Evaluation of a corticotropin releasing hormone type 1 receptor antagonist in women with posttraumatic stress disorder: study protocol for a randomized controlled trial

Background: Pharmacologic treatment options for posttraumatic stress disorder (PTSD) are limited in number and effectiveness. Medications currently in use to treat PTSD were originally approved based on their efficacy in other disorders, such as major depression. Substantial research in PTSD suggests that increased activity of corticotropin releasing hormone (CRH)-containing circuits are involved in the pathophysiology of the disease. This Phase II trial aims to evaluate the efficacy of a CRH type 1 receptor (CRHR1) antagonist in the treatment of PTSD. Methods/design: Currently untreated adult women, ages 18 to 65 years, with a primary psychiatric diagnosis of PTSD of at least 3 months' duration, are being enrolled in a parallel-group, double-blind, placebo-controlled, randomized clinical trial evaluating the efficacy and safety of GSK561679, a novel CRHR1 receptor antagonist. GSK561679 (or matching placebo) is prescribed at a fixed dose of 350 mg nightly for six weeks. The primary trial hypothesis is that GSK561679 will reduce symptoms of PTSD, as measured by the Clinician-Administered PTSD Scale (CAPS), significantly more than placebo after six weeks of treatment. Putative biological markers of PTSD which may influence treatment response are measured prior to randomization and after five weeks' exposure to the study medication, including: fear conditioning and extinction using psychophysiological measures; variants of stress-related genes and gene expression profiles; and indices of HPA axis reactivity. In addition, the impact of PTSD and treatment on neuropsychological performance and functional capacity are assessed at baseline and after the fifth week of study medication. After completion of the six-week double blind treatment period, subjects enter a one-month follow-up period to monitor for sustained response and resolution of any adverse effects. Discussion: Considerable preclinical and human research supports the hypothesis that alterations in central nervous system CRH neuronal activity are a potential mediator of PTSD symptoms. This study is the first to assess the efficacy of a specific antagonist of a CRH receptor in the treatment of PTSD. Furthermore, the biological and neuropsychological measures included in this trial will substantially inform our understanding of the mechanisms of PTSD

Event-related potential studies of post-traumatic stress disorder: a critical review and synthesis

Despite the sparseness of the currently available data, there is accumulating evidence of information processing impairment in post-traumatic stress disorder (PTSD). Studies of event-related potentials (ERPs) are the main tool in real time examination of information processing. In this paper, we sought to critically review the ERP evidence of information processing abnormalities in patients with PTSD. We also examined the evidence supporting the existence of a relationship between ERP abnormalities and symptom profiles or severity in PTSD patients. An extensive Medline search was performed. Keywords included PTSD or post-traumatic stress disorder, electrophysiology or EEG, electrophysiology, P50, P100, N100, P2, P200, P3, P300, sensory gating, CNV (contingent negative variation) and MMN (mismatch negativity). We limited the review to ERP adult human studies with control groups which were reported in the English language. After applying our inclusion-exclusion review criteria, 36 studies were included. Subjects exposed to wide ranges of military and civilian traumas were studied in these reports. Presented stimuli were both auditory and visual. The most widely studied components included P300, P50 gating, N100 and P200. Most of the studies reported increased P300 response to trauma-related stimuli in PTSD patients. A smaller group of studies reported dampening of responses or no change in responses to trauma-related and/or unrelated stimuli. P50 studies were strongly suggestive of impaired gating in patients with PTSD. In conclusion, the majority of reports support evidence of information processing abnormalities in patients with PTSD diagnosis. The predominance of evidence suggests presence of mid-latency and late ERP components differences in PTSD patients in comparison to healthy controls. Heterogeneity of assessment methods used contributes to difficulties in reaching firm conclusions regarding the nature of these differences. We suggest that future ERP-PTSD studies utilize standardized assessment scales that provide detailed information regarding the symptom clusters and the degree of symptom severity. This would allow assessment of electrophysiological indices-clinical symptoms relationships. Based on the available data, we suggest that ERP abnormalities in PTSD are possibly affected by the level of illness severity. If supported by future research, ERP studies may be used for both initial assessment and treatment follow-up

Childhood adversities and risk of posttraumatic stress disorder and major depression following a motor vehicle collision in adulthood

AIMS: Childhood adversities (CAs) predict heightened risks of posttraumatic stress disorder (PTSD) and major depressive episode (MDE) among people exposed to adult traumatic events. Identifying which CAs put individuals at greatest risk for these adverse posttraumatic neuropsychiatric sequelae (APNS) is important for targeting prevention interventions. METHODS: Data came from n = 999 patients ages 18-75 presenting to 29 U.S. emergency departments after a motor vehicle collision (MVC) and followed for 3 months, the amount of time traditionally used to define chronic PTSD, in the Advancing Understanding of Recovery After Trauma (AURORA) study. Six CA types were self-reported at baseline: physical abuse, sexual abuse, emotional abuse, physical neglect, emotional neglect and bullying. Both dichotomous measures of ever experiencing each CA type and numeric measures of exposure frequency were included in the analysis. Risk ratios (RRs) of these CA measures as well as complex interactions among these measures were examined as predictors of APNS 3 months post-MVC. APNS was defined as meeting self-reported criteria for either PTSD based on the PTSD Checklist for DSM-5 and/or MDE based on the PROMIS Depression Short-Form 8b. We controlled for pre-MVC lifetime histories of PTSD and MDE. We also examined mediating effects through peritraumatic symptoms assessed in the emergency department and PTSD and MDE assessed in 2-week and 8-week follow-up surveys. Analyses were carried out with robust Poisson regression models. RESULTS: Most participants (90.9%) reported at least rarely having experienced some CA. Ever experiencing each CA other than emotional neglect was univariably associated with 3-month APNS (RRs = 1.31-1.60). Each CA frequency was also univariably associated with 3-month APNS (RRs = 1.65-2.45). In multivariable models, joint associations of CAs with 3-month APNS were additive, with frequency of emotional abuse (RR = 2.03; 95% CI = 1.43-2.87) and bullying (RR = 1.44; 95% CI = 0.99-2.10) being the strongest predictors. Control variable analyses found that these associations were largely explained by pre-MVC histories of PTSD and MDE. CONCLUSIONS: Although individuals who experience frequent emotional abuse and bullying in childhood have a heightened risk of experiencing APNS after an adult MVC, these associations are largely mediated by prior histories of PTSD and MDE

Prior Sexual Trauma Exposure Impacts Posttraumatic Dysfunction and Neural Circuitry Following a Recent Traumatic Event in the AURORA Study

Background: Prior sexual trauma (ST) is associated with greater risk for posttraumatic stress disorder after a subsequent traumatic event; however, the underlying neurobiological mechanisms remain opaque. We investigated longitudinal posttraumatic dysfunction and amygdala functional dynamics following admission to an emergency department for new primarily nonsexual trauma in participants with and without previous ST. Methods: Participants (N = 2178) were recruited following acute trauma exposure (primarily motor vehicle collision). A subset (n = 242) completed magnetic resonance imaging that included a fearful faces task and a resting-state scan 2 weeks after the trauma. We investigated associations between prior ST and several dimensions of posttraumatic symptoms over 6 months. We further assessed amygdala activation and connectivity differences between groups with or without prior ST. Results: Prior ST was associated with greater posttraumatic depression (F1,1120 = 28.35, p = 1.22 × 10−7, ηp2 = 0.06), anxiety (F1,1113 = 17.43, p = 3.21 × 10−5, ηp2 = 0.05), and posttraumatic stress disorder (F1,1027 = 11.34, p = 7.85 × 10−4, ηp2 = 0.04) severity and more maladaptive beliefs about pain (F1,1113 = 8.51, p = .004, ηp2 = 0.02) but was not related to amygdala reactivity to fearful versus neutral faces (all ps \u3e .05). A secondary analysis revealed an interaction between ST and lifetime trauma load on the left amygdala to visual cortex connectivity (peak Z value: −4.41, corrected p \u3c .02). Conclusions: Findings suggest that prior ST is associated with heightened posttraumatic dysfunction following a new trauma exposure but not increased amygdala activity. In addition, ST may interact with lifetime trauma load to alter neural circuitry in visual processing regions following acute trauma exposure. Further research should probe the relationship between trauma type and visual circuitry in the acute aftermath of trauma

Structural covariance of the ventral visual stream predicts posttraumatic intrusion and nightmare symptoms: a multivariate data fusion analysis

Visual components of trauma memories are often vividly re-experienced by survivors with deleterious consequences for normal function. Neuroimaging research on trauma has primarily focused on threat-processing circuitry as core to trauma-related dysfunction. Conversely, limited attention has been given to visual circuitry which may be particularly relevant to posttraumatic stress disorder (PTSD). Prior work suggests that the ventral visual stream is directly related to the cognitive and affective disturbances observed in PTSD and may be predictive of later symptom expression. The present study used multimodal magnetic resonance imaging data (n = 278) collected two weeks after trauma exposure from the AURORA study, a longitudinal, multisite investigation of adverse posttraumatic neuropsychiatric sequelae. Indices of gray and white matter were combined using data fusion to identify a structural covariance network (SCN) of the ventral visual stream 2 weeks after trauma. Participant\u27s loadings on the SCN were positively associated with both intrusion symptoms and intensity of nightmares. Further, SCN loadings moderated connectivity between a previously observed amygdala-hippocampal functional covariance network and the inferior temporal gyrus. Follow-up MRI data at 6 months showed an inverse relationship between SCN loadings and negative alterations in cognition in mood. Further, individuals who showed decreased strength of the SCN between 2 weeks and 6 months had generally higher PTSD symptom severity over time. The present findings highlight a role for structural integrity of the ventral visual stream in the development of PTSD. The ventral visual stream may be particularly important for the consolidation or retrieval of trauma memories and may contribute to efficient reactivation of visual components of the trauma memory, thereby exacerbating PTSD symptoms. Potentially chronic engagement of the network may lead to reduced structural integrity which becomes a risk factor for lasting PTSD symptoms

Convergent functional genomics of anxiety disorders: translational identification of genes, biomarkers, pathways and mechanisms

Anxiety disorders are prevalent and disabling yet understudied from a genetic standpoint, compared with other major psychiatric disorders such as bipolar disorder and schizophrenia. The fact that they are more common, diverse and perceived as embedded in normal life may explain this relative oversight. In addition, as for other psychiatric disorders, there are technical challenges related to the identification and validation of candidate genes and peripheral biomarkers. Human studies, particularly genetic ones, are susceptible to the issue of being underpowered, because of genetic heterogeneity, the effect of variable environmental exposure on gene expression, and difficulty of accrual of large, well phenotyped cohorts. Animal model gene expression studies, in a genetically homogeneous and experimentally tractable setting, can avoid artifacts and provide sensitivity of detection. Subsequent translational integration of the animal model datasets with human genetic and gene expression datasets can ensure cross-validatory power and specificity for illness. We have used a pharmacogenomic mouse model (involving treatments with an anxiogenic drug—yohimbine, and an anti-anxiety drug—diazepam) as a discovery engine for identification of anxiety candidate genes as well as potential blood biomarkers. Gene expression changes in key brain regions for anxiety (prefrontal cortex, amygdala and hippocampus) and blood were analyzed using a convergent functional genomics (CFG) approach, which integrates our new data with published human and animal model data, as a translational strategy of cross-matching and prioritizing findings. Our work identifies top candidate genes (such as FOS, GABBR1, NR4A2, DRD1, ADORA2A, QKI, RGS2, PTGDS, HSPA1B, DYNLL2, CCKBR and DBP), brain–blood biomarkers (such as FOS, QKI and HSPA1B), pathways (such as cAMP signaling) and mechanisms for anxiety disorders—notably signal transduction and reactivity to environment, with a prominent role for the hippocampus. Overall, this work complements our previous similar work (on bipolar mood disorders and schizophrenia) conducted over the last decade. It concludes our programmatic first pass mapping of the genomic landscape of the triad of major psychiatric disorder domains using CFG, and permitted us to uncover the significant genetic overlap between anxiety and these other major psychiatric disorders, notably the under-appreciated overlap with schizophrenia. PDE10A, TAC1 and other genes uncovered by our work provide a molecular basis for the frequently observed clinical co-morbidity and interdependence between anxiety and other major psychiatric disorders, and suggest schizo-anxiety as a possible new nosological domain

Post-traumatic stress and future substance use outcomes: leveraging antecedent factors to stratify risk

Background: Post-traumatic stress disorder (PTSD) and substance use (tobacco, alcohol, and cannabis) are highly comorbid. Many factors affect this relationship, including sociodemographic and psychosocial characteristics, other prior traumas, and physical health. However, few prior studies have investigated this prospectively, examining new substance use and the extent to which a wide range of factors may modify the relationship to PTSD. Methods: The Advancing Understanding of RecOvery afteR traumA (AURORA) study is a prospective cohort of adults presenting at emergency departments (N = 2,943). Participants self-reported PTSD symptoms and the frequency and quantity of tobacco, alcohol, and cannabis use at six total timepoints. We assessed the associations of PTSD and future substance use, lagged by one timepoint, using the Poisson generalized estimating equations. We also stratified by incident and prevalent substance use and generated causal forests to identify the most important effect modifiers of this relationship out of 128 potential variables. Results: At baseline, 37.3% (N = 1,099) of participants reported likely PTSD. PTSD was associated with tobacco frequency (incidence rate ratio (IRR): 1.003, 95% CI: 1.00, 1.01, p = 0.02) and quantity (IRR: 1.01, 95% CI: 1.001, 1.01, p = 0.01), and alcohol frequency (IRR: 1.002, 95% CI: 1.00, 1.004, p = 0.03) and quantity (IRR: 1.003, 95% CI: 1.001, 1.01, p = 0.001), but not with cannabis use. There were slight differences in incident compared to prevalent tobacco frequency and quantity of use; prevalent tobacco frequency and quantity were associated with PTSD symptoms, while incident tobacco frequency and quantity were not. Using causal forests, lifetime worst use of cigarettes, overall self-rated physical health, and prior childhood trauma were major moderators of the relationship between PTSD symptoms and the three substances investigated. Conclusion: PTSD symptoms were highly associated with tobacco and alcohol use, while the association with prospective cannabis use is not clear. Findings suggest that understanding the different risk stratification that occurs can aid in tailoring interventions to populations at greatest risk to best mitigate the comorbidity between PTSD symptoms and future substance use outcomes. We demonstrate that this is particularly salient for tobacco use and, to some extent, alcohol use, while cannabis is less likely to be impacted by PTSD symptoms across the strata

Neighborhood Disadvantage and Neural Correlates of Threat and Reward Processing in Survivors of Recent Trauma

IMPORTANCE: Differences in neighborhood socioeconomic characteristics are important considerations in understanding differences in risk vs resilience in mental health. Neighborhood disadvantage is associated with alterations in the function and structure of threat neurocircuitry. OBJECTIVE: To investigate associations of neighborhood disadvantage with white and gray matter and neural reactivity to positive and negative stimuli in the context of trauma exposure. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, survivors of trauma who completed sociodemographic and posttraumatic symptom assessments and neuroimaging were recruited as part of the Advancing Understanding of Recovery After Trauma (AURORA) study between September 2017 and June 2021. Data analysis was performed from October 25, 2022, to February 15, 2023. EXPOSURE: Neighborhood disadvantage was measured with the Area Deprivation Index (ADI) for each participant home address. MAIN OUTCOMES AND MEASURES: Participants completed separate threat and reward tasks during functional magnetic resonance imaging. Diffusion-weighted and high-resolution structural images were also collected. Linear models assessed the association of ADI with reactivity, microstructure, and macrostructure of a priori regions of interest after adjusting for income, lifetime trauma, sex at birth, and age. A moderated-mediation model tested whether ADI was associated with neural activity via microstructural changes and if this was modulated by PTSD symptoms. RESULTS: A total of 280 participants (183 females [65.4%]; mean [SD] age, 35.39 [13.29] years) completed the threat task and 244 participants (156 females [63.9%]; mean [SD] age, 35.10 [13.26] years) completed the reward task. Higher ADI (per 1-unit increase) was associated with greater insula (t274 = 3.20; β = 0.20; corrected P = .008) and anterior cingulate cortex (ACC; t274 = 2.56; β = 0.16; corrected P = .04) threat-related activity after considering covariates, but ADI was not associated with reward reactivity. Greater disadvantage was also associated with altered microstructure of the cingulum bundle (t274 = 3.48; β = 0.21; corrected P = .001) and gray matter morphology of the ACC (cortical thickness: t273 = -2.29; β = -0.13; corrected P = .02; surface area: t273 = 2.53; β = 0.13; corrected P = .02). The moderated-mediation model revealed that ADI was associated with ACC threat reactivity via cingulum microstructural changes (index of moderated mediation = -0.02). However, this mediation was only present in individuals with greater PTSD symptom severity (at the mean: β = -0.17; standard error = 0.06, t= -2.28; P = .007; at 1 SD above the mean: β = -0.28; standard error = 0.08; t = -3.35; P \u3c .001). CONCLUSIONS AND RELEVANCE: In this study, neighborhood disadvantage was associated with neurobiology that supports threat processing, revealing associations of neighborhood disadvantage with neural susceptibility for PTSD and suggesting how altered structure-function associations may complicate symptoms. Future work should investigate specific components of neighborhood disadvantage that may be associated with these outcomes

Predicting At-Risk Opioid Use Three Months After Ed Visit for Trauma: Results from the AURORA Study

OBJECTIVE: Whether short-term, low-potency opioid prescriptions for acute pain lead to future at-risk opioid use remains controversial and inadequately characterized. Our objective was to measure the association between emergency department (ED) opioid analgesic exposure after a physical, trauma-related event and subsequent opioid use. We hypothesized ED opioid analgesic exposure is associated with subsequent at-risk opioid use. METHODS: Participants were enrolled in AURORA, a prospective cohort study of adult patients in 29 U.S., urban EDs receiving care for a traumatic event. Exclusion criteria were hospital admission, persons reporting any non-medical opioid use (e.g., opioids without prescription or taking more than prescribed for euphoria) in the 30 days before enrollment, and missing or incomplete data regarding opioid exposure or pain. We used multivariable logistic regression to assess the relationship between ED opioid exposure and at-risk opioid use, defined as any self-reported non-medical opioid use after initial ED encounter or prescription opioid use at 3-months. RESULTS: Of 1441 subjects completing 3-month follow-up, 872 participants were included for analysis. At-risk opioid use occurred within 3 months in 33/620 (5.3%, CI: 3.7,7.4) participants without ED opioid analgesic exposure; 4/16 (25.0%, CI: 8.3, 52.6) with ED opioid prescription only; 17/146 (11.6%, CI: 7.1, 18.3) with ED opioid administration only; 12/90 (13.3%, CI: 7.4, 22.5) with both. Controlling for clinical factors, adjusted odds ratios (aORs) for at-risk opioid use after ED opioid exposure were: ED prescription only: 4.9 (95% CI 1.4, 17.4); ED administration for analgesia only: 2.0 (CI 1.0, 3.8); both: 2.8 (CI 1.2, 6.5). CONCLUSIONS: ED opioids were associated with subsequent at-risk opioid use within three months in a geographically diverse cohort of adult trauma patients. This supports need for prospective studies focused on the long-term consequences of ED opioid analgesic exposure to estimate individual risk and guide therapeutic decision-making

Socio-demographic and trauma-related predictors of PTSD within 8 weeks of a motor vehicle collision in the AURORA study

This is the initial report of results from the AURORA multisite longitudinal study of adverse post-traumatic neuropsychiatric sequelae (APNS) among participants seeking emergency department (ED) treatment in the aftermath of a traumatic life experience. We focus on n = 666 participants presenting to EDs following a motor vehicle collision (MVC) and examine associations of participant socio-demographic and participant-reported MVC characteristics with 8-week posttraumatic stress disorder (PTSD) adjusting for pre-MVC PTSD and mediated by peritraumatic symptoms and 2-week acute stress disorder (ASD). Peritraumatic Symptoms, ASD, and PTSD were assessed with self-report scales. Eight-week PTSD prevalence was relatively high (42.0%) and positively associated with participant sex (female), low socioeconomic status (education and income), and several self-report indicators of MVC severity. Most of these associations were entirely mediated by peritraumatic symptoms and, to a lesser degree, ASD, suggesting that the first 2 weeks after trauma may be a uniquely important time period for intervening to prevent and reduce risk of PTSD. This observation, coupled with substantial variation in the relative strength of mediating pathways across predictors, raises the possibility of diverse and potentially complex underlying biological and psychological processes that remain to be elucidated with more in-depth analyses of the rich and evolving AURORA data