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)

CRF(1) receptor antagonists have been proposed as novel pharmacological treatments for depression, anxiety and stress disorders. The primary goal of the present study was to evaluate the effects of the CRF(1) receptor antagonist, CP 154,526, in the separation-induced vocalization (SIV) model of anxiety. Nine- to 11-day-old rat pups were separated from their litter and the effects of intraperitoneally administered test compounds on the elicited ultrasonic vocalizations were measured. Side-effect potential was assessed using a modified inclined plane test ('time on an inclined plane', or TIP), and using negative geotaxis. SIV was reduced by CP 154,526 at doses that did not affect TIP or negative geotaxis, a profile like that of the 5-HT(1A) partial agonist buspirone. The benzodiazepine anxiolytic, diazepam, decreased SIV but also produced significant side effects at one to three-fold higher doses. Additional pharmacological characterization of SIV demonstrated anxiolytic-like effects of the atypical antipsychotic, clozapine, but not the typical antipsychotic, haloperidol, and of the serotonin reuptake inhibitor, zimelidine, but not the norepinephrine reuptake inhibitor, desipramine. In summary, the data support the conclusion that selective CRF(1) receptor antagonists may have utility in anxiety and stress disorders. The data further support the use of separation-induced vocalizations for identifying mechanistically diverse compounds with anxiolytic actions in man.
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PMID:Effects of the CRF(1) receptor antagonist, CP 154,526, in the separation-induced vocalization anxiolytic test in rat pups. 1081 52

Cardiac arrhythmias are noted in a significant proportion of chronic renal failure (CRF) patients on hemodialysis (HD), and may contribute to cardiovascular mortality. A number of factors have been implicated in the genesis of these arrhythmias. The role of silent myocardial ischemia (SMI), however, has not been evaluated systematically. We prospectively studied 38 unselected CRF patients on regular HD by continuous Holter monitoring starting 24 hours before HD, lasting through the dialysis session and continued for 20 hours thereafter. The recordings were analyzed for frequency, timing and severity of supraventricular and ventricular arrhythmias and SMI as identified by ST-segment depression. Ventricular arrhythmias during HD were noted in 11 (29%) patients (group I), and were potentially life-threatening (Lown Class III and IVa) in 13%. The remaining 27 patients (group II) had no ventricular arrhythmias during HD. There was no difference in the age, sex ratio, duration of HD, blood pressure, fluctuations in weight, hematocrit, predialysis creatinine, sodium, potassium, calcium or inorganic phosphate levels between patients in the two groups. The number of patients with clinical ischemic heart disease was significantly greater in group I. SMI was noted in 72% and 33% of group I and II patients respectively (p = 0.026). 46% of those with and 25% of those without ST changes during HD developed ventricular arrhythmias during HD. Both SMI and ventricular arrhythmias were noted most frequently during the last hour of dialysis. Hypertension, diabetes mellitus and ischemic heart disease were observed more frequently amongst patients with SMI. Ventricular arrhythmias are detected in a significant proportion of CRF patients on HD. These are probably related to coronary artery disease since silent myocardial ischemia is also noted more frequently during HD in these patients. Further studies incorporating coronary angiography are needed in a larger number of patients to establish a definite causal relationship.
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PMID:Cardiac arrhythmias and silent myocardial ischemia during hemodialysis. 1084 46

Corticotropin-releasing factor 1 (CRF(1)) receptor antagonists may represent a novel group of drugs for the pharmacotherapy of depression and/or anxiety disorders. We have investigated the behavioral, endocrine, and neurochemical effects of chronic administration of a selective CRF(1) receptor antagonist, CP-154,526. After 9 to 10 days of treatment with CP-154,526 (3.2 mg/kg/day), defensive withdrawal behavior was significantly decreased suggesting anxiolytic activity. In animals treated for 14 days with the low dose of CP-154,526, serum corticosterone concentrations returned to baseline levels faster after application of an airpuff startle. Using in situ hybridization, no changes in CRF(1) receptor mRNA expression were detected in parietal cortex, basolateral amygdala, or cerebellum after chronic treatment with CP-154,526. A dose-dependent decrease in CRF mRNA expression was observed in the hypothalamic paraventricular nucleus (PVN) and the Barrington's nucleus, an effect that was significant at the high but not the low dose of CP-154,526. CP-154,526 did not alter central CRF(2A) receptor binding or mRNA expression, or urocortin mRNA expression. The present findings suggest that chronic administration of CP-154, 526 produces anxiolytic-like effects but no evidence of adrenal insufficiency. Previous postmortem studies revealed increased CRF peptide and mRNA levels in the PVN of depressed patients, which may mediate the hyperactivity of the hypothalamic-pituitary-adrenal axis observed in such patients. In view of a possible use for CRF(1) receptor antagonists in the treatment of depression, the present finding that CP-154,526 decreases CRF synthesis in the PVN is of considerable interest.
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PMID:Chronic administration of the selective corticotropin-releasing factor 1 receptor antagonist CP-154,526: behavioral, endocrine and neurochemical effects in the rat. 1090 Feb 36

Metabolic acidosis is a condition that is commonly encountered in both chronic renal failure (CRF) and in end-stage renal disease (ESRD). Known complications and surmised consequences associated with the acidosis of renal disease include bone lesions, depression of myocardial contractility, and growth retardation. Conversely the correction of acidosis in children with renal tubular acidosis improves growth velocity. This is also the case in children with CRF. The conclusion drawn from this study was that the correction of metabolic acidosis improved serum albumin concentrations in patients on hemodialysis and that this correction also induced a decrease in the nPCR.
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PMID:A review of the effects of correction of acidosis on nutrition in dialysis patients. 1092 54

Signs and symptoms that are characteristic for depression include changes in the setpoint of the hypothalamic-pituitary-adrenocortical (HPA) system, which in the majority of these patients result in altered regulation of corticotropin (ACTH) and cortisol secretory activity. More refined analysis of the HPA system revealed that corticosteroid receptor (CR) signaling is impaired in major depression, resulting among other changes, in increased production and secretion of corticotropin-releasing hormone (CRH, also frequently abbreviated CRF) in various brain regions postulated to be involved in the causality of depression. This article summarizes the clinical and preclinical data, supporting the concept that impaired CR signaling is a key mechanism in the pathogenesis of depression. Mouse genetics, allowing for selective inactivation of genes relevant for HPA regulation and molecular pharmacology, dissecting the intracellular cascade of CR signaling, are the most promising future research fields, suited for identifying genes predisposing to depression. Focusing on these two research lines may also allow to gain insight into understanding how current antidepressants work and further, how more specific targets for future antidepressant drugs can be identified.
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PMID:The corticosteroid receptor hypothesis of depression. 1102 14

On reviewing the literature on GAD and trying to summarize the various developments in the field of neurobiology of GAD, we see that a range of hypotheses try to explore and integrate the observations found into potentially meaningful theories. Abnormal serotonergic and GABAergic function occur in many patients with GAD. Functional imaging data have shown increased cortical activity and decreased basal ganglia activity in patients with GAD, which reverses with treatment, but it is apparent that no one theory is sufficiently comprehensive to propose a unitary hypothesis for the development of GAD and other anxiety disorders. GAD is a relatively new diagnosable condition, first introduced into the classification system of psychiatric disorders in 1980, and since then has undergone a series of changes in its conceptualization, with some investigators questioning the existence of the condition as a distinct entity. Any inferences that may be drawn from various studies must be guarded, and it is appropriate to compare studies using the same diagnostic criteria. Significant research has been done and may lead to exciting new discoveries in the treatment of anxiety disorders in general and GAD in particular. Gray's model of behavioral inhibition, in which the septohippocampal system acts by assessing stimuli for the presence of danger and, when that is detected, activates the behavioral-inhibition circuit, provides a neuroanatomic conceptualization that has been expanded by preclinical research. Some exciting work has been done on CRF and the concept of development, vulnerability, and kindling and some investigators have contributed to this area of interest. This concept supports the hypothesis that a genetic predisposition, coupled with early stress, in the crucial phases of development may result in a phenotype that is neurobiologically vulnerable to stress and may lower an individual's threshold for developing anxiety or depression on additional stress exposure. The pharmaceutical industry is exploring treatment options using CRF antagonists, and research on other neuropeptides, especially NPY, will be of interest. Research on neurosteroids also may bring the opportunity for pharmacologic treatment approaches. Future research on the startle reflex and on the NMDA and the metabotropic glutamate receptors is important. Future studies of a more homogenous patient population and using more sophisticated techniques, such as molecular genetic strategies and better imaging techniques, may answer some of the outstanding questions.
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PMID:Neurobiology of generalized anxiety disorder. 1122 10

Disturbances of sleep are typical for most depressed patients and belong to the core symptoms of the disorder. Polysomnographic sleep research has demonstrated that besides disturbances of sleep continuity, in depression sleep is characterized by a reduction of slow wave sleep and a disinhibition of REM sleep, with a shortening of REM latency, a prolongation of the first REM period and increased REM density. These findings have stimulated many sleep studies in depressive patients and patients with other psychiatric disorders. In the meantime, several theoretical models, originating from basic research, have been developed to explain sleep abnormalities of depression, like the two-process-model of sleep and sleep regulation, the GRF/CRF imbalance model and the reciprocal interaction model of non-REM and REM sleep regulation. Interestingly, most of the effective antidepressant agents suppress REM sleep. Furthermore, manipulations of the sleep-wake cycle, like sleep deprivation or a phase advance of the sleep period, alleviate depressive symptoms. These data indicate a strong bi-directional relationship between sleep, sleep alterations and depression.
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PMID:Sleep and depression--results from psychobiological studies: an overview. 1145 35

The development of addiction and vulnerability to relapse following withdrawal is proposed to be the result of neuroadaptive processes within the central nervous system that oppose the acute reinforcing actions of drugs of abuse. These changes lead to impairment in the mechanisms that mediate positive reinforcement and the emergence of affective changes such as anxiety, dysphoria, and depression during withdrawal. Considerable evidence exists implicating perturbations in DA and 5-HT transmission in the nucleus accumbens--neurochemical systems that are activated by cocaine and ethanol self-administration and deficient during withdrawal--as potential substrates for these affective changes. In addition, growing evidence suggests that enhanced CRF release in the central nucleus of the amygdala represents a mechanism underlying the anxiogenic and stress-like consequences of withdrawal that are common to all drugs of abuse. A growing body of evidence also implicates dysregulation of the non-neuroendocrine CRF stress system within the central nucleus of the amygdala as a common factor in the anxiogenic and aversive consequences of withdrawal from drugs of abuse. Moreover, a possible link may exist between long-lasting abnormalities in CRF function in the CeA and vulnerability to relapse during protracted abstinence. Another presumably critical element contributing to the chronic relapsing nature of drug addiction is the learned responses to drug-related stimuli. The long-lasting efficacy of drug- and alcohol-associated contextual stimuli in eliciting drug-seeking behavior in animal models of relapse resembles the endurance of conditioned cue reactivity and cue-induced cocaine craving in humans and confirms a significant role of learning factors in the long-lasting addictive potential of cocaine. With cocaine, D1-dependent neural mechanisms within the medial prefrontal cortex and basolateral amygdala may be important substrates for the motivating effects of drug-related environmental stimuli. With ethanol, available data suggest a role for opioid receptors in the mediation of conditioned drug-seeking behavior. Finally, conditioning factors (i.e., exposure to drug-associated stimuli) and stress can interact to augment vulnerability to relapse. This finding emphasizes that it will be important to consider the simultaneous effects of multiple environmental triggers for relapse in the development of treatment and medication strategies.
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PMID:Compulsive drug-seeking behavior and relapse. Neuroadaptation, stress, and conditioning factors. 1145 32

A 5-month-old, male, Shih Tzu dog manifesting polyuria and polydipsia since 2-month-old was presented to our hospital with additional clinical complaints of vomiting and depression during recent a few days. Despite the symptomatic therapy for chronic renal failure, he died on the day after medication. Macroscopically, both kidneys were small in size with rough surface. Microscopical examination revealed bilateral renal fibrosis with dysplastic changes consisting of immature glomeruli and tubules, and foci of adenomatoid proliferation of tubular epithelium. In addition, incomplete lobulation of medulla with pelvic structures was also noticed in the right kidney. From these findings, the present case was diagnosed as renal dysplasia in Shih Tzu dog which was documented in the literatures.
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PMID:Renal dysplasia in a Shih Tzu dog in Japan. 1171 30

A model for the pathophysiology of depression is discussed in the context of other existing theories. The classic monoamine theory of depression suggests that a deficit in monoamine neurotransmitters in the synaptic cleft is the primary cause of depression. More recent elaborations of the classic theory also implicitly include this postulate, other theories of depression frequently prefer to depart from the monoamine-based model altogether. We suggest that the primary defect emerges in the regulation of firing rates in brainstem monoaminergic neurons, which brings about a decrease in the tonic release of neurotransmitters in their projection areas, an increase in postsynaptic sensitivity, and concomitantly, exaggerated responses to acute increases in the presynaptic firing rate and transmitter release. It is proposed that the initial defect involves, in particular, the noradrenergic innervation from the locus coeruleus (LC). Dysregulation of the LC projection activities may lead in turn to dysregulation of serotonergic and dopaminergic neurotransmission. Failure of the LC function could explain the basic impairments in the processing of novel information, intensive processing of irrational beliefs, and anxiety. Concomitant impairments in the serotonergic neurotransmission may contribute to the mood changes and reduction in the mesotelencephalic dopaminergic activity to loss of motivation, and anhedonia. Dysregulation of CRF and other neuropeptides such as neuropeptide Y, galanin and substance P may reinforce the LC dysfunction and thus further weaken the adaptivity to stressful stimuli.
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PMID:Depression as a spreading adjustment disorder of monoaminergic neurons: a case for primary implication of the locus coeruleus. 1175 Sep 28


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