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 CRH has been shown to mediate stress-induced physiological and behavioral changes, it has been hypothesized that CRH receptor antagonists may have therapeutic potential in disorders that involve excessive CRH activity. CP-154,526 and its close analog antalarmin are potent, brain-penetrable, selective nonpeptide CRH1 receptor antagonists that were discovered in an effort to develop compounds with efficacy in CNS disorders precipitated by stress. Since its discovery many investigators have used CP-154,526 as a tool to study the pharmacology of CRH and its receptors and to evaluate its therapeutic potential in a variety of CNS and peripheral disorders. Systemically-administered CP-154,526 has been demonstrated to antagonize CRH- and stress-induced neuroendocrine, neurochemical, electrophysiological, and behavioral effects. These findings support the hypothesis that CRH1 receptor antagonists may have therapeutic utility in a number of neuropsychiatric disorders. CP-154,526, as well as other CRH1 receptor antagonists that have since been discovered, have also shown activity in several preclinical models of anxiety, depression, and substance abuse, while having little effect on locomotor activity and motor function. Although these effects are on occasion inconsistent among different laboratories, clinical evaluation of CRH1 antagonists appears justified on the basis of these and clinical data implicating the involvement of CRH in several CNS disorders. The effects of CRH1 antagonists on cognition, neurodegeneration, inflammation, and the gastrointestinal system have not been as extensively characterized and additional studies will be necessary to evaluate their therapeutic potential in these areas.
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PMID:The pharmacology of CP-154,526, a non-peptide antagonist of the CRH1 receptor: a review. 1259 12

This paper presents a valid animal model of innate anxiety/depression: anxious (HAB) or non-anxious (LAB) rats, which show stable and robust responses in a variety of ethological tests. In addition to their extreme anxiety-related behavior, HAB animals are characterized by passive stress coping, an activated stress (HPA) axis, and increased stress vulnerability. The enhanced expression and release of arginine vasopressin (AVP) in the hypothalamus of HAB rats seem to underlie these phenomena. Accordingly, an AVP receptor antagonist attenuates anxiety-related behavior and normalizes the HPA axis and the dexamethasone/CRH test. Treatment with the antidepressive drug paroxetine reduces the overexpression of AVP and normalizes both the depression-like behavior and neuroendocrine correlates of anxiety/depression. The complex phenotyping led us to the conclusion that the AVP gene is likely to be a candidate gene of inborn anxiety. Partial genotyping of HAB animals results in the identification of polymorphisms (SNPs) in the promoter domain of the AVP gene, thus potentially leading to novel strategies of diagnosis and therapy of anxiety disorders and depression.
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PMID:[Neurobiology and genetics of anxiety in an animal model]. 1262 44

The treatment of delusional depression is a major challenge in psychopharmacology. Hypothalamic-pituitary-adrenocortical (HPA) overdrive may contribute, via increased dopaminergic activity, to the pathophysiology of the disorder. Trimipramine appears to be an interesting potential candidate, since it is an atypical antidepressant that is known to inhibit HPA activity. In a four-week open trial we investigated its effects in 15 inpatients with delusional depression. The dosage was increased within 7 days up to 300 - 400 mg/d and was then maintained for three weeks. Psychometric assessments and safety monitoring were conducted weekly. Assessment of the HPA activity was achieved by a combined dexamethasone suppression/corticotropin-releasing hormone stimulation (Dex/CRH) test before and after four weeks of treatment. Therapeutic response was defined as a decrease in the HAMD-score of at least 50 %. Eight out of 13 completers were rated as responders. Therapeutic response was associated with L, D-trimipramine concentrations higher than 160 ng/ml. Intent-to-treat analysis showed significant improvement in psychometric variables. Despite the high dosage, the substance was generally well tolerated, with the exception of one patient who suffered from a hypotensive reaction. Mean +/- SD concentration of L-trimipramine and D-trimipramine were 138 +/- 61 ng/ml and 119 +/- 50 ng/ml at a final dose of 346 +/- 50 mg/d. The ACTH and cortisol area under the curve in the Dex/CRH tests decreased significantly, reflecting a decrease of activity in the HPA system. We suggest that the clinical use of high-dose trimipramine in delusional depression seems to be a promising treatment strategy.
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PMID:Clinical outcome after trimipramine in patients with delusional depression - a pilot study. 1264 69

The clinical correlate of chronic hypercortisolism is Cushing's syndrome (CS). After exclusion of an iatrogenic cause (glucocorticoid administration), two reliable laboratory methods for establishing the diagnosis are (i) measurement of "free" (unmetabolised) cortisol in a 24-hour urine (UFC) sample and (ii) the low-dose (1 or 1.5 mg) dexamethasone (Dex) test. For the latter, Dex is taken orally at midnight, and plasma cortisol is measured at 8 a.m. In normals and in the absence of CS, the morning cortisol (200-650 nmol/L) is suppressed to <80 nmol/L. In endogenous CS of all causes, cortisol suppression by Dex is absent or incomplete. In patients with severe mental depression or stress, suppression may also be incomplete ("false-positives"). However, UFC is normal or only slight increased in the latter group, while it is always markedly increased in clinically apparent CS. In CS, UFC rises proportionally more than plasma cortisol because the cortisol binding plasma protein (transcortin) can bind only about 500 nmol/L cortisol. Protein-bound cortisol is not excreted by the kidney. After establishing the diagnosis CS, the differentiation between its pituitary (ca. 70%), adrenocortical (ca. 20%) or "ectopic" (ACTH production by non-pituitary tumours) (ca. 10%) origin is made by plasma ACTH measurement, a corticotropin releasing hormone injection test (with plasma ACTH/cortisol measurement) and a high-dose Dex (8 mg or more) suppression test. Chronic hypocorticolism can be primary (adrenal disease, Addison's disease) or secondary (pituitary or hypothalamic disorder). UFC measurement is not an established method for confirming hypocortisolism because most analytical methods are too unspecific and insensitive in the subnormal range. Low-normal or subnormal plasma cortisol plus elevated ACTH is the hallmark of Addison's disease. Injection of high doses of ACTH does not lead to a rise in plasma cortisol in these patients. A clearly subnormal cortisol plus low ACTH proves secondary hypocortisolism. Mild forms with low-normal plasma cortisol, however, are more difficult to prove. So-called "dynamic" tests stimulating the whole hypothalamo-pituitary-adrenal axis (insulin hypoglycemia test or metyrapone test) are necessary to confirm the diagnosis. Patients with hypocortisolism, depending on disease severity, must be treated permanently or only in stressful situations with hydrocortisone unless they may die after passing the clinical state of an "adrenal crisis".
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PMID:Clinical diagnosis of hyper- and hypocortisolism. 1268 70

Anorexia nervosa (AN) and bulimia nervosa (BN) are eating disorders characterized by an aberrant pattern of eating behavior, relentless pursuit of thinness, an intense fear about weight gain and an altered perception of body shape. The pathobiology of eating disorders is complex. Several social, psychological and developmental phenomena are proposed to contribute to the etiology of eating disorders. The role of neuropeptide Y, corticotropin releasing hormone and leptin has also been investigated to understand the pathogenesis of eating disorders. However, most of the neuropeptide alterations noted in eating disorders are secondary to starvation. Several nonpharmacological approaches such as cognitive and behavior-based therapy and interpersonal therapy have been developed to assist weight gain and to modify the behavioral impairment associated with eating disorders. Pharmacotherapy serves as an adjunct in AN, whereas it plays a more significant role in the management of BN. Antidepressants are effective in a limited number of AN patients with comorbid depression. On the other hand, the efficacy of fluoxetine in BN patients in reducing the frequency of binge eating and in the severity of behavioral abnormalities is quite impressive. Several adjunct therapies such as prokinetics and anxiolytics have also been used in AN and BN to assist eating behavior. An insight into genetic and neurochemical abnormalities occurring in eating disorders will help to find better therapeutic agents for these disorders. (c) 2001 Prous Science. All rights reserved.
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PMID:Anorexia nervosa and bulimia nervosa: An appraisal. 1276 23

This review summarises behavioural, neuroendocrine, and genetic characteristics of Wistar rats bred for either high (HAB) or low (LAB) anxiety-related behaviour. Compared to LABs, HAB animals show signs of extreme trait anxiety in a variety of behavioural tests; they further prefer passive coping strategies, indicative of a genetically linked depression-like behaviour, and show signs of increased stress vulnerability. All behavioural parameters associated with trait anxiety are robust and consistent. Resembling psychiatric patients, HAB rats respond to exposure to ethologically relevant stressors with a hyper-reactivity of the hypothalamic-pituitary-adrenal axis and show a pathological outcome of the combined dexamethasone/corticotropin-releasing hormone (Dex/CRH) challenge test. Experimental evidence indicates that over-expression and -release of vasopressin in the hypothalamic paraventricular nucleus is responsible for these behavioural and neuroendocrine phenomena, making the neuropeptide gene a candidate gene of trait anxiety/depression. Indeed, preliminary molecular genetic approaches succeeded in identifying polymorphisms in the promoter structure of the vasopressin gene. This may have implications for understanding the molecular basis for individual variations in trait anxiety and for psychopathology.
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PMID:Born to be anxious: neuroendocrine and genetic correlates of trait anxiety in HAB rats. 1277 30

Data from several studies suggest that unrestrained secretion of corticotropin-releasing hormone in the CNS produces several signs and symptoms of depression. Recent evidence indicates that blockade of the CRH receptor 1 reduced depression scores in depressed patients. One of the symptoms that occur is depression is impairment in attentional processes. Whether these impairments are due to alterations in the CRH system are so far unknown. In order to investigate whether overproduction of CRH alters attentional process, transgenic mice overproducing CRH were tested on an operant five choice serial reaction time task, a task which taxes sustained and divided attention. Mutants showed impaired autoshaping. During initial discrimination learning, transgenics performed below wildtype level, but with extended training with long stimulus durations, transgenic animals reached similar accuracy levels as wildtype mice. When animals were tested at shortest stimulus duration (0.5s), a mild but significant impairment in accurate responding emerged in transgenics. This was accompanied by longer correct response latencies, while incorrect latencies did not differ between groups, suggesting attentional impairment in CRH transgenics. Because these animals have been reported to also show increased anxiety-related behaviour, animals were treated with the anxiolytic benzodiazepine diazepam. Diazepam failed to affect accuracy, but transgenic mice showed a stronger behavioural disinhibition. This suggests that the attentional impairment seen in CRH overexpressors is independent of alterations in anxiety-like behaviour. These findings may have implications for understanding the pathophysiology of psychiatric disorders such as depression, where it has been suggested that an overactivity of the CRH system accounts for a variety of symptoms, including hyper-arousal and attentional impairment.
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PMID:Reduced attention in mice overproducing corticotropin-releasing hormone. 1279 67

Galanin, a 29-30 amino-acid neuropeptide is distributed in the central and peripheral nervous systems, the pituitary gland, the gastrointestinal tract and also in the pancreas. The endogenous and exogenous effects of galanin are mediated by three receptor subtypes, which are termed: GALR1, GALR2, and GALR3. Galanin has a significant role in physiological and pathological processes in adults as well as in children. It has an ability to contract smooth muscles in GI (facilitation and inhibition), stimulates reflexes in the CNS, decreases pancreatic amylase secretion, changes transport of electrolytes Na+ and CL-. It takes part in etiopathogenesis of depression, Alzheimer's disease and diarrhoea, exerts tonic inhibition of nociceptive input to the central nervous system and regulates a function of hypothalamic-pituitary system. Galanin decreases insulin and somatostatin secretion, increases glucagon secretion, takes part in prolactin release, stimulates growth hormone-releasing hormone, hypothalamic gonadotropin releasing hormone and corticotropin releasing hormone. It causes increase of somatotropin secretion, luteinizing hormone and foliculotropin release and adrenocorticotropin secretion. The hypothalamic galanin takes part in etiopathogenesis of obesity not only in human reproductive period, but also in adolescence, increasing the appetite and changing fat metabolism. This variety of actions emphasizes the potential importance of this peptide in the regulation of cells function and the need to understand the mechanism by which they act.
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PMID:[The role of galanin in the endocrine system]. 1281 74

About 25 years ago the observation that neuropeptides serve as signalling molecules in the nervous system generated great expectations for drug industry. In this article the progress made since then in exploiting neuropeptide systems pharmacologically in psychiatry is highlighted. In affective disorders a number of neuropeptides seem to be causally involved in development and course of illness, especially corticotropin releasing hormone (CRH), vasopressin (AVP) and substance P, whose receptors are now targeted with small molecules designed to reduce depressive and anxiety symptoms. Although not exactly neuropeptides, also neurotrophins, may have a distinct role in antidepressant action and possibly also in causation of depression. Schizophrenia-like symptoms are caused by neurotensin (NT), supporting the notion that drugs interfering with NT systems are potential antipsychotics. Finally, sleep disorders, currently treated with hypnotics, that have serious adverse effects can be targeted with neuropeptides. According to the work by Axel Steiger several neuropeptides even if peripherally administered produce improvements of quality of sleep. All these observations call for intensified application of novel research tools necessary to exploit the potential of neuropeptide systems as psychopharmaceutical targets.
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PMID:The role of peptides in treatment of psychiatric disorders. 1283 Sep 27

Although lithium augmentation is the foremost and most well-documented treatment strategy for treatment resistant depression, knowledge of factors related to response remains scanty. Findings with the combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test are associated with response to treatment with a tricyclic antidepressant. This study investigated the potential predictive value of the DEX/CRH test for lithium augmentation response in major depressive disorder. The DEX/CRH test was conducted prior to lithium augmentation in 30 patients with a major depressive episode who had not responded to an antidepressant monotherapy trial of at least 4 weeks. Response status was assessed weekly using the Hamilton Rating Scale for Depression. For multivariate prediction, a logistic regression analysis was performed. Eleven (37%) patients responded to lithium augmentation within 4 weeks. Responders showed higher ACTH response and lower cortisol response in the DEX/CRH test, but results were not statistically significant. However, non-responders had a statistically significant higher cortisol/ACTH peak ratio (3.43+/-1.75) compared to responders (2.18+/-1.38) (P=0.027). This ratio is an indicator for the sensitivity of the adrenal cortex to ACTH. A cortisol/ACTH peak ratio of 1.8 was identified as the best cutoff point to differentiate responders from non-responders. In conclusion, results suggest a more sensitive adrenal cortex in non-responders to lithium augmentation. The findings would be in line with the assumption of a more chronic course of depression with more pronounced biological alterations in the non-responder group, because chronic depression is known to cause enlargement of the adrenal gland with a subsequent hypersensitivity to ACTH. Results of this study should be confirmed in a larger study group.
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PMID:Association between response to lithium augmentation and the combined DEX/CRH test in major depressive disorder. 1284 67


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