Salivary Cortisol Awakening Response as a Predictor for Depression Severity in Adult Patients with a Major Depressive Episode Performing a Daily Exercise Program

<b><i>Introduction:</i></b> The hypothalamic-pituitary-adrenal axis function in depression has been the subject of considerable interest, and its function has been tested with a variety of methods. We investigated associations between saliva cortisol at awakening and the 24-h urine cortisol output, both measured at study baseline, with endpoint depression scores. <b><i>Methods:</i></b> Patients were admitted to a psychiatric inpatient ward with a major depressive episode and were started on fixed duloxetine treatment. They delivered saliva samples at awakening and 15, 30, and 60 min post-awakening and sampled urine for 24 h. Subsequently, they started a daily exercise program maintained for a 9-week period. Clinician-rated depression severity was blindly assessed with the Hamilton Depression Rating 6-item subscale (HAM-D₆). The cortisol awakening response was quantified by the area under the curve with respect to the ground (AUC_G) and with respect to the rise (AUC_I) using saliva cortisol levels in the 1-h period after awakening. Analysis of expected associations between depression severity, AUC_G, AUC_I, exercise, and 24-h cortisol output was performed in a general linear model. <b><i>Results:</i></b> In all, 35 participants delivered saliva or 24-h urine samples. The mean age was 49.0 years (SD = 11.0) with 48.6% females with a mean baseline HAM-D₆ score of 12.2 (SD = 2.3). In a statistical model investigating the association between HAM-D₆ at week 9 as a dependent variable and AUC_I, concurrent HAM-D₆, gender, smoking, and exercise volume as covariates, we found a significant effect of AUC_I, concurrent HAM-D₆, and exercise. The following statistics were found: AUC_I (regression coefficient 0.008; <i>F</i> value = 9.1; <i>p</i> = 0.007), concurrent HAM-D₆ (regression coefficient 0.70; <i>F</i> value = 8.0; <i>p</i> = 0.01), and exercise (regression coefficient −0.005; <i>F</i> value = 5.7; <i>p</i> = 0.03). The model had an <i>R</i>² of 0.43. The association between HAM-D₆ endpoint scores and the AUC_I showed that higher AUC_I values predicted higher HAM-D₆ endpoint values. The association between HAM-D₆ endpoint scores and the exercise level showed that a high exercise level was associated with lower HAM-D₆ endpoint values. <b><i>Conclusion:</i></b> The results thus showed that high AUC_I values predicted less improvement of depression and high exercise levels predicted more improvement of depression. These findings need to be confirmed in larger samples to test if more covariates can improve prediction of depression severity.

Steroid Hormone Secretion Over the Course of the Perimenopause: Findings From the Swiss Perimenopause Study

Background: Perimenopause is characterized by a decline in the steroid hormones, estradiol, and progesterone. By contrast, the steroid hormone cortisol, a marker of the hypothalamic–pituitary–adrenal (HPA) axis, increases. Recent longitudinal studies reported fluctuations in steroid hormone levels during perimenopause, and even increases in estradiol levels. To understand these confounding results, it is necessary to conduct a longitudinal, highly standardized assessment of steroid hormone secretion patterns in perimenopausal women.Methods: This longitudinal study investigated 127 perimenopausal women aged 40–56 years for 13 months. Estradiol, progesterone, and cortisol were assessed using saliva samples, which were collected for two (during months 2 and 12 for estradiol and progesterone) or three (during months 2, 7, and 12 for cortisol) non-consecutive months over the course of the study. A total of 14 saliva samples per participant were analyzed to investigate the courses of estradiol and progesterone. Cortisol awakening response and fluctuations of cortisol throughout the day were measured using a total of 11 saliva samples per participant (on awakening, +30 min, +60 min, at 12:00 p.m., and before going to bed) for months 2, 7, and 12.Results: Multilevel analyses revealed variance in intercept and slope across participants for estradiol [intercept: SD = 5.16 (95% CI: 4.28, 6.21), slope: SD = 0.50 (95% CI: 0.39, 0.64)], progesterone [intercept: SD = 34.77 (95% CI: 25.55, 47.31), slope: SD = 4.17 (95% CI: 2.91, 5.99)], and cortisol (intercept: SD = 0.18 (95% CI: 0.14, 0.23), slope: SD = 0.02 (95% CI: 0.01, 0.02)]. Time predicted cortisol levels [b = −0.02, t(979) = −6.63, p &lt; 0.0001]. Perimenopausal status (early vs. late) did not predict estradiol [b = −0.36, t(1608) = −0.84, p = 0.400], progesterone [b = −4.55, t(1723) = −0.87, p = 0.385], or cortisol [b = 0.01, t(1124) = 0.61, p = 0.542] scores over time.Discussion: Our results are consistent with previous findings emphasizing highly individual fluctuations of estradiol and progesterone levels during perimenopause. However, our findings do not suggest a continuous decline during the observed transition phase, implying relatively stable periods of fluctuating hormone levels. Furthermore, given the lack of significant group differences, it may not be necessary to differentiate between early and late perimenopause from the standpoint of hormonal progression.

Salivary Cortisol Patterns in People Living With Dementia

Salivary cortisol has a well-documented circadian pattern in older adults. Yet, the pattern of salivary cortisol in persons living with dementia (PLWD) due to circadian rhythm disturbances is unknown. This study examined diurnal salivary cortisol patterns in 176 PLWD (mean age 73.6±8.8, 33.3% male, clinical dementia rating &gt;=0.5) by collecting saliva at waking (AM1), 30 minutes after waking (AM2) and bedtime (PM) over two consecutive days. Cortisol awakening response (CAR) was calculated as the change between AM2 and AM1 cortisol levels. The mean baseline salivary cortisol levels (ug/dl) were 0.35 (SD:0.3) at AM1, 0.40 (SD:0.39) at AM2, and 0.19 (SD:0.4) at PM. On average, cortisol levels decreased from morning to evening, with 58% exhibiting a positive CAR (mean 0.05; SD:0.34). There were no significant associations between cortisol levels with age, sex, obesity, and comorbidities. The findings demonstrated that diurnal cortisol rhythms are maintained in PLWD with a flattened CAR.

Experiences of adversity in childhood and adolescence and cortisol in late adolescence

Early life adversity influences the diurnal cortisol rhythm, yet the relative influence of different characteristics of adversity remains unknown. In this study, we examine how developmental timing (childhood vs. adolescence), severity (major vs. minor), and domain of early life adversity relate to diurnal cortisol rhythms in late adolescence. We assessed adversity retrospectively in early adulthood in a subsample of 236 participants from a longitudinal study of a diverse community sample of suburban adolescents oversampled for high neuroticism. We used multilevel modeling to assess associations between our adversity measures and the diurnal cortisol rhythm (waking and bedtime cortisol, awakening response, slope, and average cortisol). Major childhood adversities were associated with flatter daily slope, and minor adolescent adversities were associated with greater average daily cortisol. Examining domains of childhood adversities, major neglect and sexual abuse were associated with flatter slope and lower waking cortisol, with sexual abuse also associated with higher cortisol awakening response. Major physical abuse was associated with higher waking cortisol. Among adolescent adversities domains, minor neglect, emotional abuse, and witnessing violence were associated with greater average cortisol. These results suggest severity, developmental timing, and domain of adversity influence the association of early life adversity with stress response system functioning.

Stress-Hormone Dynamics and Working Memory in Healthy Women Who Use Oral Contraceptives Versus Non-Users

BackgroundWomen who use oral contraceptives (OCs) may have a higher risk of developing a depression, which is associated with both vulnerability to stress and cognitive dysfunction. OCs disrupt the hypothalamic-pituitary-gonadal (HPG) axis by suppressing endogenous sex steroid production including estradiol. The HPG axis and the hypothalamic-pituitary-adrenal (HPA) axis are known to interact, possibly through modulations driven by estradiol. OCs may affect HPA regulation capacity, i.e., disturb cortisol dynamics such as the cortisol awakening response (CAR), and influence cognition such as working memory (WM). We hypothesize that OC use is associated with blunted cortisol dynamics and impaired WM performance relative to non-users.MethodsData from 78 healthy women in the reproductive age were available from the CIMBI database. We evaluated if CAR and WM differed between OC users (n=25) and non-users (n=53) and if the level of estradiol modulated the OC use effect on CAR or WM in generalized least square models.ResultsWe found that OC users had a blunted CAR (p= 0.006) corresponding to a 61% reduction relative to non-users; however, no estradiol-BY-OC use interaction effect was observed on CAR. Also, OC users had higher cortisol levels at awakening compared to non-users (p = 0.03). We observed no effect of OC use or an estradiol-BY-OC use interaction effect on WM. Also, within the OC user group, neither CAR nor WM was associated with suppressed estradiol. CAR was not associated with WM.ConclusionHealthy women who use OCs have blunted cortisol dynamics relative to non-users. However, we could not detect OC use effects on working memory in our sample size. We speculate that disrupted cortisol dynamics may be important for the emergence of depressive symptoms in OC users.

Adult Attachment Avoidance is Associated with Cortisol Awakening Response among Young Black Sexual Minority Men as Compared to Young White Sexual Minority Men

Research suggests that young sexual minority men (YSMM), particularly YSMM of color, are more likely to have dysregulated physiological stress responses as compared to their heterosexual counterparts. In addition, the quality of social relationships has been demonstrated to impact physiological stress patterns among young adults. One key indicator of social relationships is that of adult attachment, which refers to the types of socioemotional bonds that individuals form with peers, family, and romantic partners. However, the association between adult attachment and physiological stress functioning among diverse samples of YSMM has been underexplored. Thus, the current study sought to bridge this gap in the literature by exploring how race/ethnicity moderates the association between adult attachment and physiological stress patterns among Black versus White YSMM. N = 63 YSMM participated in a 5-day daily diary study in which they completed a baseline survey and provided saliva samples over the 5-day period in order to measure diurnal cortisol. Three-level hierarchical linear modeling was used in order to examine the association between race/ethnicity, adult attachment, and diurnal cortisol over the 5-day period. Results suggest that adult attachment avoidance was associated the cortisol awakening response (CAR) among YSMM. In addition, race/ethnicity moderated the association between adult attachment avoidance and the CAR such that YSMM who identified as Black had evidence of a more dysregulated physiological stress response as compared to YSMM who identified as White. Future research should focus on further unpacking the drivers of physiological stress patterns among White and Black YSMM.

A novel bedtime pulsatile-release caffeine formula ameliorates sleep inertia symptoms immediately upon awakening

Sleep inertia is a disabling state of grogginess and impaired vigilance immediately upon awakening. The adenosine receptor antagonist, caffeine, is widely used to reduce sleep inertia symptoms, yet the initial, most severe impairments are hardly alleviated by post-awakening caffeine intake. To ameliorate this disabling state more potently, we developed an innovative, delayed, pulsatile-release caffeine formulation targeting an efficacious dose briefly before planned awakening. We comprehensively tested this formulation in two separate studies. First, we established the in vivo caffeine release profile in 10 young men. Subsequently, we investigated in placebo-controlled, double-blind, cross-over fashion the formulation’s ability to improve sleep inertia in 22 sleep-restricted volunteers. Following oral administration of 160 mg caffeine at 22:30, we kept volunteers awake until 03:00, to increase sleep inertia symptoms upon scheduled awakening at 07:00. Immediately upon awakening, we quantified subjective state, psychomotor vigilance, cognitive performance, and followed the evolution of the cortisol awakening response. We also recorded standard polysomnography during nocturnal sleep and a 1-h nap opportunity at 08:00. Compared to placebo, the engineered caffeine formula accelerated the reaction time on the psychomotor vigilance task, increased positive and reduced negative affect scores, improved sleep inertia ratings, prolonged the cortisol awakening response, and delayed nap sleep latency one hour after scheduled awakening. Based on these findings, we conclude that this novel, pulsatile-release caffeine formulation facilitates the sleep-to-wake transition in sleep-restricted healthy adults. We propose that individuals suffering from disabling sleep inertia may benefit from this innovative approach.Trials registration: NCT04975360.

Dynamic behavior of cell-free mitochondrial DNA in human saliva

Mitochondria release their genome as cell-free mitochondrial DNA (cf-mtDNA) in multiple biofluids including in the blood, where it predicts mortality and is a marker of mental and physical stress. Here we report cf-mtDNA in human saliva, an accessible biofluid used to study dynamic neuroendocrine changes. To map the natural dynamics of salivary cf-mtDNA over time, we examine cf-mtDNA and steroid hormones in a small cohort of healthy adults, and perform an intensive repeated-measures analysis of two healthy men studied at 4 daily timepoints over 53-60 consecutive days (n=412-420 observations). Salivary cf-mtDNA exhibits a robust awakening response reaching up to two orders of magnitude 30-45 minutes after awakening, varies from day-to-day, and moderately correlates with the cortisol awakening response. Moreover, we find no evidence that salivary cf-mtDNA has pro-inflammatory effects. The dynamic behavior of salivary cf-mtDNA opens the door to non-invasive studies examining the relevance of mtDNA signaling on human health.