risks, including smoking, alcohol dependence, and poor sleep quality, may mediate the relationship between PTSD and dyslipidemia. Methods To test this hypothesis, serum lipid levels were collected from 220 young adults (18–39 years old), 103 of whom were diagnosed with PTSD. Results PTSD and associated depressive symptoms were negatively related to high-density lipoprotein cholesterol (HDL-C), p = .04, and positively related to triglyceride (TG) levels, p = .04. Both associations were mediated by cigarette consumption and poor sleep quality, the latter of which accounted for 83% and 93% of the effect of PTSD and depression on HDL-C and TG, respectively. Conclusions These results complement recent findings highlighting the prominence of health behaviors in linking PTSD with cardiovascular risk.

The current study assessed antecedents and consequences of ad lib cigarette smoking in smokers diagnosed with attention-deficit/hyperactivity disorder (ADHD) using ecological momentary assessment (EMA). Adult smokers with ADHD (n = 17) completed 870 smoking and 622 nonsmoking electronic diary entries over a seven-day observation period of their naturalistic smoking behavior. Data collection occurred from 2011 to 2012. Generalized estimating equations indicated that ADHD smokers were more likely to smoke when urge to smoke, negative affect, boredom, stress, worry, and restlessness were elevated. In addition, participants were more likely to smoke in situations that elicited higher levels of nervousness and frustration. ADHD symptoms, in general, did not differ between smoking and nonsmoking contexts, though hyperactive-impulsive ADHD symptoms were elevated prior to smoking in frustrating situations. Additional situational antecedent variables were associated with smoking, including being in the presence of others smoking, being in a bar or restaurant, while outside, and while consuming caffeinated or alcoholic beverages. Participants also reported a significant improvement in urge to smoke, negative affect, stress, hunger, and ADHD symptoms after smoking a cigarette. Findings suggest certain contextual factors that may maintain ad lib cigarette smoking in smokers with ADHD and identify potential treatment targets in smoking cessation interventions for this at-risk group. Clinical implications and future research directions are discussed. Funding for this study was provided by the National Institute on Drug Abuse.

Ecological momentary assessment (EMA) has shown that smoking behavior is linked to transient variables in the smoker's immediate context. Such research suggests that daily hassles (e.g., losing one's keys) may be more likely to lead to cigarette craving and eventual lapse than infrequent, large-scale stressors (e.g., death of a loved one) among individuals attempting to quit smoking. However, individual differences in distress tolerance (DT) may moderate the relationship between daily hassles and daily cigarette craving during a quit attempt.A sample of 56 veterans and community members drawn from a larger smoking-cessation study completed structured interviews and paper-and-pencil questionnaires during an initial laboratory visit and, directly following a quit attempt, were monitored via EMA. Multilevel modeling was used to examine the relationship between daily hassles and daily cigarette craving and to determine whether DT moderated this relationship.Daily hassles were positively associated with daily cigarette craving, and this association was moderated by individual differences in DT, such that the lower one's DT, the stronger the relationship between daily hassles and daily cigarette craving. This model explained 13% of the intraindividual variability and 8% of the interindividual variability in daily cigarette craving.Smoking-cessation interventions may be strengthened by targeting smokers' individual responses to contextual factors, such as by helping smokers develop skills to cope more effectively with distress prior to and during the quit phase.

There has been a great deal of interest in the role of the neuroendocrine hormones of the hypothalamic-pituitary-adrenal (HPA) axis in the expression of stress-related psychopathology such as post-traumatic stress disorder (PTSD). This investigation examined the association of PTSD and childhood maltreatment with three key HPA axis hormones: cortisol, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS). Regression analyses were undertaken on a sample of 43 participants with and 57 participants without PTSD. Results demonstrated that after controlling for age, sex, and PTSD status, exposure to childhood maltreatment was significantly associated with cortisol secretion [F(4,95)=11.68, ΔR(2)=0.11, P=0.0009] and cortisol/DHEA ratio [F(4,95)=6.20, ΔR(2)=0.05, P=0.01]. PTSD status was not associated with any of these neuroendocrine variables. Findings are discussed in the context of the complexity of the relationship of these neuroendocrine variables with trauma exposure and trauma-related psychopathology. It is suggested that DHEA(S) or cortisol/DHEA(S) ratios may not be biomarkers of specific forms of psychopathology per se, but that, instead, the severity and developmental timing of trauma may set the HPA axis in ways that are reflected in interactions among these neuroendocrine hormones. In adulthood, these HPA axis hormones may continue to be dynamically affected by personal and environmental resources.

Introduction Smokers with posttraumatic stress disorder (PTSD) smoke at higher prevalence rates and are more likely to relapse early in a quit attempt. Innovative methods are needed to enhance quit rates, particularly in the early quit period. Web-based contingency-management (CM) approaches have been found helpful in reducing smoking among other difficult-to-treat smoker populations but are limited by the need for computers. This pilot study builds on the web-based CM approach by evaluating a smartphone-based application for CM named mobile CM (mCM). Methods Following a 2-week training period, 22 smokers with PTSD were randomized to a 4-week mCM condition or a yoked (i.e., noncontingent 4-week mCM condition). All smokers received 2 smoking cessation counseling sessions, nicotine replacement, and bupropion. Participants could earn up to $690 ($530 for mCM, $25.00 for assessments and office visits [up to 5], and $35.00 for equipment return). The average earned was $314.00. Results Compliance was high during the 2-week training period (i.e., transmission of videos) (93%) and the 4-week treatment period (92%). Compliance rates did not differ by group assignment. Four-week quit rates (verified with CO) were 82% for the mCM and 45% for the yoked controls. Three-month self-report quit rates were 50% in the mCM and 18% in the yoked controls. Conclusions mCM may be a useful adjunctive smoking cessation treatment component for reducing smoking among smokers with PTSD, particularly early in a smoking quit attempt.

This study evaluated the effect of childhood trauma exposure and the role of resilience on both depressive symptoms and suicidal ideation. The study evaluated 1,488 military personnel and veterans, who served after September 2001, for depressive, suicidal, and PTSD symptoms, combat exposure, childhood trauma exposure, and resiliency. Participants were enrolled as part of an ongoing multicenter study. Outcome measures were depressive symptoms and suicidal ideation. After controlling for the effects of combat exposure and PTSD, results revealed that childhood trauma exposures were significantly associated with depressive symptoms and suicidal ideation. In addition, resilience was negatively associated with depressive symptoms and suicidal ideation, suggesting a potential protective effect. These findings suggest that evaluation of childhood trauma is important in the clinical assessment and treatment of depressive symptoms and suicidal ideation among military personnel and veterans.

The aim of the present study was to attempt to replicate the recently reported finding associating rs2400707 of the Adrenoceptor Beta 2, Surface (ADRB2) gene and childhood trauma on PTSD symptoms. Participants included a predominantly veteran cohort of non-Hispanic blacks (NHB; n = 949) and a pre-dominantly veteran cohort of non-Hispanic whites (NHW; n = 759). No main effects were observed for rs2400707 on PTSD diagnosis. Among the NHB participants, we observed an interaction between rs2400707 and history of childhood trauma, whereby with each additional A allele, the odds of having PTSD increased by 1.31, but only among those who had experienced childhood trauma (p = 0.038). The interaction with rs2400707 and childhood trauma was not observed among the NHW study participants (p = 0.892). Taken together, the findings from the present research provide further evidence that the adrenergic system may be an important modulator of PTSD risk; however, additional work is still needed to clarify the exact nature of the relationship between PTSD and rs2400707 of the ADRB2 gene.

The literature on PTSD and metabolic disease risk factors has been limited by lacking investigation of the potential influence of commonly comorbid disorders and the role of race. In this study data were provided by a sample of 134 women (63 PTSD and 71 without PTSD). Separate sets of models examining associations of psychiatric disorder classifications with metabolic disease risk factors were used. Each model included race (African American or Caucasian), psychiatric disorder, and their interaction. There was an interaction of race and PTSD on body mass index, abdominal obesity, and triglycerides. While PTSD was not generally associated with deleterious health effects in African American participants, PTSD was related to worse metabolic disease risk factors in Caucasians. MDD was associated with metabolic disease risk factors, but there were no interactions with race. Results support the importance of race in the relationship between PTSD and metabolic disease risk factors. Future research would benefit from analysis of cultural factors to explain how race might influence metabolic disease risk factors in PTSD.

Retrospective research suggests smokers with posttraumatic stress disorder (PTSD) lapse more quickly after their quit date. Ecological momentary assessment (EMA) research is needed to confirm the presence of early smoking lapse in PTSD and form conceptualizations that inform intervention.Smokers with (n = 55) and without (n = 52) PTSD completed alarm-prompted EMA of situational and psychiatric variables the week before and after a quit date, and self-initiated EMA following smoking lapses. Blood samples at baseline and on the quit date allowed assessment of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA(S)).PTSD was related to shorter time to lapse (hazard ratio [HR] = 1.677, 95% CI: 1.106-2.544). Increased smoking abstinence self-efficacy was related to longer time to lapse (HR = 0.608, 95% CI: 0.430-0.860). Analyses of participants' real-time reports revealed that smokers with PTSD were more likely to attribute first-time lapses to negative affect ( = 5.412, p = .020), and trauma reminders (Fisher's exact p = .003**). Finally, the quit date decrease in DHEA(S) was related to shorter time to lapse (HR = 1.009, 95% CI: 1.000-1.018, p.05).Results provide evidence of shorter time to first smoking lapse in PTSD, and add to evidence that early lapse occasions are more strongly related to trauma reminders, negative affect, and cravings in smokers with PTSD.

There is evidence that individuals with posttraumatic stress disorder (PTSD) may smoke in part to regulate negative affect. This pilot fMRI study examined the effects of nicotine on emotional information processing in smokers with and without PTSD. Across groups, nicotine increased brain activation in response to fearful/angry faces (compared to neutral faces) in ventral caudate. Patch x Group interactions were observed in brain regions involved in emotional and facial feature processing. These preliminary findings suggest that nicotine differentially modulates negative information processing in PTSD and non-PTSD smokers.

INTRODUCTION Smoking prevalence among individuals with posttraumatic stress disorder (PTSD) is elevated relative to non-PTSD smokers, and there is evidence to suggest that affect regulation may be a motivation for smoking among those with this disorder. Previous studies have also indicated that (a) PTSD is frequently comorbid with attention-deficit/hyperactivity disorder (ADHD), (b) individuals with ADHD smoke at significantly higher rates than the general population, (c) subclinical ADHD symptoms are a risk factor for smoking, and (d) affect regulation is a motivation for smoking in ADHD. The goal of this study was to assess the degree to which ADHD symptoms were uniquely associated with smoking-related affective functioning (SRAF) variables above and beyond the variance already explained by PTSD symptoms. METHODS Smokers with (n = 55) and without PTSD (n = 68) completed measures assessing PTSD symptoms, ADHD symptoms, and SRAF. RESULTS The PTSD group endorsed significantly more severe levels of DSM-IV inattentive and hyperactive-impulsive ADHD symptoms. A series of hierarchical regressions among the entire sample indicated that, after accounting for PTSD symptoms, ADHD symptoms were associated with lower positive affect, higher negative affect, higher emotion dysregulation, higher anxiety sensitivity, and higher urges to smoke to increase positive affect. CONCLUSIONS Taken together, these findings suggest that ADHD symptoms may increase affective dysregulation difficulties already faced by smokers, particularly those with PTSD, which may, in turn, confer increased risk for smoking relapse in those with higher levels of symptomatology of both disorders.