UMLS:C0917801 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917801 (insomnia)
10,606 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To explore whether possible differences in central nervous system neuromodulators contribute to the differential presentation of affective symptomatology in Cushing's disease and major depression, we examined the levels of immunoreactive CRH and ACTH in the cerebrospinal fluid (CSF) of 11 patients with Cushing's disease, a patient with ectopic ACTH secretion, 34 patients with major depression, and 60 healthy subjects. We elected to measure these peptides not only because both are classically involved in pituitary-adrenal regulation, but also because their primarily arousal-producing and anorexigenic behavioral effects in experimental animals suggest that they may play a role in the symptom complex of depressive syndromes. We also explored whether the CSF levels of these peptides were more helpful in determining the often difficult differential diagnosis between major depression and Cushing's disease than the plasma ACTH response to ovine CRH, a currently used but somewhat insensitive laboratory means of distinguishing these disorders. CSF levels of immunoreactive CRH and ACTH were significantly lower in Cushing's disease patients [21.9 +/- 2.7 and 15.4 +/- 1.8 pg/mL, (mean +/- SEM), respectively] compared to patients with major depression [38.4 +/- 2.3 pg/mL (P less than 0.01) and 24.5 +/- 1.6 pg/mL (P less than 0.01), respectively] and controls [38.4 +/- 1.6 pg/mL (P less than 0.001) and 26.3 +/- 1.1 pg/mL (P less than 0.001), respectively]. The coexistence of high plasma ACTH and low CSF ACTH in Cushing's disease yielded a CSF/plasma ACTH ratio consistently less than that in depressed patients, with only 2 of 31 subjects comprising both groups showing values that overlapped. In contrast, 9 of the combined patients showed ACTH responses to ovine CRH that overlapped. These data suggest that differences in centrally directed CRH secretion may account for the differential presentation of the dysphoric syndromes seen in major depression and Cushing's disease. Hence, the classic form of major depression (melancholia), is often associated with evidence of pathological hyperarousal, such as intense anxiety, sleeplessness, and anorexia, while that of Cushing's disease is associated with evidence of pathological hyperarousal, including hyperphagia, fatigue, and inertia. Moreover, measurement of the CSF/plasma ACTH ratio may serve as a clinically useful adjunct to the ovine CRH stimulation test and other laboratory measures in determining the differential diagnosis between major depression and Cushing's disease.
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PMID:Cerebrospinal fluid immunoreactive corticotropin-releasing hormone and adrenocorticotropin secretion in Cushing's disease and major depression: potential clinical implications. 199 96

The combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test was performed in forty patients with depression (12 male, 28 female), aged 20-68 years, in the course of affective illness (16 bipolar, 24 unipolar) both during acute depressive episode and in remission. The results were compared with those of 20 healthy control subjects (10 male, 10 female), aged 22-52 years. During acute depressive episode, cortisol concentration at 16 h after dexamethasone, 1.5 mg, and cortisol release after subsequent infusion of CRH, 100 microg, were significantly elevated in bipolar patients compared with unipolar ones and with control subjects. Patients with multiple episodes of unipolar depression exhibited greater cortisol levels after CRH than control subjects. In remission, significantly higher cortisol concentrations measured at 30 min(-1) h after CRH infusion were found in bipolar than in unipolar patients. Male bipolar patients had significantly higher cortisol level than bipolar females before and at 1.5 h after CRH. First episode unipolar patients during remission had lower levels of cortisol than control subjects before and at 1.5 h after CRH. Correlation between the magnitude of cortisol response and age was found within unipolar depressed patients but not in bipolar ones. On the other hand, correlation of test results with intensity of depression measured by Hamilton scale as well as with insomnia and anxiety subscales was more robust in bipolar subjects than in unipolar ones. It is concluded that the dysregulation of hypothalamic-pituitary-adrenal (HPA) axis activity, detected by DEX/CRH test is significantly more marked in patients with depression in the course of bipolar affective illness than in unipolar depression. Within unipolar depression, this dysregulation may increase with the time course of the illness.
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PMID:The dexamethasone/corticotropin-releasing hormone test in depression in bipolar and unipolar affective illness. 1050 4

The prevalence of insomnia associated with emotional stress increases markedly in middle-age. Both the top and end hormones of the hypothalamic-pituitary-adrenal axis, i.e. CRH and glucocorticoids, stimulate arousal/wakefulness and inhibit slow wave (deep) sleep in experimental animals and man. The objective of this study was to test the hypothesis that middle-age is characterized by increased sensitivity to the sleep-disturbing effects of the hypothalamic-pituitary-adrenal axis. We studied 12 healthy middle-aged (45.1 +/- 4.9) and 12 healthy young (22.7 +/- 2.8) men by monitoring their sleep by polysomnography for 4 consecutive nights, including in tandem 1 adaptation and 2 baseline nights and a night during which we administered equipotent doses of ovine CRH (1 microg/kg, iv bolus) 10 min after sleep onset. Analyses included comparisons within and between groups using multiple ANOVA and regression analysis. Although both middle-aged and young men responded to CRH with similar elevations of ACTH and cortisol, the former had significantly more wakefulness and suppression of slow wave sleep compared with baseline sleep; in contrast, the latter showed no change. Also, comparison of the change in sleep patterns from baseline to the CRH night in the young men to the respective change observed in middle-aged men showed that middle-age was associated with significantly higher wakefulness and significantly greater decrease in slow wave sleep than in young age. We conclude that middle-aged men show increased vulnerability of sleep to stress hormones, possibly resulting in impairments in the quality of sleep during periods of stress. We suggest that changes in sleep physiology associated with middle-age play a significant role in the marked increase of prevalence of insomnia in middle-age.
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PMID:Middle-aged men show higher sensitivity of sleep to the arousing effects of corticotropin-releasing hormone than young men: clinical implications. 1129 73

Stress precipitates depression and alters its natural history. Major depression and the stress response share similar phenomena, mediators and circuitries. Thus, many of the features of major depression potentially reflect dysregulations of the stress response. The stress response itself consists of alterations in levels of anxiety, a loss of cognitive and affective flexibility, activation of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system, and inhibition of vegetative processes that are likely to impede survival during a life-threatening situation (eg sleep, sexual activity, and endocrine programs for growth and reproduction). Because depression is a heterogeneous illness, we studied two diagnostic subtypes, melancholic and atypical depression. In melancholia, the stress response seems hyperactive, and patients are anxious, dread the future, lose responsiveness to the environment, have insomnia, lose their appetite, and a diurnal variation with depression at its worst in the morning. They also have an activated CRH system and may have diminished activities of the growth hormone and reproductive axes. Patients with atypical depression present with a syndrome that seems the antithesis of melancholia. They are lethargic, fatigued, hyperphagic, hypersomnic, reactive to the environment, and show diurnal variation of depression that is at its best in the morning. In contrast to melancholia, we have advanced several lines of evidence of a down-regulated hypothalamic-pituitary adrenal axis and CRH deficiency in atypical depression, and our data show us that these are of central origin. Given the diversity of effects exerted by CRH and cortisol, the differences in melancholic and atypical depression suggest that studies of depression should examine each subtype separately. In the present paper, we shall first review the mediators and circuitries of the stress system to lay the groundwork for placing in context physiologic and structural alterations in depression that may occur as part of stress system dysfunction.
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PMID:Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. 1192 Jan 53

The hypothalamic-pituitary-adrenal (HPA) axis plays important roles in maintaining alertness and modulating sleep. Dysfunction of this axis at any level (CRH receptor, glucocorticoid receptor, or mineralocorticoid receptor) can disrupt sleep. Herein, we review normal sleep, normal HPA axis physiology and circadian rhythm, the effects of the HPA axis on sleep, as well as the effects of sleep on the HPA axis. We also discuss the potential role of CRH in circadian-dependent alerting, aside from its role in the stress response. Two clinically relevant sleep disorders with likely HPA axis dysfunction, insomnia and obstructive sleep apnea, are discussed. In insomnia, we discuss how HPA axis hyperactivity may be partially causal to the clinical syndrome. In obstructive sleep apnea, we discuss how HPA axis hyperactivity may be a consequence of the disorder and contribute to secondary pathology such as insulin resistance, hypertension, depression, and insomnia. Mechanisms by which cortisol can affect slow wave sleep are discussed, as is the role the HPA axis plays in secondary effects of primary sleep disorders.
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PMID:On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep: normal HPA axis activity and circadian rhythm, exemplary sleep disorders. 1572 14

Hypothalamic-pituitary-adrenal (HPA)-system activity is regulated by the suprachiasmatic nucleus, the primary endogenous circadian pacemaker. In addition, sleep plays an important modulatory role. However, data on HPA-system activity in sleep disorders are quite conflicting. A sensitive challenge test to assess negative feedback sensitivity of the HPA-system like the dexamethasone/corticotropin-releasing-hormone (DEX/CRH)-test has never been used so far in sleep disorders. Therefore we studied 25 obstructive sleep apnea (OSA) patients, 18 restless legs syndrome (RLS) patients, 21 patients with primary insomnia and compared them to 33 healthy controls. The dynamic response of the HPA-system was assessed by the DEX/CRH-test which combines suppression (dexamethasone) and stimulation (CRH) of the stress hormone system. After HPA-axis suppression the number of non-suppressors did not differ among groups indicating normal negative feedback sensitivity. In RLS patients ACTH levels were slightly lower compared to controls while cortisol levels were similar between groups. Following CRH stimulation we did not detect differences in ACTH- or cortisol levels and adrenocortical responsitivity to ACTH was comparable between groups. These results for the first time document normal HPA-system feedback sensitivity in various sleep disorders and suggest that abnormalities of the stress hormone system in affective disorders are unlikely due to concomitant sleep problems.
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PMID:The stress hormone system in various sleep disorders. 2150 49

Stressors are imminent or perceived challenges to homeostasis. The stress response is an innate, stereotypic, adaptive response to stressors that has evolved in the service of restoring the nonstressed homeostatic set point. It is encoded in specific neuroanatomical sites that activate a specific repertoire of cognitive, behavioral and physiologic phenomena. Adaptive responses, though essential for survival, can become dysregulated and result in disease. A clear example is autoimmune disease. I postulate that depression, like autoimmunity, represents a dysregulated adaptive response: a stress response that has gone awry. The cardinal manifestation of the normal stress response is anxiety. Cognitive programs shift from complex associative operations to rapid retrieval of unconscious emotional memories acquired during prior threatening situations. These emerge automatically to promote survival. To prevent distraction during stressful situations, the capacity to seek and experience pleasure is reduced, food intake is diminished and sexual activity and sleep are held in abeyance. Monoamines, cytokines, glutamate, GABA and other central mediators have key roles in the normal stress response. Many central loci are involved. The subgenual prefrontal cortex restrains the amygdala, the corticotropin-releasing hormone/hypothalamic-pituitary-adrenal (CRH/HPA) axis and the sympathomedullary system. The function of the subgenual prefrontal cortex is moderately diminished during normal stress to disinhibit these loci. This disinhibition promotes anxiety and physiological hyperarousal, while diminishing appetite and sleep. The dorsolateral prefrontal cortex is downregulated, diminishing cognitive regulation of anxiety. The nucleus accumbens is also downregulated, to reduce the propensity for distraction by pleasurable stimuli or the capacity to experience pleasure. Insulin resistance, inflammation and a prothrombotic state acutely emerge. These provide increased glucose for the brain and establish premonitory, proinflammatory and prothrombotic states in anticipation of either injury or hemorrhage during a threatening situation. Essential adaptive intracellular changes include increased neurogenesis, enhancement of neuroplasticity and deployment of a successful endoplasmic reticulum stress response. In melancholic depression, the activities of the central glutamate, norepinephrine and central cytokine systems are significantly and persistently increased. The subgenual prefrontal cortex is functionally impaired, and its size is reduced by as much as 40%. This leads to sustained anxiety and activations of the amygdala, CRH/HPA axis, the sympathomedullary system and their sequella, including early morning awakening and loss of appetite. The sustained activation of the amygdala, in turn, further activates stress system neuroendocrine and autonomic functions. The activity of the nucleus accumbens is further decreased and anhedonia emerges. Concomitantly, neurogenesis and neuroplasticity fall significantly. Antidepressants ameliorate many of these processes. The processes that lead to the behavioral and physiological manifestations of depressive illness produce a significant decrease in lifespan, and a doubling of the incidence of premature coronary artery disease. The incidences of premature diabetes and osteoporosis are also substantially increased. Six physiological processes that occur during stress and that are markedly increased in melancholia set into motion six different mechanisms to produce inflammation, as well as sustained insulin resistance and a prothrombotic state. Clinically, melancholic and atypical depression seem to be antithesis of one another. In melancholia, depressive systems are at their worst in the morning when arousal systems, such as the CRH/HPA axis and the noradrenergic systems, are at their maxima. In atypical depression, depressive symptoms are at their worst in the evening, when these arousal systems are at their minima. Melancholic patients experience anorexia and insomnia, whereas atypical patients experience hyperphagia and hypersomnia. Melancholia seems like an activation and persistence of the normal stress response, whereas atypical depression resembles a stress response that has been excessively inhibited. It is important that we stratify clinical studies of depressed patients to compare melancholic and atypical subtypes and establish their differential pathophysiology. Overall, it is important to note that many of the major mediators of the stress response and melancholic depression, such as the subgenual prefrontal cortex, the amygdala, the noradrenergic system and the CRH/HPA axis participate in multiple reinforcing positive feedback loops. This organization permits the establishment of the markedly exaggerated, persistent elevation of the stress response seen in melancholia. Given their pronounced interrelatedness, it may not matter where in this cascade the first abnormality arises. It will spread to the other loci and initiate each of their activations in a pernicious vicious cycle.
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PMID:The organization of the stress system and its dysregulation in depressive illness. 2548 82

Enzyme-linked immunosorbent assay(ELISA) and metabolomics were used to analyze and compare two animal models of heart-kidney insomnia, in order to explore a more ideal animal model and preliminarily explore the essence of heart-kidney insomnia. Based on the clinical symptoms and disease characteristics of heart-kidney insomnia, the animal model of heart-kidney insomnia was reproduced through intraperitoneal injection with p-chlorophenylalanine(PCPA) and multi-factor interaction. The animal model of disease-syndrome combination was evaluated by behavioral observation, ELISA and metabolomics. Wistar rats were randomly divided into normal group, PCPA group and compound model group(FH). The rats' behavior, body weight, adrenal index and spleen index were recorded. The levels of corticotropin releasing hormone(CRH) and adrenocorticotropin(ACTH) in serum were detected by ELISA, and the differential metabolites in serum were detected by UPLC-QE-MS. The body weight and adrenal index in FH group were significantly lower than those in PCPA group(P<0.05); whereas ACTH and CRH in FH group were significantly higher than those in PCPA group by ELISA; nine potential biomarkers were identified by serum sample statistics. There were four main metabolic pathways in cardiorenal insomnia: pentose phosphate metabolism, alanine, aspartic acid and glutamic acid metabolism, histidine metabolism, and taurine and subtaurine metabolism. PCPA and multi-factor interaction method can successfully replicate the insomnia model, but multi-factor modeling method is more similar to clinical traditional Chinese medicine syndrome. Animal behavior, ELISA and metabolomics were used to evaluate the rat model of cardiorenal insomnia from in vitro to in vivo, from macro to micro, and from individual to the whole.
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PMID:[Establishment of rat heart-kidney insomnia model consistent with traditional Chinese medicine syndrome and its serum metabolomics]. 3223 22

The neural substrates of insomnia/hyperarousal induced by stress remain unknown. Here, we show that restraint stress leads to hyperarousal associated with strong activation of corticotropin-releasing hormone neurons in the paraventricular nucleus of hypothalamus (CRH^PVN) and hypocretin neurons in the lateral hypothalamus (Hcrt^LH). CRH^PVN neurons directly innervate Hcrt^LH neurons, and optogenetic stimulation of LH-projecting CRH^PVN neurons elicits hyperarousal. CRISPR-Cas9-mediated knockdown of the crh gene in CRH^PVN neurons abolishes hyperarousal induced by stimulating LH-projecting CRH^PVN neurons. Genetic ablation of Hcrt neurons or crh gene knockdown significantly counteracts restraint stress-induced hyperarousal. Single-cell mass cytometry by time of flight (CyTOF) revealed extensive changes to immune cell distribution and functional responses in peripheral blood during hyperarousal upon optogenetic stimulation of CRH^PVN neurons simulating stress-induced insomnia. Our findings suggest both central and peripheral systems are synergistically engaged in the response to stress via CRH^PVN circuitry.
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PMID:Hypothalamic circuitry underlying stress-induced insomnia and peripheral immunosuppression. 3291 89