Dysregulation of hypothalamic-pituitary-adrenal axis function in depressed alcoholic patients

Hypothalamic-pituitary-adrenal (HPA) axis function was examined in 28 hospitalized, withdrawing alcoholic patients. Fourteen patients met DSM-III criteria for Major Depressive Disorder. Elevated 8 a.m. basal cortisols were noted in 7 depressed alcoholic patients (50%) and no non-depressed alcoholics (P less than 0.01). Escape from dexamethasone suppression was noted in 9 depressed alcoholics (64%) and no non-depressed alcoholics (P less than 0.005). The measurement of HPA axis function may be a useful marker for endogenous depression in an alcoholic population.     

The effects of dexamethasone administration on EEG sleep in depressed patients

Since DST non-suppression and sleep abnormalities have been shown to co-exist in depressive states, it seems important to examine what effects dexamethasone administration might have on the sleep of depressed patients. Therefore, the effects of 1 mg dexamethasone p.o. administered at 11 p.m. to a group of 12 depressed outpatients was examined. In this series of patients, the hypothesis of no significant changes in sleep continuity, sleep architecture or REM sleep features was confirmed aside from an increase in Stage 2 sleep percent and decrease in Stage 1 REM percent in these patients (both variables stayed in the normal range). It can be concluded that acute administration of dexamethasone does not influence the sleep of depressed patients in a major way.     

Repeated dexamethasone suppression test in depressed patients

In 17 depressed patients with initially abnormal results on the dexamethasone suppression test (DST), serial plasma samples for the determination of cortisol concentrations were taken every 10 days, following overnight dexamethasone administration at 11 p.m. Severity ratings were repeated on the days of blood sampling. There was a gradual normalization of the DST and progressive clinical improvement during selective antidepressant therapy. The DST was closely related (r = 0.573, P less than 0.005) to the patients' clinical mood level during the depressive episode. At the point where normalization of the DST occurred, the patients were still moderately severely ill. DST conversion occurred early in the treatment, i.e. after 23.9 (+/- 15.1) days, and preceded symptomatic improvement by 24.5 (+/- 18.1) days. Normalization of the DST was a predictor (r = 0.691, P less than 0.005) of the time of clinical improvement, but not of clinical recovery. The test was a biological discriminator between severe and less severe depressions. The time of symptomatic improvement (r = 0.505, P less than 0.05), but not of biological remission, depended on age; severe depressions lasted longer in the elderly patients.     

Effect of diphenylhydantoin on hypothalamic-pituitary-thyroid function in the rat

Chronic diphenylhydantoin (DPH) administration (5 mg x 100 g body wt-1 x day-1) to the normal rat is associated with a decrease in the serum thyroxine (T4) and triiodothyronine (T3) concentrations without an appropriate rise in the serum thyrotropin (TSH) concentration, suggesting a possible direct effect of DPH on TSH secretion. To further study this possibility, DPH was administered chronically to thyroidectomized, hypothyroid rats. In the hypothyroid rats treated chronically with DPH, serum TSH did not increase, pituitary TSH content was significantly decreased, and the serum TSH response to thyrotropin-releasing hormone (TRH) was decreased compared to that of diluent-treated, hypothyroid rats. Hypothalamic TRH content was similar in DPH and diluent-treated rats. These findings suggest that DPH suppresses pituitary TSH secretion, probably as a thyroid hormone agonist. The effect of a single large dose of DPH (20 mg/100 g body wt) administered to thyroidectomized rats also decreased serum tSH but, in contrast to the findings in chronically treated rats, hypothalamic TRH and pituitary TSH content and the serum TSH responses to TRH were increased. These differences may be due to the acute inhibitory effect of a large dose of DPH on hypothalamic TRH release. Furthermore, because the effect of thyroid hormone on regulating pituitary TSH synthesis and release is dose and time dependent, the effect of DPH as a thyroid hormone agonist on pituitary TSH dynamics may also be variable.     

Plasma dexamethasone and the dexamethasone suppression test. Initial and follow-up tests in depressed patients

Plasma dexamethasone concentrations following oral dexamethasone administration were examined in 78 patients with major depression prior to and during treatment. The test-retest stability of plasma dexamethasone levels within patients was satisfactory with an overall significant positive correlation between tests for each patient. However, significant variability was noted in individual patients. Change in pre-DST cortisol and plasma dexamethasone levels were the two variables, in that order of importance, contributing to change in DST status. In studies examining the clinical utility of serial dexamethasone suppression tests as a guide to recovery from depression, the effect of variability in plasma dexamethasone concentrations should be taken into account.     

Molecular biology and laboratory diagnosis of hypothalamic-pituitary-thyroid axis]

Recent developments in molecular biology have brought dramatic changes in laboratory medicine. Applications of molecular biology techniques have made it possible to make etiological diagnosis and produce recombinant proteins for reagents. Laboratory investigations of molecular biology in the hypothalamic-pituitary-thyroid axis include TRH gene, TRH effect, TSH gene, TSH receptor and its autoantibodies, thyroid peroxidase and thyroglobulin and their autoantibodies, thyroxine (T4) binding protein genes, deiodination of T4, thyroid hormone receptor, oncogenes of thyroid etc. The following developments are reviewed. 1) Human TSH (hTSH) beta gene and its abnormality: Two types of mutations of hTSH beta gene have been found in patients with hereditary isolated TSH deficiency. DNA diagnosis and genetic counseling are now being performed. 2) Structure and function of TSH receptor: The primary structure of hTSH receptor was identified from its gene. Relationships between its structure and function have been investigated using site specific mutagenesis and synthetic short peptides. 3) Thyroid hormone receptor gene and its abnormality: The thyroid hormone receptor gene has been successfully cloned. Several mutations of the gene have been demonstrated in patients with thyroid hormone resistance. 4) Application of recombinant hTSH (r-hTSH):r-hTSH has been produced in CHO cells. Immunological and biological properties of r-hTSH are similar to those of authentic pituitary hTSH. Clinical application of r-hTSH is now in progress.     

Environmental influences on hypothalamic-pituitary-thyroid function and behavior in Antarctica

We examined the physiological and psychological status of men and women who spent the summer (n=100) and/or winter (n=85) seasons in Antarctica at McMurdo (latitude 78.48 S, elevation 12 m) and South Pole (latitude 90 S, elevation 3880 m) stations to determine whether there were any significant differences by severity of the stations' physical environment. Physiological measures (body mass index, blood pressure, heart rate, tympanic temperature), serum measures of thyroid hormones, cortisol, and lipids and plasma catecholamines were obtained at predeployment (Sep-Oct) and the beginning of the summer (November) and winter (Mar-Apr) seasons. Cognitive performance and mood were assessed using the Automatic Neuropsychological Assessment Metric - Isolated and Confined Environments (ANAM-ICE), a computerized test battery. South Pole residents had a lower body mass index (p<0.05) and body temperature (p<0.01) and higher levels of plasma norepinephrine (p<0.05) in summer and winter than McMurdo residents. Upon deployment from the United States and during the summer, South Pole residents experienced significantly higher thyroid hormone values (free and total T(3) and T(4)) (p<0.01) than McMurdo residents; in summer they also experienced lower levels of triglycerides (p<0.01) cortisol (p<0.05) and LDL (p<0.05). In winter, South Pole residents also experienced a 39% decrease in serum TSH compared with a 31.9% increase in McMurdo (p<0.05). South Pole residents also were significantly more accurate (p<0.05) and efficient (p<0.01) in performance of complex cognitive tasks in summer and winter. Higher thyroid hormone levels, combined with lower BMI and body temperature, may reflect increased metabolic and physiological responses to colder temperatures and/or higher altitude at South Pole with no apparent adverse effect on mood and cognition.     

Serial dexamethasone suppression tests in depressed patients treated only with electroconvulsive therapy

Several systematic studies have evaluated serial dexamethasone suppression tests (DST) in patients with major depression who were treated with antidepressant medications. DST changes were noted to parallel clinical improvement in most recovering patients. If serial DSTs are a valid state-related correlate of depressive pathophysiology, all types of effective antidepressant treatment should result in DST 'normalization'. However, no treatment modalities other than antidepressant medications have been studied serially with systematic assessments. To test whether serial DSTs reflect clinical progress in depressives treated solely with electroconvulsive therapy (ECT), we studied weekly DSTs and Hamilton Rating Scales for Depression (HRSD) in 22 drug-free depressed patients. We observed progressive DST 'normalization' in most patients and moderately high correlations between weekly DST and HRSD values throughout treatment. Most patients receiving ECT became DST suppressors. In most patients the DST appeared to reflect the severity of depressive pathophysiology, perhaps providing serial feedback to clinicians monitoring the progress of treatment with ECT.     

The effect of age on cortisol and plasma dexamethasone concentrations in depressed patients and controls

The aim of this study was to identify any relationships between various patient factors such as age, gender and concurrent medication that may affect plasma cortisol or dexamethasone (DEX) concentrations. Multiple regression analysis was used to formulate an equation to predict plasma DEX levels to identify factors that may influence DEX bioavailability. Pre- and post-DST cortisol levels did not increase with age, but DEX levels were higher in elderly depressed patients. Neither gender nor psychotropic medication affected plasma cortisol or DEX levels. There was no indication that pre-DST cortisol levels influenced plasma DEX levels to account for the lower DEX values in non-suppressors. Age was the only significant factor found in this study to influence DEX levels and it could be argued that the dose of DEX should be lowered when administering the DST to elderly patients to reduce plasma DEX variability.     

The morphological effects of dexamethasone on the pituitary-adrenal axis of the rat--a quantitative study

Adult Sprague-Dawley rats received a daily intraperitoneal injection of dexamethasone (100 or 200 micrograms/kg) for 2 or 6 weeks. Quantitative assessment of the anterior pituitary corticotroph population performed using the stereological measurement of volume density (Vv). An indirect assessment of corticotroph function was also made, based on adrenal weight and histology. Adrenal changes were consistent with dose-related inhibition of corticotroph function in all dexamethasone-treated animals. Immunopositive corticotrophs were easily identified and in no treatment group was corticotroph Vv significantly less than in the appropriate vehicle-injected control group. In male animals, there was a significant increase (P less than 0.05) in Vv with 100 micrograms/kg at both 2 and 6 weeks. These results suggest that it is possible to produce inhibition of corticotroph function by the administration of such doses of dexamethasone without causing a significant reduction in the anterior pituitary corticotroph population. This may be related to the mode of negative feedback of such a regime.     

青藤碱对红斑狼疮患者外周血T细胞的抑制作用及机制探讨

目的：观察青藤碱（SIN）对系统性红斑狼疮患者T细胞功能的影响，探讨其免疫抑制作用机理。方法：分离SLE患者的PBMCs，加入anti-CD3及不同浓度SIN，以ELISA和流式细胞仪方法分析青藤碱对T淋巴细胞活化和Th1／Th2细胞因子产生的影响。结果：SIN可抑制SLE患者外周血T细胞产生IFN-γ、IL-2和IL-4。SIN能够显著降低CD4^＋T和CD8^＋T细胞表面活化分子CD69和CD25的表达。结论：SIN可通过抑制T细胞的活化及细胞因子的分泌，发挥免疫抑制作用。     

Reported weight loss and dexamethasone nonsuppression in depressed patients. A negative study

In a sample of 96 patients with DSM-III major depressive disorder and in a subset of 78 melancholic patients, there was no evidence that dexamethasone nonsuppression was more common in patients with reported weight loss.     

Plasma dexamethasone and cortisol levels in depressed outpatients

We investigated the 1-mg dexamethasone suppression test (DST) in 41 outpatients with major depressive disorder assessing the role of dexamethasone blood level, age and basal cortisol on DST results. Non-suppressors (approximately 25% of patients) had lower dexamethasone levels, and post-dexamethasone cortisol was negatively correlated with plasma dexamethasone; these findings were more significant after covarying out age and basal cortisol, factors that were also significantly associated to non-suppressors. A subgroup of patients (n = 19) also had 0.75-mg and 2.0-mg DST to evaluate whether a threshold dexamethasone blood level existed; a dexamethasone blood level greater than 1.5 ng/ml converted all non-suppressors to suppressors. Implications of these findings are discussed.     

The effects of moclobemide on nocturnal sleep of depressed patients

The effect of moclobemide, a short-acting, reversible, preferential type-A MAO inhibitor (300 mg daily in three divided doses), on the sleep of eight depressed patients was assessed by polysomnographic recordings in a 4-week therapeutic trial. Six patients showed an improvement greater than 50% on the Hamilton Depression Rating Scale. Compared to placebo, patients receiving moclobemide showed improved sleep continuity as judged by the decrease in wake time after sleep onset and total wake time, particularly during the intermediate and late stages of drug administration. Total sleep time increase was comprised of larger amounts of stage 2 NREM sleep. REM sleep latency was significantly increased and REM sleep % decreased during the drug administration period. However, in contrast to the older, non-selective and selective MAOIs, moclobemide had a mild REM sleep suppressant effect.     

The hypothalamic-pituitary-thyroid axis in agoraphobia, panic disorder, major depression and normal controls

BACKGROUND: Much interest has been drawn to the investigation of the hypothalamic-pituitary-thyroid (HPT)-axis in patients suffering from depression or panic disorder. However, there is no data concerning agoraphobia. METHODS: Patients with panic disorder, agoraphobia, major depression were compared to normal controls (total n=88) in respect to HPT axis, obtaining basal TSH and administering a TRH test. RESULTS: Normal controls and agoraphobics showed significantly higher Delta(max) TSH than depressives and panic patients. There were no differences between agoraphobics and normal controls. CONCLUSIONS: Agoraphobia, unlike depression or panic disorder, seems to be less biologically determined in respect to the HPT-axis.     

Effects of metyrapone and dexamethasone upon pro-gamma-MSH plasma levels in depressed patients and healthy controls

There is current controversy over the mechanisms underlying hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in depression. Pro-gamma-melanocyte-stimulating hormone (MSH), a portion of the N-terminal region of pro-opiomelanocortin, has been shown to act synergistically with adrenocorticotropic hormone (ACTH) in stimulating corticosteroid secretion both in vitro and in vivo. Pro-gamma-MSH and ACTH plasma levels were measured in 30 drug-free male patients with a DSM-IIIR major depressive disorder and 21 healthy controls. The baseline levels were similar in the two groups. After single-dose metyrapone stimulation, both hormones increased, but pro-gamma-MSH was significantly higher in control subjects than in depressives. After overnight 1-mg dexamethasone, ACTH was significantly less suppressed in depressives than controls. These results suggest that HPA axis dysregulation in depression may involve peptides other than ACTH and be more complex than previously reported.     

Hypothalamic-pituitary-adrenal axis function in patients with chronic depression

BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis function in patients with chronic depression has previously been shown to be normal when measured using the dexamethasone suppression test (DST). We examined patients with chronic depression using the sensitive dexamethasone/corticotropin releasing hormone (dex/CRH) test and the dexamethasone suppression test (DST) to establish whether HPA axis abnormalities are present in this group. We also compared the sensitivity of the two tests and compared the results with previous studies in depression that have not specifically selected chronic patients. METHOD: Twenty-nine patients with the chronic subtype of major depressive disorder and 28 matched controls underwent examination of HPA axis function. RESULTS: Neither the cortisol response to the DST or the dex/CRH test differed significantly between the patient and control groups. There was a trend in favour of more patients than controls having an abnormal response to the dex/CRH test (P = 0.052). Neither the patients with an abnormally enhanced response, nor the magnitude of response could be predicted by any illness or demographic variable. CONCLUSION: The HPA axis is not overtly abnormal in chronic depression. This contrasts with previous findings in acute depression and bipolar disorder and may suggest that the HPA axis abnormalities present in acute depression resolve, but are not accompanied by symptom resolution. Alternatively, a subgroup of depressives with less HPA dysfunction may progress to chronicity. This has implications for treatment and prognosis. The dex/CRH is a more sensitive test of HPA axis function than the DST in patients with chronic depression.