Interplay of combat deployment harassment, testosterone concentrations and post-deployment suicide risk in male veterans.

OBJECTIVE: Many combat veterans exhibit suicidal ideation and behaviour, but the relationships among experiences occurring during combat deployment and suicidality are still not fully understood. In this study, we tested the hypothesis that harassment during a combat deployment is associated with post-deployment suicidality and testosterone function. METHODS: Male combat veterans who made post-deployment suicide attempts and demographically matched veterans without a history of suicide attempts were enrolled in the study. Demographic and clinical parameters of study participants were assessed and recorded. Study participants were interviewed by a trained clinician using the Mini-International Neuropsychiatric Interview (MINI), the Deployment Risk and Resilience Inventory (DRRI) ­ Relationships within unit scale, the Scale for Suicidal Ideation (SSI), and the Brown­Goodwin Aggression Scale. Free testosterone levels were assessed in morning blood samples. RESULTS: DRRI harassment scores were higher and free testosterone levels were lower among suicide attempters in comparison with non-attempters. In the whole sample, DRRI harassment scores positively correlated with SSI scores and negatively correlated with free testosterone levels. Free testosterone levels negatively correlated with SSI scores. Aggression scale scores positively correlated with DRRI harassment scores among non-attempters but not among attempters. CONCLUSION: Our observations that harassment scores are associated with suicidality and testosterone levels, and suicidality is associated with testosterone levels may indicate that there is a link between deployment harassment, testosterone function and suicidality.

Circulating cell-free mitochondrial DNA levels and glucocorticoid sensitivity in a cohort of male veterans with and without combat-related PTSD.

Circulating cell-free mitochondrial DNA (ccf-mtDNA) is a biomarker of cellular injury or cellular stress and is a potential novel biomarker of psychological stress and of various brain, somatic, and psychiatric disorders. No studies have yet analyzed ccf-mtDNA levels in post-traumatic stress disorder (PTSD), despite evidence of mitochondrial dysfunction in this condition. In the current study, we compared plasma ccf-mtDNA levels in combat trauma-exposed male veterans with PTSD (n = 111) with those who did not develop PTSD (n = 121) and also investigated the relationship between ccf mt-DNA levels and glucocorticoid sensitivity. In unadjusted analyses, ccf-mtDNA levels did not differ significantly between the PTSD and non-PTSD groups (t = 1.312, p = 0.191, Cohen's d = 0.172). In a sensitivity analysis excluding participants with diabetes and those using antidepressant medication and controlling for age, the PTSD group had lower ccf-mtDNA levels than did the non-PTSD group (F(1, 179) = 5.971, p = 0.016, partial η2 = 0.033). Across the entire sample, ccf-mtDNA levels were negatively correlated with post-dexamethasone adrenocorticotropic hormone (ACTH) decline (r = -0.171, p = 0.020) and cortisol decline (r = -0.149, p = 0.034) (viz., greater ACTH and cortisol suppression was associated with lower ccf-mtDNA levels) both with and without controlling for age, antidepressant status and diabetes status. Ccf-mtDNA levels were also significantly positively associated with IC50-DEX (the concentration of dexamethasone at which 50% of lysozyme activity is inhibited), a measure of lymphocyte glucocorticoid sensitivity, after controlling for age, antidepressant status, and diabetes status (ß = 0.142, p = 0.038), suggesting that increased lymphocyte glucocorticoid sensitivity is associated with lower ccf-mtDNA levels. Although no overall group differences were found in unadjusted analyses, excluding subjects with diabetes and those taking antidepressants, which may affect ccf-mtDNA levels, as well as controlling for age, revealed decreased ccf-mtDNA levels in PTSD. In both adjusted and unadjusted analyses, low ccf-mtDNA levels were associated with relatively increased glucocorticoid sensitivity, often reported in PTSD, suggesting a link between mitochondrial and glucocorticoid-related abnormalities in PTSD.

Integrated analysis of proteomics, epigenomics and metabolomics data revealed divergent pathway activation patterns in the recent versus chronic post-traumatic stress disorder.

Metabolomics, proteomics and DNA methylome assays, when done in tandem from the same blood sample and analyzed together, offer an opportunity to evaluate the molecular basis of post-traumatic stress disorder (PTSD) course and pathogenesis. We performed separate metabolomics, proteomics, and DNA methylome assays on blood samples from two well-characterized cohorts of 159 active duty male participants with relatively recent onset PTSD (<1.5 years) and 300 male veterans with chronic PTSD (>7 years). Analyses of the multi-omics datasets from these two independent cohorts were used to identify convergent and distinct molecular profiles that might constitute potential signatures of severity and progression of PTSD and its comorbid conditions. Molecular signatures indicative of homeostatic processes such as signaling and metabolic pathways involved in cellular remodeling, neurogenesis, molecular safeguards against oxidative stress, metabolism of polyunsaturated fatty acids, regulation of normal immune response, post-transcriptional regulation, cellular maintenance and markers of longevity were significantly activated in the active duty participants with recent PTSD. In contrast, we observed significantly altered multimodal molecular signatures associated with chronic inflammation, neurodegeneration, cardiovascular and metabolic disorders, and cellular attritions in the veterans with chronic PTSD. Activation status of signaling and metabolic pathways at the early and late timepoints of PTSD demonstrated the differential molecular changes related to homeostatic processes at its recent and multi-system syndromes at its chronic phase. Molecular alterations in the recent PTSD seem to indicate some sort of recalibration or compensatory response, possibly directed in mitigating the pathological trajectory of the disorder.

Efficacy and Safety of Mifepristone in the Treatment of Male US Veterans With Posttraumatic Stress Disorder: A Phase 2a Randomized Clinical Trial.

Importance: To date, no psychopharmacologic treatment has been found to be uniformly effective in veterans with posttraumatic stress disorder (PTSD); novel targets and approaches are needed to treat this disabling disorder. Objective: To examine whether treatment with the glucocorticoid receptor antagonist mifepristone yields a signal for clinical efficacy in male veterans with PTSD. Design, Setting, and Participants: This phase 2a, double-blind, parallel-group randomized clinical trial was conducted from November 19, 2012 (accrual started), through November 16, 2016 (final follow-up), within the US Department of Veterans Affairs. Participants were male veterans with chronic PTSD and a screening Clinician-Administered PTSD Scale score of 50 or higher. A total of 181 veterans consented to participation. Statistical analysis was conducted between August 2014 and May 2017. Interventions: Participants were randomized in a 1:1 ratio to mifepristone (600 mg) or matched placebo taken orally for 7 days. Main Outcomes and Measures: The clinical outcome was whether a veteran achieved a clinical response status (a reduction of ≥30% of total Clinician-Administered PTSD Scale score from baseline) at 4- and 12-week follow-up. On the basis of a binary statistical selection rule, a difference in the proportion of treatment vs control group responders of 15% would be a clinically relevant difference. Self-report measures of PTSD and associated symptoms were also obtained. Neuroendocrine outcomes and plasma levels of mifepristone were measured. Safety was assessed throughout the study. The primary analysis was based on a multiple imputation technique to address missing outcome data; thus, some participant numbers may not appear as whole numbers. Results: A total of 81 veterans were enrolled and randomized. Excluding 1 participant randomized in error, 80 were included in the modified intention-to-treat analysis (41 randomized to mifepristone and 39 to placebo). The mean (SD) age was 43.1 (13.7) years. A total of 15.6 (38.1%) in the mifepristone group and 12.1 (31.1%) in the placebo group were clinical responders at 4 weeks in the analysis using the multiple imputation technique. The group difference in the proportion of clinical responders (7.0%) was less than the predefined margin of 15% indicating signal for clinical efficacy. In an exploratory analysis, the difference in response to mifepristone vs placebo in the subgroup with no lifetime history of traumatic brain injury (TBI) (7.0 [50.0%] vs 3.0 [27.3%]; difference, 22.7%) exceeded the efficacy margin at 4 weeks and was sustained at 12 weeks. In contrast, in veterans with PTSD and lifetime TBI, the response rate to mifepristone was lower than placebo at 12 weeks (7.4 [27.4%] vs 13.5 [48.3%]; difference, -20.9%). Conclusions and Relevance: This study did not detect a signal for efficacy for mifepristone at 600 mg/d for 1 week in male veterans with chronic PTSD. Thus, this study does not support a phase 3 trial in this population. Future studies of mifepristone for the treatment of PTSD may be of interest in those without a history of TBI or in samples with a low base rate of lifetime head trauma. Trial Registration: ClinicalTrials.gov Identifier: NCT01946685.

Molecular signatures of post-traumatic stress disorder in war-zone-exposed veteran and active-duty soldiers.

Post-traumatic stress disorder (PTSD) is a multisystem syndrome. Integration of systems-level multi-modal datasets can provide a molecular understanding of PTSD. Proteomic, metabolomic, and epigenomic assays are conducted on blood samples of two cohorts of well-characterized PTSD cases and controls: 340 veterans and 180 active-duty soldiers. All participants had been deployed to Iraq and/or Afghanistan and exposed to military-service-related criterion A trauma. Molecular signatures are identified from a discovery cohort of 218 veterans (109/109 PTSD+/-). Identified molecular signatures are tested in 122 separate veterans (62/60 PTSD+/-) and in 180 active-duty soldiers (PTSD+/-). Molecular profiles are computationally integrated with upstream regulators (genetic/methylation/microRNAs) and functional units (mRNAs/proteins/metabolites). Reproducible molecular features of PTSD are identified, including activated inflammation, oxidative stress, metabolic dysregulation, and impaired angiogenesis. These processes may play a role in psychiatric and physical comorbidities, including impaired repair/wound healing mechanisms and cardiovascular, metabolic, and psychiatric diseases.

Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression.

Post-traumatic stress disorder (PTSD) can develop following severe trauma, but the extent to which genetic and environmental risk factors contribute to individual clinical outcomes is unknown. Here, we compared transcriptional responses to hydrocortisone exposure in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons and peripheral blood mononuclear cells (PBMCs) from combat veterans with PTSD (n = 19 hiPSC and n = 20 PBMC donors) and controls (n = 20 hiPSC and n = 20 PBMC donors). In neurons only, we observed diagnosis-specific glucocorticoid-induced changes in gene expression corresponding with PTSD-specific transcriptomic patterns found in human postmortem brains. We observed glucocorticoid hypersensitivity in PTSD neurons, and identified genes that contribute to this PTSD-dependent glucocorticoid response. We find evidence of a coregulated network of transcription factors that mediates glucocorticoid hyper-responsivity in PTSD. These findings suggest that induced neurons represent a platform for examining the molecular mechanisms underlying PTSD, identifying biomarkers of stress response, and conducting drug screening to identify new therapeutics.

Cingulate and hippocampal subregion abnormalities in combat-exposed veterans with PTSD.

BACKGROUND: The hippocampus and cingulate gyrus are strongly interconnected brain regions that have been implicated in the neurobiology of post-traumatic stress disorder (PTSD). These brain structures are comprised of functionally distinct subregions that may contribute to the expression of PTSD symptoms or associated cardio-metabolic markers, but have not been well investigated in prior studies. METHODS: Two divisions of the cingulate cortex (i.e., rostral and caudal) and 11 hippocampal subregions were investigated in 22 male combat-exposed veterans with PTSD and 22 male trauma-exposed veteran controls (TC). Cardio-metabolic measures included cholesterol, body mass index, and mean arterial pressure. RESULTS: Individuals with PTSD had less caudal cingulate area compared to TC even after controlling for caudal cingulate thickness. Total hippocampus volume was lower in PTSD compared to TC, accounted for by differences in CA1-CA4, granule cell layer of the dentate gyrus, molecular layer, and subiculum. Individuals with PTSD had higher mean arterial pressure compared to TC, which correlated with hippocampus volume only in the PTSD group. LIMITATIONS: Sample size, cross-sectional analysis, no control for medications and findings limited to males. CONCLUSIONS: These data demonstrate preferential involvement of caudal cingulate area (vs. thickness) and hippocampus subregions in PTSD. The inverse association between hippocampus volume and mean arterial pressure may contribute to accelerated aging known to be associated with PTSD.

Brain-derived neurotrophic factor in war veterans with or without a history of suicide attempt.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) plays a central role in brain development and plasticity and has been demonstrated to be altered in neuropsychiatric diseases and suicidal behavior. We examined whether there is a difference with regard to plasma BDNF levels between veterans who made or did not make a suicide attempt post-deployment. METHODS: Combat veterans who made or did not make post-deployment suicide attempts were interviewed using Mini-International Neuropsychiatric Interview, the Montgomery-Åsberg Depression Rating Scale, the Barratt Impulsivity Scale (BIS) and the Scale for Suicidal Ideation (SSI). Reaction to the most recent suicide attempt was evaluated using item 16 of the Suicide Intent Scale. Plasma BDNF levels were determined by the BDNF ELISA kit. RESULTS: Controlling for age and body-mass index (BMI), BDNF levels were higher among suicide attempters than non-attempters. We observed a positive correlation between BDNF levels and SSI scores among non-attempters but not among attempters. BDNF levels positively correlated with BIS scores among suicide attempters but not among non-attempters. Suicide attempters who regretted that they made a suicide attempt had significantly higher BDNF levels in comparison to attempters who did not regret their attempts, controlling or not controlling for age and BMI. LIMITATIONS: A modest sample size is a shortcoming of our study. CONCLUSIONS: Our study demonstrates that BDNF may be involved in the pathophysiology of suicidal behavior in combat veterans. Given the relative ease of measuring plasma BDNF levels, it may be appropriate to consider adding such assessments to studies of suicidal behavior.

Altered gene expression and PTSD symptom dimensions in World Trade Center responders.

Despite experiencing a significant trauma, only a subset of World Trade Center (WTC) rescue and recovery workers developed posttraumatic stress disorder (PTSD). Identification of biomarkers is critical to the development of targeted interventions for treating disaster responders and potentially preventing the development of PTSD in this population. Analysis of gene expression from these individuals can help in identifying biomarkers of PTSD. We established a well-phenotyped sample of 371 WTC responders, recruited from a longitudinal WTC responder cohort using stratified random sampling, by obtaining blood, self-reported and clinical interview data. Using bulk RNA-sequencing from whole blood, we examined the association between gene expression and WTC-related PTSD symptom severity on (i) highest lifetime Clinician-Administered PTSD Scale (CAPS) score, (ii) past-month CAPS score, and (iii) PTSD symptom dimensions using a 5-factor model of re-experiencing, avoidance, emotional numbing, dysphoric arousal and anxious arousal symptoms. We corrected for sex, age, genotype-derived principal components and surrogate variables. Finally, we performed a meta-analysis with existing PTSD studies (total N = 1016), using case/control status as the predictor and correcting for these variables. We identified 66 genes significantly associated with total highest lifetime CAPS score (FDR-corrected p < 0.05), and 31 genes associated with total past-month CAPS score. Our more granular analyses of PTSD symptom dimensions identified additional genes that did not reach statistical significance in our analyses with total CAPS scores. In particular, we identified 82 genes significantly associated with lifetime anxious arousal symptoms. Several genes significantly associated with multiple PTSD symptom dimensions and total lifetime CAPS score (SERPINA1, RPS6KA1, and STAT3) have been previously associated with PTSD. Geneset enrichment of these findings has identified pathways significant in metabolism, immune signaling, other psychiatric disorders, neurological signaling, and cellular structure. Our meta-analysis revealed 10 genes that reached genome-wide significance, all of which were downregulated in cases compared to controls (CIRBP, TMSB10, FCGRT, CLIC1, RPS6KB2, HNRNPUL1, ALDOA, NACA, ZNF429 and COPE). Additionally, cellular deconvolution highlighted an enrichment in CD4 T cells and eosinophils in responders with PTSD compared to controls. The distinction in significant genes between total lifetime CAPS score and the anxious arousal symptom dimension of PTSD highlights a potential biological difference in the mechanism underlying the heterogeneity of the PTSD phenotype. Future studies should be clear about methods used to analyze PTSD status, as phenotypes based on PTSD symptom dimensions may yield different gene sets than combined CAPS score analysis. Potential biomarkers implicated from our meta-analysis may help improve therapeutic target development for PTSD.

Serum brain-derived neurotrophic factor remains elevated after long term follow-up of combat veterans with chronic post-traumatic stress disorder.

Attempts to correlate blood levels of brain-derived neurotrophic factor (BDNF) with post-traumatic stress disorder (PTSD) have provided conflicting results. Some studies found a positive association between BDNF and PTSD diagnosis and symptom severity, while others found the association to be negative. The present study investigated whether serum levels of BDNF are different cross-sectionally between combat trauma-exposed veterans with and without PTSD, as well as whether longitudinal changes in serum BDNF differ as a function of PTSD diagnosis over time. We analyzed data of 270 combat trauma-exposed veterans (230 males, 40 females, average age: 33.29 ± 8.28 years) and found that, at the initial cross-sectional assessment (T0), which averaged 6 years after the initial exposure to combat trauma (SD=2.83 years), the PTSD positive group had significantly higher serum BDNF levels than the PTSD negative controls [31.03 vs. 26.95 ng/mL, t(268) = 3.921, p < 0.001]. This difference remained significant after excluding individuals with comorbid major depressive disorder, antidepressant users and controlling for age, gender, race, BMI, and time since trauma. Fifty-nine of the male veterans who participated at the first timepoint (T0) were re-assessed at follow-up evaluation (T1), approximately 3 years (SD=0.88 years) after T0. A one-way ANOVA comparing PTSD positive, "subthreshold PTSD" and control groups revealed that serum BDNF remained significantly higher in the PTSD positive group than the control group at T1 [30.05 vs 24.66 ng/mL, F(2, 56)= 3.420, p = 0.040]. Serum BDNF levels did not correlate with PTSD symptom severity at either time point within the PTSD group [r(128) = 0.062, p = 0.481 and r(28) = 0.157, p = 0.407]. Serum BDNF did not significantly change over time within subjects [t(56) = 1.269, p = 0.210] nor did the change of serum BDNF from T0 to T1 correlate with change in PTSD symptom severity within those who were diagnosed with PTSD at T0 [r(27) = -0.250, p = 0.192]. Our longitudinal data are the first to be reported in combat PTSD and suggest that higher serum BDNF levels may be a stable biological characteristic of chronic combat PTSD independent of symptom severity.

A randomized, double-blind, placebo-controlled trial of hydrocortisone augmentation of Prolonged Exposure for PTSD in U.S. combat veterans.

OBJECTIVE: Cognitive behavioral therapies such as Prolonged Exposure (PE) are considered first line treatments for posttraumatic stress disorder (PTSD). Nonetheless, many continue to experience significant symptoms following treatment and there is interest in enhancing treatment effectiveness. Glucocorticoid alterations in PTSD are well documented, and these steroids have been shown to enhance extinction learning. METHODS: Augmentation of PE with the synthetic glucocorticoid hydrocortisone (HCORT) was tested in a randomized, double-blind, placebo-controlled trial in 60 veterans of wars in Iraq or Afghanistan with PTSD (NCT01525680). Participants ingested 30 mg oral HCORT or placebo 30 min prior to exposure sessions. PRIMARY OUTCOME MEASURE: PTSD severity assessed by the CAPS; secondary outcome measures: self reported PTSD symptoms assessed by the PDS and depression assessed by the BDI; all administered at pretreatment, posttreatment, and 3-month follow up. RESULTS: Across conditions, there was a robust effect of PE over time. An intent-to-treat analysis showed that HCORT did not measurably improve PTSD symptoms or secondary outcomes. However, exploratory analyses indicated that veterans with mild TBI exposure and current postconcussive symptoms showed a greater reduction in hyperarousal symptoms following PE treatment with HCORT augmentation. Additionally, veterans with higher baseline glucocorticoid sensitivity showed a greater reduction in avoidance symptoms with HCORT augmentation. CONCLUSIONS: Treatment matching based on cognitive or biological vulnerabilities might lead to greater efficacy of PE with glucocorticoid augmentation.

Longitudinal genome-wide methylation study of PTSD treatment using prolonged exposure and hydrocortisone.

Epigenetic changes are currently invoked as explanations for both the chronicity and tenacity of post-traumatic stress disorder (PTSD), a heterogeneous condition showing varying, sometimes idiosyncratic responses to treatment. This study evaluated epigenetic markers in the context of a randomized clinical trial of PTSD patients undergoing prolonged-exposure psychotherapy with and without a hydrocortisone augmentation prior to each session. The purpose of the longitudinal epigenome-wide analyses was to identify predictors of recovery (from pretreatment data) or markers associated with symptom change (based on differences between pre- and post-therapy epigenetic changes). The results of these analyses identified the CREB-BDNF signaling pathway, previously linked to startle reaction and fear learning and memory processes, as a convergent marker predicting both symptom change and severity. Several previous-reported resilience markers were also identified (FKBP5, NR3C1, SDK1, and MAD1L1) to associate with PTSD recovery in this study. Especially, the methylation levels of FKBP5 in the gene body region decreased significantly as CAPS score decreased in responders, while no changes occurred in nonresponders. These biomarkers may have future utility in understanding clinical recovery in PTSD and potential applications in predicting treatment effects.

Utilization of machine learning for identifying symptom severity military-related PTSD subtypes and their biological correlates.

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

Right parahippocampal volume deficit in an older population with posttraumatic stress disorder.

BACKGROUND: Posttraumatic Stress Disorder (PTSD) is an increasingly prevalent condition among older adults and may escalate further as the general population including veterans from recent conflicts grow older. Despite growing evidence of higher medical comorbidity, cognitive impairment and dementia, and disability in older individuals with PTSD, there are very few studies examining brain cortical structure in this population. Hence, we examined cortical volumes in a cross-sectional study of veterans and civilians aged ≥50 years, of both sexes and exposed to trauma (interpersonal, combat, non-interpersonal). METHODS: Cortical volumes were obtained from T1-weighted structural MRI and compared between individuals with PTSD and Trauma Exposed Healthy Controls (TEHC) adjusting for age, sex, estimated intracranial volume, depression severity, and time elapsed since trauma exposure. RESULTS: The PTSD group (N = 55) had smaller right parahippocampal gyrus compared to TEHC (N = 36), corrected p(pFWER) = 0.034, with an effect size of 0.75 (Cohen's d), with no significant group differences in other cortical areas. CONCLUSIONS: These findings are different from the structural brain findings reported in studies in younger age groups (larger parahippocampal volume in PTSD patients), suggesting a possible significant change in brain structure as PTSD patients age. These results need replication in longitudinal studies across the age-span to test whether they are neuroanatomical markers representing disease vulnerability, trauma resilience or pathological neurodegeneration associated with cognitive impairment and dementia.

A DNA methylation clock associated with age-related illnesses and mortality is accelerated in men with combat PTSD.

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

Epigenetic biotypes of post-traumatic stress disorder in war-zone exposed veteran and active duty males.

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

The COVID-19 Pandemic as a Traumatic Stressor: Mental Health Responses of Older Adults With Chronic PTSD.

OBJECTIVE: Individuals with post-traumatic stress disorder (PTSD) who experience additional traumas or stressful life events may undergo symptomatic worsening, but no data exist on whether exposure to the COVID-19 pandemic in a high infection area worsens mental health among older adults with chronic PTSD. METHODS: Seventy-six older adults (N = 46 with PTSD and N = 30 trauma-exposed comparison subjects [TE]) for whom prepandemic data were available were interviewed between April 1 and May 8, 2020 to quantify depressive (Hamilton Rating Scale for Depression [HRSD]) and PTSD symptom (Post-traumatic Stress Disorder Checklist [PCL-5]) levels. Group differences in baseline characteristics as well as pre-post pandemic symptom levels were examined, and participant characteristics were assessed as moderators of symptom change. RESULTS: Compared to TEs, individuals with PTSD more often reported living alone and experiencing a physical illness (χ2 = 5.1, df = 1, p = 0.02). PCL-5 scores among individuals with PTSD decreased during the COVID-19 pandemic by 7.1 points (t(69) = -3.5, p = 0.0008), whereas the TE group did not change significantly. Overall no significant differences in HRSD were found between groups, but a race or ethnicity variable was found to moderate HRSD symptom change. Non-black or Hispanic individuals with PTSD experienced significantly increased HRSD scores during the pandemic compared to black or Hispanic PTSD participants. CONCLUSION: The findings are indicative of complexity in the responses of older individuals with PTSD to further stressful life events as well as possibly unique aspects to the COVID-19 pandemic as a stressor. Sources of resilience may exist based on experience with prior traumas as well as increasing age promoting more adaptive coping styles.

Neuropeptide Y plasma levels and suicidal behavior in combat veterans.

War veterans are at increased risk of suicide that may be related to deployment and/or post-deployment stressors and to adjustment-related factors. The aim of this study was to examine whether levels of plasma neuropeptide Y (NPY) might distinguish combat veterans who have made a post-deployment suicide attempt from those who have never made a suicide attempt. We focused on NPY because of prior findings linking NPY with the neurobiology of resilience, stress-related and other disorders, and suicidal behavior. Demographic and clinical parameters of suicide attempters and non-attempters were assessed and plasma NPY was determined by radioimmunoassay. NPY levels were higher among attempters in comparison to non-attempters, controlling for sex and body-mass index. Suicide attempters had higher Scale for Suicidal Ideation (SSI) scores than non-attempters. There was a positive correlation between NPY levels and SSI scores among non-attempters but not among attempters. Likewise, NPY levels positively correlated with Brown-Goodwin Aggression Scale scores among suicide attempters but not among non-attempters. This is the first demonstration of altered plasma NPY levels in association with suicide attempt history and suicidal ideation in veterans. Our findings suggest that clinical differences between combat veterans with or without a history of suicide attempt may have a neurobiological origin.

Effect of Combat Exposure and Posttraumatic Stress Disorder on Telomere Length and Amygdala Volume.

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