Cortisol Awakening Reaction and Anxiety in Depressed Coronary Artery Disease Patients

Disturbances of HPA axis functioning as represented by cortisol awakening reaction (CAR) belong to the mediating pathways linking psychosocial distress and cardiovascular risk. Both depression and anxiety have been confirmed as independent risk factors for coronary artery disease (CAD). However, data on anxiety and cortisol output in CAD patients are scarce. Based on previous data, we hypothesized that anxiety would be associated with higher cortisol output and a more pronounced morning increase in moderately depressed CAD patients. 77 patients (60 y, 79% male) underwent saliva sampling (+0, +30, +45, +60 min after awakening, midday and late-night sample). Anxiety was measured using the Hospital Anxiety and Depression Scale (HADS) and patients were grouped into anxious versus non anxious subjects based upon the recommended score (≥11). A repeated measures ANOVA yielded a significant time and quadratic time effect referring to the typical CAR. Anxious patients showed a significantly steeper 30 min increase, higher AUCi, lower waking and late-night cortisol levels. The steeper cortisol increase in the anxious group is in line with previous data and may be interpreted as a biological substrate of affect regulation. The lower basal and late-night levels coupled with greater AUCi mirror a more dynamic reactivity pattern compared to depressed subjects without anxiety.

Loneliness Mediates the Relationship Between Early Life Stress and Perceived Stress but not Hypothalamic–Pituitary–Adrenal Axis Functioning

Many authors have proposed that early life stress (ELS) provokes a dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis and contributes negatively to the management of stress in adulthood. However, these associations have not always been observed, making it necessary to include new factors that could explain the different results found. In this regard, people with ELS experiences report less social support during adulthood, suggesting that loneliness could be a mediating factor. Thus, our aims were to investigate whether ELS was related to both perceived stress and diurnal HPA axis activity, and whether loneliness mediates these relationships, in a community sample (N=187, 18–55years old). Fourteen cortisol samples were collected on two non-consecutive days to obtain the overall diurnal cortisol, diurnal cortisol slope, and bedtime levels. Additionally, ELS was assessed with the Risky Families Questionnaire (RFQ) and the Recalled Childhood and Adolescence Perceived Stress (ReCAPS) measure. Results revealed that ELS was associated with perceived stress, but not HPA axis functioning, and loneliness mediated the relationship between ELS and perceived stress, but not between ELS and HPA axis functioning. Similar results were found for both ELS questionnaires, suggesting that the ReCAPS is an adequate tool. These results highlight the importance of loneliness in understanding the long-term effects of ELS, and they indicate different effects of ELS on subjective and physiological stress indicators.

Childhood maltreatment disrupts HPA-axis activity under basal and stress conditions in a dose–response relationship in children and adolescents

Background This study investigates the impact of childhood maltreatment (CM) on hypothalamic–pituitary–adrenal (HPA)-axis functioning and on anxiety perception. Moreover, the influence of CM severity and frequency was also explored. Methods In total, 187 participants aged 7–17 were assessed for CM history using validated questionnaires and ad hoc interviews to be classified according to the criteria of the Tool for Assessing the Severity of Situations in which Children are Vulnerable (TASSCV). Psychopathology was ascertained using the K-SADS-PL5. To assess HPA-axis functioning, salivary cortisol samples were collected throughout a normal day and during an acute psychosocial stressor, the Trier Social Stress Test for children (TSST-C). Subjective anxiety was evaluated using STAI/-C. Results Youth with a CM history had higher overall diurnal cortisol levels (p = 0.001), blunted cortisol response to acute psychosocial stress (p = 0.002) and greater perceived anxiety (p = 0.003), than those without CM. Specifically, participants exposed to moderate/severe or often/frequent CM showed the greater diurnal cortisol output (pseverity = 0.002; pfrequency = 0.003), and blunted cortisol response during the TSST-C (pseverity = 0.006; pfrequency = 0.008). Meanwhile, youth with low CM severity/frequency exhibited a similar cortisol response to those without CM. However, perceived anxiety was higher in those exposed to CM (p < 0.001), regardless of its severity/frequency. Conclusions Disturbances in HPA-axis functioning are already evident early after CM exposure, while psychological and physiological responses to an acute stressor are dissociated in youth exposed to CM. The dose–response relationship described in this paper highlights the need to comprehensively evaluate CM so that vulnerable children can be identified and assigned to proper interventions.

Impact of Fkbp5 × Early Life Adversity × Sex in Humanized Mice on Multidimensional Stress Responses and Circadian Rhythmicity

The cumulative load of genetic predisposition, early life adversity (ELA) and lifestyle shapes the prevalence of psychiatric disorders. Single nucleotide polymorphisms (SNPs) in the human FKBP5 gene were shown to modulate disease risk. To enable investigation of disease-related SNPs in behaviorally relevant context, we generated humanized mouse lines carrying either the risk (AT) or the resiliency (CG) allele of the rs1360780 locus and exposed litters of these mice to maternal separation. Behavioral and physiological aspects of their adult stress responsiveness displayed interactions of genotype, early life condition and sex. In humanized females carrying the CG- but not the AT-allele, ELA led to altered HPA-axis functioning, exploratory behavior and sociability. These changes correlated with differential expression of genes in the hypothalamus, where synaptic transmission, metabolism, and circadian entrainment pathways were deregulated. Our data suggest an integrative role of FKBP5 in shaping the sex-specific outcome of ELA in adulthood.

Maternal precarity and HPA axis functioning shape infant gut microbiota and HPA axis development in humans

Background Early life exposure to adverse environments, and maternal stress in particular, has been shown to increase risk for metabolic diseases and neurobehavioral disorders. While many studies have examined the hypothalamic-pituitary-adrenal axis (HPA axis) as the primary mechanism behind these relationships, emerging research on the brain-gut axis suggests that the microbiome may play a role. In this study, we tested the relationships among maternal precarity and HPA axis dysregulation during the peripartum period, infant gut microbiome composition, and infant HPA axis functioning. Methods Data come from 25 mother-infant dyads in the Galápagos, Ecuador. Women completed surveys on precarity measures (food insecurity, low social support, depression, and stress) and gave salivary cortisol samples during and after pregnancy. Infant salivary cortisol and stool were collected in the postpartum. Statistical significance of differences in microbial diversity and relative abundance were assessed with respect to adjusted linear regression models. Results Maternal precarity was associated with lower diversity and higher relative abundance of Enterobacteriaceae and Streptococcaceae and a lower relative abundance of Bifidobacterium and Lachnospiraceae. These patterns of colonization for Enterobacteriaceae and Bifidobacterium mirrored those found in infants with HPA axis dysregulation. Maternal HPA axis dysregulation during pregnancy was also associated with a greater relative abundance of Veillonella. Conclusions Overall, exposures to precarity and HPA axis dysregulation were associated with an increase in groups that include potentially pathogenic bacteria, including Enterobacteriaceae, Streptococcaceae, and Veillonella, and a decrease in potentially protective bacteria, including Bifidobacterium and Lachnospiraceae, as well as a decrease in overall diversity.

Diurnal cortisol profiles and exposure to stress in adolescents and young adults with 22q11.2 deletion syndrome

Background 22q11.2 deletion syndrome (22q11DS) is a neurogenetic condition associated to a high risk for psychiatric disorders, including psychosis. Individuals with 22q11DS are thought to experience increased levels of chronic stress, which could lead to alterations in hypothalamic-pituitary-adrenocortical (HPA)-axis functioning. In the current study, we investigated for the first time diurnal salivary cortisol profiles in adolescents and young adults with 22q11DS as well as their link with stress exposure, coping strategies and psychopathology, including psychotic symptoms. Methods Salivary cortisol was collected from adolescents and young adults with 22q11DS (n = 30, age = 19.7) and matched healthy controls (HC; n = 36, age = 18.5) six times a day for two days. Exposure to stressful life events, including peer victimization, coping strategies and general psychopathology were assessed with questionnaires. Psychotic symptoms were evaluated with a clinical interview.Results We observed similar daily levels and diurnal profiles of salivary cortisol in adolescents and young adults with 22q11DS compared to HCs. However, participants with 22q11DS reported less frequent exposure to stress than HCs. In 22q11DS, we observed a significant association between the use of non-adaptive coping strategies and the severity of positive psychotic symptoms. Cortisol level was not associated to severity of psychotic symptoms, but elevated cortisol awakening response (CAR) was found in participants with 22q11DS with higher levels of general psychopathology. Conclusions Our results do not support earlier propositions of altered HPA-axis functioning in 22q11DS but highlight the need to further investigate diurnal cortisol as an indicator of HPA-axis functioning and its link with (earlier) stress exposure and psychopathology in this population. Interventions should target the development of adaptive coping skills in preventing psychosis in 22q11DS.

Adverse Childhood Experiences and Implications of Perceived Stress, Anxiety, and Cortisol Among Women in Pakistan

Background: Adverse Childhood Experiences (ACEs) are linked to poor maternal mental health. By disrupting stress regulation systems, ACEs are hypothesized to impact perceived stress, anxiety, and cortisol. This study explores the associations of ACEs with different manifestations of stress. Methods: Participants were part of the Bachpan study, a longitudinal birth cohort in rural Pakistan. Data were collected at the 36-month postpartum wave. ACEs were captured retrospectively using an adapted version of the ACE International Questionaire, and represented in the following ways: as a continuous variable, binary indicator, categoric levels, and subdomains (neglect, home violence, family psychological distress, community violence). Outcomes included: perceived stress (N=889) measured with the Cohen Perceived Stress Scale (PSS), anxiety (N=623) measured with the Generalized Anixety Disorder-7 scale (GAD-7), and hair-derived cortisol (N=90). Multivariable linear mixed models estimated associations between ACEs and the outcome variables. Results: All models featured positive associations between ACE items and PSS. Both the continuous total ACE score (B=0.4; 95% CI=0.0, 0.8) and the presence of any ACEs (B=1.0; 95% CI=-1.0, 0.3) were associated with higher anxiety symptoms on the GAD-7. Home violence (B=6.7; 95% CI=2.7, 10.8) and community violence (B=7.5; 95% CI=1.4,13.6) were associated with increased hair cortisol. Conclusions: All four ACE domains were associated with elevated levels of perceived stress, anxiety, and cortisol, with varying precision and strength of estimates, indicating that the type of ACE has a differential impact. This study disentangled adversity to understand the impact of specific adverse events on hypothalamic pituitary adrenal (HPA) axis functioning and mental health conditions.

Bereavement and Physiological Dysregulations in African American Adults

This study uses data from National Survey of Midlife in the U.S. (MIDUS) to examine the effect of bereavement on physiological dysregulations in African American adults, with moderating effects of gender. Models were estimated using data from 210 Non-Hispanic African American respondents who participated in MIDUS 2 (M2: 2004-2005) and the biomarker data collection (2004-2009). We analyzed data from two groups, respondents who experienced the death of an individual(s) close to them, either family or friends (97 women, 40 men) and respondents who did not experience any deaths of close individuals during the same period (46 women, 27 men), controlling for age, education, marital status, prior family bereavement, number of negative life events since M2, and physical health prior to bereavement. Physiological dysregulations were assessed for 7 systems: HPA axis, glucose metabolism, lipids metabolism, sympathetic system, parasympathetic system, inflammation, and cardiovascular functioning. The results show that African American men and women who experienced bereavement were at higher risk of dysregulation of glucose metabolism (assessed by HbA1c, HOMA-IR, and fasting glucose) than the non-bereaved, even after adjusting prior diabetes diagnosis. In addition, African American women (but not men) who experienced recent bereavement were at higher risk of dysregulation of HPA axis functioning (assessed by urinary cortisol and blood DHEA-S) than their counterparts. The other physiological systems were not significantly associated with bereavement experience in African American adults. The findings suggest that bereavement has adverse impacts on health in African American adults via dysregulations in glucose metabolism and HPA axis functioning.