Amy Lehrner

Influences of Maternal and Paternal PTSD on Epigenetic Regulation of the Glucocorticoid Receptor Gene in Holocaust Survivor Offspring

OBJECTIVE Differential effects of maternal and paternal posttraumatic stress disorder (PTSD) have been observed in adult offspring of Holocaust survivors in both glucocorticoid receptor sensitivity and vulnerability to psychiatric disorder. The authors examined the relative influences of maternal and paternal PTSD on DNA methylation of the exon 1F promoter of the glucocorticoid receptor (GR-1F) gene (NR3C1) in peripheral blood mononuclear cells and its relationship to glucocorticoid receptor sensitivity in Holocaust offspring. METHOD Adult offspring with at least one Holocaust survivor parent (N=80) and demographically similar participants without parental Holocaust exposure or parental PTSD (N=15) completed clinical interviews, self-report measures, and biological procedures. Blood samples were collected for analysis of GR-1F promoter methylation and of cortisol levels in response to low-dose dexamethasone, and two-way analysis of covariance was performed using maternal and paternal PTSD as main effects. Hierarchical clustering analysis was used to permit visualization of maternal compared with paternal PTSD effects on clinical variables and GR-1F promoter methylation. RESULTS A significant interaction demonstrated that in the absence of maternal PTSD, offspring with paternal PTSD showed higher GR-1F promoter methylation, whereas offspring with both maternal and paternal PTSD showed lower methylation. Lower GR-1F promoter methylation was significantly associated with greater postdexamethasone cortisol suppression. The clustering analysis revealed that maternal and paternal PTSD effects were differentially associated with clinical indicators and GR-1F promoter methylation. CONCLUSIONS This is the first study to demonstrate alterations of GR-1F promoter methylation in relation to parental PTSD and neuroendocrine outcomes. The moderation of paternal PTSD effects by maternal PTSD suggests different mechanisms for the intergenerational transmission of trauma-related vulnerabilities.

Epigenetic Biomarkers as Predictors and Correlates of Symptom Improvement Following Psychotherapy in Combat Veterans with PTSD.

Epigenetic alterations offer promise as diagnostic or prognostic markers, but it is not known whether these measures associate with, or predict, clinical state. These questions were addressed in a pilot study with combat veterans with PTSD to determine whether cytosine methylation in promoter regions of the glucocorticoid related NR3C1 and FKBP51 genes would predict or associate with treatment outcome. Veterans with PTSD received prolonged exposure (PE) psychotherapy, yielding responders (n = 8), defined by no longer meeting diagnostic criteria for PTSD, and non-responders (n = 8). Blood samples were obtained at pre-treatment, after 12 weeks of psychotherapy (post-treatment), and after a 3-month follow-up. Methylation was examined in DNA extracted from lymphocytes. Measures reflecting glucocorticoid receptor (GR) activity were also obtained (i.e., plasma and 24 h-urinary cortisol, plasma ACTH, lymphocyte lysozyme IC50-DEX, and plasma neuropeptide-Y). Methylation of the GR gene (NR3C1) exon 1F promoter assessed at pre-treatment predicted treatment outcome, but was not significantly altered in responders or non-responders at post-treatment or follow-up. In contrast, methylation of the FKBP5 gene (FKBP51) exon 1 promoter region did not predict treatment response, but decreased in association with recovery. In a subset, a corresponding group difference in FKBP5 gene expression was observed, with responders showing higher gene expression at post-treatment than non-responders. Endocrine markers were also associated with the epigenetic markers. These preliminary observations require replication and validation. However, the results support research indicating that some glucocorticoid related genes are subject to environmental regulation throughout life. Moreover, psychotherapy constitutes a form of “environmental regulation” that may alter epigenetic state. Finally, the results further suggest that different genes may be associated with prognosis and symptom state, respectively.

Endocrine aspects of post-traumatic stress disorder and implications for diagnosis and treatment.

Post-traumatic stress disorder (PTSD) is a serious, multisystem disorder with multiple medical comorbidities. This article reviews the current literature on the endocrine aspects of PTSD, specifically hypothalamic-pituitary-adrenal axis alterations indicative of low cortisol and increased glucocorticoid sensitivity, and the proposed mechanisms whereby these alterations increase risk or reflect pathophysiology. Discussion includes novel treatment innovations and directions for future research.

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.

Maternal PTSD associates with greater glucocorticoid sensitivity in offspring of Holocaust survivors

Intergenerational effects of trauma have been observed clinically in a wide range of populations, and parental PTSD has been associated with an increased risk for psychopathology in offspring. In studies of Holocaust survivor offspring, parental PTSD, and particularly maternal PTSD, has been associated with increased risk for PTSD, low basal urinary cortisol excretion and enhanced cortisol suppression in response to dexamethasone. Such findings implicate maternally derived glucocorticoid programming in the intergenerational transmission of trauma-related consequences, potentially resulting from in utero influences or early life experiences. This study investigated the relative influence of Holocaust exposure and PTSD in mothers and fathers on glucocorticoid sensitivity in offspring. Eighty Holocaust offspring and 15 offspring of non-exposed Jewish parents completed evaluations and provided blood and urine samples. Glucocorticoid sensitivity was evaluated using the lysozyme suppression test (LST), an in vitro measure of glucocorticoid receptor sensitivity in a peripheral tissue, the dexamethasone suppression test (DST), and 24-h urinary cortisol excretion. Maternal PTSD was associated with greater glucocorticoid sensitivity in offspring across all three measures of glucocorticoid function. An interaction of maternal and paternal PTSD on the DST and 24-h urinary cortisol showed an effect of decreased glucocorticoid sensitivity in offspring with paternal, but not maternal, PTSD. Although indirect, these findings are consistent with the hypothesis that epigenetic programming may be involved in the intergenerational transmission of trauma-related effects on glucocorticoid regulation.

Social Change Movements and the Struggle Over Meaning-Making: A Case Study of Domestic Violence Narratives

Social movement theorists have emphasized the important role of meaning-making for social change movements (e.g., D. A. Snow and R. D. Benford, 1992, In: A. D. Morris & C. M. Mueller (Eds.) Frontiers in social movement theory. Yale University Press, New Haven, CT, pp 133–155; C. M. Mueller, 1992, In: A. D. Morris & C. M. Mueller (Eds.) Frontiers in social movement theory. Yale University Press, New Haven, CT, pp 3–26). Using the domestic violence movement as a case study, this study undertakes a close analysis of advocates’ narratives about the phenomenon of domestic violence. This analysis sheds light on the current status of the movement as a social change movement attempting to promote alternative understandings of domestic violence as a social, rather than individual, problem. Study findings provide some evidence that the domestic violence movement has become increasingly de-politicized by documenting a range of narratives that convey an apolitical, degendered, individual-level analysis of domestic violence.

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.

“Changing the Text”: Modeling Council Capacity to Produce Institutionalized Change

Collaboration is a ubiquitous approach to change, but is notoriously difficult and not definitively linked to desirable outcomes. Not surprisingly, the collaboration literature is replete with numerous facilitators and barriers to collaborative efforts. The current study aimed to develop a parsimonious model of factors influencing the success of collaborative efforts both internal and external to the council, including, (a) features of the council environment, (b) intermediate outcomes including the empowerment of members in the council context and the degree to which councils have generated social capital and (c) the extent to which collaborative efforts are occurring in a community context supportive of their aims. In particular, this study examines whether these factors affect the extent to which councils are positioned to achieve institutionalized change, or changes “in the text” that govern front line providers’ (e.g., police, advocates) practices in the community response to intimate partner violence. Results suggest that perceived member empowerment, generation of social capital, and supportive community context are the most important predictors of the extent to which councils foster shifts in institutionalized change. Features of the council environment are only indirectly related to the degree to which institutionalized change is ultimately fostered as mediated by the generation of social capital. This suggests that the ability of members to act as change agents and the extent to which those in power support council efforts figure more prominently to facilitate or constrain council efforts than council functioning itself.

A Comparative, Developmental, and Clinical Perspective of Neurobehavioral Sexual Dimorphisms

Women and men differ in a wide variety of behavioral traits and in their vulnerability to developing certain mental disorders. This review endeavors to explore how recent preclinical and clinical research findings have enhanced our understanding of the factors that underlie these disparities. We start with a brief overview of some of the important genetic, molecular, and hormonal determinants that contribute to the process of sexual differentiation. We then discuss the importance of animal models in studying the mechanisms responsible for sex differences in neuropsychiatric disorders (e.g., drug dependence) – with a special emphasis on experimental models based on the neurodevelopmental and “three hits” hypotheses. Next, we describe the most common brain phenotypes observed in vivo with magnetic resonance imaging. We discuss the challenges in interpreting these phenotypes vis-à-vis the underlying neurobiology and revisit the known sex differences in brain structure from birth, through adolescence, and into adulthood. This is followed by a presentation of pertinent clinical and epidemiological data that point to important sex differences in the prevalence, course, and expression of psychopathologies such as schizophrenia, and mood disorders including major depression and posttraumatic stress disorder. Recent evidence implies that mood disorders and psychosis share some common genetic predispositions and neurobiological bases. Therefore, modern research is emphasizing dimensional representation of mental disorders and conceptualization of schizophrenia and major depression as a continuum of cognitive deficits and neurobiological abnormalities. Herein, we examine available evidence on cerebral sexual dimorphism to verify if sex differences vary quantitatively and/or qualitatively along the psychoses-depression continuum. Finally, sex differences in the prevalence of posttraumatic disorder and drug abuse have been described, and we consider the genomic and molecular data supporting these differences.