- Email: [email protected]
Hair cortisol, stress-related psychiatric disorders and cardiometabolic risk
R. Reynolds / Psychoneuroendocrinology 61 (2015) 1–78
Results: Depression was especially associated with obesityrelated metabolic components (e.g. abdominal obesity and dyslipidemia). In addition, systemic inflammation and hyperactivity of the HPA-axis have been consistently observed among depressed patients. Less consistent observations are for autonomic dysregulation among depressed patients. However, clear pathophysiological differences were observed for melancholic versus atypical depressed patients. Metabolic syndrome and inflammation upregulations appear more specific to the atypical depression subtype, whereas hypercortisolemia appears more specific for melancholic depression. I will illustrate the extent to which these differential dysregulations may explain the increased risk for cardiovascular health outcomes among depressed patients. Discussion: Our results confirm the presence of a downward spiral in which different depressive symptom profiles and biological dysregulations may impact on each other and interact with cardiovascular – but also more general – health decline. http://dx.doi.org/10.1016/j.psyneuen.2015.07.404
PS1.3.2 Effects of posttraumatic stress disorder on cardiovascular health: Findings from the Mind Your Heart Study Beth Cohen ∗ , Mary Whooley, Thomas Neylan University of California, San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA Patients with posttraumatic stress disorder (PTSD) are at increased risk of developing cardiovascular disease, leading to decreased quality of life, impaired function, and early mortality. We will present data from the Mind Your Heart Study, an ongoing prospective study of 746 patients recruited from San Francisco area Veterans Affairs Medical Centers between 2008 and 2010. PTSD was assessed with the Clinician Administered PTSD scale (CAPS) and cardiovascular status was evaluated with resting echocardiography and exercise treadmill testing. Participants are followed with annual telephone interviews to assess cardiovascular events, including heart attack, stroke, congestive heart failure, revascularization, or emergency room visits for chest pain. Patients with PTSD were significantly more likely to have myocardial ischemia on exercise treadmill testing than those without PTSD (17% vs. 10%, p = .006). We also observed a dose-response relationship between PTSD symptom severity and prevalence of myocardial ischemia. Risk increased sharply at a CAPS score of 80, corresponding to moderate to severe PTSD. The association of PTSD and myocardial ischemia remained significant after adjusting for traditional cardiovascular risk factors, behavioral and psychosocial factors, including sleep quality and social support, and depression. Patients with PTSD did not have significant differences in baseline cardiac function on resting echocardiography. Thus far, a significantly greater proportion of patients with PTSD have reported cardiovascular events on annual telephone follow up (p = .03). We will discuss the clinical significance of the study findings as well as additional mechanisms that may explain the observed increased risk of cardiovascular disease in patients with PTSD. http://dx.doi.org/10.1016/j.psyneuen.2015.07.405
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PS1.3.3 Depression and cardiovascular risk: Role of autonomic functions, HPA axis and use of antidepressant medication Linn Kuehl Charité University Medical School Berlin, Germany Major depression is associated with an increased cardiovascular risk. Several biological and life style factors have been identified which may contribute to this association. The identified biological factors include unfavourable alterations in the two stress-systems: the autonomic nervous system and the hypothalamic–adrenal–pituitary (HPA) axis. As a further potential factor, the use of antidepressant medication may contribute to the increased cardiovascular risk. To discuss the potential role of these factors, data from different studies will be presented. In a first study, we analyzed data from the longitudinal “Heart & Soul” study including 956 patients with coronary heart disease to examine whether the use of antidepressants was associated with mortality and whether this association was mediated by autonomic functions assessed as heart rate variability and levels of norepinephrine. The use of tricyclic antidepressants was associated with increased mortality compared to patients without antidepressants or use of selective serotonin reuptake inhibitors. This association was at least partly mediated by autonomic functions. In a further study, we investigated a sample of 44 comparatively young depressed patients without a preexisting cardiovascular disease. We compared cardiovascular risk profiles between patients with vs. without antidepressants and a healthy control group. We found an increased risk, e.g. indicated by higher blood pressure, in both groups of depressed patients, but no differences between patients with vs. without antidepressants. Finally, data will be presented that investigated the cortisol awakening response as a marker of the HPA axis. Here, patients without antidepressants had a higher magnitude compared to patients using antidepressants. http://dx.doi.org/10.1016/j.psyneuen.2015.07.406
PS1.3.4 Hair cortisol, stress-related psychiatric disorders and cardiometabolic risk Tobias Stalder Department of Psychology, TU Dresden, Dresden, Germany Although a positive relationship between stress-related psychiatric disorders and an increased cardiometabolic risk has been shown, it remains unclear which biological processes are responsible for mediating this association. A potential candidate for such a mediating factor is altered secretion of the glucocorticoid cortisol, which has been observed in many psychiatric conditions and is considered to play an important role in the development of cardiometabolic pathology. Importantly, particularly persistent, long-term changes to cortisol exposure are likely to be of relevance in this process. However, to obtain reliable information on long-term cortisol secretory activity has been difficult using previous assessment methods (in blood, saliva or urine). The analysis of cortisol in hair is assumed to provide an easily-obtainable index of integrated cortisol secretion over periods of several months and may thus lead to novel opportunities for research in this field. This presentation will provide an overview of our recent
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R. Reynolds / Psychoneuroendocrinology 61 (2015) 1–78
research investigating hair cortisol concentrations in the context of stress-related psychiatric disorders and different aspects of cardiometabolic health. Concerning the latter, data will be presented showing consistent positive relationships of hair cortisol concentrations with body fat-related anthropometric measures, prevalence of diabetes mellitus type 2 and the metabolic syndrome. Potential implications and future prospects of these findings will be discussed. http://dx.doi.org/10.1016/j.psyneuen.2015.07.407 Parallel Session 2 PS2.1 Young Investigator Forum: Mechanisms of Stress-Induced Visceral Pain PS2.1.1 Stress & the microbiota–gut–brain axis in visceral pain Rachel D. Moloney 1,∗ , Timothy G. Dinan 1,2 , John F. Cryan 1,3 1 Laboratory of NeuroGastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland 2 Department of Psychiatry, University College Cork, Cork, Ireland 3 Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
Visceral pain is a global term used to describe pain originating from the internal organs of the body, which affects up to 25% of the population and is a common feature of functional gastrointestinal disorders (FGIDs) such as irritable bowel syndrome (IBS). While IBS is multifactorial, with no single etiology to completely explain the disorder, many patients also experience co-morbid behavioral disorders, such as anxiety or depression, thus IBS is described as a biopsychosocial disorder of the gut-brain axis. Currently, treatment strategies are unsatisfactory, with development of novel therapeutics hindered by a lack of detailed knowledge of the underlying mechanisms. The pathophysiology of visceral pain strongly implicates a role of stress in the development and exacerbation of symptoms. In this presentation, I will discuss our recent studies in a variety of rodent models of visceral pain, in particular early-life stress models as well as genetic susceptibility models. I will describe our data, demonstrating how stress can modify central pain circuitry at the level of the spinal cord, highlighting a key role of glutamatergic signaling. Furthermore, I will discuss the potential of employing epigenetic modifiers, specifically histone deacetylase inhibitors, as a treatment strategy for visceral pain. More recently, the role of the gut microbiota in the bi-directional communication along the gut-brain axis have been appreciated. I will present data to further support a novel role of the gut microbiota in the regulation of visceral pain processes. Taken together, these findings will enhance our knowledge of the pathophysiology of visceral pain. http://dx.doi.org/10.1016/j.psyneuen.2015.07.408
PS2.1.2 Central amygdala mechanisms regulating visceral pain Anthony C. Johnson 2,∗ , Beverley Greenwood-Van Meerveld 1,2 1
Department of Veterans Affairs, Oklahoma City, OK, USA 2 Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA Patients with irritable bowel syndrome (IBS) experience chronic abdominal pain that is worsened by stress. Functional imaging studies have demonstrated differences in stress-associated brain regions in IBS patients, with the amygdala being an area that integrates visceral pain signaling with autonomic and endocrine output. Using a rodent model, we have demonstrated that targeting the central nucleus of the amygdala (CeA) with corticosterone (CORT), the rat equivalent of cortisol, induces persistent visceral and somatic hypersensitivity, associated with increased corticotropin-releasing factor (CRF) expression and decreased glucocorticoid receptor (GR) expression. Our experimental goal was to identify the CeA-mediated mechanism linking GR, CRF, and visceral pain. In this presentation, I will describe our recent studies demonstrating two complementary CeA-mediated mechanisms for visceral pain. We found that rats with CORT on the CeA, or exposed to a repeated stressor, displayed visceral and somatic hypersensitivity. We then demonstrated that knockdown of CRF in the CeA inhibited the stress-induced visceral and somatic nociceptive behaviors. In the converse experiment, knockdown of GR in the CeA of stress-naïve rats increased CRF expression and induced visceral and somatic hypersensitivity, mimicking the stress-induced behaviors. Finally, due to the persistence of the visceral and somatic hypersensitivity, we recently demonstrated a novel epigenetic mechanism within the CeA that causes GR downregulation and CRF upregulation in response to stress. Thus, our research has provided evidence for novel mechanisms within the CeA that modulate visceral and somatic nociception, providing additional insight into the etiology of how stress can influence chronic pain disorders such as IBS. http://dx.doi.org/10.1016/j.psyneuen.2015.07.409
PS2.1.3 Mechanisms of stress-induced visceral pain in irritable bowel syndrome María Vicario Laboratory of Neuro-Immuno-Gastroenterology, Vall d’Hebron Institut de Recerca, Department of Gastroenterology, Vall d’Hebron Hospital, Barcelona, Spain Irritable bowel syndrome is a prototype of functional gastrointestinal disorder and one of the most prevalent causes of digestive consultation in our society, affecting up to 15–20% of the population. It is characterized by abdominal pain associated with changes in bowel habit in the absence of organic pathology. The pathophysiology of IBS is poorly understood, however altered brain–gut axis communication and mucosal immune activation are possible disease mechanisms. Previous episodes of gastrointestinal infection and elevated levels of psychological stress are associated with IBS
Results: Depression was especially associated with obesityrelated metabolic components (e.g. abdominal obesity and dyslipidemia). In addition, systemic inflammation and hyperactivity of the HPA-axis have been consistently observed among depressed patients. Less consistent observations are for autonomic dysregulation among depressed patients. However, clear pathophysiological differences were observed for melancholic versus atypical depressed patients. Metabolic syndrome and inflammation upregulations appear more specific to the atypical depression subtype, whereas hypercortisolemia appears more specific for melancholic depression. I will illustrate the extent to which these differential dysregulations may explain the increased risk for cardiovascular health outcomes among depressed patients. Discussion: Our results confirm the presence of a downward spiral in which different depressive symptom profiles and biological dysregulations may impact on each other and interact with cardiovascular – but also more general – health decline. http://dx.doi.org/10.1016/j.psyneuen.2015.07.404
PS1.3.2 Effects of posttraumatic stress disorder on cardiovascular health: Findings from the Mind Your Heart Study Beth Cohen ∗ , Mary Whooley, Thomas Neylan University of California, San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA Patients with posttraumatic stress disorder (PTSD) are at increased risk of developing cardiovascular disease, leading to decreased quality of life, impaired function, and early mortality. We will present data from the Mind Your Heart Study, an ongoing prospective study of 746 patients recruited from San Francisco area Veterans Affairs Medical Centers between 2008 and 2010. PTSD was assessed with the Clinician Administered PTSD scale (CAPS) and cardiovascular status was evaluated with resting echocardiography and exercise treadmill testing. Participants are followed with annual telephone interviews to assess cardiovascular events, including heart attack, stroke, congestive heart failure, revascularization, or emergency room visits for chest pain. Patients with PTSD were significantly more likely to have myocardial ischemia on exercise treadmill testing than those without PTSD (17% vs. 10%, p = .006). We also observed a dose-response relationship between PTSD symptom severity and prevalence of myocardial ischemia. Risk increased sharply at a CAPS score of 80, corresponding to moderate to severe PTSD. The association of PTSD and myocardial ischemia remained significant after adjusting for traditional cardiovascular risk factors, behavioral and psychosocial factors, including sleep quality and social support, and depression. Patients with PTSD did not have significant differences in baseline cardiac function on resting echocardiography. Thus far, a significantly greater proportion of patients with PTSD have reported cardiovascular events on annual telephone follow up (p = .03). We will discuss the clinical significance of the study findings as well as additional mechanisms that may explain the observed increased risk of cardiovascular disease in patients with PTSD. http://dx.doi.org/10.1016/j.psyneuen.2015.07.405
7
PS1.3.3 Depression and cardiovascular risk: Role of autonomic functions, HPA axis and use of antidepressant medication Linn Kuehl Charité University Medical School Berlin, Germany Major depression is associated with an increased cardiovascular risk. Several biological and life style factors have been identified which may contribute to this association. The identified biological factors include unfavourable alterations in the two stress-systems: the autonomic nervous system and the hypothalamic–adrenal–pituitary (HPA) axis. As a further potential factor, the use of antidepressant medication may contribute to the increased cardiovascular risk. To discuss the potential role of these factors, data from different studies will be presented. In a first study, we analyzed data from the longitudinal “Heart & Soul” study including 956 patients with coronary heart disease to examine whether the use of antidepressants was associated with mortality and whether this association was mediated by autonomic functions assessed as heart rate variability and levels of norepinephrine. The use of tricyclic antidepressants was associated with increased mortality compared to patients without antidepressants or use of selective serotonin reuptake inhibitors. This association was at least partly mediated by autonomic functions. In a further study, we investigated a sample of 44 comparatively young depressed patients without a preexisting cardiovascular disease. We compared cardiovascular risk profiles between patients with vs. without antidepressants and a healthy control group. We found an increased risk, e.g. indicated by higher blood pressure, in both groups of depressed patients, but no differences between patients with vs. without antidepressants. Finally, data will be presented that investigated the cortisol awakening response as a marker of the HPA axis. Here, patients without antidepressants had a higher magnitude compared to patients using antidepressants. http://dx.doi.org/10.1016/j.psyneuen.2015.07.406
PS1.3.4 Hair cortisol, stress-related psychiatric disorders and cardiometabolic risk Tobias Stalder Department of Psychology, TU Dresden, Dresden, Germany Although a positive relationship between stress-related psychiatric disorders and an increased cardiometabolic risk has been shown, it remains unclear which biological processes are responsible for mediating this association. A potential candidate for such a mediating factor is altered secretion of the glucocorticoid cortisol, which has been observed in many psychiatric conditions and is considered to play an important role in the development of cardiometabolic pathology. Importantly, particularly persistent, long-term changes to cortisol exposure are likely to be of relevance in this process. However, to obtain reliable information on long-term cortisol secretory activity has been difficult using previous assessment methods (in blood, saliva or urine). The analysis of cortisol in hair is assumed to provide an easily-obtainable index of integrated cortisol secretion over periods of several months and may thus lead to novel opportunities for research in this field. This presentation will provide an overview of our recent
8
R. Reynolds / Psychoneuroendocrinology 61 (2015) 1–78
research investigating hair cortisol concentrations in the context of stress-related psychiatric disorders and different aspects of cardiometabolic health. Concerning the latter, data will be presented showing consistent positive relationships of hair cortisol concentrations with body fat-related anthropometric measures, prevalence of diabetes mellitus type 2 and the metabolic syndrome. Potential implications and future prospects of these findings will be discussed. http://dx.doi.org/10.1016/j.psyneuen.2015.07.407 Parallel Session 2 PS2.1 Young Investigator Forum: Mechanisms of Stress-Induced Visceral Pain PS2.1.1 Stress & the microbiota–gut–brain axis in visceral pain Rachel D. Moloney 1,∗ , Timothy G. Dinan 1,2 , John F. Cryan 1,3 1 Laboratory of NeuroGastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland 2 Department of Psychiatry, University College Cork, Cork, Ireland 3 Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
Visceral pain is a global term used to describe pain originating from the internal organs of the body, which affects up to 25% of the population and is a common feature of functional gastrointestinal disorders (FGIDs) such as irritable bowel syndrome (IBS). While IBS is multifactorial, with no single etiology to completely explain the disorder, many patients also experience co-morbid behavioral disorders, such as anxiety or depression, thus IBS is described as a biopsychosocial disorder of the gut-brain axis. Currently, treatment strategies are unsatisfactory, with development of novel therapeutics hindered by a lack of detailed knowledge of the underlying mechanisms. The pathophysiology of visceral pain strongly implicates a role of stress in the development and exacerbation of symptoms. In this presentation, I will discuss our recent studies in a variety of rodent models of visceral pain, in particular early-life stress models as well as genetic susceptibility models. I will describe our data, demonstrating how stress can modify central pain circuitry at the level of the spinal cord, highlighting a key role of glutamatergic signaling. Furthermore, I will discuss the potential of employing epigenetic modifiers, specifically histone deacetylase inhibitors, as a treatment strategy for visceral pain. More recently, the role of the gut microbiota in the bi-directional communication along the gut-brain axis have been appreciated. I will present data to further support a novel role of the gut microbiota in the regulation of visceral pain processes. Taken together, these findings will enhance our knowledge of the pathophysiology of visceral pain. http://dx.doi.org/10.1016/j.psyneuen.2015.07.408
PS2.1.2 Central amygdala mechanisms regulating visceral pain Anthony C. Johnson 2,∗ , Beverley Greenwood-Van Meerveld 1,2 1
Department of Veterans Affairs, Oklahoma City, OK, USA 2 Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA Patients with irritable bowel syndrome (IBS) experience chronic abdominal pain that is worsened by stress. Functional imaging studies have demonstrated differences in stress-associated brain regions in IBS patients, with the amygdala being an area that integrates visceral pain signaling with autonomic and endocrine output. Using a rodent model, we have demonstrated that targeting the central nucleus of the amygdala (CeA) with corticosterone (CORT), the rat equivalent of cortisol, induces persistent visceral and somatic hypersensitivity, associated with increased corticotropin-releasing factor (CRF) expression and decreased glucocorticoid receptor (GR) expression. Our experimental goal was to identify the CeA-mediated mechanism linking GR, CRF, and visceral pain. In this presentation, I will describe our recent studies demonstrating two complementary CeA-mediated mechanisms for visceral pain. We found that rats with CORT on the CeA, or exposed to a repeated stressor, displayed visceral and somatic hypersensitivity. We then demonstrated that knockdown of CRF in the CeA inhibited the stress-induced visceral and somatic nociceptive behaviors. In the converse experiment, knockdown of GR in the CeA of stress-naïve rats increased CRF expression and induced visceral and somatic hypersensitivity, mimicking the stress-induced behaviors. Finally, due to the persistence of the visceral and somatic hypersensitivity, we recently demonstrated a novel epigenetic mechanism within the CeA that causes GR downregulation and CRF upregulation in response to stress. Thus, our research has provided evidence for novel mechanisms within the CeA that modulate visceral and somatic nociception, providing additional insight into the etiology of how stress can influence chronic pain disorders such as IBS. http://dx.doi.org/10.1016/j.psyneuen.2015.07.409
PS2.1.3 Mechanisms of stress-induced visceral pain in irritable bowel syndrome María Vicario Laboratory of Neuro-Immuno-Gastroenterology, Vall d’Hebron Institut de Recerca, Department of Gastroenterology, Vall d’Hebron Hospital, Barcelona, Spain Irritable bowel syndrome is a prototype of functional gastrointestinal disorder and one of the most prevalent causes of digestive consultation in our society, affecting up to 15–20% of the population. It is characterized by abdominal pain associated with changes in bowel habit in the absence of organic pathology. The pathophysiology of IBS is poorly understood, however altered brain–gut axis communication and mucosal immune activation are possible disease mechanisms. Previous episodes of gastrointestinal infection and elevated levels of psychological stress are associated with IBS