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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While many features of the adrenocortical axis are unchanged with age in humans, there is a pattern of senescent hypercortisolism. This occurs basally, following threshold doses of dexamethasone, and in synergy with depression or Alzheimer's disease. An understanding of neuroendocrine aging is important, for both its gerontological implications, and determination of normative values for comparison with neuropsychiatric states. We have investigated whether aging is associated with hypercortisolism in a population of wild primates. The subjects were 108 yellow baboons (Papio cynocephalus) that have been under long-term study of Amboseli National Park in Kenya. Animals were anesthetized by blowgun under similar circumstances that allow for determination of basal cortisol concentrations. Sixty minutes later, 5.0 mg dexamethasone was administered to each animal, and cortisol determinations were made on serum collected immediately before administration and 6 hr later. Basal cortisol concentrations rose with age (p less than 0.028; r = 0.23). This occurred in a nonprogressive manner, in that there were no differences in concentrations among the youngest three quartiles of animals, whereas animals in the oldest quartile (older than approximately 16 years) had significantly higher values. In addition, there was a significant increase in postdexamethasone cortical concentrations with age (p less than 0.01; r = 0.31). This feature emerged progressively with age in both sexes. A number of possible artifactual causes of this senescent pattern could be eliminated, including medication confound, coincident disease, and body weight. These findings suggest that hypercortisolism and glucocorticoid feedback resistance might be general features of primate aging.
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PMID:Incidence of hypercortisolism and dexamethasone resistance increases with age among wild baboons. 175 95

Because of the similarities in the psychiatric symptoms of Cushing's syndrome and those of major depression, and because the former generally remits when the hyperadrenalism is alleviated, an open clinical trial of the effect of steroid suppression in major depression was undertaken. Ten patients satisfying the DSM-III-R criteria for major depression, and classified as treatment-resistant, were included. Eight patients completed the study, which consisted of discontinuation of other psychotropic drugs and 2 months' treatment with one or more steroid suppressive agent (aminoglutethimide, ketoconazole and/or metyrapone). Six were classified as responders, and two as partial responders. In six, the improvement has been sustained for longer than 5 months after withdrawing the drugs. Side effects were mild to moderate. These results provide some evidence that steroids are involved in the maintenance of major depression, and that their suppression may lead to a readjustment of the hypothalamic-pituitary-adrenal axis with remission of the depression.
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PMID:Response to steroid suppression in major depression resistant to antidepressant therapy. 157 41

The behavioral consequences of the central administration of corticotropin releasing hormone (CRH) in rhesus monkeys was determined using food-maintained behavior. Acute doses of CRH (0.003 ng/kg-10 micrograms/kg, i.c.v.), decreased responding for food in a dose- and time-related manner. With intermediate doses, responding occurred at a high rate until food was delivered, and then abruptly ceased for several minutes. Previous studies have attributed similar effects to the noxious properties of certain drugs. Acute doses had no effect on home cage food consumption, body weight, or responding for food on subsequent days. When CRH was given repeatedly for several days, its behavioral suppressant effects increased. Home cage food intake, body weight, and subsequent responding for food decreased for up to 6 weeks before returning to normal. These results suggest that sustained elevations in central levels of CRH can result in a sensitization to its anorexigenic effects, an effect that has not been reported in other species. Because hyperaroused clinical states such as depression and anorexia nervosa are characterized biochemically by hypercortisolism and elevated CRH in CSF, these anorexigenic effects may corroborate a potential role for CRH in affective disorders.
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PMID:Corticotropin releasing hormone produces profound anorexigenic effects in the rhesus monkey. 204 89

We report here a study of the effects of alprazolam on in vivo pituitary-adrenal function in jacketed nonrestrained nonhuman primates and on in vitro CRH release from rat hypothalami and ACTH release from rat dispersed anterior pituicytes. We undertook this study because alprazolam is the only benzodiazepine effective in treating both major depressive and anxiety disorders, and recent data suggest that the hypercortisolism of major depression reflects hypersecretion of CRH. Moreover, the intracerebroventricular administration of CRH can reproduce many of the components of the symptom complex of major depression, including not only hypercortisolism, but also hypothalamic hypogonadism, decreased libido, anorexia, and intense anxiety. As a comparison, we also assessed the effects of diazepam on in vitro CRH release, because in contrast to alprazolam, diazepam is effective in anxiety states but not in depression. Alprazolam (0.01-0.3 mg/kg, iv) produced a dose-dependent inhibition of both plasma ACTH and cortisol secretion in non-restrained adult male rhesus monkeys. Our in vitro studies showed that alprazolam significantly inhibited serotonin (5HT)-induced CRH release in a dose-dependent fashion (10(-10)-10(-5) M). Diazepam also inhibited 5HT-induced CRH release, but was 40 times less potent than alprazolam. Alprazolam was ineffective in blocking basal or CRH-induced ACTH release from rat dispersed anterior pituicytes, suggesting that its in vivo effects are through inhibition of CRH secretion. As expected, the inactive benzodiazepine ligand Ro 15-1788 inhibited the effects of alprazolam on 5HT-induced CRH release, but this occurred only at doses below 10(-7) M. Interestingly, when incubated alone in higher doses with our rat hypothalamic organ culture, Ro 15-1788, like alprazolam, produced a dose-dependent inhibition of 5HT-induced CRH release (10(-7)-10(-5) M), suggesting an agonistic action of Ro 15-1788 at the benzodiazepine receptor at higher concentrations. We conclude that alprazolam is capable of suppressing the primate pituitary-adrenal axis, and that this suppression most likely reflects suppression of the CRH neuron rather than of the pituitary corticotroph cell. We speculate that the enhanced capacity of alprazolam to suppress the CRH neuron relative to other benzodiazepines may contribute to its unique efficacy among this class of drugs in the treatment of major depression. The capacity of Ro 15-1788 to reverse alprazolam-induced suppression of the CRH neuron indicates that the effects of alprazolam are mediated at least in part via its interaction with the benzodiazepine component of the gamma-aminobutyric acidA macromolecular complex.
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PMID:In vitro and in vivo effects of the triazolobenzodiazepine alprazolam on hypothalamic-pituitary-adrenal function: pharmacological and clinical implications. 215 87

Recent studies suggest that the hypercortisolism and dexamathasone resistance of depression arise, at least in part, at the level of the brain, ie, cortisol-releasing factor (CRF) and/or other corticotropin-secretagogues are hypersecreted. This article suggests a similar cause of the hypercortisolism of social subordinance. Two troops of wild olive baboons, living freely in the Serengeti Ecosystem of East Africa, have been under long-term study. Consistently, in stable dominance hierachies, subordinate males are hypercortisolemic relative to dominant animals. Furthermore, hypercortisolemic males are dexamethasone resistant. There are no rank-related difference in cortisol clearance or adrenal sensitivity to corticotropin, suggesting a pituitary and/or neural locus of the hypercortisolism. Subordinate males were shown to secrete less corticotropin in response to a CRF-challenge than did dominant males. Following the logic used in similar studies with depressives, if subordinate males were hypercortisolemic despite decreased pituitary sensitivity to CRF, then this implies that the hyperactivity of the adrenocortical axis is driven at the level of the brain. Furthermore, subordinate males were hyporesponsive to CRF after administration of metyrapone, which blocks cortisol secretion and disinhibits the pituitary from feedback inhibition. Thus, the pituitary appears to have lost sensitivity to CRF itself in these low-ranking males. These observations are interpreted in light of behavioral data suggesting that these subordinate males are under sustained social stress.
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PMID:Hypercortisolism among socially subordinate wild baboons originates at the CNS level. 255 41

Plasma ACTH and serum cortisol levels were measured at 20-min intervals for 24 h in six young women with unipolar endogenous depression and in eight normal women during the early follicular phase of the menstrual cycle. The women with depression had a marked increase (P less than 0.005) in mean ACTH pulse frequency [14.5 +/- 0.6 (+/-SE) pulses/24 h] compared with normal women (9.9 +/- 0.7 pulses/24 h), while mean ACTH pulse amplitude and 24-h transverse mean ACTH levels were similar in the two groups. In contrast, 24-h transverse mean cortisol levels were higher (P less than 0.02) in the depressed women (242 +/- 28 nmol/L) than in the normal women (163 +/- 10 nmol/L). This hypercortisolemia in the depressed women was accompanied by markedly increased (P less than 0.001) episodic cortisol secretion (286 +/- 24 X 10(2) nmol/L X min) compared with that in normal women (155 +/- 17 X 10(2) nmol/L X min), and the secretory episodes were both longer in duration (P less than 0.05) and of higher amplitude (P less than 0.05) in the depressed women. The circadian variations in ACTH and cortisol were maintained in these depressed women, and the times of the circadian nadir, as determined by cosinor analysis, were similar to those in the normal women. However, the mean length of the evening quiescent period of cortisol secretion was far shorter (P less than 0.005) in the depressed women (27 +/- 8 vs. 202 +/- 40 min). Moreover, the postlunch rise in serum cortisol was significantly higher (P less than 0.02) in the depressed women (204 +/- 29 vs. 111 +/- 15 nmol/L). These results provide evidence that the hypercortisolism in depressed women is associated with an increase in ACTH pulse frequency, expanded cortisol secretory episodes, including a greater postlunch rise in cortisol, and a shortened evening quiescent period of cortisol secretion. Our findings provide evidence for centrally mediated activation of the ACTH-cortisol system in women with depression without a phase shift in circadian rhythm.
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PMID:Pulsatile rhythms of adrenocorticotropin (ACTH) and cortisol in women with endogenous depression: evidence for increased ACTH pulse frequency. 282 56

Eighteen patients with major depressive disorder of the endogenous subtype (8 unipolars and 10 bipolars) were submitted to blood sampling at 15 min interval for 24 h with polygraphic sleep recording during an acute episode of depression. Plasma growth hormone (GH), adrenocorticotrophin (ACTH) and cortisol were measured in each sample. The depressed patients hypersecreted GH during the daytime and had hypercortisolism which was evident throughout the 24 h span. The nadir of ACTH and cortisol rhythms was advanced by an average of 3 h as compared to the timing observed in normal subjects. These abnormalities were more pronounced and more consistent in patients with unipolar rather than bipolar depression. These results are consistent with the hypothesis that disorders of circadian time-keeping may characterize major endogenous depression.
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PMID:[Neuroendocrine rhythms in uni- and bipolar depressions]. 283 36

The current article suggests that the neuroendocrine system constitutes a bidirectional link between the brain and humoral homeostasis in the periphery. Any change of neuronal activity in the brain--regardless whether induced by external stimuli or endogenous errors of metabolism--may result in altered composition of gene products. Among these are peptides which directly or indirectly alter endocrine activity and may concomitantly induce a variety of behavioral effects. This has been experimentally demonstrated by neuropeptidergic manipulation of sleep-electroencephalographic (EEG) measures and behavioral studies in animals. An integral part of the neuroendocrine communication are effects of peripheral hormones upon brain structures and their interactions with the immune system. Within this framework all hormones of the limbic-hypothalamic- pituitary-adrenocortical (LHPA)-axis play a dominant role, because: (1) corticotropin-releasing hormone (CRH) was shown to integrate centrally behavioral and metabolic responses to stress; and (2) corticosteroids exert a host of neurochemical changes within the CNS which by far exceed their primary endocrine feedback action. As a corollary, hyperexposure to corticosteroids induces widespread changes of neuronal cell biology which are of clinical significance for depression research (e.g. neuronal cell loss in the hippocampus, down-regulation of glucocorticoid receptors within monoaminergic neurons). Clinical neuroendocrine research over the past years focussed upon evaluation of pathophysiology underlying dexamethasone resistant cortisol levels or hypercortisolism linked to depression and utilized advanced methods for multihormonal analysis and newly synthesized neuropeptides (e.g. CRH) for challenge studies in combination with neurophysiological assessments.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Implications of altered limbic-hypothalamic-pituitary-adrenocortical (LHPA)-function for neurobiology of depression. 284 59

Neuroendocrine abnormalities in depression have been regarded, by many authors, as relatively specific markers of nosological subtypes of the disorder, e.g. primary vs. secondary, endogenous vs. non-endogenous or unipolar vs. bipolar depression. They should reflect the same changes in central neurotransmitters (e.g. noradrenergic insufficiency and/or cholinergic hyperactivity) that were hypothesized as the cause of clinical symptoms. This view is challenged on the basis of our own neuroendocrine investigations in 317 psychiatric patients and 103 normal controls. According to these studies the abnormalities are nosologically rather unspecific. They are induced by a large variety of factors, e.g. emotional stress associated with the clinical symptomatology, weight loss due to malnutrition as a consequence of reduced appetite, medication and drug withdrawal. Stress-induced hypercortisolism appears to be the most common abnormality that may trigger other neuroendocrine dysfunctions, such as a blunted TSH response to TRH. Differences in neuroendocrine abnormalities of depressives are probably due to variations in the manifold factors influencing the hormonal axes involved, to temporal changes in hormonal patterns (e.g. one abnormality triggering another) and to individual differences in the basic activity and the responsiveness of the various axes.
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PMID:The nature of neuroendocrine abnormalities in depression: a controversial issue in contemporary psychiatry. 288 Mar 46

A patient with Cushing's syndrome due to ectopic ACTH secretion was treated successfully with the new glucocorticoid antagonist RU 486 [17 beta-hydroxy-11 beta-(4-dimethylamino phenyl) 17 alpha-(1-propynyl)estra-4,9-dien-3-one]. This compound is a 19-nor steroid with substitutions at positions C11 and C17 which antagonizes cortisol action competitively at the receptor level. Oral RU 486 was given in increasing doses of 5, 10, 15, and 20 mg/kg . day for a 9-week period. Treatment efficacy was monitored by assessment of clinical status and by measuring several glucocorticoid-sensitive variables, including fasting blood sugar, blood sugar 120 min after oral glucose administration, and plasma concentrations of TSH, corticosteroid-binding globulin, LH, testosterone-estradiol-binding globulin, and total and free testosterone. With therapy, the somatic features of Cushing's syndrome (buffalo hump, central obesity, and moon facies) ameliorated, mean arterial blood pressure normalized, suicidal depression resolved, and libido returned. All biochemical glucocorticoid-sensitive parameters normalized. No side-effects of drug toxicity were observed. We conclude that RU 486 may provide a safe, well tolerated, and effective medical treatment for hypercortisolism.
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PMID:Successful treatment of Cushing's syndrome with the glucocorticoid antagonist RU 486. 299 27


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