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

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

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

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

Intergenerational trauma is associated with expression alterations in glucocorticoid- and immune-related genes.

Offspring of trauma survivors are more likely to develop PTSD, mood, and anxiety disorders and demonstrate endocrine and molecular alterations compared to controls. This study reports the association between parental Holocaust exposure and genome-wide gene expression in peripheral blood mononuclear cells (PBMC) from 77 Holocaust survivor offspring and 15 comparison subjects. Forty-two differentially expressed genes (DEGs) were identified in association with parental Holocaust exposure (FDR-adjusted p < 0.05); most of these genes were downregulated and co-expressed in a gene network related to immune cell functions. When both parental Holocaust exposure and maternal age at Holocaust exposure shared DEGs, fold changes were in the opposite direction. Similarly, fold changes of shared DEGs associated with maternal PTSD and paternal PTSD were in opposite directions, while fold changes of shared DEGs associated with both maternal and paternal Holocaust exposure or associated with both maternal and paternal age at Holocaust exposure were in the same direction. Moreover, the DEGs associated with parental Holocaust exposure were enriched for glucocorticoid-regulated genes and immune pathways with some of these genes mediating the effects of parental Holocaust exposure on C-reactive protein. The top gene across all analyses was MMP8, encoding the matrix metalloproteinase 8, which is a regulator of innate immunity. To conclude, this study identified a set of glucocorticoid and immune-related genes in association with parental Holocaust exposure with differential effects based on parental exposure-related factors.

Intergenerational Effects of Maternal Holocaust Exposure on FKBP5 Methylation.

OBJECTIVE: There is growing evidence that exposure to trauma prior to conception can affect offspring. The authors have reported that adult offspring of Holocaust survivors showed lower methylation of FK506 binding protein 5 (FKBP5) intron 7, site 6 compared with Jewish comparison volunteers. The present study sought to replicate this finding in a larger sample and to examine parental and offspring correlates of observed effects. METHODS: Cytosine methylation was measured in blood using pyrosequencing. The independent replication sample consisted of 125 Holocaust offspring and 31 control subjects. Additional analyses, performed in a larger sample of 147 offspring and 40 control subjects that included the 31 previously studied participants, examined associations of parental trauma-related variables (i.e., sex of the exposed parent, parental posttraumatic stress disorder, age at Holocaust exposure) and offspring characteristics (i.e., childhood trauma exposure, lifetime psychiatric diagnoses, psychotropic medication use, FKBP5 rs1360780 genotype, FKBP5 gene expression, and neuroendocrine measures) with offspring FKBP5 methylation. RESULTS: FKBP5 site 6 methylation was significantly lower in Holocaust offspring than in control subjects, an effect associated with maternal Holocaust exposure in childhood and with lower offspring self-reported anxiety symptoms. FKBP5 gene expression was elevated in Holocaust offspring. FKBP5 methylation was associated with indices of glucocorticoid sensitivity but not with basal FKBP5 gene expression. CONCLUSIONS: This study replicates and extends the previously observed decrement in FKBP5 intron 7, site 6 methylation in Holocaust offspring. The predominance of this effect in offspring of mothers exposed during childhood implicates maternal developmental programming as a putative mechanism.

Cultural trauma and epigenetic inheritance.

The question of whether and how the effects of cultural trauma can be transmitted intergenerationally from parents to offspring, or even to later generations, has evoked interest and controversy in academic and popular forums. Recent methodological advances have spurred investigations of potential epigenetic mechanisms for this inheritance, representing an exciting area of emergent research. Epigenetics has been described as the means through which environmental influences "get under the skin," directing transcriptional activity and influencing the expression or suppression of genes. Over the past decade, this complex environment-biology interface has shown increasing promise as a potential pathway for the intergenerational transmission of the effects of trauma. This article reviews challenges facing research on cultural trauma, biological findings in trauma and posttraumatic stress disorder, and putative epigenetic mechanisms for transmission of trauma effects, including through social, intrauterine, and gametic pathways. Implications for transmission of cultural trauma effects are discussed, focused on the relevance of cultural narratives and the possibilities of resilience and adaptivity.

Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms.

This paper reviews the research evidence concerning the intergenerational transmission of trauma effects and the possible role of epigenetic mechanisms in this transmission. Two broad categories of epigenetically mediated effects are highlighted. The first involves developmentally programmed effects. These can result from the influence of the offspring's early environmental exposures, including postnatal maternal care as well as in utero exposure reflecting maternal stress during pregnancy. The second includes epigenetic changes associated with a preconception trauma in parents that may affect the germline, and impact fetoplacental interactions. Several factors, such as sex-specific epigenetic effects following trauma exposure and parental developmental stage at the time of exposure, explain different effects of maternal and paternal trauma. The most compelling work to date has been done in animal models, where the opportunity for controlled designs enables clear interpretations of transmissible effects. Given the paucity of human studies and the methodological challenges in conducting such studies, it is not possible to attribute intergenerational effects in humans to a single set of biological or other determinants at this time. Elucidating the role of epigenetic mechanisms in intergenerational effects through prospective, multi-generational studies may ultimately yield a cogent understanding of how individual, cultural and societal experiences permeate our biology.

The public reception of putative epigenetic mechanisms in the transgenerational effects of trauma.

There has been great interest in the possibility that effects of trauma might be passed from parent to offspring through epigenetic mechanisms. This topic has stimulated discussion and controversy in the scientific literature, the popular press, and culture at large. This article describes the initial observations that have led to recent examinations of epigenetic mechanisms in association with effects of parental trauma exposure on offspring. Epigenetic research in animals has provided models for how such effects might be transmitted. However, the attribution of any specific epigenetic mechanisms in human studies of offspring of trauma survivors is premature at this time. The article describes some of the ways in which initial epigenetic findings in the offspring of trauma survivors have been represented in the popular media. Reports have ranged from overly simplistic and sensationalistic claims to global dismissals. The authors discuss the importance of clarity in language when describing epigenetic findings for lay audiences, the need to emphasize the limitations as well as the promise of research on intergenerational transmission of trauma effects, and the importance of countering popular interpretations that imply a reductionist biological determinism. Scientists have an obligation to assist in translating important research findings and nascent avenues of research to the public. It is important to recognize the ways in which this research may unintentionally be received as supporting a narrative of permanent and significant damage in offspring, rather than contributing to discussions of potential resilience, adaptability, and mutability in biological systems affected by stress.

Glucocorticoids and Hippocampal Structure and Function in PTSD.

This review examines the putative link between glucocorticoid and hippocampal abnormalities in posttraumatic stress disorder (PTSD). Increased glucocorticoid receptor (GR) sensitivity in PTSD may permit enhanced negative feedback inhibition of cortisol at the pituitary, hypothalamus, or other brain regions comprising the hypothalamic-pituitary-adrenal (HPA) axis and would be expected to affect other physiological systems that are regulated by glucocorticoids. Molecular and transcriptional studies of cortisol are consistent with the hypothesis that cortisol actions may be amplified in PTSD as a result of enhanced GR sensitivity in monocytes and some brain regions, although cortisol levels themselves are unchanged and oftentimes lower than normal. Concurrently, magnetic resonance imaging studies have demonstrated that individuals with PTSD have smaller hippocampal volume than individuals without PTSD. Initial hypotheses regarding the mechanism underlying hippocampal alterations in PTSD focused on elevated glucocorticoid levels in combination with extreme stress as the primary cause, but this explanation has not been well supported in human studies. Lack of data from neuroimaging studies preclude a firm link between PTSD onset and hippocampal volume changes. Rather, the available evidence is consistent with the possibility that smaller hippocampal volume (like reduced cortisol levels and enhanced GR sensitivity) may be a vulnerability factor for developing the disorder; limitations of hippocampal-based models of PTSD are described. We further review neuroimaging studies examining hippocampal structure and function following manipulation of glucocorticoid levels and also examining changes in the hippocampus in relationship to other brain regions. Evidence that the GR may be an important therapeutic target for the treatment of PTSD, especially for functions subserved by the hippocampus, is discussed. Implications of the current review for future research are described, with an emphasis on the need to integrate findings of glucocorticoid abnormalities with functional-imaging paradigms to formulate a comprehensive model of HPA-axis functioning in PTSD.

A Qualitative Investigation of the Role of Gender in Young Women's Dating Violence in the United States.

The relevance of gender has been a central debate in the intimate partner violence (IPV) literature. The current qualitative study explored the role of gender in shaping the social context, meaning, and reception of young women's IPV in the United States. A total of 36 undergraduate women were recruited from a larger sample for in-depth interviews. Emergent themes suggest that women's violence was construed as nonequivalent to men's violence, including the perceived triviality of women's violence, contingencies under which women's violence is deemed acceptable, and the status of male IPV as unacceptable. Gender was important for participants and bystanders in determining whether they interpreted behaviors as meaningful acts of violence.

Trauma across generations and paths to adaptation and resilience.

OBJECTIVE: There is a growing literature on the intergenerational transmission of trauma, representing approaches across psychodynamic, family systems, epidemiological, sociological, and biological levels of analysis. Embitterment has been proposed as a response to severe, but normative, stressful events, different from the life-threatening trauma that precedes posttraumatic stress disorder (PTSD). METHOD: This article reviews the potential applicability of the construct of embitterment to trauma and intergenerational effects through (a) a historical review of the intergenerational transmission of trauma literature, (b) a discussion of embitterment versus PTSD, (c) a brief review of theories of mechanisms of transmission, and (d) a discussion of biological findings and their interpretation. RESULTS: Mechanisms of intergenerational transmission of trauma, which may include psychodynamic processes, vicarious trauma, learning and modeling, parenting and family environment, and biological influences, are reviewed. Survivor coping and resilience, and specifically the presence of PTSD, has emerged as an important moderator of parental trauma effects on the second generation. A table comparing posttraumatic embitterment disorder and PTSD is provided. CONCLUSION: The discussion emphasizes the importance of construing biological findings as flexible adaptations to stressors rather than deterministic indicators of damage, the relevance of context in interpreting such findings, and the role of community-level processes for healing. (PsycINFO Database Record

Sexual dysfunction and neuroendocrine correlates of posttraumatic stress disorder in combat veterans: Preliminary findings.

Sexual dysfunction is not a symptom of PTSD but is a common clinical complaint in trauma survivors with this disorder. In that there are biological parallels in the neuroendocrine processes underlying both PTSD and sexual behavior, we conducted an exploratory investigation of the relationship of PTSD and related neuroendocrine indicators with sexual dysfunction in armed service veterans. Major Depressive Disorder, highly comorbid with PTSD and sexual dysfunction, was also assessed. In veterans with PTSD, sexual problems were associated with plasma DHEA and cortisol, urinary catecholamines, and glucocorticoid sensitivity, even when controlling for the effects of comorbid depression. In a subsample analysis, testosterone levels did not distinguish PTSD or sexual dysfunction, suggesting that sexual problems reported by veterans in this sample were not the result of organic disorder. PTSD did predict higher dihydrotestosterone (DHT) levels, which were associated with sexual problems. More detailed assessment of sexual dysfunction in biologically informed studies of PTSD is warranted to clarify the relationships of PTSD symptomatology and related neurobiology with sexual dysfunction.

PTSD and Sexual Dysfunction in Men and Women.

INTRODUCTION: Difficulties in sexual desire and function often occur in persons with posttraumatic stress disorder (PTSD), but many questions remain regarding the mechanisms underlying the occurrence of sexual problems in PTSD. AIM: The aim of this review was to present a model of sexual dysfunction in PTSD underpinned by an inability to regulate and redirect the physiological arousal needed for healthy sexual function away from aversive hyperarousal and intrusive memories. METHOD: A literature review pertaining to PTSD and sexual function was conducted. Evidence for the comorbidity of sexual dysfunction and PTSD is presented, and biological and psychological mechanisms that may underlie this co-occurrence are proposed. MAIN OUTCOME MEASURES: This manuscript presents evidence of sexual dysfunction in conjunction with PTSD, and of the neurobiology and neuroendocrinology of PTSD and sexual function. RESULTS: Sexual dysfunction following trauma exposure may be mediated by PTSD-related biological, cognitive, and affective processes. CONCLUSIONS: The treatment of PTSD must include attention to sexual dysfunction and vice versa.

Lower methylation of glucocorticoid receptor gene promoter 1F in peripheral blood of veterans with posttraumatic stress disorder.

BACKGROUND: Enhanced glucocorticoid receptor (GR) sensitivity is present in people with posttraumatic stress disorder (PTSD), but the molecular mechanisms of GR sensitivity are not understood. Epigenetic factors have emerged as one potential mechanism that account for how trauma exposure leads to sustained PTSD symptoms given that PTSD develops in only a subset of trauma survivors. METHODS: Cytosine methylation of a relevant promoter of the GR gene (NR3C1-1F promoter) and three functional neuroendocrine markers of hypothalamic-pituitary-adrenal axis function were examined in a sample of 122 combat veterans. RESULTS: Lower NR3C1-1F promoter methylation in peripheral blood mononuclear cells (PBMCs) was observed in combat veterans with PTSD compared with combat-exposed veterans who did not develop PTSD. NR3C1-1F promoter methylation was also associated with three functional measures of glucocorticoid activity that have been associated with PTSD in combat veterans: PBMCs' lysozyme inhibition on the lysozyme suppression test, plasma cortisol decline on the low-dose (.50 mg) dexamethasone suppression test, and 24-hour urinary cortisol excretion. Finally, NR3C1-1F promoter methylation was inversely correlated with clinical markers and symptoms associated with PTSD. CONCLUSIONS: Alterations in NR3C1-1F promoter methylation may reflect enduring changes resulting from combat exposure that lead to functional neuroendocrine alterations. Because epigenetic measures are thought to reflect enduring effects of environmental exposures, they may be useful in distinguishing combat-exposed veterans who do or do not develop PTSD.

Cortisol augmentation of a psychological treatment for warfighters with posttraumatic stress disorder: Randomized trial showing improved treatment retention and outcome.

BACKGROUND: Prolonged exposure (PE) therapy for post-traumatic stress disorder (PTSD) in military veterans has established efficacy, but is ineffective for a substantial number of patients. PE is also associated with high dropout rates. We hypothesized that hydrocortisone augmentation would enhance symptom improvement and reduce drop-out rates by diminishing the distressing effects of traumatic memories retrieved during imaginal exposure. We also hypothesized that in responders, hydrocortisone augmentation would be more effective in reversing glucocorticoid indices associated with PTSD than placebo augmentation. METHOD: Twenty-four veterans were randomized to receive either 30 mg oral hydrocortisone or placebo prior to PE sessions 3-10 in a double-blind protocol. Glucocorticoid receptor sensitivity was assessed in cultured peripheral blood mononuclear cells (PBMC) using the in vitro lysozyme inhibition test and was determined before and after treatment. Intent-to-treat analysis was performed using latent growth curve modeling of treatment effects on change in PTSD severity over time. Veterans who no longer met diagnostic criteria for PTSD at post-treatment were designated as responders. RESULTS: Veterans randomized to hydrocortisone or placebo augmentation did not differ significantly in clinical severity or glucocorticoid sensitivity at pre-treatment. Hydrocortisone augmentation was associated with greater reduction in total PTSD symptoms compared to placebo, a finding that was explained by significantly greater patient retention in the hydrocortisone augmentation condition. A significant treatment condition by responder status interaction for glucocorticoid sensitivity indicated that responders to hydrocortisone augmentation had the highest pre-treatment glucocorticoid sensitivity (lowest lysozyme IC50-DEX) that diminished over the course of treatment. There was a significant association between decline in glucocorticoid responsiveness and improvement in PTSD symptoms among hydrocortisone recipients. CONCLUSIONS: The results of this pilot study suggest that hydrocortisone augmentation of PE may result in greater retention in treatment and thereby promote PTSD symptom improvement. Further, the results suggest that particularly elevated glucocorticoid responsiveness at pre-treatment may identify veterans likely to respond to PE combined with an intervention that targets glucocorticoid sensitivity. Confirmation of these findings will suggest that pharmacologic interventions that target PTSD-associated glucocorticoid dysregulation may be particularly helpful in promoting a positive clinical response to PTSD psychotherapy.

Glucocorticoid-related predictors and correlates of post-traumatic stress disorder treatment response in combat veterans.

The identification of biomarkers for post-traumatic stress disorder (PTSD) and resilience/recovery is critical for advancing knowledge about pathophysiology and treatment in trauma-exposed persons. This study examined a series of glucocorticoid-related biomarkers prior to and in response to psychotherapy. Fifty-two male and female veterans with PTSD were randomized 2 : 1 to receive either prolonged exposure (PE) therapy or a weekly minimal attention (MA) intervention for 12 consecutive weeks. Psychological and biological assessments were obtained prior to and following treatment and after a 12-week naturalistic follow-up. Response was defined dichotomously as no longer meeting criteria for PTSD at post-treatment based on the Clinician Administered PTSD Scale for DSM-IV (CAPS). Clinical improvement on the CAPS was apparent for both PE and MA, with no significant difference according to treatment condition. Biomarkers predictive of treatment gains included the BCLI polymorphism of the glucocorticoid receptor gene. Additional predictors of treatment response were higher bedtime salivary cortisol and 24 h urinary cortisol excretion. Pre-treatment plasma dehydroepiandrosterone/cortisol ratio and neuropetide Y (NPY) levels were predictors of reductions in PTSD symptoms, and, for NPY only, of other secondary outcomes as well, including anxiety and depression ratings. Glucocorticoid sensitivity changed in association with symptom change, reflecting clinical state. It is possible to distinguish prognostic and state biomarkers of PTSD using a longitudinal approach in the context of treatment. Identified markers may also be relevant to understanding mechanisms of action of symptom reduction.

Biomarkers of PTSD: military applications and considerations.

BACKGROUND: Although there are no established biomarkers for posttraumatic stress disorder (PTSD) as yet, biological investigations of PTSD have made progress identifying the pathophysiology of PTSD. Given the biological and clinical complexity of PTSD, it is increasingly unlikely that a single biomarker of disease will be identified. Rather, investigations will more likely identify different biomarkers that indicate the presence of clinically significant PTSD symptoms, associate with risk for PTSD following trauma exposure, and predict or identify recovery. While there has been much interest in PTSD biomarkers, there has been less discussion of their potential clinical applications, and of the social, legal, and ethical implications of such biomarkers. OBJECTIVE: This article will discuss possible applications of PTSD biomarkers, including the social, legal, and ethical implications of such biomarkers, with an emphasis on military applications. METHOD: Literature on applications of PTSD biomarkers and on potential ethical and legal implications will be reviewed. RESULTS: Biologically informed research findings hold promise for prevention, assessment, treatment planning, and the development of prophylactic and treatment interventions. As with any biological indicator of disorder, there are potentially positive and negative clinical, social, legal, and ethical consequences of using such biomarkers. CONCLUSIONS: Potential clinical applications of PTSD biomarkers hold promise for clinicians, patients, and employers. The search for biomarkers of PTSD should occur in tandem with an interdisciplinary discussion regarding the potential implications of applying biological findings in clinical and employment settings.

PTSD in the military: special considerations for understanding prevalence, pathophysiology and treatment following deployment.

Given the unique context of warzone engagement, which may include chronic threat, multiple and lengthy deployments, and loss, there is a need to understand whether and to what extent knowledge about PTSD derived from studies of civilian trauma exposure is generalizeable to the military. This special issue on PTSD in the military addresses a range of issues and debates related to mental health in military personnel and combat veterans. This article provides an overview of the issues covered in selected contributions that have been assembled for a special volume to consider issues unique to the military. Several leading scholars and military experts have contributed papers regarding: 1) prevalence rates of PTSD and other post-deployment mental health problems in different NATO countries, 2) the search for biomarkers of PTSD and the potential applications of such findings, and 3) prevention and intervention approaches for service members and veterans. The volume includes studies that highlight the divergence in prevalence rates of PTSD and other post-deployment mental health problems across nations and that discuss potential causes and implications. Included studies also provide an overview of research conducted in military or Veteran's Affairs settings, and overarching reviews of military-wide approaches to research, promotion of resilience, and mental health interventions in the Unites States and across NATO and allied ISAF partners.

Maternal Age at Holocaust Exposure and Maternal PTSD Independently Influence Urinary Cortisol Levels in Adult Offspring.

BACKGROUND: Parental traumatization has been associated with increased risk for the expression of psychopathology in offspring, and maternal posttraumatic stress disorder (PTSD) appears to increase the risk for the development of offspring PTSD. In this study, Holocaust-related maternal age of exposure and PTSD were evaluated for their association with offspring ambient cortisol and PTSD-associated symptom expression. METHOD: Ninety-five Holocaust offspring and Jewish comparison subjects received diagnostic and psychological evaluations, and 24 h urinary cortisol was assayed by RIA. Offspring completed the parental PTSD questionnaire to assess maternal PTSD status. Maternal Holocaust exposure was identified as having occurred in childhood, adolescence, or adulthood and examined in relation to offspring psychobiology. RESULTS: Urinary cortisol levels did not differ for Holocaust offspring and comparison subjects but differed significantly in offspring based on maternal age of exposure and maternal PTSD status. Increased maternal age of exposure and maternal PTSD were each associated with lower urinary cortisol in offspring, but did not exhibit a significant interaction. In addition, offspring PTSD-associated symptom severity increased with maternal age at exposure and PTSD diagnosis. A regression analysis of correlates of offspring cortisol indicated that both maternal age of exposure and maternal PTSD were significant predictors of lower offspring urinary cortisol, whereas childhood adversity and offspring PTSD symptoms were not. CONCLUSION: Offspring low cortisol and PTSD-associated symptom expression are related to maternal age of exposure, with the greatest effects associated with increased age at exposure. These effects are relatively independent of the negative consequences of being raised by a trauma survivor. These observations highlight the importance of maternal age of exposure in determining a psychobiology in offspring that is consistent with increased risk for stress-related pathology.