Dataset Information

Lithium monotherapy increases ACTH and cortisol response in the DEX/CRH test in unipolar depressed subjects. A study with 30 treatment-naive patients.

ABSTRACT:

Background

Distorted activity of the hypothalamic-pituitary-adrenocortical (HPA) system is one of the most robustly documented biological abnormalities in major depression. Lithium is central to the treatment of affective disorders, but little is known about its effects on the HPA system of depressed subjects.

Objective

To assess the effects of lithium monotherapy on the HPA system of patients with major depression by means of the combined DEX/CRH test.

Method

Thirty drug-naive outpatients with major depression (single episode or unipolar recurrent; SCID I- and II-confirmed) were treated with lithium monotherapy for four weeks. The DEX/CRH test was conducted directly before intake of the first lithium tablet and four weeks thereafter. Weekly ratings with the HDRS(21) were used to determine response (?50% symptom reduction) and remission (HDRS ?7).

Results

Lithium levels within the therapeutic range were achieved rapidly. Tolerability was good; no patient terminated the treatment prematurely. Response and remission rates were 50% and 33% respectively. Compared to the DEX/CRH test before the start of the treatment, a considerable and significant increase in all CRH-stimulated ACTH and cortisol parameters could be detected in the second DEX/CRH test. When analysed with particular regard to responders and non-responders, that significant increase was only present in the responders.

Conclusions

We were able to demonstrate that lithium leads to a significant activation of the HPA system. This is possibly connected to stimulation of hypothalamic arginine vasoporessin (AVP), to direct intracellular effects of lithium on pituitary cells and to an induction of gene expression.

Trial registration

drks-nue.uniklinik-freiburg.de DRKS00003185.

SUBMITTER: Bschor T

PROVIDER: S-EPMC3223180 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Publications

Lithium monotherapy increases ACTH and cortisol response in the DEX/CRH test in unipolar depressed subjects. A study with 30 treatment-naive patients.

Bschor Tom T Ritter Dirk D Winkelmann Patricia P Erbe Sebastian S Uhr Manfred M Ising Marcus M Lewitzka Ute U

PloS one 20111123 11

<h4>Background</h4>Distorted activity of the hypothalamic-pituitary-adrenocortical (HPA) system is one of the most robustly documented biological abnormalities in major depression. Lithium is central to the treatment of affective disorders, but little is known about its effects on the HPA system of depressed subjects.<h4>Objective</h4>To assess the effects of lithium monotherapy on the HPA system of patients with major depression by means of the combined DEX/CRH test.<h4>Method</h4>Thirty drug-n ...[more]

PMID: 22132117

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Project description:BACKGROUND: Recently, hypothalamus-pituitary-adrenal (HPA) axis function assessed with the combined dexamethasone (DEX)/corticotropin releasing hormone (CRH) test has been shown to be associated with response to antidepressant treatment. A polymorphism (rs16944) in the interleukin-1beta (IL-1?) gene has also been reported to be associated with the medication response in depression. These findings prompted us to examine the possible association between IL-1? gene polymorphisms and HPA axis function assessed with the DEX/CRH test. METHODS: DEX/CRH test was performed in 179 healthy volunteers (45 males: mean age 40.5 ± 15.8 years; 134 females: mean age 47.1 ± 13.2 years). Five tagging single nucleotide polymorphisms (SNPs) of IL-1? gene (rs2853550, rs1143634, rs1143633, rs1143630, rs16944) were selected at an r2 threshold of 0.80 with a minor allele frequency > 0.1. Genotyping was performed by the TaqMan allelic discrimination assay. A two-way factorial analysis of variance (ANOVA) was performed with the DEX/CRH test results as the dependent variable and genotype and gender as independent variables. To account for multiple testing, P values < 0.01 were considered statistically significant for associations between the genotypes and the cortisol levels. RESULTS: The cortisol levels after DEX administration (DST-Cortisol) showed significant associations with the genotypes of rs16944 (P = 0.00049) and rs1143633 (P = 0.0060), with no significant gender effect or genotype × gender interaction. On the other hand, cortisol levels after CRH administration (DEX/CRH-Cortisol) were affected by gender but were not significantly influenced by the genotype of the examined SNPs, with no significant genotype × gender interaction. CONCLUSIONS: Our results suggest that genetic variations in the IL-1? gene contribute to the HPA axis alteration assessed by DST-Cortisol in healthy subjects. On the other hand, no significant associations of the IL-1? gene polymorphisms with the DEX/CRH-Cortisol were observed. Confirmation of our findings in futures studies may add new insight into the communication between the immune system and the HPA axis.

Project description:BackgroundSepsis is typically hallmarked by high plasma (free) cortisol and suppressed cortisol breakdown, while plasma adrenocorticotropic hormone (ACTH) is not increased, referred to as 'ACTH-cortisol dissociation.' We hypothesized that sepsis acutely activates the hypothalamus to generate, via corticotropin-releasing hormone (CRH) and vasopressin (AVP), ACTH-induced hypercortisolemia. Thereafter, via increased availability of free cortisol, of which breakdown is reduced, feedback inhibition at the pituitary level interferes with normal processing of pro-opiomelanocortin (POMC) into ACTH, explaining the ACTH-cortisol dissociation. We further hypothesized that, in this constellation, POMC leaches into the circulation and can contribute to adrenocortical steroidogenesis.MethodsIn two human studies of acute (ICU admission to day 7, N = 71) and prolonged (from ICU day 7 until recovery; N = 65) sepsis-induced critical illness, POMC plasma concentrations were quantified in relation to plasma ACTH and cortisol. In a mouse study of acute (1 day), subacute (3 and 5 days) and prolonged (7 days) fluid-resuscitated, antibiotic-treated sepsis (N = 123), we further documented alterations in hypothalamic CRH and AVP, plasma and pituitary POMC and its glucocorticoid-receptor-regulated processing into ACTH, as well as adrenal cortex integrity and steroidogenesis markers.ResultsThe two human studies revealed several-fold elevated plasma concentrations of the ACTH precursor POMC from the acute to the prolonged phase of sepsis and upon recovery (all p < 0.0001), coinciding with the known ACTH-cortisol dissociation. Elevated plasma POMC and ACTH-corticosterone dissociation were confirmed in the mouse model. In mice, sepsis acutely increased hypothalamic mRNA of CRH (p = 0.04) and AVP (p = 0.03) which subsequently normalized. From 3 days onward, pituitary expression of CRH receptor and AVP receptor was increased. From acute throughout prolonged sepsis, pituitary POMC mRNA was always elevated (all p < 0.05). In contrast, markers of POMC processing into ACTH and of ACTH secretion, negatively regulated by glucocorticoid receptor ligand binding, were suppressed at all time points (all p ≤ 0.05). Distorted adrenocortical structure (p < 0.05) and lipid depletion (p < 0.05) were present, while most markers of adrenocortical steroidogenic activity were increased at all time points (all p < 0.05).ConclusionTogether, these findings suggest that increased circulating POMC, through CRH/AVP-driven POMC expression and impaired processing into ACTH, could represent a new piece in the puzzling ACTH-cortisol dissociation.

Project description:BackgroundPsychological stress is a crucial parameter in defining the symptoms of burning mouth syndrome (BMS). We hypothesized that the level of psychological stress in patients with BMS would correlate with severity of clinical symptoms, cortisol levels, and cortisol/ adrenocorticotropic hormone (ACTH) ratio. We aimed to comprehensively investigate the influence of clinical and hematologic parameters on the hypothalamic-pituitary-adrenal axis, particularly concerning the presence or absence of self-perceived psychological stress in patients with BMS. In addition, we aimed to identify parameters predicting psychological stress in these patients.MethodsOne hundred and forty-one patients with BMS (117 women, 82.98%; 56.21 ± 13.92 years) were divided into psychological stress (n = 68; 55 females, 56.39 ± 12.89 years) and non-psychological stress groups (n = 73; 62 females, 56.03 ± 14.90 years), and inter- and intra-group statistical analyses were conducted. Significant predictors of psychological stress in patients with BMS were investigated through multiple logistic regression analysis.ResultsThe prevalence of xerostomia was significantly higher (67.6% vs. 34.2%, p < 0.001), while unstimulated salivary flow rate was lower (0.66 ± 0.59 vs. 0.91 ± 0.53 mL/min, p < 0.01) in the psychological stress group than in the non-psychological stress group. SCL-90R subscale values for somatization, hostility, anxiety, and depression, as well as cortisol and ACTH levels and the cortisol/ACTH ratio, were also higher in the psychological stress group (all p < 0.05). Above-mean values for cortisol (AUC = 0.980, 95%CI: 0.959-1.000) and cortisol/ACTH (AUC = 0.779; 95%CI, 0.701-0.856) were excellent predictors of psychological stress, with cortisol (r = 0.831, p < 0.01) and cortisol/ACTH (r = 0.482, p < 0.01) demonstrating substantial correlations. Above-average values for cortisol (OR = 446.73) and cortisol/ACTH (OR = 6.159) significantly increased incidence of psychological stress in patients with BMS (all p < 0.001).ConclusionsAmong patients with BMS, xerostomia, decreased salivary flow rate, increased cortisol levels, and cortisol/ACTH ratio were associated with psychological stress, highlighting the psycho-neuro-endocrinological features of this condition. Cortisol and cortisol/ACTH ratio were strong predictors of psychological stress in patients with BMS.

Project description:BackgroundPsychosocial stress and activation of neutrophil granulocytes are increasingly recognized as major risk factors of coronary artery disease (CAD), but the possible relationship of these two factors in CAD patients is largely unexplored. Activation of neutrophils was reported to be associated with stenting; however, the issue of neutrophil state in connection with percutaneous coronary intervention (PCI) is incompletely understood from the aspect of stress and its hypothalamic-pituitary-adrenal axis (HPA) background. Thus, we aimed to study cortisol- and ACTH-associated changes in granulocyte activation in patients undergoing PCI.Methodology/principal findingsBlood samples of 21 stable angina pectoris (SAP) and 20 acute coronary syndrome (ACS) patients were collected directly before (pre-PCI), after (post-PCI) and on the following day of PCI (1d-PCI). Granulocyte surface L-selectin, CD15 and (neutrophil-specific) lactoferrin were analysed by flow cytometry. Plasma cortisol, ACTH, and lactoferrin, IL-6 were also assayed. In both groups, pre- and post-PCI ratios of lactoferrin-bearing neutrophils were relatively high, these percentages decreased substantially next day; similarly, 1d-PCI plasma lactoferrin was about half of the post-PCI value (all p?0.0001). Post-PCI ACTH was reduced markedly next day, especially in ACS group (SAP: p<0.01, ACS: p?0.0001). In ACS, elevated pre-PCI cortisol decreased considerably a day after stenting (p<0.01); in pre-PCI samples, cortisol correlated with plasma lactoferrin (r?0.5, p<0.05). In 1d-PCI samples of both groups, ACTH showed negative associations with the ratio of lactoferrin-bearing neutrophils (SAP: r?=?-0.601, p<0.005; ACS: r?=?-0.541, p<0.05) and with plasma lactoferrin (SAP: r?=?-0.435, p<0.05; ACS: r?=?-0.609, p<0.005).Conclusions/significancePre- and post-PCI states were associated with increased percentage of activated/degranulated neutrophils indicated by elevated lactoferrin parameters, the 1d-PCI declines of which were associated with plasma ACTH in both groups. The correlation of plasma cortisol with plasma lactoferrin in the extremely stressed ACS before stenting, however, suggests an association of cortisol with neutrophil activation.

Dataset Information

Lithium monotherapy increases ACTH and cortisol response in the DEX/CRH test in unipolar depressed subjects. A study with 30 treatment-naive patients.

Background

Objective

Method

Results

Conclusions

Trial registration

Publications

Lithium monotherapy increases ACTH and cortisol response in the DEX/CRH test in unipolar depressed subjects. A study with 30 treatment-naive patients.

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