The prednisolone suppression test in depression: Dose-response and changes with antidepressant treatment

Depressed patients have reduced glucocorticoid receptor (GR) function, as demonstrated by resistance to the suppressive effects of the synthetic glucocorticoid hormone, and GR agonist, dexamethasone. We have developed a suppressive test with prednisolone, a synthetic glucocorticoid that is similar to cortisol in its pharmacodynamics and pharmacokinetics, and binds to both the GR and the mineralocorticoid receptor (MR). We have found that depressed patients suppress normally to prednisolone, unless they are particularly non-responsive to treatment. In the present study, we evaluated 28 inpatients with treatment-resistant depression (TRD), and compared salivary cortisol secretion (at 0900 h, 1200 h and 1700 h) after placebo or after prednisolone (5 mg), before and after an inpatient treatment admission. Half of the patients (n = 14) reached treatment response. When comparing the assessment between admission and discharge, cortisol output after placebo fell (-26% of area under the curve; p = 0.024) while the output after prednisolone did not change. Moreover, there was no change in the response to prednisolone (percentage suppression) between admission at discharge, and this was not influenced by treatment response. Finally, we could confirm and extend our previously published data with prednisolone (5 mg), showing that depressed patients (n = 12) and controls (n = 12) suppressed equally to both 5 and 10 mg doses of prednisolone. This study suggests that the response to prednisolone is similar in depressed patients and controls at different doses of prednisolone, and does not change with symptomatic improvement. This is in contrast with findings, from us and others, using other measures of hypothalamic-pituitary-adrenal axis function, such as basal cortisol levels or the response to dexamethasone. Thus, we propose that the prednisolone suppression test may offer specific biological and clinical information, related to its action at both the GR and the MR. (C) 2010 Elsevier Ltd. All rights reserved.

Effects of type II pyrethroid cyhalothrin on rat innate immunity: A flow cytometric study

Synthetic type II pyrethroids induce anxiety, immunosuppresion or, alternatively, immunostimulatory effects in laboratory animals. Macrophages and neutrophils are known to be key elements in cellular immune responses. The present study was designed to investigate the in vivo effects of cyhalothrin (1.0 and 3.0 mg/kg/once daily for 7 days) on macrophage and neutrophil activities, using a flow cytometry method. Results showed that cyhalothrin treatment decreased the percentage and intensity of phagocytosis performed by macrophages, but did not alter these parameters in neutrophils: and also decreased basal neutrophil oxidative burst and increased S. aureus-induced neutrophil oxidative burst, but did not alter these responses in macrophages. The present results are discussed in the light of a possible indirect action of cyhalothrin on macrophage and neutrophil activities via hypothalamic pituitary adrenal (HPA) axis activation. A possible direct effect of cyhalothrin on macrophage and neutrophil activities is also considered. (C) 2008 Elsevier B.V. All rights reserved.

The insulin hypoglycemia test: Hypoglycemic criteria and reproducibility

The insulin hypoglycemia test (IHT) is widely regarded as the 'gold standard' for dynamic stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. This study aimed to investigate the temporal relationship between a rapid decrease in plasma glucose and the corresponding rise in plasma adenocorticotropic hormone (ACTH), and to assess the reproducibility of hormone responses to hypoglycemia in normal humans. Ten normal subjects underwent IHTs, using an insulin dose of 0.15 U/kg. Of these, eight had a second IHT (IHT2) and three went on to a third test (IHT3). Plasma ACTH and cortisol were measured at 15-min intervals and, additionally, in four IHT2s and the three IHT3s, ACTH was measured at 2.5- or 5-min intervals. Mean glucose nadirs and mean ACTH and cortisol responses were not significantly different between IHT1, IHT2 and IHT3. Combined data from all 21 tests showed the magnitude of the cortisol responses, but not the ACTH responses, correlated significantly with the depth and duration of hypoglycemia. All subjects achieved glucose concentrations of of less than or equal to 1.6 mmol/l before any detectable rise in ACTH occurred. In the seven tests performed with frequent sampling, an ACTH rise never preceeded the glucose nadir, but occurred at the nadir, or up to 15 min after. On repeat testing, peak ACTH levels varied markedly within individuals, whereas peak cortisol levels were more reproducible (mean coefficient of variation 7%). In conclusion, hypoglycemia of less than or equal to 1.6 mmol/l was sufficient to cause stimulation of the HPA axis in all 21 IHTs conducted in normal subjects. Nonetheless; our data cannot reveal whether higher glucose nadirs would stimulate increased HPA axis activity in all subjects. Overall, the cortisol response to hypoglycemia is more reproducible than the ACTH response but, in an individual subject, the difference in peak cortisol between two IHTs may exceed 100 nmol/l.

Personality, Brain Asymmetry, and Neuroendocrine Reactivity in Two Immune-Mediated Disorders: a Preliminary Report

Development of some immune-mediated disorders may depend on dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. To explore neuropsychologic mechanisms in relation to the abnormal endocrine reactivity in patients with systemic lupus erythematosus (SLE) and chronic hepatitis C (CHC) we used the corticotropin releasing hormone (CRH) test, the Minnesota Multiphasic Personality Inventory (MMPI), and the Edinburgh Inventory of Manual Preference Inventory (EIMP). Compared to controls, the adrenocorticotrophic hormone (ACTH) response to CRH was reduced in CHC, while SLE presented reduced baseline dehydroepiandrosterone sulfate levels; higher neurotic scores were found in SLE and higher behavior deviant scores in CHC. Peak ACTH levels were a significant factor for the MMPI profile variability, while the manual preference score was a significant factor for the ACTH response. Personality and manual preference contribute to neuroendocrine abnormalities. Different behavioral and neuroimmunoendocrine models emerge for these disorders.

Methylation at the CpG island shore region upregulates Nr3c1 promoter activity after early-life stress

Early-life stress (ELS) induces long-lasting changes in gene expression conferring an increased risk for the development of stress-related mental disorders. Glucocorticoid receptors (GR) mediate the negative feedback actions of glucocorticoids (GC) in the paraventricular nucleus (PVN) of the hypothalamus and anterior pituitary and therefore play a key role in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and the endocrine response to stress. We here show that ELS programs the expression of the GR gene (Nr3c1) by site-specific hypermethylation at the CpG island (CGI) shore in hypothalamic neurons that produce corticotropin-releasing hormone (Crh), thus preventing Crh upregulation under conditions of chronic stress. CpGs mapping to the Nr3c1 CGI shore region are dynamically regulated by ELS and underpin methylation-sensitive control of this region's insulation-like function via Ying Yang 1 (YY1) binding. Our results provide new insight into how a genomic element integrates experience-dependent epigenetic programming of the composite proximal Nr3c1 promoter, and assigns an insulating role to the CGI shore.

Adult attachment representations predict cortisol and oxytocin responses to stress.

There are many factors contributing to individual variations in the response to stressful experiences. The present study evaluated the patterns of stress responses according to attachment representations in 28 adults from a community sample, plus 46 subjects expected to be particularly sensitive to stress, having been exposed during childhood and/or adolescence to traumatizing events such as abuse or potentially lethal illnesses. Subjects were given the Adult Attachment Interview, which provides attachment classifications, and the Trier Social Stress Test (TSST), involving an experimental psychosocial challenge. Subjective responses to the TSST, as well as saliva samples (assayed for cortisol) and blood plasma samples (assayed for ACTH and oxytocin) were collected before, during and after the stress procedure. The stress responses presented specific patterns according to attachment classifications. Subjects with an autonomous attachment classification reported relatively low subjective stress, they presented a moderate response of the hypothalamic-pituitary-adrenal (HPA) axis (ACTH and cortisol), and a high level of oxytocin. Subjects with a dismissing classification reported a moderate subjective stress, they presented an elevated response of the HPA axis, and moderate levels of oxytocin. Subjects with a preoccupied classification presented moderate levels of subjective stress, and of HPA response, and a relatively low level of oxytocin. Finally, subjects with an unresolved classification reported elevated subjective stress; they presented a suppressed HPA response, and moderate levels of oxytocin. These data support the notion that attachment representations may affect stress responses, and suggest a specific role of oxytocin in both the attachment system and the stress system.

Planifier un sevrage aux glucocorticoïdes: stratégie diagnostique et thérapeutique [How to plan glucocorticoid withdrawal: diagnostic and therapeutic strategies]

Glucocorticoïds are widely used in medicine and associated with numerous complications. Whenever possible, dosage reduction or treatment withdrawal should be considered as soon as possible depending on the underlying disease being treated. Administration of glucocorticoids induces a physiologic negative feed-back on the hypothalamic-pituitary-adrenal (HPA) axis and three clinical situations can be distinguished during treatment withdrawal: reactivation of the disease for which the glucocorticoids were prescribed, acute adrenal insufficiency and steroid withdrawal syndrome. Acute adrenal insufficiency is a feared complication but probably rare. It is usually seen during stress situations and can be observed long after steroid withdrawal. There is no good predictive marker to anticipate acute adrenal insufficiency and clinical evaluation of the patient remains a key element in its diagnosis. If adrenal insufficiency is suspected, HPA suppression can be assessed with dynamic tests. During stress situation, steroid administration is then recommended depending on the severity of the stress.

Effects of perinatal stress and maternal traumatic stress on the cortisol regulation of preterm infants.

Preterm infants experience intense stress during the perinatal period because they endure painful and intense medical procedures. Repeated activation of the hypothalamic-pituitary-adrenal (HPA) axis during this period may have long-term effects on subsequent cortisol regulation. A premature delivery may also be intensely stressful for the parents, and they may develop symptoms of posttraumatic stress disorder (PTSD). Usable saliva samples were collected (4 times per day over 2 days, in the morning at awakening, at midday, in the afternoon, and in the evening before going to bed) to assess the diurnal cortisol regulation from 46 preterm infants when the infants were 12 months of corrected age (∼ 14 months after birth). Mothers reported their level of PTSD symptoms. The results showed an interaction between perinatal stress and maternal traumatic stress on the diurnal cortisol slope of preterm infants (R(2) = .32). This suggests that the HPA axis of preterm infants exposed to high perinatal stress may be more sensitive to subsequent environmental stress.

Immune and stress responses covary with melanin-based coloration in the barn swallow

Eumelanin and pheomelanin are the main endogenous pigments in animals and melanin-based coloration has multiple functions. Melanization is associated with major life-history traits, including immune and stress response, possibly because of pleiotropic effects of genes that control melanogenesis. The net effects on pheo- versus eumelanization and other life-history traits may depend on the antagonistic effects of the genes that trigger the biosynthesis of either melanin form. Covariation between melanin-based pigmentation and fitness traits enforced by pleiotropic genes has major evolutionary implications particularly for socio-sexual communication. However, evidence from non-model organisms in the wild is limited to very few species. Here, we tested the hypothesis that melanin-based coloration of barn swallow (Hirundo rustica) throat and belly feathers covaries with acquired immunity and activation of the hypothalamic-pituitary-adrenal (HPA) axis, as gauged by corticosterone plasma levels. Individuals of both sexes with darker brownish belly feathers had weaker humoral immune response, while darker males had higher circulating corticosterone levels only when parental workload was experimentally reduced. Because color of belly feathers depends on both eu- and pheomelanin, and its darkness decreases with an increase in the concentration of eu- relative to pheomelanin, these results are consistent with our expectation that relatively more eu- than pheomelanized individuals have better immune response and smaller activation of the HPA-axis. Covariation of immune and stress response arose for belly but not throat feather color, suggesting that any function of color as a signal of individual quality or of alternative life-history strategies depends on plumage region.

Cerebrospinal fluid cortisol and clinical disease progression in MCI and dementia of Alzheimer's type.

Increased peripheral and central nervous system cortisol levels have been reported in Alzheimer's disease (AD) and may reflect dysfunction of cerebral components of the hypothalamic-pituitary-adrenal (HPA) axis. However, brain exposure to high cortisol concentrations may also accelerate disease progression and cognitive decline. The objectives of this study were to investigate whether HPA-axis dysregulation occurs at early clinical stages of AD and whether plasma and CSF cortisol levels are associated with clinical disease progression. Morning plasma and CSF cortisol concentrations were obtained from the subjects with AD dementia, mild cognitive impairment of AD type (MCI-AD), MCI of other type (MCI-O), and controls with normal cognition included in a multicenter study from the German Dementia Competence Network. A clinical and neuropsychological follow-up was performed in a subgroup of participants with MCI-AD, MCI-O, and AD dementia. CSF cortisol concentrations were increased in the subjects with AD dementia or MCI-AD compared with subjects with MCI-O or normal cognition. After controlling for possible confounders including CSF measures of amyloid beta1-42 and total tau, higher baseline CSF cortisol levels were associated with faster clinical worsening and cognitive decline in MCI-AD. The findings suggest that HPA-axis dysregulation occurs at the MCI stage of AD and may accelerate disease progression and cognitive decline.

Negative affect mediates the relationship between the Cortisol Awakening Response and Conduct Problems in boys

Ce mémoire débute avec deux chapitres portant sur les problèmes des conduites et la régulation du stress, notamment sur l’axe hypothalamique-pituitaire-surrénal (HPS). Ensuite, la littérature est résumée et nous voyons que les études qui cherchent à établir un lien entre les problèmes des conduites et l’axe HPS ont trouvé des résultats différents et parfois contradictoires. Le chapitre suivant illustre les problèmes méthodologiques qui pourraient expliquer ces résultats différents. Vient ensuite l’étude présentée dans ce mémoire qui cherche à établir un lien entre la réponse cortisolaire à l’éveil (RCE), considérée comme un bon indice du fonctionnent de l’axe HPS, et les problèmes de conduites chez l’enfant. De plus, les émotions négatives ont été associées avec les problèmes des conduites ainsi qu’aux dysfonctions de l’axe HPS, notamment le RCE. L’étude présentée dans ce mémoire cherche aussi à établir si les émotions négatives pourrait être une variable médiatrice dans la relation potentielle entre la RCE et les problèmes des conduites. L’étude révèle que pour les garçons mais pas pour les filles, une RCE réduite est associée avec les émotions négatives, ce qui est successivement associé avec les problèmes des conduites. Le dernier chapitre du mémoire examine les implications théoriques de cette médiatisation et propose également des pistes psychobiologiques pour expliquer les différences sexuelles observées.

La détermination d’un sous-groupe de contrevenants de la conduite avec capacités affaiblies à risque élevé de récidive : l’utilité de l’axe hypothalamo-hypophyso-surrénalien

Les contrevenants de la conduite avec capacités affaiblies (CCA) n’entrent pas tous dans les registres de la sécurité routière avec le même risque de récidive. Pour pallier cette hétérogénéité, cette thèse propose de modéliser les interrelations entre les traits de personnalité et les comportements à risque associés à la récidive et de détecter un sous-groupe de contrevenants au risque de récidive élevé à l’aide de l’axe hypothalamo-hypophyso-surrénalien (HHS). Plus particulièrement, les trois articles de cette thèse s’intéressent au cortisol, l’hormone du stress. Le premier article élabore un modèle théorique réconciliant les connaissances sur l’axe HHS issues du domaine de la CCA et de domaines connexes. Lors de précédentes études, le nombre de condamnations antérieures pour CCA a été associé négativement à la réactivité du cortisol à la suite d’une situation stressante. Chez les récidivistes, cette faible réactivité s’explique partiellement par la recherche d’expériences, une dimension de la recherche de sensations. Au-delà ce trait de personnalité désinhibiteur, une faible activité de l’axe HHS a été associée à d’autres traits (c.-à-d. impulsivité et tendances antisociales) et d’autres comportements à risque (c.-à-d. infractions routières, arrestations criminelles et consommation problématique de substances psychoactives). Ce modèle intégrant la réactivité du cortisol permet une conceptualisation approfondie des diverses caractéristiques des contrevenants de la CCA et explique hypothétiquement la répétition des comportements à risque. Les deux articles suivants se penchent sur l’intérêt empirique d’utiliser l’axe HHS pour déterminer un sous-groupe de contrevenants à risque élevé de récidive. Plus précisément, le deuxième article émet l’hypothèse que les récidivistes (n = 30) ayant une faible activité de leur cortisol (c.-à-d. médiane de la surface sous la courbe relative au niveau de base et relative à la réactivité) ont davantage de traits de personnalité désinhibiteurs et de comportements à risque que les récidivistes ayant une forte activité. L’hypothèse n’a pas été confirmée. Au contraire, les récidivistes présentant une faible réactivité commettent moins d’infractions routières et d’arrestations criminelles que ceux ayant une forte réactivité. Quant à lui, le troisième article investigue une hypothèse similaire auprès des contrevenants primaires (n = 139). Les contrevenants manifestant une faible réactivité du cortisol (c.-à-d. différence entre prélèvements post-stress et pré-stress) ont davantage d’impulsivité attentionnelle, de non-planification, d’arrestations criminelles et de cigarettes fumées par jour que les contrevenants ayant une forte réactivité. Lors d’analyses exploratoires, la présence d’une variété de traits de personnalité désinhibiteurs et de comportements à risque chez les contrevenants primaires présentant une faible réactivité lorsque comparé au groupe contrôle (n = 31) suggère encore une fois leur risque élevé de récidive. L’intérêt d’ajouter un mécanisme neurobiologique pour modéliser les interrelations entre les traits de personnalité désinhibiteurs et les comportements à risque des contrevenants de la CCA a été exploré dans cette thèse. La détermination d’un sous-groupe de contrevenants présentant un risque élevé de récidive, à l’aide de l’axe HHS, semble davantage profitable auprès de l’hétérogène population des contrevenants primaires. En contrepartie, l’axe HHS ne permet pas de déterminer un sous-groupe ayant une problématique sévère auprès des récidivistes à l’extrême du continuum du risque.

Disturbances in early parenting of depressed mothers and cortisol secretion in offspring: A preliminary study

Background: Disturbances in cortisol secretion are associated with risk for psychiatric disorder, including depression. Animal research indicates that early care experiences influence hypothalamic-pituitary-adrenal (HPA) axis functioning in offspring. Similar effects are suggested in human development, but evidence of longitudinal associations between observed early parenting and offspring cortisol secretion is extremely limited. We studied associations between parenting disturbances occurring in the context of maternal postnatal depression (PND), and elevations in morning cortisol secretion in the adolescent offspring of PND mothers. Methods: We observed maternal parenting behaviour on four occasions through the first year and at five-year follow up in postnatally depressed (n = 29) and well (n = 20) mothers. Observations were coded for maternal sensitivity and withdrawal. Basal offspring salivary cortisol secretion was measured at 13-years, using collections over 10-days. Results: Postnatal, but not five-year, maternal withdrawal predicted elevated mean and maximum morning cortisol secretion in 13-year-old offspring. There were no significant associations between maternal sensitivity and offspring cortisol secretion. Limitations: The sample size was relatively small, and effects tended to be reduced to trend level when covariates were considered. The correlational nature of the study (albeit longitudinal) limits conclusions regarding causality. Conclusions: Individual differences in early maternal parenting behaviour may influence offspring cortisol secretion, and thereby risk for depression. Parenting interventions that facilitate active maternal engagement with the infant may be indicated for high risk populations.

O Tratamento com a fluoxetina (mas não com outros farmacos antidepressivo e ansioíiticos) reverte o déficit de memória aversiva causado por estresse agudo de contenção em camundongos

The physiologist H. Selye defined stress as the nonspecific response of the body to any factors that endanger homeostasis (balance of internal environment) of the individual. These factors, agents stressors, are able to activate the Hypothalamic-Pituitary-Adrenal (HPA) axis, thus resulting in the physiological responses to stress by the release of glucocorticoids that leads to psychophysiological changes, including effects on cognitive functions such as learning and memory. When this axis is acutely stimulated occurs a repertoire of behavioral and physiological changes can be adaptive to the individual. Notwithstanding, when the HPA axis is chronically stimulated, changes may favor the development of, such as anxiety disorders. Some drugs used in the clinic for the treatment of anxiety disorders these can exert effects on cognitive function, on the HPA axis and on the anxiety. In this context, the aim of our study was to investigate the effects of administration i.p. acute of diazepam (DZP, 2 mg/kg), buspirone (BUS, 3 mg/kg), mirtazapine (MIR, 10 mg/kg) and fluoxetine (FLU, 10 mg/kg) in male mice submitted to acute restraint stress, and evaluated using plus-maze discriminative avoidance task (PMDAT), which simultaneously evaluates parameters such as learning, memory and anxiety. Our results demonstrated that (1) the administration of DZP and BUS, but not FLU, promoted anxiolytic effects in animals; (2) administration mirtazapine caused sedative effect to animals; (3) in the training session, the animals treated with BUS, MIR and FLU learned the task, on the other hand DZP group showed impairment in learning; (4) in the test session, animals treated with DZP, BUS, and MIR showed deficits in relation to discrimination between the enclosed arms, aversive versus non-aversive arm, demonstrating an impairment in memory, however, animals treated with FLU showed no interference in the retrieval of this memory; (5) acute stress did not interfere in locomotor activity, anxiety, or learning on the learning task, but induced impairment in retrieval memory, and the group treated with FLU did not demonstrated this deficit of memory . These results suggest that acute administration of drugs with anxiolytic and antidepressant activity does not interfere with the learning process this aversive task, but impair its retrieval, as well as the acute restraint stress. However, the antidepressant fluoxetine was able to reverse memory deficits promoted by acute stress, which may suggest that modulation, even acutely serotonergic neurotransmission, by selectively inhibiting the reuptake of this neurotransmitter, interferes on the process of retrieval of an aversive memory

Baseline and stress-induced plasma corticosterone concentrations of mice selectively bred for high voluntary wheel running

The hypothalamic-pituitary-adrenal (HPA) axis is important in regulating energy metabolism and in mediating responses to stressors, including increasing energy availability during physical exercise. In addition, glucocorticoids act directly on the central nervous system and influence behavior, including locomotor activity. To explore potential changes in the HPA axis as animals evolve higher voluntary activity levels, we characterized plasma corticosterone (CORT) concentrations and adrenal mass in four replicate lines of house mice that had been selectively bred for high voluntary wheel running (HR lines) for 34 generations and in four nonselected control (C) lines. We determined CORT concentrations under baseline conditions and immediately after exposure to a novel stressor (40 min of physical restraint) in mice that were housed without access to wheels. Resting daytime CORT concentrations were approximately twice as high in HR as in C mice for both sexes. Physical restraint increased CORT to similar concentrations in HR and C mice; consequently, the proportional response to restraint was smaller in HR than in C animals. Adrenal mass did not significantly differ between HR and C mice. Females had significantly higher baseline and postrestraint CORT concentrations and significantly larger adrenal glands than males in both HR and C lines. Replicate lines showed significant variation in body mass, length, baseline CORT concentrations, and postrestraint CORT concentrations in one or both sexes. Among lines, both body mass and length were significantly negatively correlated with baseline CORT concentrations, suggesting that CORT suppresses growth. Our results suggest that selection for increased locomotor activity has caused correlated changes in the HPA axis, resulting in higher baseline CORT concentrations and, possibly, reduced stress responsiveness and a lower growth rate. © 2007 by The University of Chicago. All rights reserved.