Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since the discovery of CRH in 1981, several investigators have reported abnormalities of the hypothalamic-pituitary-adrenal (HPA) system in response to direct stimulation of the corticotroph cells in patients with psychiatric disorders. To further explore HPA system integrity in major depressive disorders, 13 drug-free patients and normal subjects matched for age, sex, ovarian status, and body weight received 100 micrograms synthetic human CRH as an iv bolus dose. Compared to that in the normal subjects, in the depressed patients a significant attenuation of the net ACTH release after CRH administration (772 +/- 597 vs. 263 +/- 286 pmol/min.L; P less than 0.02) was observed, while beta-endorphin and cortisol responses did not differ significantly between the groups. The magnitudes of ACTH and cortisol release were negatively correlated in the patient group only (r = -0.67; P less than 0.01). Thus, the blunted ACTH response to CRH in depression might be related to hypercortisolemia, while the implications of the apparent dissociation of ACTH and beta-endorphin after CRH administration still remain unclear. Our data support the hypothesis that the hyperactivity of the HPA system in depression most likely is a consequence of CRH hypersecretion, the origin of which may be explained by abnormal central glucocorticoid receptor or neurotransmitter regulation.
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PMID:Blunted adrenocorticotropin but normal beta-endorphin release after human corticotropin-releasing hormone administration in depression. 254 28

A wide range of abnormalities of the hypothalamo-pituitary-adrenal (HPA) axis has been described in depression. This paper reviews recent advances in the understanding of this system, and draws them together to construct a model for the purposes of further research and discussion. It is proposed that there are two fundamental changes which both originate in the hypothalamus: an increased secretion of corticotropin-releasing hormone, and a neurally mediated adrenal hyper-responsivity to ACTH. The resulting changes in hormone regulation would be expected to produce all the characteristic HPA axis abnormalities commonly seen in depression. The model makes several predictions which could be tested by future experiment.
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PMID:Hypothalamo-pituitary-adrenal axis abnormalities in depression: a review and a model. 254 24

(1) The availability of short amino acid sequences of the naturally occurring ACTH 1-39 molecule has made it possible to separate the corticotropic characteristics of the parent molecule from its neurotrophic effects. Potent neurotrophic fragments are ACTH 4-10, an analog of ACTH 4-9 (Org 2766), and alpha-MSH (ACTH 1-13), peptide fragments that do not evoke corticosteroid secretion, yet clearly affect both the development and regeneration of peripheral nerve. (2) Early postnatal administration of either ACTH 4-10 or Org 2766 accelerates the neuromuscular development of the immature rat, increasing the contractile strength of the EDL muscle and inducing more rapid muscle contractions. Grasping strength and motor activity are increased; these are all changes indicative of more rapid neuromuscular maturation. Prenatal peptide treatment elicits a more complex pattern of response since administration early in gestation (GD 3-12) accelerates neuromuscular development whereas later administration (GD 13-21) decelerates maturation. (3) ACTH peptides have a similar accelerating effect on the morphology of the developing neuromuscular junction. At two weeks of age, nerve arborization is conspicuously increased by postnatal administration of either ACTH 4-10 or Org 2766, as is nerve terminal branching within the endplate itself. However, this is preceded by an initial depression of nerve branching in the 7-day-old rat pup. We conclude that while the developing neuromuscular system is sensitive to ACTH peptides, this susceptibility is age-related. The crucial role of these peptides may be limited to very brief, defined periods during which the peptides may interact with trophic or growth-associated substances, each of which may have its own decisive, circumscribed time frame of influence. (4) Perinatal administration of ACTH peptides affects CNS development. One measurable indication of this is an acceleration of eye opening. Early exposure to ACTH peptides has long-lasting effects on behavior, apparent when these animals are tested as adults. Increased spontaneous motor activity, heightened states of arousal and agitation, and changes in social behavior have been reported. Certain avoidance responses and tests of visual discrimination in male rats are improved by neonatal treatment with alpha-MSH. Overall motor activity is increased and the normal period of hyperactivity is initiated earlier. Male sexual behavior is decreased and sexually dimorphic behaviors in males are eliminated. alpha-MSH may alter the development of its own dopaminergic feedback circuitry while ACTH affects serotonin levels in the preoptic nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:ACTH modulation of nerve development and regeneration. 254 30

To explore and to compare hypothalamic-pituitary-somatotropic (HPS), hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-adrenocortical (HPA) axis function in depression, 30 subjects (15 patients with a major depressive episode and individually matched controls) received 50 micrograms growth hormone-releasing hormone-44 amide at 9:00, 200 micrograms thyrotropin-releasing hormone (TRH) at 9:00 and 100 micrograms human corticotropin-releasing hormone (CRH) at 18:00 on consecutive days as an i.v. bolus dose. Compared with controls, depressed patients showed blunted growth hormone (GH) responses to GHRH, decreased TRH-induced thyrotropin (TSH) release and reduced corticotropin (ACTH) but normal cortisol secretion following CRH. ACTH secretion following CRH and TRH-induced TSH release were positively correlated across depressed patients and controls but no significant correlations between GH responses to GHRH and TRH-induced TSH release or ACTH and cortisol secretion following CRH administration were demonstrated. Our findings suggest that altered HPT and HPA axis function associated with depression are triggered by factors that are at least partly different from those that cause HPS system dysfunction. We conclude that the pathophysiological process resulting in aberrant neuroendocrine secretory dynamics associated with depression may primarily occur at a suprapituitary site, and that HPS, HPT and HPA axis dysfunction may be precipitated by complex central and peripheral regulatory mechanisms involving largely independent factors.
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PMID:Endocrine responses to growth hormone-releasing hormone, thyrotropin-releasing hormone and corticotropin-releasing hormone in depression. 254 70

The effects of chronic cortisol treatment on neuroendocrine and behavioral responses to serotonin1 (5-HT1) receptor agonists were studied in conscious, freely moving rats. Seven-day cortisol treatment (25 mg/kg/day with osmotic minipumps) markedly suppressed basal plasma corticotropin (ACTH) and corticosterone concentrations, indicating a suppression of the hypothalamo-pituitary-adrenocortical axis. Cortisol also decreased body weight, food intake, plasma norepinephrine (NE), and epinephrine (E) levels. In the drug challenge studies, we used two 5-HT1 agonists, the 5-HT1B and 5-HT1C agonist, m-chlorophenylpiperazine (m-CPP), and the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT), to examine the effect of cortisol on their behavioral and neuroendocrine effects. After 7-day cortisol treatment, plasma prolactin responses to both m-CPP and 8-OHDPAT were significantly decreased. While the plasma NE, E, and food intake responses to m-CPP were also significantly reduced by cortisol treatment, these same responses to 8-OHDPAT were unchanged. The effect of m-CPP on locomotor activity was also decreased. Since only the responses to m-CPP and 8-OHDPAT previously shown to be antagonized by pretreatment with the 5-HT1/5-HT2 antagonist, metergoline, were significantly attenuated after cortisol treatment, these changes may be specific to 5-HT receptors. These data indicate that chronic exposure to high glucocorticoid levels alters 5-HT1 receptor-mediated functions and provides additional evidence relevant to the contribution of glucocorticoid elevation to the symptoms of depression.
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PMID:Long-term cortisol treatment impairs behavioral and neuroendocrine responses to 5-HT1 agonists in the rat. 255 39

Alprazolam, a novel benzodiazepine derivative is thought to be effective in the treatment of anxiety, panic, and depressive disorders. There is considerable interest in alprazolam's mechanism of action, particularly whether its profile of actions might resemble that of the alpha 2 adrenoreceptor agonist, clonidine. The present study assessed the biochemical, cardiovascular, and behavioral responses of healthy volunteers to acute intravenous infusions of alprazolam and placebo. Alprazolam reduced ACTH and cortisol while increasing growth hormone. There was a transient reduction in plasma norepinephrine and only modest effects on cardiovascular parameters. Subjects became quite sedated after intravenous alprazolam. This pharmacodynamic profile resembles that previously reported for traditional benzodiazepines, although alprazolam may be a more potent stimulator of growth hormone release. Alprazolam's effects on growth hormone resemble those of clonidine, but unlike clonidine, alprazolam has relatively little effect on plasma catecholamine and cardiovascular parameters. This suggests that alpha 2 mechanisms do not play a primary role in alprazolam's mode of action. Since alprazolam infusion affects three different measures (ACTH/cortisol, growth hormone, and plasma norepinephrine) thought to be dysregulated in depression, challenge with intravenous alprazolam may prove to be a useful "probe" in affective disorders.
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PMID:Intravenous alprazolam challenge in normal subjects. Biochemical, cardiovascular, and behavioral effects. 255 27

Eleven patients with major depression and 12 control subjects were administered corticotropin-releasing hormone (CRH), aqueous arginine vasopressin (AVP), and insulin hypoglycaemia (IH) to test for differences in hypothalamic-pituitary-adrenal (HPA) axis function. Patients with major depression demonstrated lower ACTH responses to CRH when compared with controls, and a trend toward such after administration of AVP. Despite lower ACTH responses in patients with depression, there were no differences in cortisol responses to these stimuli. In the CRH and AVP tests, there was no correlation between the basal cortisol and ACTH responses in either controls or patients, but in the IH test there was a negative correlation between these responses for both groups. The ACTH responses to CRH and AVP were positively correlated in controls and patients. Cortisol responses to all three provocative stimuli were positively correlated in both subject groups. These findings are consistent with the hypothesis that hypothalamic or supra-hypothalamic overactivity may be involved in the development of HPA-axis abnormalities in patients with depression.
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PMID:Consistent reduction of ACTH responses to stimulation with CRH, vasopressin and hypoglycaemia in patients with major depression. 255 71

The authors studied 8 patients (4 males and 4 females) with Cushing's syndrome due to ectopic ACTH secretion. Chronological age ranged from 15 to 45 years and duration of the disease ranged from 3 to 48 months. All patients presented typical signs of Cushing's syndrome, blood hypertension, and four of them had hyperpigmentation of the skin. Five patients had fasting hyperglycemia and all patients but one had serum hypokalemia (serum K = 2.2 to 3.9mEq/l). The circadian rhythm of cortisol was absent in all patients and basal cortisol levels were elevated in all patients but one. Basal ACTH levels evaluated in 7 patients were elevated in 6 (29 to 1050 pg/ml-MRC). One patient presented normal depression of urinary 17-OH after two days of dexamethasone and normal increase of urinary 17-OH and serum 11-dexycortisol after methyrapone. Four patients had carcinoid tumor (3 thymic and 1 bronchial), two had pancreatic islets cell tumors, one had bilateral pheochromocytoma and medular carcinoma of the thyroid, and one had oat cell carcinoma of the lung and medular carcinoma of the thyroid. Thoracic X-rays identified the ectopic ACTH secretion tumor in four cases, all confirmed by CT scan. Abdominal CT showed a difuse enlargement of the adrenals in seven cases and bilateral nodules in one case (pheochromocytomas). Six patients died within 3 years of the diagnosis. The authors concluded that clinical and hormonal findings could mislead the findings of ACTH ectopic secretion and Cushing's disease, and suggest that thoracic X-rays and CT scans of the skull, thorax, and abdome should be done in all cases of Cushing's syndrome.
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PMID:[Cushing syndrome due to ectopic ACTH secretion]. 255 51

We compared the baseline cortisol secretory pattern and ACTH and cortisol responses to hCRH (100 micrograms) in eight patients acutely withdrawn from ethanol and 12 patients who abstained from ethanol for two to six weeks. Acute withdrawal from ethanol was characterized by elevated baseline cortisol and blunted ACTH release after hCRH, while medium-term abstention was associated with normalized cortisol secretion but persistence of decreased ACTH output following stimulation. These findings support an altered corticotrophic CRH receptor function in detoxified sober alcoholics. The pathophysiology underlying the blunted ACTH response to hCRH in medium-term ethanol abstention appears to be different from that in acute alcohol withdrawal and hypercortisolemic depression.
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PMID:Human CRH stimulation response during acute withdrawal and after medium-term abstention from alcohol abuse. 256 Feb 22

A 45 year old female with Cushing's syndrome due to non-ACTH dependent bilateral adrenal macronodular hyperplasia (AMH) is reported. The diagnosis of Cushing's syndrome was based on the typical clinical features and on the demonstration of high urinary levels of free cortisol (microF) (630 micrograms/24 h) and 17 hydroxysteroids (17-OHS) which failed to suppress during the Liddle test (17-OHS, (mg/g creat), Basal: 68.5, post Dexamethasone 2 mg: 59.6 and post Dexamethasone 8 mg: 69.9). The adrenal CT scan showed bilateral multinodular enlargement while the pituitary CT scan was normal. Due to the presence of severe hypertension (240/150) and depression, the patient was treated with ketoconazole (800 mg/d) during 8 months achieving eucortisolism (microF 14-39 micrograms/24 h); however, plasma ACTH was not detectable at the end of this period. A bilateral adrenalectomy was performed, and both adrenals showed multiple nodules (0.3-4.5 cm in diameter) and weighed 136 and 31 g respectively. The lack of suppression of the 17-OHS with 8 mg of Dexamethasone, the persistence of an adequate inhibition of cortisol biosynthesis with ketoconazole, and the absence of plasma ACTH suggest that the patient had a non-ACTH dependent AMH. The possible pathogenic factors involved in this case are discussed.
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PMID:[Cushing syndrome caused by macronodular adrenal hyperplasia, independent of ACTH: report of a case]. 256 12


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