Integration of peripheral transcriptomics, genomics, and interactomics following trauma identifies causal genes for symptoms of post-traumatic stress and major depression.

Posttraumatic stress disorder (PTSD) is a debilitating syndrome with substantial morbidity and mortality that occurs in the aftermath of trauma. Symptoms of major depressive disorder (MDD) are also a frequent consequence of trauma exposure. Identifying novel risk markers in the immediate aftermath of trauma is a critical step for the identification of novel biological targets to understand mechanisms of pathophysiology and prevention, as well as the determination of patients most at risk who may benefit from immediate intervention. Our study utilizes a novel approach to computationally integrate blood-based transcriptomics, genomics, and interactomics to understand the development of risk vs. resilience in the months following trauma exposure. In a two-site longitudinal, observational prospective study, we assessed over 10,000 individuals and enrolled >700 subjects in the immediate aftermath of trauma (average 5.3 h post-trauma (range 0.5-12 h)) in the Grady Memorial Hospital (Atlanta) and Jackson Memorial Hospital (Miami) emergency departments. RNA expression data and 6-month follow-up data were available for 366 individuals, while genotype, transcriptome, and phenotype data were available for 297 patients. To maximize our power and understanding of genes and pathways that predict risk vs. resilience, we utilized a set-cover approach to capture fluctuations of gene expression of PTSD or depression-converting patients and non-converting trauma-exposed controls to find representative sets of disease-relevant dysregulated genes. We annotated such genes with their corresponding expression quantitative trait loci and applied a variant of a current flow algorithm to identify genes that potentially were causal for the observed dysregulation of disease genes involved in the development of depression and PTSD symptoms after trauma exposure. We obtained a final list of 11 driver causal genes related to MDD symptoms, 13 genes for PTSD symptoms, and 22 genes in PTSD and/or MDD. We observed that these individual or combined disorders shared ESR1, RUNX1, PPARA, and WWOX as driver causal genes, while other genes appeared to be causal driver in the PTSD only or MDD only cases. A number of these identified causal pathways have been previously implicated in the biology or genetics of PTSD and MDD, as well as in preclinical models of amygdala function and fear regulation. Our work provides a promising set of initial pathways that may underlie causal mechanisms in the development of PTSD or MDD in the aftermath of trauma.

Prior trauma-related experiences predict the development of posttraumatic stress disorder after a new traumatic event.

BACKGROUND: Many reports have documented the relationship between previous traumatic experiences, including childhood trauma, and the development of later life psychopathology, including posttraumatic stress disorder (PTSD). Identification of individuals at greatest risk for the development of PTSD could lead to preventative interventions. The present study examined the developmental course of PTSD after trauma exposure, using histories of previous traumatic experiences and the severity of the reaction to the trauma as predictors. METHODS: Participants (N = 713) were recruited from Emergency Departments in Miami and Atlanta immediately following a traumatic experience. Histories of previous traumatic experiences and the immediate reaction to the new trauma were examined at baseline. Follow-up assessments of PTSD severity were conducted at 1, 3, and 6 months. RESULTS: Histories of child abuse and pre-existing trauma symptoms predicted the immediate response to stress (R2 = .21, p < .001) and the initial trauma reaction (p < .005).) A mixed-model repeated-measures analysis of variance found that immediate stress response and a history of prior trauma (p < .001) significantly predicted the course of PTSD symptoms. Area under the curve (AUC) analyses suggested that the presence of PTSD at each successive assessment was predicted most substantially by the severity of PTSD at the immediately prior follow-up assessment (AUC > 0.86). CONCLUSIONS: The current findings suggest that previous traumatic experiences lead to a greater immediate reaction to trauma and combine to predict the development of PTSD, the maintenance of which is not moderated by these earlier experiences. The identification of people likely to develop PTSD may be aided by the assessment of prior experiences and immediate reactions.

Revisiting how People with Schizophrenia Spend Their Days: Associations of lifetime milestone Achievements with Daily Activities examined with Ecological Momentary Assessment.

Milestone achievements are reduced in people with schizophrenia and are lower in comparison to people with bipolar disorder. However, it is not clear what the implications are for engagement in momentary activities based on milestone achievements. Further, some recent research has suggested that psychotic symptoms are associated with challenges in self-assessment of activities, but there is less information about the correlations of milestone achievements and ongoing psychotic symptoms. We examined momentary activities and symptoms as a function of lifetime milestone achievement in 102 individuals with schizophrenia and 71 with bipolar disorder. Ecological Momentary Assessment (EMA) was used to sample daily activities and concurrent symptoms 3 times per day for 30 days. Each survey asked the participant where they were, who they were with, and what they were doing, as well as sampling the concurrent presence of psychotic symptoms. Not being financially responsible for their residence was associated with engaging in fewer productive activities. Participants who never had a relationship were more commonly home and alone and engaged in fewer social interactions. A lifetime history of employment was correlated with engaging in more productive activities, including at home. More common momentary psychosis was seen in participants who failed to achieve each of the functional milestones. Lifetime milestone achievements were associated with greater frequencies of productive behaviors and with fewer momentary experiences of psychosis, suggesting that psychotic symptoms may have importance for sustaining disability that would be challenging to detect without momentary information.

The relationship between substance use, prior trauma history, and risk of developing post-traumatic stress disorder in the immediate aftermath of civilian trauma.

Many reports have documented the relationship between post-traumatic stress disorder (PTSD) and substance use. Substance use is commonly comorbid with PTSD and is a risk factor for trauma exposure. The aim of this study was to prospectively examine how recent substance use, abuse, or dependence influenced the development of PTSD in the context of a prior trauma history, including child abuse, and the severity of initial trauma reactions. Participants (N = 81) were recruited and assessed at the emergency department of a large urban hospital in Miami and serum levels of common drugs of abuse were measured. Although substance use appeared to be a risk factor for trauma exposure, neither self-reported nor blood toxicology influenced the development of PTSD. Positive toxicology screens were more likely to be associated with a diagnosis of substance abuse or dependence, χ2 (1) = 4.11, p = .04. Participants with a history of physical abuse were more likely to have a positive toxicology screen, χ2 (1) = 4.03, p = .05. The majority of our trauma-exposed subjects (66%) were found to be positive for one or more illicit substances at presentation at the ED. The current findings provide support for the "high risk" hypothesis in which substance use is associated with increased trauma exposure.

Sex Differences in Peritraumatic Inflammatory Cytokines and Steroid Hormones Contribute to Prospective Risk for Nonremitting Posttraumatic Stress Disorder.

Women are at higher risk for developing posttraumatic stress disorder (PTSD) compared to men, yet little is known about the biological contributors to this sex difference. One possible mechanism is differential immunological and neuroendocrine responses to traumatic stress exposure. In the current prospective study, we aimed to identify whether sex is indirectly associated with the probability of developing nonremitting PTSD through pro-inflammatory markers and whether steroid hormone concentrations influence this effect. Female (n = 179) and male (n = 197) trauma survivors were recruited from an emergency department and completed clinical assessment within 24 h and blood samples within ∼three hours of trauma exposure. Pro-inflammatory cytokines (IL-6, IL-1 ß , TNF, IFNγ), and steroid hormone (estradiol, testosterone, progesterone, cortisol) concentrations were quantified in plasma. Compared to men, women had a higher probability of developing nonremitting PTSD after trauma (p = 0.04), had lower pro-inflammatory cytokines and testosterone (p's<0.001), and had higher cortisol and progesterone (p's<0.001) concentrations. Estradiol concentrations were not different between the sexes (p = 0.24). Pro-inflammatory cytokines were a significant mediator in the relationship between sex and probability of developing nonremitting PTSD (p < 0.05), such that men had higher concentrations of pro-inflammatory cytokines which were associated with lower risk of nonremitting PTSD development. This effect was significantly moderated by estradiol (p < 0.05), as higher estradiol levels in men were associated with higher pro-inflammatory cytokine concentrations and lower risk for developing nonremitting PTSD. The current results suggest that sex differences in the pro-inflammatory cytokine response to trauma exposure partially mediate the probability of developing nonremitting PTSD, and that the protective ability to mount an pro-inflammatory cytokine response in men may depend on higher estradiol levels in the aftermath of trauma exposure.

Transcriptome-wide association study of post-trauma symptom trajectories identified GRIN3B as a potential biomarker for PTSD development.

Biomarkers that predict symptom trajectories after trauma can facilitate early detection or intervention for posttraumatic stress disorder (PTSD) and may also advance our understanding of its biology. Here, we aimed to identify trajectory-based biomarkers using blood transcriptomes collected in the immediate aftermath of trauma exposure. Participants were recruited from an Emergency Department in the immediate aftermath of trauma exposure and assessed for PTSD symptoms at baseline, 1, 3, 6, and 12 months. Three empirical symptom trajectories (chronic-PTSD, remitting, and resilient) were identified in 377 individuals based on longitudinal symptoms across four data points (1, 3, 6, and 12 months), using latent growth mixture modeling. Blood transcriptomes were examined for association with longitudinal symptom trajectories, followed by expression quantitative trait locus analysis. GRIN3B and AMOTL1 blood mRNA levels were associated with chronic vs. resilient post-trauma symptom trajectories at a transcriptome-wide significant level (N = 153, FDR-corrected p value = 0.0063 and 0.0253, respectively). We identified four genetic variants that regulate mRNA blood expression levels of GRIN3B. Among these, GRIN3B rs10401454 was associated with PTSD in an independent dataset (N = 3521, p = 0.04). Examination of the BrainCloud and GTEx databases revealed that rs10401454 was associated with brain mRNA expression levels of GRIN3B. While further replication and validation studies are needed, our data suggest that GRIN3B, a glutamate ionotropic receptor NMDA type subunit-3B, may be involved in the manifestation of PTSD. In addition, the blood mRNA level of GRIN3B may be a promising early biomarker for the PTSD manifestation and development.

Association of Prospective Risk for Chronic PTSD Symptoms With Low TNFα and IFNγ Concentrations in the Immediate Aftermath of Trauma Exposure.

OBJECTIVE: Although several reports have documented heightened systemic inflammation in posttraumatic stress disorder (PTSD), few studies have assessed whether inflammatory markers serve as prospective biomarkers for PTSD risk. The present study aimed to characterize whether peripheral immune factors measured in blood samples collected in an emergency department immediately after trauma exposure would predict later chronic development of PTSD. METHODS: Participants (N=505) were recruited from a hospital emergency department and underwent a 1.5-hour assessment. Blood samples were drawn, on average, about 3 hours after trauma exposure. Follow-up assessments were conducted 1, 3, 6, and 12 months after trauma exposure. Latent growth mixture modeling was used to identify classes of PTSD symptom trajectories. RESULTS: Three distinct classes of PTSD symptom trajectories were identified: chronic (N=28), resilient (N=160), and recovery (N=85). Multivariate analyses of covariance revealed a significant multivariate main effect of PTSD symptom trajectory class membership on proinflammatory cytokines. Univariate analyses showed a significant main effect of trajectory class membership on plasma concentrations of proinflammatory tumor necrosis factor α (TNFα) and interferon-γ (IFNγ). Concentrations of proinflammatory TNFα and IFNγ were significantly lower in individuals in the chronic PTSD class compared with those in the recovery and resilient classes. There were no significant differences in interleukin (IL) 1ß and IL-6 concentrations by PTSD symptom trajectory class. Anti-inflammatory and other cytokines, as well as chemokines and growth factor concentrations, were not associated with development of chronic PTSD. CONCLUSIONS: Overall, the study findings suggest that assessing the proinflammatory immune response to trauma exposure immediately after trauma exposure, in the emergency department, may help identify individuals most at risk for developing chronic PTSD in the aftermath of trauma.

Temporal Stability of Cognitive Functioning and Functional Capacity in Women with Posttraumatic Stress Disorder.

OBJECTIVE: In addition to clinical symptoms, patients with posttraumatic stress disorder (PTSD) often experience considerable disability and may evidence minor impairments in performance on measures of cognition and functional capacity (FC). The objective of the present study was to determine if cognitive and functional skills manifest temporal stability as observed in other neuropsychiatric conditions in the presence of greater fluctuations in clinical symptoms. METHOD: Assessments of cognition, FC, and clinical symptoms were conducted over two time points as part of a pre- and post-treatment assessment in a placebo-controlled clinical trial in 96 women with PTSD. The goal of these analyses was to examine the relative stability of scores and intercorrelations of measures of cognition, FC, and clinical symptoms. RESULTS: Cognitive and FC performance manifested considerably greater cross-temporal stability compared to clinical symptoms. FC performance did not change over time. Similar to previous findings in patients with schizophrenia and bipolar disorder measures of symptoms and self-reported disability did not correlate with measures of functional skills or cognitive performance. CONCLUSIONS: Cognitive performance and functional capacity were temporally stable in women with PTSD. In contrast, clinical symptoms had much more cross-temporal fluctuation. Self-reported disability was correlated with current symptomatology but unrelated to objective measures of performance. Similar to other neuropsychiatric conditions, mood symptoms likely influence estimates of current level of functioning more than cognitive or functional skills.

Social cognition, social competence, negative symptoms and social outcomes: Inter-relationships in people with schizophrenia.

Social deficits are common in people with schizophrenia and the treatment of deficits in social competence has been a long-time treatment strategy. However, negative symptoms and social cognitive deficits also contribute to social dysfunction. In this study, we examined the correlations between everyday social outcomes, a performance based measure of social competence, and performance on 8 different social cognition tests in 179 patients with schizophrenia. Social cognition, social competence, and motivation-related negative symptoms accounted for 32% of the variance in real-world social outcomes. In addition, two different social cognition tests, along with expression-related negative symptoms accounted for 32% of the variance in performance-based assessments of social competence. These data suggest that negative symptoms exert an important influence on social outcomes and social competence, but not social cognition, and that social cognition and social competence exert separable influences on real-world social outcomes. Improving social outcomes seems to require a multi-faceted approach which considers social cognition, social competence, and negative symptoms.

Factors influencing self-assessment of cognition and functioning in schizophrenia: implications for treatment studies.

Awareness of illness is a major factor in schizophrenia and extends into unawareness of cognitive and functional deficits. This unawareness of functional limitations has been shown to be influenced by several different predictive factors, including greater impairment and less severe depression. As treatment efforts are aimed at reducing cognitive deficits, discovery of the most efficient assessment strategies for detection of cognitive and functional changes is critical. In this study, we collected systematic assessments from high contact clinicians focusing on their impressions of the cognitive deficits and everyday functioning in a sample of 169 community dwelling patients with schizophrenia. The patients provided self-report on those same rating scales, as well as self-reporting their depression and performing an assessment of cognitive performance and functional skills. There was essentially no correlation between patients' self-reports of their cognitive performance and functional skills and either clinician ratings of these skills or the results of the performance-based assessments. In contrast, clinician reports of cognitive impairments and everyday functioning were correlated with objective performance data. Depression on the part of patients was associated with ratings of functioning that were both more impaired and more congruent with clinician impressions, while overall patients reported less impairment than clinicians. These results underscore the limitations of self-reported cognitive functioning even with structured rating scales. Concurrently, clinicians provided ratings of cognitive performance that were related to scores on objective tests, even though they were unaware of the results of those assessments.

Self-assessment in schizophrenia: Accuracy of evaluation of cognition and everyday functioning.

OBJECTIVE: Self-assessment deficits, often referred to as impaired insight or unawareness of illness, are well established in people with schizophrenia. There are multiple levels of awareness, including awareness of symptoms, functional deficits, cognitive impairments, and the ability to monitor cognitive and functional performance in an ongoing manner. The present study aimed to evaluate the comparative predictive value of each aspect of awareness on the levels of everyday functioning in people with schizophrenia. METHOD: We examined multiple aspects of self-assessment of functioning in 214 people with schizophrenia. We also collected information on everyday functioning rated by high contact clinicians and examined the importance of self-assessment for the prediction of real-world functional outcomes. The relative impact of performance-based measures of cognition, functional capacity, and metacognitive performance on everyday functioning was also examined. RESULTS: Misestimation of ability emerged as the strongest predictor of real-world functioning and exceeded the influences of cognitive performance, functional capacity performance, and performance-based assessment of metacognitive monitoring. The relative contribution of the factors other than self-assessment varied according to which domain of everyday functioning was being examined, but, in all cases, accounted for less predictive variance. CONCLUSION: These results underscore the functional impact of misestimating one's current functioning and relative level of ability. These findings are consistent with the use of insight-focused treatments and compensatory strategies designed to increase self-awareness in multiple functional domains.

The course of vocational functioning in patients with schizophrenia: Re-examining social drift.

Vocational functioning is markedly impaired in people with schizophrenia. In addition to low rates of employment, people with schizophrenia have been reported to be underachieved compared to other family members. Among the causes of this vocational impairment may be cognitive deficits and other skills deficits, as well as social factors impacting on opportunities for employment. In this study, we examined two separate samples of people with schizophrenia who differed in their educational and social backgrounds. We compared personal and maternal education in people with schizophrenia attending an outpatient rehabilitation facility (n = 57) or receiving outpatient services at a VA medical center (n = 39). The sample as a whole showed evidence of decline in vocational status from their best job to their most recent job. Patients attending a rehabilitation facility had completed less education than their mothers, while the VA patients completed more. Differences between personal and maternal education predicted the difference in status between best and latest jobs in the sample as a whole. VA patients were more likely to be living independently and performed better on a measure of functional capacity than the rehabilitation sample. These data implicate vocational decline in schizophrenia and also suggest that this decline may originate prior to the formal onset of the illness. At the same time, vocational outcomes appear to be related to social opportunities.

Self-assessment of functional ability in schizophrenia: milestone achievement and its relationship to accuracy of self-evaluation.

Between 50% and 80% of patients with schizophrenia do not believe they have any illness, and their self-assessment of cognitive impairments and functional abilities is also impaired compared to other information, including informant reports and scores on performance-based ability measures. The present article explores self-assessment accuracy in reference to real world functioning as measured by milestone achievement such as employment and independent living. Our sample included 195 people with schizophrenia examined with a performance-based assessment of neurocognitive abilities and functional capacity. We compared patient self-assessments across achievement of milestones, using patient performance on cognitive and functional capacity measures as a reference point. Performance on measures of functional capacity and cognition was better in people who had achieved employment and residential milestones. Patients with current employment and independence in residence rated themselves as more capable than those who were currently unemployed or not independent. However, individuals who had never had a job rated themselves at least as capable as those who had been previously employed. These data suggest that lifetime failure to achieve functional milestones is associated with overestimation of abilities. As many patients with schizophrenia never achieve milestones, their self-assessment may be overly optimistic as a result.

The influence of demographic factors on functional capacity and everyday functional outcomes in schizophrenia.

Patients with schizophrenia have impaired everyday living and social outcomes. Performance-based measures, including neuropsychological (NP) performance and functional capacity (FC) measures have demonstrated usefulness in predicting these outcomes. We examined the correlation of demographic factors (race, age, and education) and FC measures, and the relative ability of NP performance, FC, and demographic factors to predict real-world outcomes in social, vocational, and residential domains in 194 outpatients with schizophrenia. Age, education, sex, and racial status were significantly, but modestly, associated with performance-based measures of everyday functioning, while, in addition, age and education had a similar modest relationship with social competence. Age, but none of the other demographic variables, contributed to the prediction of all three domains of everyday functioning. Functional capacity variables predicted everyday outcomes even when demographic variables were entered into a predictive equation first. These data suggest a similar and modest but detectable effect of demographic factors on performance-based measures of functional capacity as seen with NP performance in schizophrenia populations. Older age contributed to poorer everyday functioning even after consideration of functional capacity, which seems similar to findings in healthy populations without clinically notable cognitive decline.

The effects of child abuse and neglect on cognitive functioning in adulthood.

AIMS: Recent research has revealed that early life trauma (ELS), including abuse (sexual and/or physical) and neglect, produce lasting changes in the CNS. We posited that cognitive deficits, often observed in psychiatric patients, result, in part, due to the neurobiological consequences of ELS. Additionally, we hypothesized that the nature and magnitude of cognitive deficits would differ according to the subtype of ELS experienced. METHOD: The Cambridge Neuropsychological Test Automated Battery (CANTAB) was used to assess neurocognitive functioning in 93 subjects (60 with ELS and 33 without). In the patients with a history of ELS, 35% and 16.7%, respectively, met criteria for current major depression and PTSD. RESULTS: Significant associations between ELS status and CANTAB measures of memory and executive and emotional functioning were found. CONCLUSIONS: These data suggest that exposure to ELS results in a cascade of neurobiological changes associated with cognitive deficits in adulthood that vary according to the type of trauma experienced.

Neurocognition, health-related reading literacy, and numeracy in medication management for HIV infection.

Successful medication management is an essential ingredient for effective treatment for HIV. Risk factors for poor medication adherence, including neurocognitive impairment and low health literacy, are common in HIV patients. To better understand the most salient risks for poor management of HIV medications, we tested the interrelation of neurocognitive functioning, reading literacy for health related information, and numeracy and their effect on self-management of a simulated HIV medication regimen. Cross-sectional data on 191 HIV-positive men and women recruited from HIV outpatient clinics in South Florida were collected. Exploratory factor analysis was conducted with literacy, numeracy, and neurocognitive scores and suggested that four factors were present representing executive skill, verbal memory, planning, and motor speed. Both the literacy and numeracy scores loaded on the executive factor. Adjusted analyses showed that executive and planning skills were significantly related to medication management. Findings suggest that patients must rely on higher order cognitive skills to successfully navigate medication self-management, and that efforts to simplify health information that merely lowers readability are likely to meet with limited success.