The cortisol awakening response in patients remitted from depression

An impressive number of data has been accumulated on dysfunctions of the hypothalamo-pituitary–adrenal (HPA) axis and cortisol hypersecretion in depression. To assess the dynamic HPA functioning, the cortisol awakening response (CAR) is an easily accessible and reliable approach. Some data suggest that elevated CAR in depressed patients has trait-like characteristics. Therefore we investigated whether patients in remission from a depressive episode have elevated CAR compared to control subjects. CAR of thirty-eight patients in remission from depression (11 men, 27 women, age range 24–66) and 52 control participants were analyzed (18 men, 34 women, age range 24–63). All patients had experienced ≥3 previous depressive episodes and were off psychotropic medication since at least 3 months. Saliva samples were collected only once, at home, either on weekend or weekday at 0, 15, 30, 45 and 60 min post-awakening.The area under the curve (AUC) above minimum cortisol concentration displayed large interindividual variability (6.4-fold in remitted patients and 8.1-fold in controls, based on 80% range). Investigation of possible variability factors showed that percent explained variance increased from 3.9% when group was considered alone to 8.8%, 12.3% and 19.2% after adjusting for significant effects of weekday vs. weekend, wake-up time and sleep duration, respectively. According to the latter model, AUC was estimated to be 51% higher in remitted patients than in controls (p = 0.007), while a 21% AUC decrease was associated with a 1-h longer sleep duration (p < 0.001). In future studies, detection of between-group differences might benefit from adjusting for sleep duration and other possible confounders.     

The cortisol awakening response: a pilot study on the effects of shift work, morningness and sleep duration

This study concerned the possible influence of experimental shift work, morningness and sleep length on the cortisol awakening response (CAR). Eight morning-oriented (MT) and eight evening-oriented (ET) healthy young men (19-27 years) slept after three consecutive day shifts during the night and after three consecutive night shifts during the day in the laboratory. Salivary cortisol concentrations were ascertained after each sleep period upon awakening and half an hour later, half-hourly during work shifts, and hourly during two 24-h periods, after the three day shift/night sleep sequences and after the three night shift/day sleep sequences. Statistical analyses considered the temporal position of sleep (night, day), the succession of sleep periods, the diurnal type and the polysomnographically verified total sleep time. The CAR was significantly smaller after day than after night sleep and increased significantly with total sleep time in ET. MT had moderately higher cortisol concentrations upon awakening than ET probably because they wake up at a later time of their circadian rhythm. But neither the CARs nor the cortisol concentrations during the following work shifts or during the 24h profiles were different in both diurnal types. The cortisol concentrations during work shifts correlated significantly with the previous post-awakening concentrations in MT but not in ET. Due to the small samples further studies are needed.     

The cortisol awakening response: More than a measure of HPA axis function

In most healthy people morning awakening is associated with a burst of cortisol secretion: the cortisol awakening response (CAR). It is argued that the CAR is subject to a range physiological regulatory influences that facilitate this rapid increase in cortisol secretion. Evidence is presented for reduced adrenal sensitivity to rising levels of ACTH in the pre-awakening period, mediated by an extra-pituitary pathway to the adrenal from the suprachiasmatic nucleus (SCN). A role for the hippocampus in this pre-awakening regulation of cortisol secretion is considered. Attainment of consciousness is associated with ‘flip-flop’ switching of regional brain activation, which, it is argued, initiates a combination of processes: (1) activation of the hypothalamic pituitary adrenal (HPA) axis; (2) release of pre-awakening reduced adrenal sensitivity to ACTH; (3) increased post-awakening adrenal sensitivity to ACTH in response to light, mediated by a SCN extra-pituitary pathway. An association between the CAR and the ending of sleep inertia is discussed.     

The cortisol awakening response in relation to objective and subjective measures of waking in the morning

Studies of the salivary cortisol awakening response (CAR) may be confounded by delays between waking in the morning and obtaining the 'waking' salivary sample. We used wrist actigraphy to provide objective information about waking time, and studied the influence of delays in taking the waking sample on the CAR. Eighty-three men and women (mean age 61.30 years) who were referred to hospital with suspected coronary artery disease were studied. Saliva samples were obtained on waking and 15 and 30 min later. The mean interval between waking defined by actigraphy and reported waking time was 6.12+/-(S.D.) 14.8 min, with 55.4% having no delay. The waking saliva sample was obtained an average 5.78+/-15.0 min after self-reported waking, and 12.24+/-20.3 min after objective waking. The waking cortisol value was significantly higher in participants who had a delay between waking and sampling >15 min (mean 14.46+/-6.34 nmol/l) than in those with zero (mean 10.45+/-6.41 nmol/l) or 1-15 min delays (mean 11.51+/-5.99 nmol/l, p=0.043). Cortisol did not increase between 15 and 30 min after waking in those who delayed >15 min. There were no differences in CAR between participants with zero and 1-15 min delays from objectively defined waking to reported sample times. A small proportion (14.7%) of participants who did not delay saliva sampling showed no increase in cortisol over the 30 min after waking. These CAR nonresponders did not differ from the remainder on sleep patterns, waking time, clinical or medication characteristics, but were more likely to be of higher socioeconomic status (p=0.009). We conclude that long delays between waking and obtaining 'waking' cortisol samples will lead to misleading CAR results, but that delays up to 15 min may not be problematic. A small minority of individuals do not show a positive CAR despite not delaying saliva sampling after waking.     

Naturalistic stress and cortisol response to awakening: adaptation to seafaring

Study of the hypothalamic-pituitary adrenal (HPA) axis has been critical to advancing our understanding of human adaptation to stress. The cortisol response to awakening (CRA) is a potentially useful measure for understanding group and individual differences in HPA axis regulation. In this study, the CRA was examined in the context of a naturalistic stressor--a 6-week voyage of work and study aboard an oceangoing ship, including both experienced and novice sailors. Thirty-one subjects provided weekday and weekend baseline CRA data onshore prior to boarding, followed by three CRAs at sea and one shore leave CRA. Subjective measures of sleep, stress and control were also collected. Results suggest that novice sailors' cortisol response to awakening was elevated at sea relative to both a shoreside weekend and a shore leave during the voyage, but the most striking elevation was found during a workday onshore. Inexperienced students' profiles changed differently over the course of the voyage from those of professional crew. CRAs were not affected by sleep variables and were not predicted by subjective ratings. These data support the value of the cortisol response to awakening as a neuroendocrine marker of HPA regulatory responses to a naturalistic stressor, influenced by changes in work and living environment, and perhaps prior experience with the stressor.     

The association of the cortisol awakening response with experimental pain ratings

Cortisol is a key stress hormone that is implicated in a variety of physiological responses. Attenuated Cortisol Awakening Response (CAR) is associated with many negative health outcomes, but little research has investigated CAR and pain. The current study examines the association of CAR with experimental acute-pain ratings in healthy men and women. Attenuated CAR was related to greater pain intensity and unpleasantness ratings. Future research should examine this association across various pain populations.     

Decreased cortisol response to awakening is associated with cognitive vulnerability to depression in a nonclinical sample of young adults

Due to its high intraindividual stability, the cortisol awakening response (CAR) may be regarded as a trait measure of the dynamics of the HPA-axis activity. The present study aimed at investigating associations of the CAR with rumination as a cognitive vulnerability marker for depression assessed by both a trait measure and by experimental manipulation. After induction of sad mood by viewing a sad sequence of a movie, 42 healthy university students were randomly induced to either ruminatively self-focus on their feelings or to distract themselves from their mood by concentrating on respective text cards for 8min. Trait rumination and distraction were measured by the Response Styles Questionnaire (RSQ) at baseline (T0), while current mood was recorded before (T1) and after (T2) the mood induction as well as after the rumination/distraction induction (T3) using the Positive and Negative Affect Schedule (PANAS). Basal saliva cortisol levels were measured independently on a different day. After mood induction, levels of mood were lowered significantly. Participants subsequently induced to ruminate kept their negative mood whereas participants induced to distract themselves showed a reduction in negative mood. Self-focused trait rumination amplified low mood in both induction conditions. A decreased CAR was associated with self-focused rumination and with less improvement of sad mood after induced distraction. We conclude that the two variables apparently share specific vulnerability qualities towards depression by hampering the adaptive shift of attention to external cues during dysphoric moods, probably involving lowered disinhibition of task-irrelevant negative emotional processing. The present study provided first indications of a possible relationship between a cognitive vulnerability marker for depression and characteristics of basal neuroendocrine activity regarding their association with the course of experimentally induced dysphoric mood.     

Trait and state perseverative cognition and the cortisol awakening response

Perseverative cognition (i.e., rumination, worry) may amplify or maintain cortisol stress responses. The present study examined the effects of trait and state perseverative cognition (PC) on the cortisol awakening response (CAR). We hypothesized that trait PC and state (prior day's) PC would be associated with greater CARs. Undergraduates scoring high (N=77) and low (N=42) on trait PC were included. Participants reported worries about upcoming events and ruminations on past events that occurred throughout the day as a measure of state PC. The next morning, saliva samples were collected 0, 30, 45, and 60min after awakening to assess the CAR. Area under the curve (AUC) and 30-min increase (30-min Inc) were calculated to capture the salivary cortisol total output and increase relative to baseline in the hour after awakening. There was no effect of trait PC on the CAR. In contrast, reports of worrying and/or ruminating the night before predicted greater increases in cortisol concentration and total cortisol output compared to those who neither ruminated nor worried the night before. These effects were not accounted for by depressed mood, anxiety, sleep, or recent stressors. Findings suggest differential effects of trait and state PC on the CAR and highlight the importance of using proximal measures in examining individual differences in the CAR.