Gonadotropin release after administration of GnRH in depressed patients and healthy volunteers

Considerable attention has been paid to studies of hormonal response abnormalities in depressed patients, and functional changes have been demonstrated in a number of neuroendocrine axes. The findings from the present study extend the results of previous investigations but demonstrate a functionally intact HPG axis in depressed patients. A number of statements can be made concerning the gonadotropin-releasing hormone (GnRH) strategy: (1) Previous studies utilizing GnRH challenge have been limited in number and poorly controlled. (2) We chose to utilize our normative data because standard gonadotropin response ranges to GnRH have not previously been established in studies with depressed patients. Moreover, hormonal responses may be affected by age, sex, menstrual status, dose, and method and rate of GnRH administration. The assessment of the hormonal responses to GnRH in depressed patients and healthy controls studied under identical conditions provides the most accurate basis for comparison. (3) The incidence of abnormal LH and FSH release in depressed subjects was similar to controls, in contrast to response abnormalities found with other neuroendocrine axes. (4) Alterations in gonadotropin were limited to FSH, were sporadic, and did not differ significantly from controls. This finding is of interest and suggests that neuroendocrine alterations in depression do not necessarily affect all neuroendocrine axes.     

Adrenocortical responsiveness to novelty in the hamster

The adrenocortical response to increasing periods of exposure to a novel cage, as well as the effects of returning hamsters to their familiar home cages, were examined. We found that a five min exposure to a novel cage was insufficient to activate the pituitary-adrenal system, but that cortisol levels increased significantly as duration of exposure increased from 15 to 30 min. In contrast, returning hamsters to their home cages for at least 15 min following the 15 min novel cage exposure produced a significant drop in plasma levels of cortisol. Finally we found that males exhibit a greater cortisol response to novelty than females, indicating a sexual dimorphism which is the reverse of that reported in other rodents.     

Age effects on cortisol levels in depressed patients with and without comorbid post-traumatic stress disorder, and healthy volunteers

BACKGROUND: Post-traumatic stress disorder (PTSD) and major depression are frequently comorbid. Age and major depression are associated with higher cortisol levels and dexamethasone resistance, whereas PTSD is associated with lower cortisol and dexamethasone supersensitivity. Therefore, we examined the effect of age on the hypothalamic-pituitary-adrenal (HPA) system in depressed patients with and without PTSD. METHODS: Thirty-one depressed patients without PTSD, 12 depressed patients with PTSD, and 23 healthy volunteers were studied on 2 days. Subjects received single-blind placebo on day 1 and fenfluramine on day 2. Cortisol levels were drawn before challenge and for 5 h thereafter. RESULTS: Cortisol levels increase with age in depressed patients without PTSD but not in depressed patients with PTSD or in healthy volunteers. Number of previous major depressive episodes was a predictor of the cortisol response to fenfluramine administration in depressed patients without PTSD. CONCLUSIONS: The results of our study highlight the importance of considering age in psychobiology. Further research is needed to fully delineate the role of age in abnormalities of the HPA axis found in major depression and PTSD.     

Nycthemeral rhythm in adrenal responsiveness to ACTH.

Adrenal adenosine 3',5'-cyclic monophosphate (cAMP) and corticosterone responses to exogenous ACTH were found to be about 2.5 times greater in the evening (at lights off) than in the morning (at lights on) in rats. The rhythm in adrenal responsiveness to ACTH was found to persist in rats treated with dexamethasone 15 and 3 h before exogenous ACTH (in the presumed absence of a rhythm in endogenous ACTH). Treatment with p-chlorophenylalanine did not affect the daily rise in circulating ACTH levels but did abolish the rhythm in adrenal responsiveness to ACTH. The magnitude of the rhythm in adrenal responsiveness to ACTH is greater than the magnitude of the rhythm in ACTH. Because the rhythms are dissociable, we conclude that in vivo measurements of adrenal corticosteroid levels do not necessarily reflect ACTH levels.     

Pre- and post-dexamethasone plasma ACTH levels in depressed patients and normal controls

Levels of plasma ACTH in relation to dexamethasone administration were evaluated in 16 medication-free patients with a major depressive episode and 39 normal controls. Depressed patients had significantly higher levels of plasma ACTH than controls both at 4:00 p.m. predexamethasone and 4:00 p.m. postdexamethasone. The significance of this finding is discussed.     

Timing of movements in depressed patients and healthy controls

BACKGROUND: Psychomotor disturbances are fundamental psychopathological features of major depression and observable components of behaviour. Human behaviour is segmented into action units with duration of a few seconds due to central nervous motor processing. Timing may depend on cognitive and emotional functions which are affected in depression. Therefore, time structure of action units in depressed patients was compared to healthy controls. METHODS: Included were patients with major depression and melancholic features. Upper limb movements (total n = 566) of depressed patients and matched controls were evaluated using videotaped interviews and frame-by-frame analysis with a temporal resolution of 40 ms. RESULTS: Behaviour of depressed patients in interview sessions was organised in action units with a narrow time span of only a few seconds. Single, non-repetitive action units were significantly shorter (median = 1.20 s) and repetitive units longer (median = 4.92 s) in patients compared to controls (median = 2.08 and 2.96, respectively). LIMITATIONS: Behaviour in interview sessions might differ from activities of daily living. DISCUSSION: Altered temporal segmentation of movements appears to be an observable, measurable sign of melancholic depression and may allow further insights in pathophysiological dysfunctions of the disease. Clinical implications of these motor changes for differential diagnosis, course and treatment of depression are discussed and need further evaluation.     

A neuroendocrine study of serotonin function in depressed stroke patients compared to non depressed stroke patients and healthy controls.

OBJECTIVES: We employed a neuroendocrine challenge paradigm to study serotonergic abnormalities associated with poststroke depression. METHOD: Twelve depressed stroke patients (major depression N= 5, minor depression N = 7), 8 nondepressed stroke patients and 12 healthy volunteers completed a single-blind, placebo-controlled, challenge tests. Baseline cortisol (CORT) and prolactin (PRL) values, and these hormonal responses to 30 mg of oral d-FEN and placebo over a 4 hour period were measured in the three groups. RESULTS: There were intergroup differences for baseline adjusted PRL responses (change scores from baseline) to d-FEN (group effect F = 4.38, df = 2,29, p = 0.02) while these responses to placebo were comparable between groups (group effect F = 1.82, df = 2,29, p = 0.18). Peak PRL responses (post d-FEN maximal PRL change from baseline scores) in depressed stroke patients were significantly greater than in nondepressed patients (p = 0.005) but comparable to healthy normals (p = 0.47). However, these responses between major and minor depression were not significant (p = 0.34). There was a trend suggesting a negative correlation between peak PRL response and severity of depression (p = 0.056). Depressed patients were younger than the controls (p = 0.054). Also, the depressed group was more functionally impaired (p = 0.04) and more likely to have right-sided lesions (p = 0.009) compared with the nondepressed group. Differences in baseline adjusted PRL changes between depressed and nondepressed groups became non significant when the influence of laterality of lesions was covaried, whereas covariation of functional scores and age did not alter the significance. CORT responses did not show intergroup differences. LIMITATIONS: The study group was small and was heterogenous in lesion characteristics, time since stroke and type of depression. A fixed-order design was used in the challenge test paradigm. CONCLUSIONS: When laterality of stroke lesion was taken into account, depressed and nondepressed stroke patients did not differ in PRL responses to d-FEN.     

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.     

Amygdala volumes in a sample of current depressed and remitted depressed patients and healthy controls

BackgroundMajor Depressive Disorder is associated with amygdala volumetric alterations. To date, it is still unclear (I) whether amygdala volumetric alterations constitute a state or a trait marker of MDD; (II) what influences the direction of amygdala morphometric changes (i.e., enlargement versus shrinkage); and (III) what the role of laterality is in amygdala volumetric alterations in MDD.MethodsWe investigated amygdala volume in a sample of 31 currently depressed patients (cMDD), 31 healthy subjects with a previous diagnosis of MDD (rMDD) and 31 healthy controls, using images obtained from a 1.5 Tesla MRI scanner. The groups were matched for age and gender.ResultsWe found that left amygdala volumes of rMDD subjects were significantly larger as compared to healthy controls, and tended to be larger when compared to cMDD subjects. There was no difference in left amygdala volumes between cMDD patients and healthy controls. Right amygdala volumes did not differ between groups.ConclusionsGiven that amygdala alterations were present only in remitted patients, we suggest that such alterations appear to be a state marker of MDD. Further, we found evidence of a lateralization effect, with changes in the left hemisphere only. Left amygdala enlargement in the rMDD group may represent a neurobiological marker of vulnerability to relapse, or may reflect recovery from MDD, whereby volumetric changes have resulted from stress associated with the last depressive episode.     

Testing of analgesics by electrical stimulation of the dental pulp in healthy volunteers

A modified method of electrical stimulation of the dental pulp suitable for testing non-narcotic analgesic substances in healthy volunteers is described. This technique makes it possible to demonstrate dose-response relationships with acetylsalicylic acid and to make accurate comparisons of different substances under double-blind conditions.deceased     

Similar sleep EEG topography in middle-aged depressed patients and healthy controls

OBJECTIVES: One of the early hypotheses relating sleep disturbances in depression to a model of sleep regulation is the S-deficiency hypothesis. It is postulated that, in depressed patients, sleep propensity during wakefulness does not rise to the level attained by nondepressed subjects, resulting in altered sleep structure or changes in the electroencephalogram during sleep. We aimed to test this hypothesis by assessing topographic changes in the sleep electroencephalogram associated with depression. DESIGN: Cross-sectional clinical study. SETTING: Mental Health Clinical Research Center. PARTICIPANTS: Sixteen unmedicated depressed outpatients (mean age: 41.2 years) and 16 pair-matched healthy controls (mean age: 41.1 years). Interventions: None. MEASUREMENTS: Baseline sleep electroencephalogram recordings were obtained from a central referential electrode and from 3 bipolar derivations (frontocentral, centroparietal, parietooccipital) along the anteroposterior axis. RESULTS: Symptoms of depression at the time of sleep recordings were moderate (24-item Hamilton Rating Scale of Depression range: 16-31). No differences between patients and controls were found in sleep variables and all-night electroencephalogram spectra in non-rapid-eye-movement and rapid-eye-movement sleep. The ultradian modulation of slow-wave activity (power within 0.75-4.5 Hz), as well as the exponential decline of slow-wave activity, during sleep did not differ between the groups. The statistical analyses of electroencephalogram power gradients between adjacent derivations revealed no Group x Derivation interactions. An anterior dominance in non-rapid-eye-movement sleep power was present in the 0.75- to 2-Hz range, which diminished throughout the night. CONCLUSIONS: These findings in moderately depressed patients do not support the existence of an S-deficiency during sleep. Because the build up of sleep propensity during waking can be dissociated from its decline, future studies need to investigate the waking electroencephalogram spectra in depression.     

Comparison of CRH test and ACTH test in patients with bronchial asthma]

Although glucocorticoid is the most effective agent for bronchial asthma, its systemic administration leads to suppression of adrenocortical function. Rapid ACTH test has been performed for assessing the function of the hypothalamic-pituitary-adrenocortical (HPA) system of asthmatics. Recently human corticotropin-releasing hormone (CRH) has been chemically synthesized. In order to evaluate clinical usefulness of CRH, we compared CRH test with ACTH test in 17 patients with bronchial asthma (3 patients out of them concurrently receiving prednisolone 5-10 mg/day). Both tests were carried out within 2 weeks after 6 month treatment with fluticasone propionate (800 micrograms/day) inhaled via pMDI. There is no significant difference between results obtained from the both tests. Thus, dividing subjects into high and low responders based on an extent of increases in plasma ACTH levels after the CRH injection, we found a significant difference in maximal plasma concentrations of cortisol between after CRH and ACTH injections in the low responders. Therefore, in some patients, CRH test provides more accurate assessment of the function of HPA system than ACTH test.     

Fecal antibodies to Cryptosporidium parvum in healthy volunteers

This study examined the intestinal antibody response in 26 healthy volunteers challenged with Cryptosporidium parvum oocysts. Fecal extracts were assayed for total secretory immunoglobulin A (IgA) and C. parvum-specific IgA reactivity. Specific IgA reactivity was standardized to IgA concentration and expressed as a reactivity index (RI). Anti-C. parvum fecal IgA (fIgA) increased significantly in 17 of 26 (65.4%) following oocyst ingestion. Of those with detectable responses, 59, 76.5, and 94.1% were positive by days 7, 14, and 30, respectively. Volunteers receiving high challenge doses (>1,000 and 300 to 500 oocysts) had higher RIs (RI = 5.57 [P = 0. 027] and RI = 1.68 [P = 0.039], respectively) than those ingesting low doses (30 to 100 oocysts; RI = 0.146). Subjects shedding oocysts and experiencing a diarrheal illness had the highest fIgA reactivity. When evaluated separately, oocyst excretion was associated with an increased fIgA response compared to nonshedders (RI = 1.679 versus 0. 024, respectively; P = 0.003). However, in subjects experiencing diarrhea with or without oocyst shedding, a trend toward a higher RI (P = 0.065) was seen. Extracts positive for fecal IgA were further examined for IgA subclass. The majority of stools contained both IgA1 and IgA2, and the relative proportions did not change following challenge. Also, no C. parvum-specific IgM or IgG was detected in fecal extracts. Thus, fecal IgA to C. parvum antigens was highly associated with infection in subjects who had no evidence of previous exposure and may provide a useful tool in detecting recent infections.     

Tyrosine transport in fibroblasts from healthy volunteers and patients with schizophrenia

Aberrant tyrosine transport across the fibroblast membrane, as measured by lower Vmax and/or lower Km is a repeated finding in patients with schizophrenia. The aim of this study was to investigate the importance of two major transporters, the L- and A-systems and tyrosine transport in fibroblast cell lines from patients with schizophrenia and healthy volunteers. Fibroblast cell lines, n=6 from healthy volunteers and n=6 from patients with schizophrenia, were included in the study. Uptake of [14-C] L-tyrosine in fibroblasts was measured using the cluster tray method in absence and presence of inhibitors. The uptake of tyrosine by the L-system was evaluated with the inhibitor 2-aminobicyclo heptane-2-carboxylic acid (BCH) and the A-system with the inhibitor nonmetabolized methyl-aminoisobutyric acid (MeAIB). Using [14-C] MeAIB the functionality of system A isoform 2, ATA2, was tested. BCH inhibited the uptake of tyrosine with 90%, showing that tyrosine transport in fibroblasts is mainly transported by the L-system. Not more than 10% could be contributed by the A-system. Excess of MeAIB did not influence tyrosine kinetics. Moreover, MeAIB kinetics did not differ between the patients and the controls. In conclusion, aberrant tyrosine transport observed in patients with schizophrenia is probably linked to the one of the L-systems and does not seem to involve the ATA2 transporter.     

30 Min ACTH stimulation test as predictor of hypothalamic-pituitary-adrenocortical function. Comparison with metyrapone test

In 32 subjects the hypothalamic-pituitary-adrenocortical (HPA) response to metyrapone was found to correlate significantly with the adrenocortical response to exogenous ACTH. This report provides additional evidence suggesting that a 30 min exogenous ACTH stimulation test accurately predicts the integrated responsiveness of the HPA system to various stimuli.