Lotte Kok

Stress and Depression: a Crucial Role of the Mineralocorticoid Receptor

Cortisol and corticosterone act on the appraisal process, which comprises the selection of an appropriate coping style and the encoding of the experience for storage in the memory. This action exerted by the stress hormones is mediated by mineralocorticoid receptors (MRs), which are expressed abundantly in the limbic circuitry, particularly in the hippocampus. Limbic MR is down‐regulated by chronic stress and during depression but induced by antidepressants. Increased MR activity inhibits hypothalamic‐pituitary‐adrenal axis activity, promotes slow wave sleep, reduces anxiety and switches circuit connectivity to support coping. Cortisol and emotion‐cognition are affected by MR gene haplotypes based on rs5522 and rs2070951. Haplotype 1 (GA) moderates the effects of (early) life stressors, reproductive cycle and oral contraceptives. MR haplotype 2 (CA) is a gain of function variant that protects females against depression by association with an optimistic, resilient phenotype. Activation of MR therefore may offer a target for alleviating depression and cognitive dysfunction. Accordingly, the MR agonist fludrocortisone was found to enhance the efficacy of antidepressants and to improve memory and executive functions in young depressed patients. In conclusion, CORT coordinates via MR the networks underlying how an individual copes with stress, and this action is complemented by the widely distributed lower affinity glucocorticoid receptor (GR) involved in the subsequent management of stress adaptation. In this MR:GR regulation, the MR is an important target for promoting resilience.

The Effect of Dexamethasone on Symptoms of Posttraumatic Stress Disorder and Depression after Cardiac Surgery and Intensive Care Admission : Longitudinal Follow-Up of a Randomized Controlled Trial

Objective:Cardiac surgery and postoperative admission to the ICU may lead to posttraumatic stress disorder and depression. Perioperatively administered corticosteroids potentially alter the risk of development of these psychiatric conditions, by affecting the hypothalamic-pituitary-adrenal axis. However, findings of previous studies are inconsistent. We aimed to assess the effect of a single dose of dexamethasone compared with placebo on symptoms of posttraumatic stress disorder and depression and health-related quality of life after cardiac surgery and ICU admission. Design:Follow-up study of a randomized clinical trial. Setting:Five Dutch heart centers. Patients:Cardiac surgery patients (n = 1,244) who participated in the Dexamethasone for Cardiac Surgery trial. Interventions:A single intraoperative IV dose of dexamethasone or placebo was administered in a randomized, double-blind way. Measurements and Main Results:Symptoms of posttraumatic stress disorder, depression, and health-related quality of life were assessed with validated questionnaires 1.5 years after randomization. Data were available for 1,125 patients (90.4%); of which 561 patients received dexamethasone and 564 patients received placebo. Overall, the prevalence of psychopathology was not influenced by dexamethasone. Posttraumatic stress disorder and depression were present in, respectively, 52 patients (9.3%) and 69 patients (12.3%) who received dexamethasone and in 66 patients (11.7%) and 78 patients (13.8%) who received placebo (posttraumatic stress disorder: odds ratio, 0.82; 95% CI, 0.55–1.20; p = 0.30; depression: odds ratio, 0.92; 95% CI, 0.64–1.31; p = 0.63). Subgroup analysis revealed a lower prevalence of posttraumatic stress disorder (odds ratio, 0.23; 95% CI, 0.07–0.72; p < 0.01) and depression (odds ratio, 0.29; 95% CI, 0.11–0.77; p < 0.01) in female patients after dexamethasone administration. Health-related quality of life did not differ between groups and was not associated with psychopathology. Conclusions:Overall, our findings suggest that exogenous administration of the glucocorticoid receptor agonist dexamethasone—compared with placebo—during cardiac surgery does not positively or negatively affect the prevalence of posttraumatic stress disorder and depression. However, in female patients, beneficial effects on the occurrence of posttraumatic stress disorder and depression may be present.

Long-Term Mental Health Problems After Delirium in the ICU.

Objectives:To determine whether delirium during ICU stay is associated with long-term mental health problems defined as symptoms of anxiety, depression, and posttraumatic stress disorder. Design:Prospective cohort study. Setting:Survey study, 1 year after discharge from a medical-surgical ICU in the Netherlands. Patients:One-year ICU survivors of an ICU admission lasting more than 48 hours, without a neurologic disorder or other condition that would impede delirium assessment during ICU stay. Interventions:None. Measurements and Main Results:One year after discharge, ICU survivors received a survey containing the Hospital Anxiety and Depression Scale with a subscale for symptoms of depression and a subscale for symptoms of anxiety, and the Impact of Event Scale 15 item measuring symptoms of posttraumatic stress disorder. Participants were classified as having experienced no delirium (n = 270; 48%), a single day of delirium (n = 86; 15%), or multiple days of delirium (n = 211; 37%) during ICU stay. Log-binomial regression was used to assess the association between delirium and symptoms of anxiety, depression, and posttraumatic stress disorder. The study population consisted of 567 subjects; of whom 246 subjects (43%) reported symptoms of anxiety (Hospital Anxiety and Depression Scale with a subscale for anxiety, ≥ 8), and 254 (45%) symptoms of depression (Hospital Anxiety and Depression Scale with a subscale for depression, ≥ 8). In 220 patients (39%), the Impact of Event Scale 15 item was greater than or equal to 35, indicating a high probability of posttraumatic stress disorder. There was substantial overlap between these mental health problems—63% of the subjects who scored positive for the presence of any three of the mental health problems, scored positive for all three. No association was observed between either a single day or multiple days of delirium and symptoms of anxiety, depression, or posttraumatic stress disorder. Conclusions:Although symptoms of anxiety, depression, and posttraumatic stress disorder were found to be common 1 year after critical illness, the occurrence of delirium during ICU stay did not increase the risk of these long-term mental health problems.

Individual susceptibility to stress-related psychopathology after cardiac surgery.

Abstracts of the 45th Annual Meeting of the International Society of Psychoneuroendocrinology Stress and the Brain: From Fertility to Senility John McIntyre Conference Centre, Edinburgh, 8th – 10th September 2015

Genetic variation in the glucocorticoid receptor and psychopathology after dexamethasone administration in cardiac surgery patients

The glucocorticoid receptor (GR) agonist dexamethasone is frequently used for its anti-inflammatory properties. We recently showed that a single high-dose of dexamethasone had long-lasting protective effects on the development of psychopathology after cardiac surgery and postoperative intensive care unit stay. In this study, we investigated whether common genetic variation in the hypothalamic-pituitary-adrenal (HPA)-axis would influence the susceptibility for PTSD and depression after dexamethasone administration. Participants (n = 996) of the Dexamethasone for Cardiac Surgery (DECS) randomized clinical trial were followed after receiving a single high intraoperative dose of dexamethasone (1 mg/kg), a GR agonist, or placebo. PTSD and depressive symptoms were assessed up to four years after cardiac surgery. We focused primarily on five common single nucleotide polymorphisms (SNPs) in the glucocorticoid receptor (GR). Secondarily, we comprehensively assessed common genetic variation in the FK506 binding protein (FKBP5) and the mineralocorticoid receptor (MR). The protective effects of dexamethasone on postoperative PTSD symptoms were dependent on the GR polymorphisms rs41423247 (p = .009), rs10052957 (p = .003), and rs6189 (p = .002), but not on rs6195 (p = .025) or rs6198, (p = .026) after Bonferroni correction. No genotype-dependent effects were found for postoperative depressive symptoms. Also, no associations of FKBP5 and MR polymorphisms were found on PTSD and depression outcomes. Protective effects of dexamethasone on PTSD symptoms after cardiac surgery and ICU stay seem to depend on common genetic variation in its target receptor, the GR. These effects indicate that pre-operative genetic screening could potentially help in stratifying patients for their vulnerability for developing PTSD symptoms after surgery.

Relating C-reactive Protein to Psychopathology after Cardiac Surgery and Intensive Care Unit Admission: A Mendelian Randomization Study

Patients admitted to an intensive care unit (ICU) are subjected to a high burden of stress, rendering them prone to develop stress-related psychopathology. Dysregulation of inflammation and, more specifically, upregulation of inflammatory markers such as C-reactive protein (CRP) is potentially key in development of post-ICU psychopathology. To investigate the effects of state-independent CRP on symptoms of post-traumatic stress disorder (PTSD) and depression after ICU admission, we analysed the three leading single nucleotide polymorphisms (SNPs) of loci most strongly associated with blood CRP levels (i.e. rs2794520, rs4420638, and rs1183910) in an ICU survivor cohort. Genetic association was estimated by linear and logistical regression models of individual SNPs and genetic risk score (GRS) profiling. Mendelian Randomization (MR) was used to investigate potential causal relationships. Single-SNP analyses were non-significant for both quantitative and binary trait analyses after correction for multiple testing. In addition, GRS results were non-significant and explained little variance in psychopathology. Moreover, MR analysis did not reveal any causality and MR-Egger regression showed no evidence of pleiotropic effects (p-pleiotropy >0.05). Furthermore, estimation of causality between these loci and other psychiatric disorders was similarly non-significant. In conclusion, by applying a range of statistical models we demonstrate that the strongest plasma CRP-influencing genetic loci are not associated with post-ICU PTSD and depressive symptoms. Our findings add to an expanding body of literature on the absence of associations between trait CRP and neuropsychiatric phenotypes.