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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.

Objectives We sought to describe the course and correlates of psychological distress in frontline healthcare workers (FHCWs) during the COVID-19 pandemic in New York City (NYC). Methods A prospective cohort study of FHCWs at the Mount Sinai Hospital was conducted during the initial 2020 surge (T1) and 7 months later (T2). Psychological distress [i.e., positive screen for pandemic-related post-traumatic stress disorder (PTSD), major depressive disorder (MDD), and/or generalized anxiety disorder (GAD)], occupational and personal exposures to COVID-19, coping strategies, and psychosocial characteristics were assessed. Four courses of psychological distress response were identified: no/minimal, remitted, persistent, and new-onset. Multinomial logistic regression and relative importance analyses were conducted to identify factors associated with courses of distress. Results Of 786 FHCWs, 126 (16.0%) FHCWs had persistent distress; 150 (19.1%) remitted distress; 35 (4.5%) new-onset distress; and 475 (60.4%) no/minimal distress. Relative to FHCWs with no/minimal distress, those with persistent distress reported greater relationship worries [19.8% relative variance explained (RVE)], pre-pandemic burnout (18.7% RVE), lower dispositional optimism (9.8% RVE), less emotional support (8.6% RVE), and feeling less valued by hospital leadership (8.4% RVE). Relative to FHCWs with remitted symptoms, those with persistent distress reported less emotional support (29.7% RVE), fewer years in practice (28.3% RVE), and psychiatric history (23.6% RVE). Conclusions One-fifth of FHCWs in our study experienced psychological distress 7 months following the COVID-19 surge in NYC. Pandemic-related worries, pre-pandemic burnout, emotional support, and feeling valued by leaders were linked to persistent distress. Implications for prevention, treatment, and organizational efforts to mitigate distress in FHCWs are discussed. Supplementary Information The online version contains supplementary material available at 10.1007/s00420-022-01832-0.

This study tested the efficacy of repeated intravenous ketamine doses to reduce symptoms of posttraumatic stress disorder (PTSD). Veterans and service members with PTSD (n = 158) who failed previous antidepressant treatment were randomized to 8 infusions administered twice weekly of intravenous placebo (n = 54), low dose (0.2 mg/kg; n = 53) or standard dose (0.5 mg/kg; n = 51) ketamine. Participants were assessed at baseline, during treatment, and for 4 weeks after their last infusion. Primary analyses used mixed effects models. The primary outcome measure was the self-report PTSD Checklist for DSM-5 (PCL-5), and secondary outcome measures were the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and the Montgomery Åsberg Depression Rating Scale (MADRS). There were no significant group-by-time interactions for PTSD symptoms measured by the PCL-5 or CAPS-5. The standard ketamine dose ameliorated depression measured by the MADRS significantly more than placebo. Ketamine produced dose-related dissociative and psychotomimetic effects, which returned to baseline within 2 h and were less pronounced with repeated administration. There was no evidence of differential treatment discontinuation by ketamine dose, consistent with good tolerability. This clinical trial failed to find a significant dose-related effect of ketamine on PTSD symptoms. Secondary analyses suggested that the standard dose exerted rapid antidepressant effects. Further studies are needed to determine the role of ketamine in PTSD treatment. ClinicalTrials.gov identifier: NCT02655692.

Polygenic risk scores (PRS) may help inform the etiology of suicidal thoughts and behaviors. In this study, we evaluated whether a suicidality PRS derived from a large genome-wide association study (GWAS) of suicidality from the UK Biobank (N = 122,935) predicted suicidal ideation (SI) in a 7-year population-based, prospective cohort of European-American US veterans (N = 1326). Results revealed that 8.8% (n = 115) of veterans developed new-onset SI, 4.0% (n = 52) had chronic SI, 3.4% (n = 31) had remitted SI, and 83.8% (n = 1128) denied SI over the study period. Suicidality PRSstandardized was positively associated with chronic SI (relative risk ratio [RRR] = 4.54, 95% confidence interval [CI] = 1.01-20.48) and new-onset SI (RRR = 2.97, 95%CI = 1.22-7.23), and negatively associated with remitted SI (RRR = 0.12, 95% CI = 0.02-0.60). Among veterans with higher suicidality PRS, those with higher baseline dispositional optimism had a lower likelihood of chronic SI (RRR = 0.67, 95% CI = 0.49-0.91) and higher likelihood of remitted SI (RRR = 1.98, 95% CI = 1.18-3.31). Among veterans with higher suicidality PRS, those with higher baseline levels of social support were less likely to develop new-onset SI (RRR = 0.95, 95% CI = 0.92-0.99). These interaction effects were enriched for genes implicated in neuron recognition and development, while the PRS main effect was enriched for genes involved in mannosylation. Collectively, results of this study suggest that suicidality PRS is linked prospectively to symptomatic courses of SI, and that dispositional optimism and social support moderate these associations. Interventions targeting these modifiable psychosocial factors may help mitigate risk of SI in veterans with high polygenic risk for suicidality.

Supplemental Digital Content is available in the text., Purpose To examine the psychological impact of the COVID-19 pandemic on medical trainees (residents and fellows) working at Mount Sinai Hospital (MSH) in New York City (NYC), the initial epicenter of the United States pandemic. Method The authors administered a survey to 991 trainees in frontline specialties working at MSH in NYC between April and May 2020. The instrument assessed symptoms of major depressive disorder, generalized anxiety disorder, COVID-19-related posttraumatic stress disorder, and burnout. Psychiatric screens were aggregated into 1 composite measure, and meeting criteria on any of the 3 scales was considered a positive screen for psychiatric symptoms. The survey also assessed COVID-19-related exposures, worries, coping strategies, and desired interventions. Multivariable logistic regressions were conducted to identify factors associated with psychiatric symptoms and burnout. Results Of the 560 respondents (56.6% response rate), 29.7% screened positive for psychiatric symptoms and 35.8% screened positive for burnout. History of a mental illness, COVID-19-related duties and personal/career worries, and coping by substance use were associated with increased likelihood of screening positive for psychiatric symptoms. Positive emotion-focused coping and feeling valued by supervisors were associated with decreased likelihood. Internal medicine and surgical specialties, a history of mental illness, increased duty hours, duty-related worries, personal/career worries, coping via self-blame and venting, and coping via substance use were associated with higher odds of burnout. Feeling valued by supervisors was associated with decreased burnout odds. The most common crisis-related needs included access to personal protective equipment, food provisions, and financial support. Conclusions Psychological distress and burnout affected approximately one-third of trainees sampled during the height of the pandemic in NYC. As the pandemic surged beyond NYC, these findings suggest that interventions should include addressing basic needs, promoting leadership affirmation, moderating duty hours, supporting trainees financially, and enhancing mental health support.

Background The COVID-19 pandemic has led to significant mental health consequences for frontline health care workers (FHCWs). However, no known study has examined the prevalence, determinants, or correlates of posttraumatic growth (PTG) in this population. Methods Data were analyzed from a prospective cohort of FHCWs at an urban tertiary care hospital in New York City (NYC). Assessments were conducted during the spring 2020 pandemic peak (Wave 1) and seven months later (Wave 2). Multivariable logistic regression analyses were conducted to identify Wave 1 sociodemographic, occupational, and psychosocial factors associated with PTG at Wave 2, and the association between aspects of PTG with burnout and pandemic-related PTSD symptoms at Wave 2. Results A total 76.8% of FHCWs endorsed moderate or greater PTG; the most prevalent domains were increased appreciation of life (67.0%), improved relationships (48.7%), and greater personal strength (44.1%). Non-White race/ethnicity, greater levels of positive emotions, pandemic-related PTSD symptoms, dispositional gratitude, and feelings of inspiration were independently associated with PTG. At Wave 2, endorsement of spiritual growth during the pandemic was associated with 52% and 44% lower odds of screening positive for pandemic-related PTSD symptoms and burnout, respectively; greater improvement in relationships was associated with 36% lower odds of screening positive for burnout. Limitations Single institution study and use of self-report instruments. Conclusions Nearly 4-of-5 FHCWs report pandemic-related PTG, driven largely by salutogenic factors assessed during the pandemic surge. Interventions to bolster these factors may help promote PTG and mitigate risk for burnout and pandemic-related PTSD symptoms in this population.

While social support has been linked to better health, most research has focused on the receipt of social support. In this study, we evaluated associations between provided support and mental health in a nationally representative cohort of 4069 US veterans. The majority (60–72%) of veterans reported providing support on a consistent basis. Veterans who scored higher on certain aspects of personality (i.e., agreeableness, conscientiousness, and extraversion) and received greater support were more likely to provide support. Further, each standard deviation increase in provided support was independently associated with 22–32% reduced odds of internalizing psychiatric disorders and suicidal ideation, and veterans who scored higher on both provided and received support had 3.5- to 14-fold lower odds of these outcomes relative to those with high received support but low provided support. Results suggest that interventions to promote the provision of support may help mitigate risk for adverse mental health outcomes in veterans.

OBJECTIVES: To examine whether attachment style moderates the relationship between polygenic risk scores (PRS) for posttraumatic stress disorder (PTSD) re-experiencing (PTSD(REX)) symptoms and the severity of and positive screen for traumatic loss-related PTSD. METHODS: Data were analyzed from 631 U.S. veterans who endorsed “unexpected death of a loved one” as their ‘worst’ traumatic event. Multivariable models evaluated the association between PRS for PTSD(REX,) attachment style, and their interaction in predicting severity and positive screen for PTSD. A gene enrichment analysis was conducted to identify possible molecular mechanisms underlying the association between PTSD(REX) PRS and PTSD. RESULTS: PTSD(REX) PRS (β=0.17; odds ratio [OR]=1.85), attachment style (β= −0.33; OR=0.14), and PTSD(REX) PRS x attachment style interaction (β= −0.12; OR=0.53) were significant predictors of the severity and positive screen for PTSD. The most significant gene set detected was the gene ontology (GO) cellular component podosome set (GO:0002102, p

Dispositional gratitude may be linked to positive mental health outcomes, yet population-based data on this association are lacking. Military veterans are an ideal population in which to examine this question given high rates of psychiatric morbidities and efforts to promote psychological resilience in this population. Data were analyzed from a nationally representative sample of 3151 U.S. veterans. Veterans were separated into three groups based on an assessment of level of dispositional gratitude: high gratitude (weighted 79.8%), moderate gratitude (9.6%), and low gratitude (10.5%). Multivariable analyses examined the associations between level of dispositional gratitude, and measures of mental health and psychosocial variables. A “dose-response” association was observed between levels of dispositional gratitude and odds of psychiatric morbidities. Higher dispositional gratitude was associated with decreased risk for lifetime history of posttraumatic stress disorder (PTSD), major depressive disorder (MDD), social phobia, nicotine dependence, and suicide attempts, and decreased risk for current PTSD, MDD, generalized anxiety disorder, and suicidal ideation (odds ratio range = 0.16–0.65). Higher dispositional gratitude was additionally associated with resilience-promoting characteristics such as optimism, curiosity, purpose in life, perceived social support, and religiosity/spirituality (Cohen's d range = 0.11–0.73). Dispositional gratitude is prevalent in U.S. veterans, is negatively associated with psychiatric morbidities, and may help promote psychosocial factors linked to resilience in this population. Stratification of veterans with low, moderate, and high dispositional gratitude may help identify those who are at increased risk for psychiatric illness and in need of additional support.

Background Military combat trauma is often associated with negative outcomes, including high rates of posttraumatic stress disorder (PTSD). Less is known, however, about whether military combat trauma may foster posttraumatic growth (PTG), which has been observed in relation to other trauma types, in representative samples of veterans. Methods We analyzed data from veterans who participated in the National Health and Resilience in veterans Study who reported a military-related trauma (n = 210). Participants completed measures of trauma history, combat exposure, PTSD symptoms, PTG, functioning, and quality of life (QOL). Bivariate correlations, regression analyses, analyses of covariance, and fit of linear and quadratic functions were used to examine relationships between PTSD symptom clusters, PTG and its subdomains, and functioning. Results Number of deployments (β=0.23) and lifetime PTSD symptom severity (β=0.19), particularly re-experiencing symptoms (β=0.37), were independently associated with greater PTG. An inverted-U-shaped quadratic function provided the best fit for the relationship between PTSD symptoms and PTG (R2 =0.22). Greater PTG was associated with greater mental functioning (β=0.15) and QOL (β=0.24). Limitations The inability to make casual inferences in this cross-sectional study; possible bias related to self-report measures; and the lengthy time period between index trauma and assessment of PTSD and PTG. Conclusions PTG is relatively common among combat veterans, particularly among those with PTSD, and is associated with better mental functioning and QOL. Positive psychology interventions to bolster PTG may help promote functional outcomes in this population.

BACKGROUND: Dispositional gratitude has been implicated as a psychological characteristic that may modulate risk for mental health outcomes. Using a population-based sample of U.S. military veterans, this study evaluated the association between dispositional gratitude and the development of psychopathology and suicidal behaviors over a 7-year period. METHODS: A nationally representative sample of U.S. veterans was surveyed at four timepoints across seven years. Analyses were restricted to veterans without incident outcomes at baseline. Multivariable analyses were conducted to examine the relation between baseline levels of dispositional gratitude and risk of developing (a) major depressive disorder (MDD), generalized anxiety disorder (GAD), or posttraumatic stress disorder (PTSD); (b) suicidal ideation; and (c) suicide attempts. RESULTS: A total 9.6% of veterans developed MDD, GAD, and/or PTSD, 9.5% developed suicidal ideation, and 2.8% reported having attempted suicide over the 7-year follow-up period. Among veterans with high levels of dispositional gratitude, incidence was lower for MDD/GAD/PTSD (8.0%), suicidal ideation (6.8%), and suicide attempts (1.5%). Conversely, veterans with low dispositional gratitude were at substantially higher risk of developing MDD/GAD/PTSD (27.7%), suicidal ideation (33.6%), and suicide attempts (20.3%). CONCLUSIONS: High dispositional gratitude may help protect against the development of psychopathology and suicidal behaviors in U.S. military veterans, whereas low gratitude may increase risk of developing these outcomes. Collectively, these results support the potential utility of enhancing gratitude as part of primary prevention efforts for veterans, service members, and other populations at heightened risk for adverse mental health outcomes.

Objective Exposure to traumatic life events is associated with increased risk of posttraumatic stress disorder (PTSD) and other mental health problems such as suicidal ideation (SI), alcohol use disorder (AUD), and decreased quality of life (QOL). Mindfulness, which involves attending to the present moment, may help individuals cope with traumatic events by increasing acceptance of trauma-related experiences and decreasing trauma-related negative affect and avoidance of trauma reminders. The current study evaluated whether mindful attention to the present moment mediated the association between number of lifetime traumas and mental health. Method The sample consisted of 1,268 trauma-exposed U.S. veterans who participated in the National Health and Resilience in Veterans Study, a nationally representative study of U.S. veterans. On average, the sample was 60.6 years of age (SD = 15.2, range = 20-94), predominantly male (89.8%), Caucasian (75.0%), and noncombat veterans (59.2%). Results Path analyses revealed that mindfulness partially mediated the relation between number of lifetime traumas and PTSD symptoms (β = -.55), AUD (β = -.17), and QOL (β = .38), and fully mediated the relation between number of lifetime traumas and SI (β = -.36). Conclusions The relationship between lifetime trauma burden and various mental health issues of relevance to U.S. veterans may be mediated by mindfulness, or the ability to pay attention to the present moment. Interventions that bolster mindfulness may help mitigate the negative impact of cumulative traumas in this population. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

This study examined differences in public knowledge and attitudes about homelessness and posttraumatic stress disorder (PTSD) among US Veterans and other adults. A national online survey of 541 US adults from the general population was conducted in November 2016 about knowledge and attitudes about homelessness and PTSD both in reference to the general population and the Veteran population. Results found that participants reported more positive attitudes and endorsed more federal funding for homelessness and PTSD for Veterans than other adults. Participants also reported greater safety concerns about PTSD among Veterans than other adults. Among various background characteristics, only political identification with the Republican party was consistently associated with attitudes in favor of Veterans. The US public reports greater support for addressing homelessness and PTSD among Veterans than other adults, supporting various government and private programs dedicated to Veterans. It is important that publicly supported programs and policies must be evaluated.

Subthreshold post-traumatic stress disorder (PTSD) is more prevalent than PTSD, yet its role as a potential risk factor for PTSD is unknown. To address this gap, we analysed data from a 7-year, prospective national cohort of USA veterans. Of veterans with subthreshold PTSD at wave 1, 34.3% developed PTSD compared with 7.6% of trauma-exposed veterans without subthreshold PTSD (relative risk ratio 6.4). Among veterans with subthreshold PTSD, specific PTSD symptoms, greater age, cognitive difficulties, lower dispositional optimism and new-onset traumas predicted incident PTSD. Results suggest that preventive interventions targeting subthreshold PTSD and associated factors may help mitigate risk for PTSD in USA veterans.

Background Nearly 20 years after the terrorist attacks of September 11, 2001, multiple studies have documented the adverse mental consequences among World Trade Center (WTC) rescue, recovery, and clean-up workers. However, scarce research has examined mental health stigma and barriers to care in WTC-exposed individuals, and no known study has examined whether rates of endorsement may differ between police and "nontraditional" responders, the latter comprising a heterogeneous group of workers and volunteers. Objective To identify the prevalence and correlates of mental health stigma and barriers to care in WTC responders. Methods Mental health stigma and barriers to care and their correlates were examined in 6,777 police and 6,272 nontraditional WTC responders. Results Nontraditional responders endorsed more stigma or barriers to care concerns than police responders. Within a subsample who screened positive for a psychiatric disorder, police were more likely than nontraditional responders to endorse "concerns that negative job consequences might result" (17.9% vs. 9.1%), while nontraditional responders were more likely to endorse "I don't know where to go to find counseling services" (18.4% vs.6.6%). Within this subsample, mental health service need and more severe WTC-related posttraumatic stress disorder symptoms were associated with increased likelihood of endorsing stigma or barriers; pre-9/11 psychiatric history and non-Hispanic Black race/ethnicity were associated with lower likelihood of endorsing stigma or barriers. Conclusions Results of this study underscore the burden of mental health stigma and barriers to care in WTC responders, and highlight the need for targeted interventions to address these concerns and promote mental healthcare utilization in this population.

Objective Physical exercise may serve as a protective factor for posttraumatic stress disorder (PTSD), but little is known about whether physical exercise is associated with PTSD in population-based samples of military veterans. Methods We analyzed cross-sectional data on the relation between self-reported physical exercise frequency and the prevalence of probable PTSD in a nationally representative sample of 2832 U.S. military veterans who participated in the National Health and Resilience in Veterans Study. Results A "U-shaped" association best explained the relation between self-reported exercise frequency and the prevalence of probable PTSD. Compared to veterans without probable PTSD, those with probable PTSD were nearly twice as likely to report no weekly exercise (52.3% vs. 29.3%) or daily (7 days/week) exercise (15.2% vs. 8.5%) and were nearly half as likely to report exercising a median of 3.5 days/week (32.6% vs. 62.1%). No exercise was associated with greater severity of emotional numbing and lower severity of anxious arousal symptoms, while daily exercise was associated with greater severity of re-experiencing symptoms. Conclusions Results of this study suggest a "U-shaped" association between self-reported exercise frequency and the prevalence of probable PTSD among U.S. veterans. Veterans with probable PTSD were more likely than those without probable PTSD to report not exercising at all or exercising every day and were less likely to report exercising 1-6 days per week. Clinical implications of these findings are discussed.

Low treatment utilization in Soldiers with combat-related Posttraumatic Stress Disorder (PTSD) is an ongoing issue. The critical concern is to better understand factors which prohibit a Soldier with PTSD who wants help from seeking treatment (an “inclined abstainer”). A total of 537 Active Duty Soldiers on a US Army post completed a brief survey comprising psychometrically validated measures of stigma, behavioral health treatment beliefs, resilience, PTSD symptoms, and treatment intentions. Health-care records were prospectively tracked for 12 months to determine the relation between survey answers and treatment utilization. Sixty-three percent of those who acknowledged having a mental health-related problem did not seek help within a one-year period. Greater severity of PTSD symptoms was associated with an increased likelihood of behavioral health engagement. Soldiers that were classified as “inclined abstainers” were also more likely to endorse negative beliefs about psychotherapy and report higher levels of resilience as compared to “inclined actors.” These results suggest that a treatment model of PTSD emphasizing self-efficacy and self-reliance, while addressing negative beliefs about psychotherapy, may help promote engagement of behavioral health services among Active Duty Soldiers.

Objective Depression is associated with increased risk for cognitive dysfunction, yet little is known about genetic and behavioral factors that may moderate this association. Using data from a nationally representative sample of older U.S. military veterans, we examined the direct and interactive effects of depression, brain-derived neurotropic factor (BDNF) Val66Met genotype, and physical exercise on cognitive functioning. Methods One thousand three hundred eighty-six older European-American U.S. military veterans (mean age = 63) completed a web-based survey and cognitive assessment. Analyses of covariance were conducted to evaluate the effects of depression, BDNF Met allele carrier status, and physical exercise on these measures. Results Depressed veterans scored worse than nondepressed veterans on subjective measures of cognitive functioning (Cohen d's = 0.34–0.57) and objective measures of visual learning (d = 0.39) and working memory (d = 0.28). Among depressed veterans, those who were Met allele carriers scored worse than Val/Val homozygotes on subjective cognitive measures (d's = 0.52–0.97) and an objective measure of visual learning (d = 0.36). Engagement in physical exercise moderated the association between depression and cognitive function, with depressed exercisers scoring better than depressed nonexercisers on a subjective measure of reasoning, and objective measures of processing speed, attention, and visual learning (d = 0.58–0.99): further, in depressed Met allele carriers, exercisers scored better than nonexercisers on subjective cognitive (d's = 0.80–1.92), and objective measures of visual learning (d = 0.8–1.31) and working memory (d = 0.67). Conclusion Depression is associated with moderate decrements in cognitive functioning in older U.S. military veterans, and this association is moderated by BDNF Val66Met genotype and physical exercise. Prevention and treatment efforts designed to promote physical exercise may help preserve cognitive functioning in at-risk veterans.

Suicide is a public health crisis with limited treatment options. Ketamine has demonstrated rapid and robust improvements in suicidal ideation (SI). The parent study for the secondary pilot analyses presented here was a double-blind, cross-over trial that found pretreatment with the mechanistic target of rapamycin complex 1 (mTORC1) prolonged the antidepressant effects of ketamine. Here we examined the effect of mTORC1 inhibition on ketamine's antisuicidal effects. Twenty patients in a major depressive episode were randomized to pretreatment with oral rapamycin (6 mg) or placebo prior to IV ketamine (0.5 mg/kg). We found ketamine administration resulted in significant improvements across all measures with the largest effect at 24 h with only the Beck Scale for Suicide remaining significant at the two-week follow-up. There were no significant main effects of pretreatment. While these analyses are pilot in nature and overall severity of SI was relatively low, the antisuicidal findings (no effect of rapamycin) being in contrast to the antidepressant effects (prolonged effect with rapamycin), suggest the rapid-acting antisuicidal and antidepressant effects of ketamine may be mechanistically distinct and the trajectories of response, recovery, and relapse may be independent. These findings provide additional evidence of ketamine's antisuicidal effects and highlight the importance of future studies that continue to examine potential differences in mechanisms and trajectory of outcomes.

Background Posttraumatic growth (PTG) refers to positive psychological changes that may occur after experiencing a traumatic event. While cross-sectional studies have suggested that posttraumatic stress disorder (PTSD) is associated with greater PTG, few longitudinal studies have evaluated interrelationships between PTSD and PTG. Further, little is known about which specific symptom clusters of PTSD and coping mechanisms may drive PTG over time. Methods We evaluated interrelationships between PTSD symptoms and PTG using data from a 4-year, nationally representative, prospective cohort study of 2,006 older trauma-exposed U.S. veterans. Results Autoregressive cross-lagged panel regression analyses revealed that greater severity of PTSD symptoms was associated with greater PTG over time. Specifically, greater severity of the avoidance and anxious arousal (e.g., hypervigilance) symptoms at Wave 1 predicted greater PTG at Wave 2; and greater severity of avoidance and lower severity of dysphoric arousal (e.g., sleep disturbance) at Wave 2 predicted greater PTG at Wave 3. Engagement in active coping and religious coping were associated with greater subsequent PTG above and beyond autoregressive associations between PTSD and PTG. Limitations The self-report nature of the assessments, discrete assessment periods assessed, and focus on older military veterans are study limitations. Conclusions Greater severity of PTSD symptoms, particularly avoidance and hyperarousal symptoms, may contribute to and maintain PTG over time in older veterans. Interventions that promote deliberate, constructive attempts to manage chronic PTSD symptoms via active coping and religious coping may help veterans better manage PTSD symptoms and experience greater PTG in late-life.

Twenty-four hours after administration, ketamine exerts rapid and robust antidepressant effects that are thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine. Twenty patients suffering a major depressive episode were randomized to pretreatment with oral rapamycin (6 mg) or placebo 2 h prior to the intravenous administration of ketamine 0.5 mg/kg in a double-blind cross-over design with treatment days separated by at least 2 weeks. Depression severity was assessed using Montgomery–Åsberg Depression Rating Scale (MADRS). Rapamycin pretreatment did not alter the antidepressant effects of ketamine at the 24-h timepoint. Over the subsequent 2-weeks, we found a significant treatment by time interaction (F(8,245) = 2.02, p = 0.04), suggesting a prolongation of the antidepressant effects of ketamine by rapamycin. Two weeks following ketamine administration, we found higher response (41%) and remission rates (29%) following rapamycin + ketamine compared to placebo + ketamine (13%, p = 0.04, and 7%, p = 0.003, respectively). In summary, single dose rapamycin pretreatment failed to block the antidepressant effects of ketamine, but it prolonged ketamine’s antidepressant effects. This observation raises questions about the role of systemic vs. local blockade of mTORC1 in the antidepressant effects of ketamine, provides preliminary evidence that rapamycin may extend the benefits of ketamine, and thereby potentially sheds light on mechanisms that contribute to depression relapse after ketamine administration.

The current study examined the nature and correlates of seven-year posttraumatic stress disorder (PTSD) symptom courses in a nationally representative, prospective cohort of U.S. military veterans. Data were analyzed from 2,307 trauma-exposed veterans who completed at least one follow-up assessment over a 7-year period, a subsample of n = 3,157 veterans who participated in the first wave of the National Health and Resilience in Veterans Study. Latent growth mixture modeling (LGMM) was used to identify PTSD symptom courses over four survey waves conducted in 2011, 2013, 2015, and 2018. Sociodemographic, health, and psychosocial variables were examined as potential correlates of symptomatic trajectories. PTSD symptoms were best characterized by three courses: No/Low (89.2%), Moderate Symptom (7.6%), and High Symptom (3.2%). Relative to the No/Low Symptom course, symptomatic courses were positively associated with a greater number of lifetime traumatic events, higher scores on measures of physical health difficulties and lifetime psychiatric history (relative risk ratio [RRR] range = 1.19–2.74), and were negatively associated with time since index trauma, household income, and social connectedness (RRR range = 0.14–0.97). Veterans in the Moderate Symptom course additionally had lower scores on a measure of protective psychosocial characteristics (RRR = 0.78) and were more likely to have received mental health treatment (RRR = 1.62), while those in the High PTSD Symptom course were more likely to be exposed to combat and to more traumas since Wave 1 (RRR range = 1.23–4.63). Three PTSD symptom courses in U.S. veterans were identified, with more than 10% of veterans exhibiting a moderate or high symptom course. Prevention and treatment efforts targeting modifiable correlates, such as social connectedness, may help mitigate symptomatic PTSD symptom courses in this population.

BACKGROUND Hazardous alcohol consumption has significant adverse medical consequences. These effects may be mediated, in part, by alterations in DNA methylation. Thus, DNA methylation signatures in peripheral cells may provide biomarkers of the medical impact of alcohol use and the risk for future alcohol consumption. METHOD Using a high-density methylation array, we characterized epigenome-wide DNA methylation in saliva cells with respect to alcohol consumption in a large cohort of male European American veterans. In this study, DNA methylation of over 870,000 CpG DNA sites was profiled in 1,135 European American men. Alcohol consumption was assessed using the Alcohol Use Disorder Identification Test-Consumption (AUDIT-C). Linear regression was applied in an epigenome-wide association study (EWAS), adjusted for confounders. Gene set enrichment analysis was performed in the KEGG database with a correction for gene length. RESULTS We found that a total of 70 CpG sites reached EWAS-corrected significance (p

Background Although the e4 allele of the apolipoprotein E (APOE) gene and posttraumatic stress disorder (PTSD) have been linked to cognitive dysfunction and dementia risk, it is unknown whether they interact to predict cognitive dysfunction. Methods We analyzed data from European-American (EA) veterans who participated in the National Health and Resilience in Veterans Study (NHRVS): main sample (n = 1,386) and primary replication sample (n = 509). EAs from the Yale-Penn Study cohort (n = 948) served as a second replication sample. Multivariable analyses were conducted to evaluate the predictive effects of e4 carrier status and PTSD on cognitive functioning, with a focus on whether PTSD moderates the effect of e4 carrier status. Results APOE e4 allele carrier status (d = 0.15 and 0.17 in the main and primary replication NHRVS samples, respectively) and PTSD (d = 0.31 and 0.17, respectively) were independently associated with lower cognitive functioning. e4 carriers with PTSD scored lower than those without PTSD (d = 0.68 and 1.29, respectively) with the most pronounced differences in executive function (d's = 0.75-1.50) and attention/concentration (d's = 0.62-1.33). A significant interaction was also observed in the Yale-Penn sample, with e4 carriers with PTSD making more perseverative errors on a measure of executive function than those without PTSD (24.7% vs. 17.6%; d = 0.59). Conclusions APOE e4 allele carriers with PTSD have substantially greater cognitive difficulties than e4 carriers without PTSD. These results underscore the importance of assessing, monitoring, and treating PTSD in trauma-affected individuals who are at genetic risk for cognitive decline and dementia.

ObjectiveThis study aimed to characterize the current prevalence of loneliness, and the relation between loneliness severity and mental and physical health conditions, suicidality, and functional measures in a predominantly older sample of U.S. military veterans.MethodsThis cross-sectional study used data from the National Health and Resilience in Veterans Study, which surveyed a nationally representative sample of U.S. veterans (N=4,069; mean age=62) from November 2019 through March 2020. Veterans were classified into one of 3 groups based on their current level of loneliness (hardly ever, sometimes, often) on an adapted version of the Revised UCLA Loneliness Scale. A comprehensive range of mental and physical health, and functioning variables were assessed using valid and reliable self-report assessments.ResultsA total of 56.9% of veterans endorsed feeling lonely sometimes (37.2%) or often (19.7%). Loneliness severity was independently associated with a range of mental health (odds ratios [ORs]=1.21-33.30), physical health (ORs = 1.21-6.80), and functional difficulties (d's=0.09-0.59). Relative to hardly ever feeling lonely, feeling lonely often or sometimes was associated with a more than 12- and three-fold greater likelihood of current suicidal ideation (29.0% versus 7.3% versus 1.5%), even after adjustment for sociodemographic, military, and psychiatric risk factors.ConclusionsLoneliness is highly prevalent in U.S. military veterans, with more than half endorsing feeling lonely sometimes or often, and 1-of-5 reporting feeling lonely often. Loneliness severity was independently associated with a broad range of mental and physical health and functional measures, ias well as suicidal ideation. Results underscore the importance of loneliness as a transdiagnostic prevention and intervention target in the U.S. veteran population.

Background Posttraumatic stress disorder (PTSD) develops consequent to complex gene-environment interactions beyond the precipitating trauma. To date, however, no known study has used a prospective design to examine how polygenic risk scores (PRS) interact with social-environmental factors such as attachment style to predict PTSD development. Methods PRS were derived from a GWAS of PTSD symptoms (N=186,689, Million Veteran Program cohort). We evaluated combined effects of PRS and attachment style in predicting incident PTSD in a 7-year, nationally representative cohort of trauma-exposed, European-American (EA) U.S. military veterans without PTSD (N=1,083). We also conducted multivariate gene-by-environment interaction and drug repositioning analyses to identify loci that interact with multiple environmental factors and potential pharmacotherapies that may be repurposed for this disorder. Results Veterans with higher PTSD PRS were more likely to have an incident positive screen for PTSD over 7 years. A gene-environment interaction was also observed, such that higher PRS only predicted incident PTSD in veterans with an insecure attachment style, and not those with a secure attachment style. At an individual locus level, the strongest gene-environment interaction was observed for the rs4702 variant of the FURIN gene with cumulative lifetime trauma burden. Drug repositioning revealed that genes implicated in the PRS are perturbated by the drug doxylamine. Conclusions Attachment style moderates polygenic risk for the development of PTSD in EA veterans. These findings may inform PTSD prevention and treatment for veterans with high polygenic risk for PTSD, and suggest a potential pharmacotherapeutic target for risk genes moderated by social-environmental factors.

Sleep disturbance is a risk factor for future suicidal behaviours (e.g. suicidal ideation, suicide attempt, death by suicide), and military veterans are at increased risk for both poor sleep and death by suicide relative to civilians. The purpose of this study was to evaluate whether self-reported sleep quality was associated with risk of new-onset suicidal ideation in a 7-year prospective nationally representative cohort study of US military veterans. Multivariable logistic regression analyses were conducted to identify the relation between self-rated sleep quality and incident suicidal ideation in 2,059 veterans without current suicidal ideation or lifetime suicide attempt history at baseline. Relative importance analyses were then conducted to identify the relative variance explained by sleep quality and other significant determinants of incident suicidal ideation. A total of 169 (weighted 8.9%, 95% confidence interval =7.7%-10.3%) veterans developed suicidal ideation over the 7-year study period. Poor self-rated sleep quality was associated with a more than 60% greater likelihood of developing suicidal ideation (relative risk ratio = 1.62, 95% confidence interval = 1.11-2.36), even after adjustment for well-known suicide risk factors such as major depressive disorder. Relative importance analysis revealed that poor self-rated sleep quality accounted for 44.0% of the explained variance in predicting incident suicidal ideation. These results underscore the importance of assessing, monitoring and treating sleep difficulties as part of suicide prevention efforts in military veterans.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has led to an increased risk of psychiatric symptoms among frontline health care workers (FHCWs). In the current study, a novel "symptomics" approach was employed to examine the association between acute transdiagnostic symptoms of posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and generalized anxiety disorder (GAD) and burnout and work and relationship difficulties in FHCWs at an urban tertiary care hospital in New York City. METHODS: Symptoms of COVID-19-related PTSD (4-item PTSD Checklist-5), MDD (Patient Health Questionnaire-8), GAD (Generalized Anxiety Disorder-7), burnout (Single-Item Mini-Z Burnout Assessment), and functional difficulties (Brief Inventory of Psychosocial Functioning) were assessed. Relative importance analyses were conducted to identify PTSD, MDD, and GAD symptoms associated with burnout and functional difficulties. RESULTS: The total number of eligible participants included 6,026 presumed FHCWs, of which 3,360 (55.8%) completed the survey and 2,579 (76.8%) of whom endorsed directly treating patients with COVID-19 and provided sufficient responses to our outcome variables for analysis. Feeling tired/having little energy, being easily annoyed or irritable, and feeling nervous, anxious, or on edge were most strongly associated with burnout; feeling tired/having little energy accounted for the greatest amount of explained variance (> 15%). Negative expectations of oneself or the world, trouble concentrating, and feeling easily annoyed or irritable were most strongly associated with work difficulties; negative expectations of oneself or the world accounted for the greatest amount of explained variance (> 9%). Feeling easily annoyed or irritable, negative expectations about oneself or the world, and feeling bad about oneself were most strongly associated with relationship difficulties; feeling easily annoyed or irritable accounted for the greatest amount of explained variance (> 10%). CONCLUSIONS: Results of this study underscore the importance of a transdiagnostic, symptom-based approach when examining associations between acute psychopathology and burnout and functional difficulties in FHCWs. Further work is needed to determine if early interventions aimed at ameliorating specific psychiatric symptoms may help mitigate risk for peri- and posttraumatic burnout and functional difficulties in this population.

BackgroundThis study tested the efficacy of repeated intravenous ketamine doses to reduce antidepressant-resistant symptoms of posttraumatic stress disorder (PTSD).MethodsVeterans and service members with PTSD (n=158) who failed previous antidepressant treatment were randomized to 8 infusions administered twice weekly of intravenous placebo (n=54), low dose (0.2mg/kg; n=53) or standard dose (0.5mg/kg; n=51) ketamine. Participants were assessed at baseline, during treatment, and for 4 weeks after their last infusion. Primary analyses used mixed effects models. The primary outcome measure was the self-report PTSD Checklist for DSM-5 (PCL-5), and secondary outcome measures were the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and the Montgomery Åsberg Depression Rating Scale (MADRS).ResultsThere were no significant group-by-time interactions for PTSD symptoms measured by the PCL-5 or CAPS-5. The standard dose ketamine significantly reduced symptoms after the first infusion, while the low dose showed significant symptom reduction after the last infusion and at the 4-week follow-up. The standard ketamine dose also significantly ameliorated depression measured by the MADRS. Ketamine produced dose-related dissociative and psychotomimetic effects, which returned to baseline within 2 hours and were less pronounced with repeated administration. There was no evidence of differential treatment discontinuation by ketamine dose, consistent with good tolerability.ConclusionsThis clinical trial failed to find a significant dose-related effect of ketamine on PTSD symptoms. Secondary analyses suggested that the low dose reduced PTSD symptoms and the standard dose exerted rapid antidepressant effects. Further studies are needed to determine the role of ketamine in PTSD treatment.ClinicalTrials.gov identifierNCT02655692

Introduction Little is known about the relationship between moral distress and mental health problems. We examined moral distress in 2579 frontline healthcare workers (FHCWs) caring for coronavirus disease 2019 (COVID‐19) patients during the height of the spring 2020 pandemic surge in New York City. The goals of the study were to identify common dimensions of COVID‐19 moral distress; and to examine the relationship between moral distress, and positive screen for COVID‐19‐related posttraumatic stress disorder (PTSD) symptoms, burnout, and work and interpersonal functional difficulties. Method Data were collected in spring 2020, through an anonymous survey delivered to a purposively‐selected sample of 6026 FHCWs at Mount Sinai Hospital; 2579 endorsed treating COVID‐19 patients and provided complete survey responses. Physicians, house staff, nurses, physician assistants, social workers, chaplains, and clinical dietitians comprised the sample. Results The majority of the sample (52.7%–87.8%) endorsed moral distress. Factor analyses revealed three dimensions of COVID‐19 moral distress: negative impact on family, fear of infecting others, and work‐related concerns. All three factors were significantly associated with severity and positive screen for COVID‐19‐related PTSD symptoms, burnout, and work and interpersonal difficulties. Relative importance analyses revealed that concerns about work competencies and personal relationships were most strongly related to all outcomes. Conclusion Moral distress is prevalent in FHCWs and includes family‐, infection‐, and work‐related concerns. Prevention and treatment efforts to address moral distress during the acute phase of potentially morally injurious events may help mitigate risk for PTSD, burnout, and functional difficulties.

BACKGROUND: Investigations of stress dysregulation in posttraumatic stress disorder (PTSD) have focused on peripheral cortisol, but none have examined cortisol in the human brain. This study used positron emission tomography (PET) to image 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a cortisol-producing enzyme, as a putative brain cortisol marker in PTSD. METHODS: Sixteen individuals with PTSD and 17 healthy, trauma-exposed controls (TCs) underwent PET imaging with [(18)F]AS2471907, a radioligand for 11β-HSD1. RESULTS: Prefrontal-limbic 11β-HSD1 availability, estimated as [(18)F]AS2471907 volume of distribution (V(T)), was significantly higher in the PTSD group compared with the TC group (β = 1.16, P = 0.0057). Lower prefrontal-limbic 11β-HSD1 availability was related to greater overall PTSD severity (R(2) = 0.27, P = 0.038) in the PTSD group. 11β-HSD1 availability was not related to plasma cortisol levels (R(2) = 0.026, P = 0.37). In a PTSD subset (n = 10), higher 11β-HSD1 availability was associated with higher availability of translocator protein (TSPO), a microglial marker (β = 4.40, P = 0.039). CONCLUSION: Higher brain cortisol–producing 11β-HSD1 in the PTSD group may represent a resilience-promoting neuroadaptation resulting in lower PTSD symptoms. Along with preliminary associations between 11β-HSD1 and TSPO, corroborating previous evidence of immune suppression in PTSD, these findings collectively challenge previous hypotheses of the deleterious effects of both excessive brain glucocorticoid and brain immune signaling in PTSD. FUNDING: Brain and Behavior Research Foundation Independent Investigator Grant, National Institute of Mental Health grants F30MH116607 and R01MH110674, the Veterans Affairs National Center for PTSD, the Gustavus and Louise Pfeiffer Foundation Fellowship, Clinical and Translational Science Awards grant UL1 TR000142 from the NIH National Center for Advancing Translational Science.

This survey study uses self-reported data from the 2019-2020 National Health and Resilience in Veterans Study to assess the association of symptoms of posttraumatic stress disorder (PTSD) with posttraumatic psychological growth among US veterans during the COVID-19 pandemic.

STUDY OBJECTIVES: Veterans experience high levels of trauma, psychiatric, and medical conditions that may increase their risk for insomnia. To date, however, no known study has examined the prevalence, risk correlates, and comorbidities of insomnia in a nationally representative sample of veterans. METHODS: A nationally representative sample of 4,069 US military veterans completed a survey assessing insomnia severity; military, trauma, medical, and psychiatric histories; and health and psychosocial functioning. Multivariable analyses examined the association between insomnia severity, psychiatric and medical comorbidities, suicidality, and functioning. RESULTS: A total of 11.4% of veterans screened positive for clinical insomnia and 26.0% for subthreshold insomnia. Greater age and retirement were associated with a lower likelihood of insomnia. Adverse childhood experiences, traumatic life events, lower education and income were associated with greater risk for insomnia. A “dose-response” association was observed for health comorbidities, with increasing levels of insomnia associated with elevated odds of psychiatric and medical conditions (clinical vs no insomnia odds ratio = 1.8–13.4) and greater reductions in health and psychosocial functioning (clinical vs no insomnia Cohen’s d = 0.2–0.4). The prevalence of current suicidal ideation was 3–5 times higher in veterans with clinical and subthreshold insomnia relative to those without insomnia (23.9% and 13.6% vs 4.5%, respectively). CONCLUSIONS: Nearly 2 in 5 US veterans experience clinical or subthreshold insomnia, which is associated with substantial health burden and independent risk for suicidal ideation. Results underscore the importance of assessment, monitoring, and treatment of insomnia in veterans as they transition from the military. CITATION: Byrne SP, McCarthy E, DeViva JC, Southwick SM, Pietrzak RH. Prevalence, risk correlates, and health comorbidities of insomnia in US military veterans: results from the 2019–2020 National Health and Resilience in Veterans Study. J Clin Sleep Med. 2021;17(6):1267–1277.