The role of glucocorticoid receptor phosphorylation in the model of negative affective states

Objectives. To develop a structural equation model of negative affectivity (NA) that involves interaction of glucocorticoid receptor (GR) signaling, personality dimensions and recent stressful life events. Methods. Seventy participants ? 35 diagnosed with major depression and 35 healthy controls, were enrolled in the study. Morning plasma cortisol levels were determined by chemiluminescent immunometric assays. Molecular parameters (total nuclear and cytoplasmatic GR, nuclear GR phosphorylated at serine 211 (pGR-211) and at serine 226 (pGR-226) and cytoplasmic FKBP51) were analysed from peripheral blood lymphocytes by Western blot. NA, personality dimensions and stressful life events were assessed by self-report instruments. Results. GR signalling parameters had direct independent effect on measures of NA, with pGR-226 levels showing the strongest correlation, followed by FKBP51 and pGR-211 levels. Neuroticism and extraversion also demonstrated strong independent effect on NA, while recent stressful events did not predict NA directly, but demonstrated a significant effect on personality dimensions. Cortisol, total nuclear GR and total cytoplasmatic GR levels were excluded from the model due to non-significant correlations with NA. Conclusions. Negative affectivity is a transdiagnostic factor in vulnerability to affective disorders and possible therapeutic target. Molecular signature of negative affectivity should incorporate GR phosphorylation with other known biological underpinnings.     

Depressogenic vulnerability and gender-specific patterns of neuro-immune dysregulation: What the ratio of cortisol to C-reactive protein can tell us about loss of normal regulatory control

We examined whether the ratio of cortisol (CORT) to high-sensitivity C-reactive protein (hsCRP), an index that captures the integrity of homeostatic regulation between the hypothalamic–pituitary–adrenal (HPA) axis and inflammatory processes, is associated with vulnerability to depression in a gender specific manner and whether glucocorticoid receptor (GR) sensitivity plays a role in these associations. Fasting blood samples were collected between 08:45 and 09:15 and assayed for CORT, hsCRP, and leukocyte count in 213 healthy, medication-free men and women. The NEO-Personality Inventory was used to assess neuroticism, extraversion and anxiety. We used the Hamilton Depression Interview to assess depressive symptoms, the Buss–Perry anger subscale to measure anger, and the Pittsburgh Sleep Quality Index to evaluate subjective sleep quality and its components. Log-transformed CORT/CRP values were analyzed using multiple regression with Holms’ adjusted p-values and age, body mass index (BMI), and race as covariates. GR sensitivity was estimated using the log-transformed ratio of neutrophils (N)-to-monocytes (M). The log-transformed ratio of CORT/CRP did not differ between men and women but was significantly and negatively associated with age and BMI. Severity of depressive symptoms, extraversion, anxiety, and sleep quality were associated with the CORT/CRP ratio in a gender-specific manner. For women, decreasing CORT/CRP ratios, suggestive of an insufficient release of CORT coupled with a heightened inflammatory state, were associated with increasing severity of depressive symptoms, decreasing quality of sleep, increasing frequency of sleep disturbance, and decreasing extraversion. For men, increasing frequency of daytime disturbance and levels of anxiety were associated with increasing CORT/CRP ratio, suggestive of an enhanced release of CORT relative to attenuated levels of hsCRP. For both genders, increasing anger was associated with decreasing CORT/CRP ratios. Although results suggested GR downregulation in women but not men, such differences did not mediate the observed associations. With the use of the CORT/CRP ratio, we showed that vulnerability factors for depression are associated with a loss of normal regulatory controls resulting in gender-specific patterns of neuro-immune dysregulation. That GR downregulation did not influence these associations suggests that the loss of regulatory controls in at risk individuals is primarily at the level of the hormone. Beyond the individual contribution of each component of the CORT/CRP ratio, disruption of normal neuroimmune regulatory feedback provides a plausible biological framework useful in understanding biobehavioral vulnerabilities to depression in a gender specific manner. The CORT/CRP ratio may be a viable biomarker not only for delineating risk for MDD but also progression and treatment responses among patients with MDD; possibilities that are testable in future studies.     

Genetic and environmental sources of covariation between generalized anxiety disorder and neuroticism

OBJECTIVE: The authors examined the sources of covariation between generalized anxiety disorder and the personality trait of neuroticism. Because women have higher levels of neuroticism and twice the risk of lifetime generalized anxiety disorder of men, gender-specific effects were also explored. METHOD: Lifetime generalized anxiety disorder and neuroticism were assessed in more than 8,000 twins from male-male, female-female, and opposite-sex pairs through structured diagnostic interviews. Sex-limited Cholesky structural equation models were used to decompose the correlations between generalized anxiety disorder and neuroticism into genetic and environmental components, including sex-specific factors. RESULTS: Genetic correlations between generalized anxiety disorder and neuroticism were high and differed (nonsignificantly) between men and women (1.00 and 0.58, respectively). When nonsignificant gender differences were removed from the models, correlations between generalized anxiety disorder and neuroticism were estimated at 0.80 (95% confidence interval=0.52-1.00). The individual-specific environmental correlation between generalized anxiety disorder and neuroticism was estimated at 0.20 for both genders. CONCLUSIONS: There is substantial overlap between the genetic factors that influence individual variation in neuroticism and those that increase liability for generalized anxiety disorder, irrespective of gender. The life experiences that increase vulnerability to generalized anxiety disorder, however, have only modest overlap with those that contribute to an individual's level of neuroticism.     

Enhanced early morning salivary cortisol in neuroticism

OBJECTIVE: Neuroticism is a predisposing factor for major depression. The increase in salivary cortisol that follows waking provides a reliable measure of adrenocortical activity, and this response is increased in recovered depressed patients. This study compared waking cortisol levels in healthy subjects with high and low levels of neuroticism without a previous history of depression. METHOD: Salivary cortisol levels were measured upon waking and at 15-minute intervals for the next hour in volunteers selected to have high (>19/23) or low (<4/23) neuroticism based on the Eysenck Personality Inventory. RESULTS: Subjects with high neuroticism showed significantly greater levels of salivary cortisol 30 minutes after waking, which were maintained for the next half hour. CONCLUSIONS: Abnormalities in waking cortisol are associated with neuroticism in a way similar to those seen in major depression. Elevated waking cortisol may represent a vulnerability marker for mood disorder.     

Clinical anxiety,cortisol and interleukin-6: Evidence for specificity in emotion–biology relationships

Anxiety confers increased risk for inflammatory diseases, and elevated inflammatory activity in anxious individuals may contribute to this increased risk. One complication, however, is that anxiety could be associated with inflammatory activity either through a specific anxiety pathway or through a more general negative emotionality pathway. To investigate, we measured levels of the stress hormone cortisol, the pro-inflammatory cytokine interleukin-6 (IL-6), and the systemic inflammatory marker C-reactive protein (CRP), as well as depression and neuroticism, in clinically anxious and non-anxious adults. Compared with non-anxious participants, clinically anxious participants exhibited significantly lower levels of morning cortisol and significantly higher levels of IL-6, independent of age, sex, and depressive symptoms. These group differences were robust when controlling for neuroticism. Conversely, the groups had equivalent levels of CRP in all analyses. Results are indicative of anxiety-specific effects on inflammatory activity, and highlight a pathway by which anxiety may increase risk for inflammatory diseases.     

The interrelationship of neuroticism, sex, and stressful life events in the prediction of episodes of major depression

OBJECTIVE: Three potent risk factors for major depression are female sex, the personality trait of neuroticism, and adversity resulting from exposure to stressful life events. Little is known about how they interrelate in the etiology of depressive illness. METHOD: In over 7,500 individual twins from a population-based sample, the authors used a Cox proportional hazard model to predict onsets of episodes of DSM-III-R major depression in the year before the latest interviews on the basis of previously assessed neuroticism, sex, and adversity during the past year; adversity was operationalized as the long-term contextual threat scored from 15 life event categories. RESULTS: In the best-fit Cox model for prediction of depressive onsets, neuroticism, female sex, and greater adversity all strongly increased risk for major depression. An interaction was seen between neuroticism and adversity such that individuals with high neuroticism were at greater overall risk for major depression and were more sensitive to the depressogenic effects of adversity. An interaction was also seen between adversity and sex, as the excess risk for major depression in women was confined to individuals with low stress exposure. CONCLUSIONS: Psychosocial adversity interacts both with neuroticism and with sex in the etiology of major depression. The impact of neuroticism on illness risk is greater at high than at low levels of adversity, while the effect of sex on probability of onset is the opposite--greater at low than at high levels of stress. Complete etiologic models for major depression should incorporate interactions between risk factor classes.     

Temperament and hypothalamic-pituitary-adrenal axis function in healthy adults

BACKGROUND: Traits such as behavioral inhibition and neuroticism have been linked to the development of mood and anxiety disorders. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, a manifestation of the stress response, is often seen in major depression and has also been demonstrated in animals and humans with inhibited temperaments. A recent study found HPA hyperactivity in adults with high levels of neuroticism. The present study investigated associations of temperament and HPA function in 31 healthy adults. METHODS AND MATERIALS: Subjects completed diagnostic interviews, questionnaires, and the dexamethasone-/corticotropin-releasing hormone (Dex/CRH) test. Temperament was assessed using the Tridimensional Personality Questionnaire (TPQ). RESULTS: Novelty Seeking was inversely related to plasma cortisol concentrations in the Dex/CRH test. Harm Avoidance and Reward Dependence were not significantly associated with cortisol responses in the Dex/CRH test. The results were not accounted for by psychiatric symptoms or a history of stress or childhood maltreatment. CONCLUSIONS: These findings are consistent with previous reports associating temperament factors with HPA axis hyperactivity. Further work is needed to replicate these observations and determine whether HPA axis dysfunction might account for some of the previously reported association of personality factors with mood and anxiety disorders.     

Sex-specific effects of mindfulness on romantic partners’ cortisol responses to conflict and relations with psychological adjustment

Mindfulness is known to improve individuals’ and couples’ subjective stress regulation, but little is known about how it impacts hypothalamic–pituitary–adrenal (HPA) axis responses to acute psychosocial stress. The current study tested effects of dispositional mindfulness facets on young adult couples’ cortisol responses to a conflict discussion stressor, as well as associations with psychological adjustment. One hundred heterosexual couples completed the five facet mindfulness questionnaire one week before engaging in a conflict discussion task. Each partner provided five saliva samples from pre- to post-conflict, which were assayed for cortisol. Measures of adjustment – depression and anxiety symptoms and global well-being – were also completed at this session. Hierarchical linear modeling of cortisol trajectories revealed sex-specific effects; whereas women's mindfulness (nonreactivity facet) predicted higher conflict stress cortisol levels, men's mindfulness (describing facet) predicted less pronounced cortisol reactivity/recovery curves. These patterns were related to better adjustment—lower depression symptoms for women and greater well-being for men. Implications for sex differences in mindfulness benefits are discussed.     

Polymorphisms in the FKBP5 gene region modulate recovery from psychosocial stress in healthy controls

Mood and anxiety disorders are considered stress-related diseases characterized by an impaired function of mineralocorticoid and glucocorticoid receptors (MR and GR, respectively), the major regulatory elements of the hypothalamus–pituitary–adrenocortical (HPA) axis. A number of so-called chaperone proteins moderate the function of these receptors. Genetic variations in one of these chaperones, FKBP5, were associated with antidepressant treatment response in depression and with a major risk-factor for the development of posttraumatic stress disorder. To further investigate the effect of FKPB5 polymorphisms on corticosteroid receptor-mediated HPA axis regulation we conducted the Trier Social Stress test, a standardized procedure to evaluate psychosocial stress response, in 64 healthy volunteers. We genotyped rs4713916, rs1360780 and rs3800737, the three single nucleotide polymorphisms (SNPs) in the FKBP5 region which had shown the strongest effect in previous studies. In addition, we evaluated the effects of the GR polymorphisms Bcl1 and N363S as well as the MR polymorphism I180V. Subjects homozygous for any of the FKBP5 variants displayed an incomplete normalization of the stress-elicited cortisol secretion. This was also observed following a second test additionally accompanied by an increased self-reported anxiety. Regarding GR and MR, only carriers of the Bcl1 variant displayed an altered cortisol response in the prognosticated direction. While Bcl1 was predominantly associated with anticipatory cortisol, homozygous carriers of the FKBP5 minor allele showed insufficient cortisol recovery and increased self-reported anxiety after psychosocial stress. This reaction pattern suggests that subjects carrying these variants are at risk of displaying chronically elevated cortisol levels after repeated stress constituting a risk factor for stress-related diseases.     

A common and functional mineralocorticoid receptor haplotype enhances optimism and protects against depression in females

Mineralocorticoid (MR) and glucocorticoid receptors (GR) are abundantly expressed in the limbic brain and mediate cortisol effects on the stress-response and behavioral adaptation. Dysregulation of the stress response impairs adaptation and is a risk factor for depression, which is twice as abundant in women than in men. Because of the importance of MR for appraisal processes underlying the initial phase of the stress response we investigated whether specific MR haplotypes were associated with personality traits that predict the risk of depression. We discovered a common gene variant (haplotype 2, frequency ∼0.38) resulting in enhanced MR activity. Haplotype 2 was associated with heightened dispositional optimism in study 1 and with less hopelessness and rumination in study 2. Using data from a large genome-wide association study we then established that haplotype 2 was associated with a lower risk of depression. Interestingly, all effects were restricted to women. We propose that common functional MR haplotypes are important determinants of inter-individual variability in resilience to depression in women by differentially mediating cortisol effects on the stress system.