Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Postpartum depression (PPD) affects at least 10% to 15% of postpartum women, including more than 600,000 American mothers in 2003 alone. Dramatic changes in the hypothalamic-pituitary-adrenal (HPA) system in the transition from pregnancy to postpartum coupled with research on the psychobiology of depression provided the foundation for this study. The purpose of this study was to compare the reactivity and regulation of the HPA axis components, adrenocorticotropic hormone (ACTH) and cortisol, in depressed and nondepressed postpartum women. A comparative, longitudinal study design was used with 22 normal, healthy, nondepressed pregnant women. Physiologic and postpartum depression data were collected at 6 and 12 weeks postpartum at a university clinical research center. Maximal treadmill exercise stimulated plasma ACTH and serum cortisol levels which were measured before, during, and after 20 min of exercise. Postpartum depression was measured with the Postpartum Depression Screening Scale. Lag within-subject ACTH levels predicting cortisol regression slopes were significantly different between the depressed and nondepressed groups at both 6 and 12 weeks. The depressed group showed no relationship between their ACTH and cortisol levels, with higher ACTH and lower cortisol levels when compared with the nondepressed group. The expected regulated relationship with cortisol levels rising in response to rising ACTH levels was found in the non-depressed group. These findings indicate that the HPA axis was dysregulated in the depressed group, but regulated in the nondepressed group at 6 and 12 weeks postpartum. This pattern of higher ACTH levels to stimulate less cortisol is similar to patterns found in women with early life stresses.
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PMID:Dysregulation of the hypothalamic-pituitary-adrenal axis in postpartum depression. 1717 20

There is an extensive evidence that corticotropin releasing factor (CRF) is hypersecreted in depression and anxiety, and blockade of CRF could have therapeutic benefit. We report preclinical data and the results of a clinical Phase I study with the novel nonpeptide CRF(1) antagonist NBI-34041/SB723620. Preclinical data conducted with different cell lines expressing human CRF receptors and in Wistar and Sprague-Dawley rats indicate that NBI-34041 is effective in reducing endocrine responses to pharmacological and behavioral challenge mediated by CRF(1) receptors. These specific properties and its well-documented safety profile enabled a clinical Phase I study with 24 healthy male subjects receiving NBI-34041 (10, 50, or 100 mg) or placebo for 14 days. Regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis was evaluated by intravenous stimulation with 100 microg of human CRF. Psychosocial stress response was investigated with the Trier Social Stress Test (TSST). Treatment with NBI-34041 did not impair diurnal adrenocorticotropic hormone (ACTH) and cortisol secretion or CRF evoked ACTH and cortisol responses but attenuated the neuroendocrine response to psychosocial stress. These results suggest that NBI-34041 is safe and does not impair basal regulation of the HPA system but improves resistance against psychosocial stress. NBI-34041 demonstrates that inhibition of the CRF system is a promising target for drug development against depression and anxiety disorders.
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PMID:High-affinity CRF1 receptor antagonist NBI-34041: preclinical and clinical data suggest safety and efficacy in attenuating elevated stress response. 1728 23

Disturbance of each of the three hypothalamic-pituitary-end organ systems [hypothalamic-pituitary-thyroid (HPT), -adrenal (HPA), and -gonadal (HPG)] has been reported in depressive disorders. Little is known about potential reciprocal interaction among the three HP-end organ systems in patients with depressive disorders. The present pilot study examined selective HPA and HPG hormones in a detailed time series in women with bipolar disorder (depressed type) before and after treatment with levothyroxine (L-T4), and in matched control subjects. Six medically stable, euthyroid, premenopausal women with bipolar depression, and 5 age-matched controls underwent overnight blood sampling from 2100 to 0900 h for measurement of adrenocorticotropic hormone (ACTH), cortisol, luteinizing hormone (LH), and estradiol every 15 min. Bipolar patients underwent a second overnight blood sampling procedure following 7-weeks of open-label add-on treatment with L-T4. Results revealed lower baseline cortisol parameters in bipolar patients in comparison to control subjects, while ACTH, LH, and estradiol parameters were similar. Thyroid hormones (TSH, free and total T4) were not correlated with any of the HPA or HPG hormones. ACTH and cortisol levels were correlated in control subjects, but not in bipolar patients. After L-T4 treatment, thyroid hormones increased significantly and depression scores significantly declined. No significant changes in HPA or HPG hormones parameters were observed, although the small sample size may have limited results. Upon visual inspection, ACTH and cortisol appeared to decrease after L-T4 treatment, while estradiol appeared to increase. These pilot data suggest lower levels of cortisol in women with bipolar depression, unlike previously published studies that reported higher cortisol in patients with depression. The data also suggest reciprocal changes in the HPA and HPG axes upon pharmacological modulation of the HPT system, although whether this change was due to the L-T4 treatment or the improvement of depression is unknown. The results are preliminary, and require replication in larger samples.
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PMID:Hypothalamic-pituitary-end organ function in women with bipolar depression. 1731 22

A 76-year-old man was first referred to his local hospital at the beginning of August 2005 with nausea and vomiting, and was admitted on August 15 with progressive fatigue of unknown etiology. Gastrointestinal examination was performed, but no obvious abnormalities were detected in the upper or lower digestive tract. Hematology tests also revealed no abnormalities, except for slight eosinophilia. He developed depression and was given an antidepressant agent. After suffering from hyponatremia and disorientation, he was subsequently admitted to our hospital on August 28. At that time, serum adrenocorticotropic hormone (ACTH) and cortisol levels were low, while both the ACTH and corticotrophin-releasing hormone (CRH) stress tests showed no response. Other stress tests revealed normal responses, so he was given a diagnosis isolated ACTH deficiency and received corticosteroid therapy. In summary, we report an elderly case of isolated ACTH deficiency with nonspecific initial manifestations such as nausea, fatigue, and depression.
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PMID:[Elderly case of isolated ACTH deficiency presenting with depression and digestive symptoms]. 1733 64

The present study was designed to determine whether an association exists between HPA activity and cytokine production in major depression (MD). In 9 patients with MD and 11 control subjects of both sexes, all drug-free, activity of the HPA axis was evaluated by circadian rhythm of plasma cortisol, 24-h free urinary cortisol, an overnight 1 mg dexamethasone suppression test, and an oCRF stimulation test. Spontaneous and LPS-stimulated production of IL-1beta, IL-6, and TNFalpha by peripheral blood mononuclear cells were also determined. We found a significantly elevated spontaneous production of IL-6 in patients with MD (3541.2 +/- 726.8 vs 380.4 +/- 77.5 pg/mL in controls, p < 0.05), while LPS-stimulated production was significantly lower in patients than in control subjects (19,867.7 +/- 3649.2 vs 33,142.2 +/- 15,47.2 pg/mL, p < 0.05). The adrenocorticotropic hormone response to oCRF, evaluated as the area under the curve (AUCACTH) was significantly lower in patients than in control subjects (p = 0.02). A positive correlation between AUCACTH and LPS-stimulated IL-6 secretion was observed in patients with MD (r = 0.75, p < 0.05) but not in controls. These findings suggest that the activation of the inflammatory response described in depression might be associated with long-term hyperactivity of the HPA axis.
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PMID:Interleukin-6 production and deregulation of the hypothalamic-pituitary-adrenal axis in patients with major depressive disorders. 1752 50

From basic and clinical studies, ample evidence has emerged that abnormalities of stress hormone regulation observed in depression and anxiety are caused by elevated secretion of hypothalamic corticotropin-releasing hormone (CRH). This neuropeptide acts through CRH1 receptors to produce a number of anxiety- and depression-like symptoms, which has resulted in extensive validation of CRH1 receptors as a potential drug target. A number of orally available nonpeptidergic small molecules that are able to pass the blood-brain barrier have been discovered. Some of these compounds have entered clinical development. The authors summarize results from clinical studies of 2 CRH1 antagonists. One study designed as a safety and tolerability study also monitored amelioration of depression under 2 dose-escalation regimens. The compound studied, NBI-30775/R121919, was found to have a clinical profile comparable to that of paroxetine. In a second study the effect of another CRH1 antagonist, NBI-34041, on stress hormone secretion in response to a psychosocial stressor was investigated. Administration of this compound to healthy controls was found to reduce the stress-elicited secretion of stress hormones. However, neither compound impaired the CRH-induced release of adrenocorticotropic hormone and cortisol, rejecting the possibility that the stress hormone system is impaired by CRH1 antagonists. From these studies the authors conclude that both CRH1 antagonists have psychotropic effects unrelated to their neuroendocrine action, in line with behavioral data obtained from transgenic mice with CRH1 gene deletions. The psychotropic effects observed in the clinical studies underscore that CRH1 antagonists constitute a novel treatment of depression and anxiety but may also serve to prevent negative sequelae of severe stressors.
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PMID:CRH-sub-1 receptor antagonists for the treatment of depression and anxiety. 1817 4

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has been reported to be involved in vulnerability to alcohol and drug dependence in humans, possibly underlying both addictive behaviour and depression susceptibility. The aim of the present study was to investigate the possible interactions between childhood adverse experiences, depressive symptoms and HPA axis function in addicted patients, in comparison with healthy control. Eighty-two abstinent heroin or cocaine dependent patients and 44 normal controls, matched for age and sex, completed the symptoms Check List-90 (SCL-90), measuring depressive symptoms, and the Childhood Experience of Care and Abuse Questionnaire. Blood samples were collected to determine adrenocorticotropic hormone (ACTH) and cortisol basal plasma levels at 8:00 and 8:30 a.m. Addicted individuals showed significantly higher neglect and depression scores and ACTH-cortisol plasma levels respect to control subjects. Depression scores at SCL-90 in addicted patients positively correlated with plasma ACTH and cortisol values. In turn, plasma ACTH levels were directly associated with childhood neglect measures, reaching statistical significance with 'mother-neglect' scores. Plasma cortisol levels were related to 'father antipathy' among cocaine addicts. These findings suggest the possibility that childhood experience of neglect and poor parent-child attachment may have a persistent effect on HPA axis function as an adult, partially contributing, together with genetic factors and other environmental conditions, to both depressive traits and substance abuse neurobiological vulnerability.
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PMID:Adrenocorticotropic hormone and cortisol plasma levels directly correlate with childhood neglect and depression measures in addicted patients. 1820 Dec 94

The use of carbamazepine has been reported to be an effective treatment for severe depression. We have already shown that the antidepressant-like effects of tricyclic antidepressants in the rat forced swim test (FST) are blocked by chronic treatment with adrenocorticotropic hormone (ACTH). In the present study, we examined the effect of the chronic administration of carbamazepine on the FST and the wet-dog shakes induced by (+/-) -1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT(2A) receptor agonist, in ACTH-treated rats. Chronic administration of carbamazepine did not affect the duration of immobility in saline-treated and ACTH-treated rats. The reduction of immobility, induced by chronic administration of imipramine, was blocked by treatment with ACTH. When carbamazepine was administered concurrently with imipramine, we observed a significant decrease in immobility in rats treated with ACTH. Chronic ACTH treatment increased the number of the wet-dog shakes induced by DOI. This effect of ACTH was significantly increased by the coadministration of carbamazepine and imipramine. These results suggest that the use of carbamazepine together with tricyclic antidepressants had the effect of reducing immobility time in the FST in a tricyclic antidepressant-treatment-resistant depressive model induced by chronic ACTH treatment.
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PMID:Chronic coadministration of carbamazepine together with imipramine produces antidepressant-like effects in an ACTH-induced animal model of treatment-resistant depression: involvement of 5-HT(2A) receptors? 1825 30

It is increasingly clear that significant differential regulation of pituitary and adrenal gland activation exists, leading to a dissociation of plasma adrenocorticotropic hormone and corticosteroid secretion during fetal, postnatal and adult life. An increasing number of preclinical and clinical studies report dissociation of adrenocorticotropic hormone and cortisol levels in critical illness, inflammation and mental disorders. Mechanisms involve an altered adrenal sensitivity, aberrant receptor expression or modulation of adrenal function by cytokines, vasoactive factors or neuropeptides. The degree of dissociation has been associated with the level of complications of sepsis, surgery, malignant disease and depression. The separation of adrenocorticotropic hormone and corticosteroid secretion is of clinical relevance and should be incorporated into our view on endocrine stress regulation.
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PMID:Dissociation of ACTH and glucocorticoids. 1839 19

Psychoendocrinological studies have focused on the hypothalamic-pituitary-adrenal axis in patients with depression. We have already reported that in rats, repeated adrenocorticotropic hormone (ACTH) treatment blocks the effect of tricyclic antidepressants in decreasing immobility time in a forced swim test, a widely used animal experiment for predicting antidepressant activity. Furthermore, chronic coadministration of lithium or carbamazepine, an agent that potentiates the actions of antidepressants in patients with depression, including those with treatment-resistant depression, significantly decreased the duration of immobility, even when given concurrently with ACTH. Recently, clinical and animal studies have shown that neurogenesis/neuroprotection in the adult brain is important for the therapeutic actions of antidepressants. We indicated that repeated ACTH treatment decreased the expression of BDNFmRNA and the number of newborn cells in the rat hippocampus. Namely, we recognized that ACTH-treated rats served as a useful animal model of tricyclic antidepressant treatment-resistant conditions.
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PMID:[Development of animal models of treatment-resistant depression in rats]. 1851 88


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