In search of the HPA axis activity in unipolar depression patients with childhood trauma: Combined cortisol awakening response and dexamethasone suppression test

The aim of the present study was to examine the impact of childhood trauma on HPA axis activity both in depression patients and healthy controls in order to determine the role of HPA axis abnormalities in depression and to find the differences in HPA axis functioning that may lead certain individuals more susceptible to the depressogenic effects of childhood trauma. Eighty subjects aged 18–45 years were recruited into four study groups (n = 18, depression patients with childhood trauma exposures, CTE/MDD; n = 17, depression patients without childhood adversity, non-CTE/MDD; n = 23, healthy persons with childhood trauma, CTE/non-MDD; and n = 22, healthy persons without childhood adversity, non-CTE/non-MDD). Each participant collected salivary samples in the morning at four time points: immediately upon awakening, 30, 45, and 60 min after awakening for the assessment of CAR and underwent a 1 mg-dexamethasone suppression test (DST). Regardless of depression, subjects with CTE exhibited an enhanced CAR and the CAR areas under the curve to ground (AUCg) were associated with their childhood trauma questionnaire (CTQ) physical neglect scores and CTQ total scores. In addition, the CTE/MDD group also showed a highest post-DST cortisol concentration and a decreased glucocorticoid feedback inhibition among four groups of subjects. The present findings suggested that childhood trauma was associated with hyperactivity of HPA axis as measured with CAR, potentially reflecting the vulnerability for developing depression after early life stress exposures. Moreover, dysfunction of the GR-mediated negative feedback control might contribute to the development of depression after CTE.     

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.     

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.     

Use of saliva cortisol in the dexamethasone suppression test

In a sample of 26 inpatients (15 primary endogenous depressives and a heterogeneous comparison group of 11 psychiatric patients), results of the dexamethasone suppression test (DST) for endogenous depression were compared when cortisol was measured in plasma (total and free) and in saliva. Results showed a close linear relationship among plasma total and free cortisol, plasma total cortisol, and saliva cortisol, and between free plasma and saliva cortisol. A saliva cortisol cutoff point of 70 ng/dl achieved the same sensitivity (67%), specificity (91%), and diagnostic confidence (91%) as the best cutoff scores of plasma total cortisol (5 μ/dl) and plasma free cortisol (0.15 μ/dl). These results suggest that saliva cortisol, which directly reflects the biologically active fraction of cortisol, can be used as a reliable and more practical index in the DST, especially in outpatients.     

抑郁症伴或不伴糖尿病患者过夜小剂量地塞米松抑制试验的对照研究

目的 探讨下丘脑-垂体-肾上腺轴(HPA)功能异常在抑郁症患者伴发的糖尿病发病机制中的意义.方法 首次诊断为糖尿病的抑郁症患者(病例组)、正常血糖稳态的抑郁症患者(对照组)各40例,于药物治疗前测定空腹血糖、糖负荷后2 h血糖,并行过夜小剂量(1 mg)地塞米松抑制试验.结果 (1)病例组抑制前8:00、16:00及...     

Number of cortisol time-points and dexamethasone suppression test sensitivity for major depression

Failure to suppress cortisol secretion after administration of dexamethasone has been reported to be a diagnostic marker for major depression and to have prognostic implications when repeated after antidepressant treatment. The pulsatile pattern of cortisol secretion suggested to us that increasing the number of post-dexamethasone cortisol determinations might significantly increase the sensitivity of the dexamethasone suppression test (DST) for major depression. With a conventional two-point DST (1600 h and midnight), 5% of 20 normal volunteers, 8% of 13 inpatients with non-major depressions, and 31% of 65 inpatients with primary major depression failed to suppress. With six post-dexamethasone points (0800 h, 1200 h, 1600 h, 2000 h, 2200 h, midnight), the respective percentages were 10, 15 and 44%. The additional points increased the sensitivity from 31 to 44%, mostly by identifying more major depressives with a "late escape" pattern. If a clinician is using the DST to establish a marker for major depression that can be repeated to monitor response to treatment and the likelihood of relapse, then perhaps the increased sensitivity of the six-point DST would be helpful, despite a modest decrease in specificity from 94 to 88%.     

A longitudinal study on cortisol and complaint reduction in burnout

Several studies have investigated the association between burnout and HPA-axis functioning, but the results are far from consistent. This does not preclude the possibility that within a group of burnout patients a recovery of symptoms in a longitudinal course corresponds to (changes in) cortisol parameters. The latter possibility is tested in the present study before and after treatment, and at follow-up. HPA-axis functioning and burnout complaints were assessed in burned-out participants at baseline (n=74), post-treatment (n=62) and at follow-up (n=53). Multilevel regression analysis was used to test the hypothesis. Burnout complaints were significantly reduced at 8.5 months post-treatment, but there was no further reduction in complaints at follow-up 6.3 months later. Cortisol after awakening, and after dexamethasone intake showed no changes from baseline to post-treatment and follow-up. There was a small decline in cortisol during the day over the longitudinal course. The cortisol level after awakening in the longitudinal course showed significant positive association with the initial exhaustion level, a negative association with the change in the burnout exhaustion score, and a positive association with the change in depression. Although these associations are statistically significant, they only explain a small fraction of the variance in cortisol after awakening between and within persons. This implies that changes at symptom level are hardly related to changes in cortisol functioning, therefore the clinical implications of this finding are limited.     

Enhanced cortisol suppression in response to dexamethasone administration in traumatized veterans with and without posttraumatic stress disorder

BACKGROUND: While enhanced cortisol suppression in response to dexamethasone is one of the most consistent biological findings in posttraumatic stress disorder (PTSD), the relative contribution of trauma exposure to this finding remains unclear. METHODS: Assessment of diurnal salivary cortisol levels and 1600 h salivary cortisol before and after oral administration of 0.5mg dexamethasone in veterans with PTSD, veterans without PTSD (trauma controls) and healthy controls. Assessment of 1600 h plasma cortisol, ACTH and corticotrophin binding globulin (CBG) in response to dexamethasone in PTSD patients and trauma controls. RESULTS: Both PTSD patients and trauma controls demonstrated significantly more salivary cortisol suppression compared to healthy controls. Salivary cortisol, plasma cortisol and ACTH suppression as well as CBG levels did not differ between PTSD patients and trauma controls. PTSD patients showed a reduced awakening cortisol response (ACR) compared to healthy controls that correlated significantly with PTSD symptoms. No significant differences were observed in ACR between PTSD patients and trauma controls. CONCLUSIONS: These data suggest that enhanced cortisol suppression to dexamethasone is related to trauma exposure and not specifically to PTSD. The correlation between the ACR and PTSD severity suggests that a flattened ACR may be a result of clinical symptoms.     

Abnormal dexamethasone suppression test in primary obsessive-compulsive patients: A confirmatory report

The dexamethasone suppression test (DST) was administered after baseline cortisol measurements in 20 patients (10 males, 10 females) who met DSM-III criteria for obsessive-compulsive disorder (OCD). Six patients (30%) showed an abnormal escape from dexamethasone suppression. DST suppressors vs. DST nonsuppressors showed no differences in age, rate of secondary depressive disorders, or scores on the Hamilton Rating Scale for Depression, the Minnesota Multiphasic Personality Inventory D scale, or OCD rating scales. Surprisingly, there was a trend for suppressors to have a stringer family history of depressive disorders, and for nonsuppressors to include an excess of male subjects. Moreover, there was a significant correlation between levels of cortisol before and after DST. In five of six nonsuppressors, both depressive symptoms and obsessive- compulsive behaviors showed a diminution in response to antidepressant therapy combined, in one case, with intensive behavior therapy. The relationships between OCD and endogenous depression, as well as the specificity of the DST, are discussed.     

The dexamethasone suppression test in depressive and schizophrenic patients under controlled treatment conditions

Summary Endogenous depressive and schizophrenic patients demonstrated the same frequency of pathological DST results after admission. After 3 weeks of psychopharmacological treatment the percentage of abnormal DST results was significantly reduced in both groups, although the treatment conditions were different. A correlation between the DST non-suppression and intensity of depression was observed only in the depressive group, not in the schizophrenic group. Normalization of DST results in depressive patients was mostly associated with an improvement of depressive scores. Other course patterns of DST results did not seem to be combined with psychopathological changes. From this data it has to be concluded that DST non-suppression is in some part related to depressive symptoms, but is not characteristic or specific for endogenous depression or for depressivity.     

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.     

Adrenocorticotropin and cortisol response to lysine vasopressin in relation to the outcome of the dexamethasone suppression test in major depressive disorder

The pathophysiology behind the abnormalities of the hypothalamic pituitary adrenal cortex axis found in patients with major depressive disorder was studied by the use of the vasopressin test. The response of plasma adrenocorticotropin (ACTH) and cortisol to the injection of 10 IU lysine-vasopressin (LVP) was investigated in 18 patients meeting the DSM-III criteria for major depressive episode. The response was correlated to the outcome of the dexamethasone suppression test (DST) with the use of two different cut-off points, 139 nmol/l and 200 nmol/l respectively. The results show that no significant difference was found in ACTH or cortisol response between patients having a normal or abnormal DST. The results do not seem to support the hypothesis that the abnormalities of the hypothalamic pituitary adrenal cortex axis involve a hypersecretion of corticotropin-releasing factor (CRF) and a subsequent desensitization of the corticotrophs to CRF-stimulated ACTH release.     

Evidence for altered hypothalamus-pituitary-adrenal axis functioning in systemic hypertension: blunted cortisol response to awakening and lower negative feedback sensitivity

BACKGROUND: Hypothalamus-pituitary-adrenal (HPA) axis functioning in systemic hypertension is not fully understood. We explored HPA axis activity and feedback sensitivity to oral administration of dexamethasone in systemic hypertension via assessment of the cortisol awakening response (CAR) and the circadian cortisol profile. METHODS: The CAR and circadian cortisol profile were assessed in 20 unmedicated and otherwise healthy middle-aged hypertensive men and in 22 normotensive male controls. Salivary free cortisol measures for the CAR were obtained immediately after awakening and 15, 30, 45, and 60 min thereafter. Circadian cortisol secretion was sampled at 08:00, 11:00, 15:00, and 20:00 h. Assessment of the CAR was repeated on the next day after administration of 0.5mg dexamethasone at 23:00 h on the previous night. RESULTS: Hypertensives had a significantly lower CAR (p<0.02) and significantly reduced suppression of the CAR after dexamethasone administration (p<0.01) than normotensive controls. There were no significant differences in cortisol levels at awakening and in circadian cortisol profiles between hypertensives and normotensives. CONCLUSION: We found evidence for altered HPA axis activity in men with systemic hypertension evident with the CAR. Hypertensives showed relative attenuation in the CAR and in the HPA axis feedback sensitivity following dexamethasone suppression. Such alterations in HPA axis regulation might contribute to the atherosclerotic risk in hypertensive individuals.     

Discrimination between patients with melancholic depression and healthy controls: comparison between 24-h cortisol profiles, the DST and the Dex/CRH test

Diurnal (24-h) cortisol profiles were compared to DST and Dex/CRH test outcomes with regard to their discriminative power in depressive disorder. With regard to several statistical measures (effect sizes, area under the curve) we found 24-h cortisol profiles to better discriminate between healthy controls and inpatients with the melancholic subtype of depression compared to the DST and Dex/CRH test. In search of a shortened time interval we found the 2-h time window 1000-1200 h of the cortisol profile to be the one with the highest sensitivity (83.3%) and specificity (87.9%). The specificity of the DST was 93.3% and somewhat higher than that of the cortisol profiles and the Dex/CRH test (87.9% and 78.8.%, respectively). However, the sensitivity of the DST was very low (30.8%), in fact similar to that of the Dex/CRH test (30.8%), but much lower than that of the 1000-1200 h interval (83.3%). The assessment of cortisol in plasma is an easy to perform, cost-saving method for the evaluation of the HPA system activity, which may have a series of clinical and scientific implications for the depressive disorder.