Hypothalamic-pituitary-adrenal axis function and exposure to stress factors and cannabis use in recent-onset psychosis

Abstract

Objectives: Previous studies suggest that childhood trauma, stressful life events, and cannabis use are associated with psychosis. We aimed to explore whether these environmental factors have an effect on hypothalamic–pituitary–adrenal (HPA) axis indices in recent-onset psychosis.

Methods: We studied 56 recent-onset psychosis outpatients and 47 healthy controls. Childhood trauma was assessed with the Childhood Trauma Questionnaire. Stressful life events were assessed with the Holmes-Rahe Social Readjustment Scale. Cannabis use was assessed by semistructured interviews. Several HPA axis measures were analysed in saliva: cortisol awakening response (CAR), diurnal cortisol slope, and dexamethasone suppression test ratio (DSTR) after 0.25?mg of dexamethasone. Multiple linear regression analyses were conducted to explore the contribution of environmental factors to each HPA axis measure while adjusting for covariates (diagnosis, age, gender, smoking, body mass index and treatments).

Results: There were no significant differences in HPA axis measures between diagnostic groups. Cannabis use was associated with a more flattened diurnal cortisol slope (standardized β?=?0.21, p?=?0.038), independent of recent-onset psychosis diagnosis. No associations were found between environmental factors and other HPA axis measures (CAR, DSTR).

Conclusions: Our study provides evidence for the effect of cannabis exposure in cortisol secretion patterns in both healthy controls and recent-onset psychosis patients.     

Co-occurring manic symptomatology influences HPA axis alterations in depression

Although dysfunctioning of the HPA axis is considered to be a core pathophysiological process in mood disorders, the evidence with regard to depression remains conflicting. This could partly be due to the large heterogeneity within mood disorders, since HPA axis abnormalities may also be associated with the extent of co-occurring manic symptomatology as is seen in bipolar disorder. In this study, patients with depressive disorder and bipolar spectrum disorders were studied with regard to their HPA axis functioning. In 304 healthy controls, 1134 patients with pure unipolar depressive disorder (UP), and 133 bipolar spectrum disorder patients (BD spectrum), cortisol was measured in 7 saliva samples to determine the 1 h cortisol awakening response (CAR), evening cortisol levels and cortisol suppression after a 0.5 mg dexamethasone suppression test. Both patient groups had overall higher CAR levels compared to controls, but only UP patients showed a higher increase over time in the CAR. A linear association was found between increasing bipolarity and cortisol diurnal slope: BD spectrum patients had a significantly higher diurnal slope than UP patients. Dexamethasone suppression did not differ between mood disorder diagnoses. The heterogeneity in HPA axis functioning in patients with depression can partially be explained by co-existing manic symptomatology, since an increase in the CAR appears to be more specific for pure depression whereas the presence of bipolarity is associated with an increase in the diurnal slope of cortisol.     

Hypothalamic-pituitary-adrenal axis function in survivors of childhood acute lymphoblastic leukemia and healthy controls

Of all malignancies in children, acute lymphoblastic leukemia (ALL) is the most common type. Since survival significantly improves over time, treatment-related side effects become increasingly important. Glucocorticoids play an important role in the treatment of ALL, but they may suppress the hypothalamic-pituitary-adrenal (HPA) axis. The duration of HPA axis suppression is not yet well defined. The present study aimed at assessing the function of the HPA axis by determining the cortisol awakening response (CAR) and the dexamethasone (DEX) suppression test in children that were treated for childhood ALL, compared to a healthy age and sex matched reference group. In addition, questionnaires regarding sleep, fatigue, depression and quality of life were completed by the children and their parents. Fourty-three survivors who finished their treatment for childhood ALL 37 (interquartile range 22-75) months before and 57 healthy controls were included. No differences in CAR were observed between ALL survivors and the reference group, but survivors of ALL had higher morning cortisol levels and an increased cortisol suppression in response to oral dexamethasone. Higher cortisol levels in childhood ALL survivors were associated with more fatigue and poorer quality of life. We conclude that the experience of a stressful life event in the past may have caused a long-term dysregulation of the HPA axis in childhood ALL survivors, as reflected in an increased cortisol production and an enhanced negative feedback mechanism.     

Increased saliva cortisol awakening response in patients with mild cognitive impairment

BACKGROUND: It is unknown whether HPA-axis dysfunction is present in patients with mild cognitive impairment (MCI). The aim of the present study was to investigate whether cortisol levels are elevated among patients with MCI and/or whether the individuals have adequate feedback control of their HPA axis. MATERIAL AND METHODS: 27 patients with MCI and 15 healthy controls were included in the study. Saliva samplings were performed 5 times a day before intake of 0.5 mg dexamethasone, and 5 times a day after intake of dexamethasone, respectively. RESULTS: Significantly higher cortisol levels were found 15 min after awakening among patients with MCI in comparison with the controls, both before and after dexamethasone administration (p<0.05). Also, the ratio between cortisol at awakening time and 15 min after awakening was lower in the patient group after dexamethasone administration (p<0.05). There were no significant differences in basal cortisol levels before or after dexamethasone between groups. CONCLUSION: The results indicate that there is an HPA-axis disturbance, with normal basal cortisol levels and increased awakening response among patients with MCI. The dissociation between basal values and the awakening response may be of pathophysiological importance for the cognitive impairment.     

Hypothalamic-pituitary-adrenal axis function in patients with complex regional pain syndrome type 1

An exaggerated inflammatory process is considered an important pathophysiological feature of complex regional pain syndrome type 1 (CRPS-1). The hypothalamic-pituitary-adrenal (HPA) axis serves as a negative feedback mechanism for inflammatory processes. The present study examined the HPA axis function in patients with CRPS-1 by a determination of cortisol concentrations in saliva. Three sets of saliva samples were sequentially collected from 24 patients with CRPS-1 during medication (on-Med), 72 h after stopping medication (off-Med) and 8h after the oral administration of 1mg dexamethasone. One set of saliva samples was collected from healthy controls. The cortisol awakening response (CAR) and diurnal cortisol decline (DCD) were used as indices for HPA axis function. Cortisol levels during the post-awakening period in patients were increased following withdrawal of medications. The CAR during the off-Med condition was disappeared after administration of dexamethasone. Among the examined CRPS-related numerical variables, the frequency of spontaneous pain attacks showed relationships with the indices of HPA axis function. After classifying the patients into two subgroups, we observed that the CAR and DCD in patient who had a relatively high frequency of spontaneous pain attacks (subgroup 5 ≤) were lower and less steep than those in patient who had a relatively low frequency of spontaneous pain attacks (subgroup 0-4) for the on- and off-Med conditions. The CAR and DCD in subgroup 5 ≤ during their off-Med condition were comparable to those in controls. These results suggest that the increase in frequency of spontaneous pain attacks is associated with a reduced CAR and flattened DCD in patients CRPS-1.     

The relation between early life adversity, cortisol awakening response and diurnal salivary cortisol levels in postpartum women

Early life adversity has been associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction in both children and adults. However, in adulthood, most studies have focused on the effects of early adversity on HPA axis stress reactivity rather than the cortisol awakening response or diurnal cortisol profiles. The goal of this study was to examine the cumulative effects of early life adversity on the cortisol awakening response (CAR) and diurnal cortisol profiles in a sample of postpartum women. Ninety women between 2 and 6 months postpartum completed two retrospective reports assessing adverse early life experiences (maltreatment and consistency of care). Eighteen women reported having experienced both parental loss and some form of childhood maltreatment and 36 women reported having experienced one type of early life adversity, either parental loss or maltreatment. HPA axis function was assessed through salivary cortisol collections over two consecutive days for measurement of the cortisol awakening response (n=61) and diurnal cortisol rhythm (n=90). Women who reported experiencing adverse early life experiences exhibited a tendency towards higher levels of awakening cortisol compared to women who reported no adverse early life experiences (p=.07). These higher awakening cortisol levels were sustained throughout the morning in the groups who experienced early adversity, with all groups exhibiting the typical diurnal decline in the afternoon and evening (p<.05). Women reporting early adversity exhibited more heterogeneity in their diurnal cortisol levels across the two collection days (p<.01). Our findings suggest that in a community sample of postpartum women, early adversity is associated with current HPA axis function. These findings may have implications for the nature of mother-infant interactions.     

Enhanced feedback sensitivity to prednisolone in chronic fatigue syndrome

OBJECTIVE: Enhancement of negative feedback control of the HPA axis in patients with chronic fatigue syndrome (CFS) has been reported using the low dose dexamethasone suppression test. We have developed the use of prednisolone (5mg) as a more physiologically appropriate alternative to dexamethasone in the investigation of mild degrees of glucocorticoid resistance or supersensitivity. The objective of the study was to use this test to look for alterations in negative feedback control of the HPA axis in CFS patients. METHODS: Fifteen patients with CFS were recruited after fulfilling strict criteria including the absence of comorbid psychiatric diagnosis. They collected urine between 0900 and 1800h and saliva at 0900h pre-prednisolone. At midnight, they took prednisolone (5mg) orally and then collected urine and saliva at the same intervals the following day. RESULTS: Salivary cortisol was lower in CFS subjects pre-prednisolone than controls. Urinary cortisol metabolites were lower in CFS subjects pre-prednisolone, but did not reach significance. Both measures were significantly lower in CFS subjects post-dose. Mean percentage suppression of both salivary cortisol and urinary cortisol metabolites was significantly higher in CFS compared to controls. CONCLUSION: There is enhanced sensitivity of the HPA axis to negative feedback in CFS as demonstrated using the prednisolone suppression test. This provides further evidence of alterations in the control of the HPA axis in patients with established CFS.     

Hypothalamic-pituitary-adrenal axis functioning in Huntington's disease mutation carriers compared with mutation-negative first-degree controls

Neurodegeneration in Huntington's disease (HD) occurs in various brain regions including the hypothalamus. In this cross-sectional study, hypothalamic-pituitary-adrenal (HPA) axis functioning was studied in 26 presymptomatic and 58 symptomatic HD mutation carriers, and 28 controls. HPA axis functioning was measured through salivary cortisol in the day curve, the cortisol awakening response (CAR), the area under the curve (AUC), the morning rise, and the dexamethasone suppression test (DST). Only the CAR was statistically different between the three groups, being explained by higher cortisol concentrations at 45 and 60 min post-awakening for presymptomatic mutation carriers compared to both symptomatic mutation carriers and controls. No differences were found for the AUC, evening and post-DST cortisol concentrations. Our study indicates a mild disturbance in morning cortisol secretion in HD mutation carriers that precedes the onset of motor symptoms.     

The association between long-term accumulation of temporary employment, the cortisol awakening response and circadian cortisol levels

Temporary employment is an increasingly common contract type, which has not been investigated in a psychoneuroendocrinological context despite previous observations of associations between adverse work and employment conditions and hypothalamic-pituitary-adrenal (HPA) axis dysregulations. The present study aims to examine whether the 12-year accumulation of temporary employment is related to circadian cortisol levels, and if any association is independent of current employment conditions. Participants were drawn from the prospective Northern Swedish Cohort (n=791, 74% of the original cohort). At age 43 years, retrospective reports of employments over the last 12 years and of current social conditions were collected by questionnaire, and one-day salivary cortisol profile was measured (at awakening, +15 min post-awakening, pre-lunch, bedtime). Results indicated a gradually higher magnitude of the cortisol awakening response (CAR) in subjects with no (0 months in temporary employment; mean CAR=34%), moderate (1-25 months in temporary employment; mean CAR=41%) and heavy (>25 months in temporary employment; mean CAR=51%) exposure (p=.020), remaining after adjustment for potential confounders and for current employment conditions (p=.028). The higher CAR was explained by lower awakening rather than higher post-awakening cortisol levels. Cortisol levels at all times of the day except post-awakening displayed tendencies to negative relations to temporary employment; as indicated by a lower Area Under of Curve (regression coefficient=5.0%, p=.038 after adjustment). This study thus suggests that the long-term exposure to temporary employment might confer HPA dysregulations in the form of increased dynamics of the CAR and circadian suppression.     

Salivary cortisol and psychopathology in children bereaved by the september 11, 2001 terror attacks.

BACKGROUND: Studies suggest that stressful events increase risk for childhood anxiety and depression and hypothalamic-pituitary-adrenal (HPA) axis dysregulation. This prospective longitudinal study evaluated relationships among severe psychosocial stress, psychiatric morbidity, and HPA axis function in children. METHODS: Forty-five children (mean age: 8.9 +/- 2.9 years) suffering parent death from September 11, 2001 terror attacks and 34 nonbereaved children (mean age: 9.3 +/- 2.5 years) were evaluated prospectively at 6-month intervals in this 2-year study. Assessments involved diagnostic interviews (Child Schedule for Affective Disorders and Schizophrenia [K-SADS]) for psychopathology and 3 days of baseline salivary cortisol and a salivary dexamethasone suppression test for HPA axis function. RESULTS: Bereaved children, but not nonbereaved children, had significantly increased rates of psychiatric disorders involving anxiety disorders, especially posttraumatic stress disorder (PTSD), after September 11, 2001 compared with retrospective assessments before September 11, 2001. Morning (AM) and 4:00 pm baseline cortisol were significantly and persistently higher for bereaved than nonbereaved children. Compared with bereaved children without psychopathology, bereaved children with PTSD had significantly lower 4:00 pm baseline cortisol and significantly greater 4:00 pm cortisol suppression. Children with generalized anxiety disorder had significantly less AM cortisol suppression than children without psychopathology. CONCLUSIONS: Children bereaved by sudden, unexpected parent death had persistent psychological dysfunction and HPA axis dysregulation in this study.     

Endocrine stress responses in TH1-mediated chronic inflammatory skin disease (psoriasis vulgaris)--do they parallel stress-induced endocrine changes in TH2-mediated inflammatory dermatoses (atopic dermatitis)?

In previous research we reported attenuated responsiveness of the hypothalamus-pituitary-adrenal (HPA) axis and further, an increased reactivity of the sympathetic adrenomedullary (SAM) system to stress in patients suffering from atopic dermatitis (AD). AD is a chronic inflammatory skin disease mainly triggered by TH(2)-dependent inflammatory processes. The specific goal of the present study was to investigate whether altered HPA axis and SAM system responsiveness to stress can also be found in TH(1)-mediated inflammatory conditions. Patients with psoriasis (PSO; n=23), a TH(1)-mediated inflammatory (autoimmune) skin disease and healthy controls (n=25) were exposed to a standardized laboratory stressor (TSST) which mainly consists of a free speech and a mental arithmetic task in front of an audience. To investigate HPA axis and SAM system responsiveness, cortisol, ACTH, and catecholamines were determined before and after the stress test. In addition, cortisol levels after awakening and cortisol levels during the day (short diurnal profile) were determined. In order to test feedback sensitivity of the HPA axis, a dexamethasone (DEX) suppression test (0.5 mg) was performed. Analysis of cortisol and ACTH levels after the stress test yielded no significant differences between PSO subjects and controls indicating no altered HPA axis function in this patient group. Further, no between-group differences were found in cortisol levels after awakening or during the day (short diurnal profile). Additionally, no difference between PSO and healthy subjects in the feedback sensitivity of the system could be found (DEX test). However, PSO patients showed elevated epinephrine (F(3,102)=4.7; p<0.005) and norepinephrine (F(3,135)=2.7; p<0.05) levels in response to the stress test when compared to the controls. These findings suggest no altered HPA axis responsiveness, but increased reactivity of the SAM system in TH(1)-mediated chronic inflammatory skin disease.     

Plasma ACTH and cortisol concentrations before and after dexamethasone

Alteration in the hypothalamic-pituitary-adrenal (HPA) axis occurs in up to 50% of depressed patients and is demonstrated by the failure to suppress cortisol concentrations after dexamethasone administration. Evidence suggesting that these cortisol abnormalities reflect hypothalamic-pituitary dysfunction has been inconsistent. We administered the dexamethasone suppression test to 28 psychiatric inpatients, including 17 cortisol suppressors and 11 nonsuppressors. Adrenocorticotropic hormone (ACTH) concentrations at 8 a.m. pre- and postdexamethasone were significantly greater in cortisol nonsuppressors than in suppressors. Our data support the hypothesis that pituitary ACTH secretion is altered in depressed patients who have HPA axis abnormalities demonstrated by plasma cortisol measurements.     

No effects of repeated forced wakings during three consecutive nights on morning cortisol awakening responses (CAR): a preliminary study

OBJECTIVE: The cortisol awakening response (CAR) is considered a reliable measure for the acute reagibility of the hypothalamus-pituitary-adrenal (HPA) axis. Whether repeated nightly awakenings at different times during the night also stimulate the HPA-axis and whether, consequently, the CAR is altered has not been tested, so far. We aimed to investigate whether three experimentally induced awakenings during three consecutive nights would be associated with HPA-axis stimulation and an altered morning CAR. METHODS: The study sample consisted of 13 healthy adult women who were waken up three times in each of three consecutive nights. Cortisol levels were measured immediately and 15 min after each awakening in the night and in the morning, respectively. Also, the morning CARs after three nights of undisturbed sleep were assessed. RESULTS: A significant difference between night time cortisol responses to awakening and the morning CAR was found. While cortisol levels during the first half of the night did not rise significantly after awakening in the night, some reactivity was seen during awakenings in the very early morning hours, and pronounced awakening responses were observed in the morning before getting out of bed. Interestingly, the morning CAR after disturbed sleep did not differ from the morning CAR following undisturbed sleep. CONCLUSION: In healthy female individuals, the morning CAR appears to be unchanged even if sleep was repeatedly interrupted by forced wakings.     

Do neonatal bilateral ibotenic acid lesions of the hippocampal formation or of the amygdala impair HPA axis responsiveness and regulation in infant rhesus macaques (Macaca mulatta)?

In response to stressful events, the HPA axis is activated triggering the successive release of CRF, ACTH, and glucocorticoids. The glucocorticoids in turn provide a negative feedback signal to terminate the stress response. The amygdala and the hippocampus are involved in the regulation of the HPA axis. In rodents, their respective roles have been identified; the amygdala exerts a stimulatory effect, whereas the hippocampus provides negative feedback control. In primates, however, their regulatory roles are still not well defined. The present study compared HPA axis responsiveness and regulation in 3- to 5-month-old rhesus macaques that received neonatal (15 +/- 3 days old) bilateral ibotenic acid lesions of the hippocampus or amygdala, or sham lesions. Group differences in plasma cortisol response to separation from the mother and relocation in a novel environment were assessed as well as response to dexamethasone suppression and ACTH challenge. Results revealed that the initial cortisol levels after separation/relocation did not differ between groups. Subjects with hippocampus lesions did not show a suppression of cortisol in response to dexamethasone, suggesting a loss of negative feedback control of HPA regulation. Subjects with amygdala and sham lesions did not differ in response to dexamethasone. Indeed, bilateral neonatal lesions of the amygdala have little impact on HPA axis responsiveness and regulation in contrast to lesions in adult monkeys. Finally, females displayed higher cortisol levels than males, independently of their lesion, indicating that the development of sex differences in the regulation of the HPA axis does not involve the amygdala or hippocampus.     

Free cortisol awakening responses are influenced by awakening time

Psychobiological investigations on the hypothalamus-pituitary-adrenal (HPA) axis depend on markers that adequately describe the activity of this system. There is evidence that the free cortisol response to awakening, proposed as a marker for the HPA axis, can be influenced by time of awakening. To further investigate this possible confounder, 24 shift working nurses and 31 female students on a regular sleep-wake cycle collected saliva samples 0, 30, 45 and 60 minutes after awakening. Nurses were investigated on the first and second day of their early (awakening: 04:00-05:30 h), late (awakening: 06:00-09:00 h), and night shift (awakening: 11:00-14:00 h), respectively. Students were studied after taking a short nap on two consecutive weekdays (awakening: 18:45-20:30 h). Mean cortisol levels after awakening increased significantly under all three shift conditions (p<0.01), but decreased in the student sample (p<.05). Within the three shift conditions, cortisol responses following waking in the early shift were more pronounced than in late (p<.01) and night shift (p<.05). The present study shows that in a sample with a large range of awakening times, an impact of this variable on the cortisol awakening response can be observed. The data furthermore strongly suggest that waking up per se is insufficient for adrenocortical stimulation.     

The effect of depression, anxiety and early life trauma on the cortisol awakening response during pregnancy: preliminary results

The purpose of this study was to examine the effects of maternal depression and anxiety on the cortisol awakening response (CAR), a marker of the hypothalamic-pituitary-adrenal (HPA) axis function, during pregnancy. Sixty-six pregnant women were studied between 25 and 33 weeks of gestation and were identified as either Depressed (n=33) or healthy, Control (n=33), based on depression scores and lifetime psychiatric history. Saliva samples were collected (passive drool) upon awakening and at +30 and +60 min thereafter. The CAR was not significantly different between women who were depressed during pregnancy compared to healthy control women. However, women taking antidepressant (AD) medication showed an attenuated CAR (time x AD use interaction, p=0.06). Childhood maltreatment (as measured with the Childhood Trauma Questionnaire) was associated with a lower baseline cortisol concentration explaining 12% of the variance, controlling for wake-up time and AD use. There is a complex interplay of factors involved in the HPA axis regulation of vulnerable women during pregnancy, including depression, anxiety, early life stress and psychotropic medication use, which remain unclear. The CAR may provide important information about the maternal HPA axis during pregnancy and warrants further investigation in larger cohorts.     

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.     

Sleep deprivation and hypothalamic-pituitary-adrenal (HPA) axis activity in depressed patients

In the present study we investigated HPA axis activity in depressed patients treated with partial sleep deprivation (PSD) in order to identify endocrinological characteristics related to PSD responsiveness. Thirty-three drug-free patients (14 men, 19 women) suffering from major depression according to DSM-IV criteria were treated with PSD. Response to PSD was defined as a reduction of at least 30% according to the 6-item version of the Hamilton Depression Scale (6-HAMD). Subsequently, the combined dexamethasone-suppression/CRH-stimulation test (DEX/CRH test) was performed. Patients were pretreated with 1.5 mg dexamethasone (DEX) at 23:00 h and challenged with 100 microg corticotropin-releasing hormone (CRH) the following day. Postdexamethasone cortisol concentrations (before CRH administration) served as parameters for the DST status (dexamethasone suppression test). The cortisol stimulation after CRH was used as measurement for the DEX/CRH test status. Of the depressive patients, 54.5% (18 out of 33) responded to PSD. DST suppressors (postdexamethasone cortisol levels < 15 ng/ml) showed a significantly greater reduction in 6-HAMD scores after PSD than DST nonsuppressors. Furthermore, a significant negative correlation between postdexamethasone cortisol levels and reduction in 6-HAMD scores after PSD could be established. However, there was no relationship between the cortisol stimulation following CRH challenge and response to PSD. Although the combined DEX/CRH challenge test is a more sensitive marker for HPA axis dysregulation in depression than the standard DST, the negative feedback of the HPA system reflected by the DST status is apparently more closely associated with response to partial sleep deprivation in major depressive disorder.     

Circadian regulation of cortisol after hippocampal damage in humans.

BACKGROUND: There is substantial evidence that the hippocampus (HC) regulates the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis. Damage to the HC in animals produces a transient alteration in diurnal and stress-related HPA activity. This study was designed to examine the effects of HC damage on basal cortisol secretion in humans. METHODS: Salivary cortisol was measured in 22 patients with HC damage (12 with bilateral damage and 10 with unilateral damage), 7 brain-damaged comparison participants, 10 healthy, age-matched comparison participants, and 6 of the patients' caregivers. Salivary cortisol samples were taken immediately after awakening, 30 min after awakening, at 8:00 am, 11:00 am, 3:00 pm, 6:00 pm, and at bedtime on a single day. Brain-injured patients underwent a structural magnetic resonance imaging scan to examine quantitative volumes of the HC. RESULTS: Both bilateral and unilateral HC damage abolished the cortisol response to awakening documented in the comparison groups. Caregivers of bilateral HC patients showed a reduced response to awakening. The remainder of the circadian pattern was not affected in the HC patients; all groups showed a significant diurnal variation. There was no association between HC volume and cortisol secretion. CONCLUSIONS: Hippocampal damage in humans abolishes the cortisol response to awakening, whereas the remainder of the diurnal cycle is unaffected in these patients. These data suggest a unique role of the HC in the control of basal cortisol secretion.     

PCLO rs2522833 impacts HPA system activity in healthy young adults

Recent genetic studies showed evidence for a role of the single-nucleotide polymorphism rs2522833 within the PCLO gene in the etiology of major depression, and rs2522833 has been shown to modulate hypothalamic pituitary adrenal (HPA) axis activity during antidepressant treatment. Monoaminergic modulation of the HPA system may be one possible pathomechanism by which PCLO exerts its effect on depression. In the present study, we investigated the effect of rs2522833 on the cortisol awakening response (CAR) in healthy young adults. A total of 66 healthy volunteers from the community (36 men and 30 women) aged 18–25 years without individual or family history of affective disorders and schizophrenia collected saliva cortisol samples at 0, 30, 45 and 60 min after awakening on two consecutive working days. We identified a blunted CAR (AUCinc) in rs2522833 risk-allele (C) carriers, possibly indicating exhausted regulatory mechanisms underlying the HPA system. We also identified higher neuroticism scores in rs2522833 risk-allele carriers but no phenotypic correlation between the CAR (AUCinc) and neuroticism. These findings suggest that the rs2522833 risk variant might increase vulnerability to depression both by physiological and behavioral pathways, which appear, however, not to be substantially overlapped. Replication with larger samples is warranted.