Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder.

Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed health problems, prior pharmacological treatments, and polygenic scores (PGS) has potential to inform risk stratification. We examined self-reported SB and ideation using the Columbia Suicide Severity Rating Scale (C-SSRS) among 3,942 SCZ and 5,414 BPI patients receiving care within the Veterans Health Administration (VHA). These cross-sectional data were integrated with electronic health records (EHRs), and compared across lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. PGS were constructed using available genomic data for related traits. Genome-wide association studies were performed to identify and prioritize specific loci. Only 20% of the veterans who reported SB had a corroborating ICD-9/10 EHR code. Among those without prior SB, more than 20% reported new-onset SB at follow-up. SB were associated with a range of additional clinical diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking initiation, suicide attempt, and major depressive disorder were associated with SB. The GWAS for SB yielded no significant loci. Among individuals with a diagnosed mental illness, self-reported SB were strongly associated with clinical variables across several EHR domains. Analyses point to sequelae of substance-related and psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in health records, underscoring the value of regular screening with direct, in-person assessments, especially among high-risk individuals.

Genome-wide DNA methylation analysis of cannabis use disorder in a veteran cohort enriched for posttraumatic stress disorder.

Cannabis use has been increasing over the past decade, not only in the general US population, but particularly among military veterans. With this rise in use has come a concomitant increase in cannabis use disorder (CUD) among veterans. Here, we performed an epigenome-wide association study for lifetime CUD in an Iraq/Afghanistan era veteran cohort enriched for posttraumatic stress disorder (PTSD) comprising 2,310 total subjects (1,109 non-Hispanic black and 1,201 non-Hispanic white). We also investigated CUD interactions with current PTSD status and examined potential indirect effects of DNA methylation (DNAm) on the relationship between CUD and psychiatric diagnoses. Four CpGs were associated with lifetime CUD, even after controlling for the effects of current smoking (AHRR cg05575921, LINC00299 cg23079012, VWA7 cg22112841, and FAM70A cg08760398). Importantly, cg05575921, a CpG strongly linked to smoking, remained associated with lifetime CUD even when restricting the analysis to veterans who reported never smoking cigarettes. Moreover, CUD interacted with current PTSD to affect cg05575921 and cg23079012 such that those with both CUD and PTSD displayed significantly lower DNAm compared to the other groups. Finally, we provide preliminary evidence that AHRR cg05575921 helps explain the association between CUD and any psychiatric diagnoses, specifically mood disorders.

High dimensional predictions of suicide risk in 4.2 million US Veterans using ensemble transfer learning.

We present an ensemble transfer learning method to predict suicide from Veterans Affairs (VA) electronic medical records (EMR). A diverse set of base models was trained to predict a binary outcome constructed from reported suicide, suicide attempt, and overdose diagnoses with varying choices of study design and prediction methodology. Each model used twenty cross-sectional and 190 longitudinal variables observed in eight time intervals covering 7.5 years prior to the time of prediction. Ensembles of seven base models were created and fine-tuned with ten variables expected to change with study design and outcome definition in order to predict suicide and combined outcome in a prospective cohort. The ensemble models achieved c-statistics of 0.73 on 2-year suicide risk and 0.83 on the combined outcome when predicting on a prospective cohort of [Formula: see text] 4.2 M veterans. The ensembles rely on nonlinear base models trained using a matched retrospective nested case-control (Rcc) study cohort and show good calibration across a diversity of subgroups, including risk strata, age, sex, race, and level of healthcare utilization. In addition, a linear Rcc base model provided a rich set of biological predictors, including indicators of suicide, substance use disorder, mental health diagnoses and treatments, hypoxia and vascular damage, and demographics.

Posttraumatic stress disorder, trauma, and accelerated biological aging among post-9/11 veterans.

People who experience trauma and develop posttraumatic stress disorder (PTSD) are at increased risk for poor health. One mechanism that could explain this risk is accelerated biological aging, which is associated with the accumulation of chronic diseases, disability, and premature mortality. Using data from 2309 post-9/11 United States military veterans who participated in the VISN 6 MIRECC's Post-Deployment Mental Health Study, we tested whether PTSD and trauma exposure were associated with accelerated rate of biological aging, assessed using a validated DNA methylation (DNAm) measure of epigenetic aging-DunedinPACE. Veterans with current PTSD were aging faster than those who did not have current PTSD, ß = 0.18, 95% CI [0.11, 0.27], p < .001. This effect represented an additional 0.4 months of biological aging each year. Veterans were also aging faster if they reported more PTSD symptoms, ß = 0.13, 95% CI [0.09, 0.16], p < 0.001, or higher levels of trauma exposure, ß = 0.09, 95% CI [0.05, 0.13], p < 0.001. Notably, veterans with past PTSD were aging more slowly than those with current PTSD, ß = -0.21, 95% CI [-0.35, -0.07], p = .003. All reported results accounted for age, gender, self-reported race/ethnicity, and education, and remained when controlling for smoking. Our findings suggest that an accelerated rate of biological aging could help explain how PTSD contributes to poor health and highlights the potential benefits of providing efficacious treatment to populations at increased risk of trauma and PTSD.

Large epigenome-wide association study identifies multiple novel differentially methylated CpG sites associated with suicidal thoughts and behaviors in veterans.

Introduction: The U.S. suicide mortality rate has steadily increased during the past two decades, particularly among military veterans; however, the epigenetic basis of suicidal thoughts and behaviors (STB) remains largely unknown. Methods: To address this issue, we conducted an epigenome-wide association study of DNA methylation (DNAm) of peripheral blood samples obtained from 2,712 U.S. military veterans. Results: Three DNAm probes were significantly associated with suicide attempts, surpassing the multiple testing threshold (FDR q-value <0.05), including cg13301722 on chromosome 7, which lies between the genes SLC4A2 and CDK5; cg04724646 in PDE3A; and cg04999352 in RARRES3. cg13301722 was also found to be differentially methylated in the cerebral cortex of suicide decedents in a publicly-available dataset (p = 0.03). Trait enrichment analysis revealed that the CpG sites most strongly associated with STB in the present sample were also associated with smoking, alcohol consumption, maternal smoking, and maternal alcohol consumption, whereas pathway enrichment analysis revealed significant associations with circadian rhythm, adherens junction, insulin secretion, and RAP-1 signaling, each of which was recently associated with suicide attempts in a large, independent genome-wide association study of suicide attempts of veterans. Discussion: Taken together, the present findings suggest that SLC4A2, CDK5, PDE3A, and RARRES3 may play a role in STB. CDK5, a member of the cyclin-dependent kinase family that is highly expressed in the brain and essential for learning and memory, appears to be a particularly promising candidate worthy of future study; however, additional work is still needed to replicate these finding in independent samples.

Which Types of Stress Are Associated With Accelerated Biological Aging? Comparing Perceived Stress, Stressful Life Events, Childhood Adversity, and Posttraumatic Stress Disorder.

OBJECTIVE: Stress and stressful events are associated with poorer health; however, there are multiple ways to conceptualize and measure stress and stress responses. One physiological mechanism through which stress could result in poorer health is accelerated biological aging. This study tested which types of stress were associated with accelerated biological aging in adulthood. METHODS: Studying 955 participants from the Dunedin Longitudinal Study, we tested whether four types of stress assessed from ages 32 to 45 years-perceived stress, number of stressful life events, adverse childhood experiences, and posttraumatic stress disorder-were associated with accelerated biological aging. RESULTS: Higher levels of all four measures of stress were significantly associated with accelerated aging in separate models. In a combined model, more perceived stress and more stressful life events remained associated with faster aging, and the stress measures explained 6.9% of the variance in aging. The magnitudes of the associations between the four measures of stress and biological aging were comparable to associations for smoking and low education, two established risk factors for accelerated aging. People with high levels of perceived stress, numerous adverse childhood experiences (4+), high stressful life event counts, or posttraumatic stress disorder were aging an additional estimated 2.4 months, 1.1 additional months, 1.4 months, and 1.4 months per year, respectively. CONCLUSIONS: Assessing stress, particularly perceived stress, could help identify people at risk of accelerated aging. Intervening to treat stress or the health-relevant sequelae of stress could potentially slow the rate at which people are aging, improving their health as they age.

Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder.

Objective: Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed mental and physical health problems, prior pharmacological treatments, and aggregate genetic factors has potential to inform risk stratification and mitigation strategies. Methods: In this study of 3,942 SCZ and 5,414 BPI patients receiving VA care, self-reported SB and ideation were assessed using the Columbia Suicide Severity Rating Scale (C-SSRS). These cross-sectional data were integrated with electronic health records (EHR), and compared by lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. Polygenic scores (PGS) for traits related to psychiatric disorders, substance use, and cognition were constructed using available genomic data, and exploratory genome-wide association studies were performed to identify and prioritize specific loci. Results: Only 20% of veterans who self-reported SB had a corroborating ICD-9/10 code in their EHR; and among those who denied prior behaviors, more than 20% reported new-onset SB at follow-up. SB were associated with a range of psychiatric and non-psychiatric diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking, suicide attempt, and major depressive disorder were also associated with attempt and ideation. Conclusions: Among individuals with a diagnosed mental illness, a GWAS for SB did not yield any significant loci. Self-reported SB were strongly associated with clinical variables across several EHR domains. Overall, clinical and polygenic analyses point to sequelae of substance-use related behaviors and other psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in clinical settings, underscoring the value of regular screening based on direct, in-person assessments, especially among high-risk individuals.

Bariatric Surgery and Suicide Risk in Patients With Obesity.

OBJECTIVE: In a large multisite cohort of Veterans who underwent Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy, we compared the 5-year suicidal ideation and attempt rates with matched nonsurgical controls. BACKGROUND: Bariatric surgery has significant health benefits but has also been associated with adverse mental health outcomes. METHODS: Five-year rates of suicidal ideation and suicide attempts of Veterans who underwent Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy from the fiscal year 2000-2016 to matched nonsurgical controls using sequential stratification using cumulative incidence functions (ideation cohort: n=38,199; attempt cohort: n=38,661 after excluding patients with past-year outcome events). Adjusted differences in suicidal ideation and suicide attempts were estimated using a Cox regression with a robust sandwich variance estimator. RESULTS: In the matched cohorts for suicidal ideation analyses, the mean age was 53.47 years and the majority were males (78.7%) and White (77.7%). Over 40% were treated for depression (41.8%), had a nonrecent depression diagnosis (40.9%), and 4.1% had past suicidal ideation or suicide attempts >1 year before index. Characteristics of the suicide attempt cohort were similar. Regression results found that risk of suicidal ideation was significantly higher for surgical patients (adjusted hazard ratio=1.21, 95% CI: 1.03-1.41), as was risk of suicide attempt (adjusted hazard ratio=1.62, 95% CI: 1.22-2.15). CONCLUSIONS: Bariatric surgery appears to be associated with a greater risk of suicidal ideation and attempts than nonsurgical treatment of patients with severe obesity, suggesting that patients need careful monitoring for suicidal ideation and additional psychological support after bariatric surgery.

Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans.

Importance: Suicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown. Objective: To identify novel, replicable genomic risk loci for SITB. Design, Setting, and Participants: This 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 Measures: SITB. Results: A 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 < 5 × 10-8) 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 Relevance: The 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.

Experiential avoidance is associated with medical and mental health diagnoses in a national sample of deployed Gulf War veterans.

A substantial minority of deployed Gulf War veterans developed posttraumatic stress disorder (PTSD), depression, and several chronic illnesses. Although military combat and exposure to certain nuclear, biological, and chemical agents (NBCs) increase risk for post-deployment health problems, they do not fully explain many Gulf War veteran health diagnoses and are not viable treatment targets. Experiential avoidance (EA; one's unwillingness to remain in contact with unpleasant internal experiences) is a modifiable psychosocial risk factor associated with PTSD and depression in veterans as well as pain and gastrointestinal diseases in the general population. In this study, we recruited a national sample of deployed Gulf War veterans (N = 454) to test the hypothesis that greater EA would be significantly associated with higher lifetime odds of PTSD, depression, "Gulf War Illness" (GWI/CMI), and other chronic illnesses common in this veteran cohort. Participants completed a self-report battery assessing demographic, military-related, and health-related information. Multivariate analyses showed that after adjusting for age, sex, race, combat exposure, and NBC exposure, worse EA was associated with higher lifetime odds of PTSD, depression GWI/CMI, gastrointestinal problems, irritable bowel syndrome, arthritis, fibromyalgia, and chronic fatigue syndrome (ORs ranged 1.25 to 2.89; effect sizes ranged small to large), but not asthma or chronic obstructive pulmonary disease. Our findings suggest medical and mental health providers alike should assess for EA and potentially target EA as part of a comprehensive, biopsychosocial approach to improving Gulf War veterans' health and wellbeing. Study limitations and future research directions are also discussed.

Exploring the role of anger in nonsuicidal self-injury in veterans.

Up to 14% of veterans engage in nonsuicidal self-injury (NSSI) in their lifetime and this behavior is a relatively strong predictor of suicidal behavior compared to other identified risk factors. Further, NSSI is a clinically relevant behavior in its own right; it is associated with more severe psychopathology as well as bodily harm that sometimes requires medical intervention. Therefore, a better understanding of NSSI may help inform suicide prevention efforts as well as mental healthcare strategies for veterans. Anger may be relevant to understanding NSSI in veterans. Over 60% of veterans report difficulties managing anger and this emotion is strongly associated with engagement in NSSI. However, no research has explored the extent to which anger is present prior to NSSI or whether anger is associated with specific NSSI methods or functions in veterans. The purpose of this study was to explore whether anger was associated with engagement in specific NSSI methods, and whether anger uniquely predicted any functions of NSSI while controlling for the presence of other basic negative emotions (fear and sadness). An existing dataset of 61 veterans who reported engaging in NSSI in the past year was analyzed. Results indicated anger was the most common emotional antecedent to NSSI. Further, anger was associated with several methods of NSSI including burning oneself with a cigarette, carving pictures, designs or other marks into skin, sticking sharp objects into skin, severely scratching oneself, head banging, punching oneself, and punching walls or objects. Finally, when controlling for the presence of other negative emotions, anger was associated with engaging in NSSI to relieve tension, stop feeling numb, communicate with others, feel alive, get help from others, and prove to oneself how bad things are. These results highlight the importance of assessing and treating dysregulated anger in veterans who engage in self-harming behavior.

Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR.

Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.

An epigenome-wide association study of posttraumatic stress disorder in US veterans implicates several new DNA methylation loci.

BACKGROUND: Previous studies using candidate gene and genome-wide approaches have identified epigenetic changes in DNA methylation (DNAm) associated with posttraumatic stress disorder (PTSD). METHODS: In this study, we performed an EWAS of PTSD in a cohort of Veterans (n = 378 lifetime PTSD cases and 135 controls) from the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort assessed using the Illumina EPIC Methylation BeadChip which assesses DNAm at more than 850,000 sites throughout the genome. Our model included covariates for ancestry, cell heterogeneity, sex, age, and a smoking score based on DNAm at 39 smoking-associated CpGs. We also examined in EPIC-based DNAm data generated from pre-frontal cortex (PFC) tissue from the National PTSD Brain Bank (n = 72). RESULTS: The analysis of blood samples yielded one genome-wide significant association with PTSD at cg19534438 in the gene G0S2 (p = 1.19 × 10-7, padj = 0.048). This association was replicated in an independent PGC-PTSD-EWAS consortium meta-analysis of military cohorts (p = 0.0024). We also observed association with the smoking-related locus cg05575921 in AHRR despite inclusion of a methylation-based smoking score covariate (p = 9.16 × 10-6), which replicates a previously observed PGC-PTSD-EWAS association (Smith et al. 2019), and yields evidence consistent with a smoking-independent effect. The top 100 EWAS loci were then examined in the PFC data. One of the blood-based PTSD loci, cg04130728 in CHST11, which was in the top 10 loci in blood, but which was not genome-wide significant, was significantly associated with PTSD in brain tissue (in blood p = 1.19 × 10-5, padj = 0.60, in brain, p = 0.00032 with the same direction of effect). Gene set enrichment analysis of the top 500 EWAS loci yielded several significant overlapping GO terms involved in pathogen response, including "Response to lipopolysaccharide" (p = 6.97 × 10-6, padj = 0.042). CONCLUSIONS: The cross replication observed in independent cohorts is evidence that DNA methylation in peripheral tissue can yield consistent and replicable PTSD associations, and our results also suggest that that some PTSD associations observed in peripheral tissue may mirror associations in the brain.

Cannabis Use Disorder and Post-Deployment Suicide Attempts in Iraq/Afghanistan-Era Veterans.

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. 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. 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. Although 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.

Contingency Management Versus Psychotherapy for Prenatal Smoking Cessation: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: Prenatal smoking is the leading preventable cause of poor obstetric outcomes, yet treatment options are limited. Past reviews of prenatal smoking cessation have often grouped all counseling into a single category, which ignores the fact that psychotherapy is distinct from brief counseling. The objective of this study was to compare the effect sizes of two intensive interventions for prenatal smoking cessation: contingency management (i.e., financial incentives for abstinence) and psychotherapy. METHODS: A systematic search for randomized controlled trials testing the efficacy of contingency management or psychotherapy was completed using PubMed, PsycINFO, Web of Science, the Cochrane Library, and EMBASE. Independent raters extracted data and assessed trials for risk of bias. Treatment effects were analyzed for three times points: late pregnancy, early postpartum, and late postpartum. RESULTS: The search yielded 22 studies, and meta-analytic results indicated that interventions (compared with control groups) generally increased the odds of abstinence. Moderator analyses indicated that intervention type (contingency management vs. psychotherapy) accounted for variability in effect sizes. When comparing treatment type, effects of contingency management interventions were significantly greater than those of psychotherapeutic interventions. Although psychotherapy did not affect smoking abstinence, contingency management interventions had significant treatment effects at all three time points. CONCLUSIONS: Contingency management seems to be a safe and efficacious prenatal smoking cessation treatment. Although psychotherapy alone did not show an effect on prenatal smoking abstinence, future research may seek to combine this approach with contingency management to promote prenatal smoking cessation.

Traumatic stress and accelerated DNA methylation age: A meta-analysis.

BACKGROUND: Recent studies examining the association between posttraumatic stress disorder (PTSD) and accelerated aging, as defined by DNA methylation-based estimates of cellular age that exceed chronological age, have yielded mixed results. METHODS: We conducted a meta-analysis of trauma exposure and PTSD diagnosis and symptom severity in association with accelerated DNA methylation age using data from 9 cohorts contributing to the Psychiatric Genomics Consortium PTSD Epigenetics Workgroup (combined N = 2186). Associations between demographic and cellular variables and accelerated DNA methylation age were also examined, as was the moderating influence of demographic variables. RESULTS: Meta-analysis of regression coefficients from contributing cohorts revealed that childhood trauma exposure (when measured with the Childhood Trauma Questionnaire) and lifetime PTSD severity evidenced significant, albeit small, meta-analytic associations with accelerated DNA methylation age (ps = 0.028 and 0.016, respectively). Sex, CD4T cell proportions, and natural killer cell proportions were also significantly associated with accelerated DNA methylation age (all ps < 0.02). PTSD diagnosis and lifetime trauma exposure were not associated with advanced DNA methylation age. There was no evidence of moderation of the trauma or PTSD variables by demographic factors. CONCLUSIONS: Results suggest that traumatic stress is associated with advanced epigenetic age and raise the possibility that cells integral to immune system maintenance and responsivity play a role in this. This study highlights the need for additional research into the biological mechanisms linking traumatic stress to accelerated DNA methylation age and the importance of furthering our understanding of the neurobiological and health consequences of PTSD.

Mobile contingency management as an adjunctive treatment for co-morbid cannabis use disorder and cigarette smoking.

INTRODUCTION: Cannabis is the most widely used illicit drug in the U.S. with 19.8 million current users. Population-based data indicate that almost all cannabis users (90%) have a lifetime history of tobacco smoking and the majority (74%) currently smoke tobacco. Among cannabis users, smoking tobacco is associated with increased frequency of cannabis use, increased morbidity, and poorer cannabis cessation outcomes. There is a lack of research, however, focused on addressing cessation of both substances simultaneously. The purpose of the current pilot study was to evaluate the feasibility and acceptability of a multi-component tobacco/cannabis abstinence treatment. METHODS: Five participants completed Abstinence Reinforcement Therapy, an intervention that included five sessions of cognitive-behavioral telephone counseling for tobacco/cannabis, pharmacotherapy for smoking cessation, and five weeks of mobile contingency management to remain abstinent from tobacco and cannabis. RESULTS: Feasibility of recruitment, retention and treatment completion was high. Satisfaction with the treatment was also high. CONCLUSION: Results support the feasibility and acceptability of this approach with dual cannabis and tobacco users and suggest that further research examining the efficacy of this approach is warranted.

Trauma and Autonomic Dysregulation: Episodic-Versus Systemic-Negative Affect Underlying Cardiovascular Risk in Posttraumatic Stress Disorder.

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 (ß = .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.

Cannabis use disorder and suicide attempts in Iraq/Afghanistan-era veterans.

The objective of the present research was to examine the association between lifetime cannabis use disorder (CUD), current suicidal ideation, and lifetime history of suicide attempts in a large and diverse sample of Iraq/Afghanistan-era veterans (N = 3233) using a battery of well-validated instruments. As expected, CUD was associated with both current suicidal ideation (OR = 1.683, p = 0.008) and lifetime suicide attempts (OR = 2.306, p < 0.0001), even after accounting for the effects of sex, posttraumatic stress disorder, depression, alcohol use disorder, non-cannabis drug use disorder, history of childhood sexual abuse, and combat exposure. Thus, the findings from the present study suggest that CUD may be a unique predictor of suicide attempts among Iraq/Afghanistan-era veterans; however, a significant limitation of the present study was its cross-sectional design. Prospective research aimed at understanding the complex relationship between CUD, mental health problems, and suicidal behavior among veterans is clearly needed at the present time.

Supplemental nicotine preloading for smoking cessation in posttraumatic stress disorder: Results from a randomized controlled trial.

BACKGROUND: Individuals with posttraumatic stress disorder (PTSD) are more likely to smoke and more likely to relapse following a quit attempt than individuals without PTSD. Thus, there is a significant need to study promising interventions that might improve quit rates for smokers with PTSD. One such intervention, supplemental nicotine patch-preloading, entails the use of nicotine replacement therapy prior to quitting. Objective The objective of this study was to conduct a randomized controlled trial of the efficacy of supplemental nicotine patch-preloading among smokers with PTSD. We hypothesized that, relative to participants in the placebo condition, participants in the nicotine patch-preloading condition would: (1) smoke less and experience reduced craving for cigarettes during the nicotine patch-preloading phase; (2) experience less smoking-associated relief from PTSD symptoms and negative affect during the preloading phase; and (3) exhibit greater latency to lapse, and higher short- and long-term abstinence rates. METHODS: Sixty-three smokers with PTSD were randomized to either nicotine or placebo patch for three weeks prior to their quit date. Ecological momentary assessment was used to assess craving, smoking, PTSD symptoms, and negative affect during the preloading period. RESULTS: Nicotine patch-preloading failed to reduce smoking or craving during the preloading phase, nor was it associated with less smoking-associated relief from PTSD symptoms and negative affect. Moreover, no differences were observed between the treatment conditions for time to lapse, 6-week abstinence, or 6-month abstinence. CONCLUSIONS: The findings from the present research suggest that supplemental nicotine patch-preloading is unlikely to substantially enhance quit rates among smokers with PTSD.