Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

'A striking and specific loss of the messenger RNA that encodes a non-N-methyl D-aspartate (non-NMDA) glutamate receptor was found in hippocampal tissue obtained at necropsy from 6 patients with schizophrenia, when compared to specimens from 8 controls without neurological or psychiatric signs or symptoms. These findings support suggestions of aberrant glutamatergic function in schizophrenia. Evidence that gene expression may be abnormal in schizophrenia, with decreased production of an excitatory neurotransmitter receptor, may have therapeutic as well as pathogenetic implications.'
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PMID:Decreased hippocampal expression of a glutamate receptor gene in schizophrenia. 166 98

A striking and specific loss of the messenger RNA that encodes a non-N-methyl D-aspartate (non-NMDA) glutamate receptor was found in hippocampal tissue obtained at necropsy from 6 patients with schizophrenia, when compared to specimens from 8 controls without neurological or psychiatric signs or symptoms. These findings support suggestions of aberrant glutamatergic function in schizophrenia. Evidence that gene expression may be abnormal in schizophrenia, with decreased production of an excitatory neurotransmitter receptor, may have therapeutic as well as pathogenetic implications.
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PMID:Decreased hippocampal expression of a glutamate receptor gene in schizophrenia. 167 70

An improvement in tardive dystonia in a patient who had received ECT for a schizophrenic psychosis is reported. The improvement suggests that the pathophysiology of tardive dystonia may involve neurotransmitter receptor changes similar to those seen in schizophrenia.
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PMID:Temporary remission of tardive dystonia following electroconvulsive therapy. 234 49

Fear is an adaptive response of the organism to external threat and the physiologic and behavioral responses to stimuli that induce fear involves activation of the sympathetic nervous system. Drugs that alter the function of two of the major brain monoamine neurotransmitter systems involved in sympathetic nervous system regulation (NE and 5-HT) have been shown to alter levels of "fear and anxiety" in laboratory animals, healthy humans, and patients. The relative clinical efficacy in the treatment of anxiety disorders with many of these drugs also emphasizes the importance of these two systems in anxiety. Recent advances in neuropharmacology have led to an improved understanding of how drugs that interact at specific NE and 5-HT receptors alter the function of these two neurotransmitter systems, and a few of the drugs that selectively interact at NE and 5-HT receptors have been used in studies of patients with anxiety disorders. Stimulation of the 5-HT system does not produce marked abnormalities in patients, but stimulation of the NE system does produce abnormal changes in measures of anxiety, somatic symptoms, blood pressure, and a plasma NE metabolite and cortisol levels in patients with panic disorder but not in patients with generalized anxiety disorder, obsessive-compulsive disorder, depression, or schizophrenia. This indicates that some patients with panic disorder have an abnormality in the regulation of the NE system that could explain many of the clinical features of this syndrome. Progress in assessing neurochemistry in the brains of living patients through brain imaging and new advances in the molecular biology of neurotransmitter receptor proteins will offer important new methods to be used in the study of these possible abnormalities.
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PMID:Monoamine receptor systems and anxiety disorders. 284 38

At the present time, the following summary statements can be made as to 24-hour changes in receptor binding. In all receptors studied in homogenates from whole rat forebrain (alpha 1, alpha 2, beta-adrenergic, muscarinic cholinergic, dopaminergic, 5HT-1, 5HT-2, adenosine, opiate, benzodiazepine, GABA, imipramine), significant variations over 24 hours have been documented. The receptor rhythms measured change in wave form, amplitude, and phase throughout the year, even though the animals have been kept on a defined and constant LD cycle. Whether these rhythms are truly seasonal requires further investigation. The rhythms are circadian: i.e. they persist in the absence of time cues, and the unimodal rhythms do not persist after lesion of the putative circadian pacemaker in the suprachiasmatic nuclei. The rhythms can be uni- or bimodal, and each brain region shows a particular pattern. The pattern can be different for the same ligand in different nuclei of a given brain region (e.g. hypothalamus). Nearly all studies of receptor rhythms have been carried out in rats; the results vary according to strain and even within the same strain from different breeding lines. Receptor rhythm characteristics are modified by age: e.g. the amplitude, phase, as well as the 24-hour mean of binding to a given ligand in a defined brain region. The changes in number of binding sites over 24 hours can be correlated with amine turnover, second messenger, or function of that brain region; however these relationships, although consistent within a region, do not hold for all regions. If gradual changes in CNS neurotransmitter receptor function are considered important in the pathogenesis of schizophrenia and affective disorders and the mode of action of psychopharmacological agents, then consideration of the short term rapid change over 24 hours is equally necessary. Chronic treatment with a number of psychoactive drugs known to induce up- or down-regulation of receptor number, also induces marked changes in circadian rhythm parameters of wave form, amplitude, phase and 24-hour mean. This is of methodological importance for single time-point studies, since the interpretation of the results will depend on time of day. Preliminary evidence supports the assumption that the significant variation in receptor binding throughout the day may underlie the well-known circadian rhythms of susceptibility to many CNS drugs. New findings of circadian rhythms in receptors on blood cells indicate the relevance of these changes also in human physiology.
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PMID:Circadian rhythms in mammalian neurotransmitter receptors. 303 6

The introduction of the atypical neuroleptic, clozapine, has had widespread influence not only on the treatment of the seriously mentally ill patient, but also on new drug development and on hypotheses of the pathophysiology of schizophrenia. While clozapine differs from traditional neuroleptics in its lack of extrapyramidal side effects (EPS), it also is distinct in its profile of neurotransmitter receptor affinities. In our work examining the clinical and biological effects of clozapine in patients with schizophrenia, we have identified the presence of EPS during typical neuroleptic treatment as a consistent predictor of subsequent good response to clozapine. Further, our data suggest that clozapine should not be reserved for the most chronically ill patients, but rather be utilized in patients with less chronic courses of schizophrenia. Biological predictors of clozapine response are consistent with dopaminergic, serotonergic, and noradrenergic facets to its mechanism of action.
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PMID:Predictors of clozapine response in schizophrenia. 752 41

In the introductory section an overview is given of the strategies which have been proposed in the search for side-effect free antipsychotics. Special attention is paid to the role of predominant 5HT2 receptor blockade over D2 blockade. Whereas D2 receptor blockade seems to be essential for the treatment of positive symptoms of schizophrenia, it also underlies the induction of extrapyramidal side effects (EPS). Predominant 5HT2 receptor blockade may reduce the EPS liability and can ameliorate negative symptoms of schizophrenia. We further report a nearly complete list of neuroleptics that are on the European market and eight new antipsychotics that recently entered clinical trial, 5HT2 and D2 receptor binding affinity (Ki values) and the rank order in affinity for various neurotransmitter receptor subtypes are also discussed. For the eight new antipsychotics and for six reference compounds the complete receptor binding profile (including 33 radioligand receptor binding and neurotransmitter uptake models) is reported. Furthermore, for a series of 120 compounds the relative affinity for D2 receptors and D3 receptors (a recently cloned new dopamine receptor subtype) is compared. Finally, original findings are reported for the new antipsychotic risperidone and for haloperidol and clozapine on the in vivo occupation of neurotransmitter receptors in various brain areas after systemic treatment of rats or guinea pigs. The receptor occupation by the drugs was measured ex vivo by quantitative receptor autoradiography. The receptor occupancy was related to the motor activity effects of the test compounds (measurements were done in the same animals) and to the ability of the drugs to antagonize various 5HT2 and D2 receptor mediated effects. With risperidone a high degree of central 5HT2 receptor occupation was achieved before other neurotransmitter receptors became occupied. This probably co-underlies the beneficial clinical properties of the drug. Antagonism of the various D2 receptor-mediated effects was achieved at widely varying degrees of D2 receptor occupancy, from just about 10% to more than 70%. For therapeutic application it may be of prime importance to carefully titrate drug dosages. Antipsychotic effects may be achieved at a relatively low degree of D2 receptor occupancy at which motor disturbances are still minimal. With drugs such as risperidone that produce shallow log dose-effect curves, differentiation between the various D2 receptor mediated effects may be made more easily, allowing EPS-free maintenance therapy of schizophrenic patients.
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PMID:Interaction of antipsychotic drugs with neurotransmitter receptor sites in vitro and in vivo in relation to pharmacological and clinical effects: role of 5HT2 receptors. 753 Mar 77

Diminished suppression of the P50 component of the evoked potential following repeated auditory stimuli is one example of a deficit in elementary sensory processing in schizophrenia. Normal subjects suppress the P50 evoked potential to the second of two paired auditory stimuli. Although normal P50 suppression is occasionally observed in schizophrenic patients, it generally disappears with subsequent testing. The object of this experiment was to determine conditions for the reproducible normalization of P50 suppression in schizophrenic patients. After baseline recordings, 12 schizophrenic subjects were allowed to sleep for 10 minutes. The depth of sleep obtained was assessed by electroencephalography (EEG). Normalization of P50 suppression was observed for approximately 3 minutes in all subjects who entered slow wave sleep, but not in those whose EEG records remained desynchronized. Some change was even observed in subjects who had only persistent alpha waves. The amount of normalization was correlated with the deepest stage of sleep reached. Normal control subjects did not show this phenomenon but instead had a transient decrease in sensory gating after waking from sleep. The results suggest that schizophrenic patients may have a defect that causes a neuronal mechanism critical to sensory gating to fail after brief use, although its activity can be transiently restored by a short period of inactivity. A rapidly desensitized neurotransmitter receptor is one possible mechanism of such an effect.
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PMID:Normalization of auditory sensory gating in schizophrenic patients after a brief period for sleep. 814 Jan 80

There is increasing evidence that oxidative injury contributes to pathophysiology of schizophrenia, indicated by the increased lipid peroxidation products in plasma and CSF, and altered levels of both enzymatic and non-enzymatic antioxidants in chronic and drug-naive first-episode schizophrenic patients. The increased plasma lipid peroxidation is also supported by concomitant lower levels of esterified polyunsaturated essential fatty acids of red blood cell plasma membrane phospholipids. Because membrane phospholipids play a critical role in neuronal signal transduction, oxidative damage of these lipids may contribute to the proposed altered neurotransmitter receptor-mediated signal transduction and thereby alter information processing in schizophrenia. Adjunctive treatment with antioxidants (e.g. vitamins E and C, beta-carotene and quinones) at the initial stages of illness may prevent further oxidative injury and thereby ameliorate and prevent further possible deterioration of associated neurological and behavioral deficits in schizophrenia.
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PMID:Oxidative injury and potential use of antioxidants in schizophrenia. 888 22

Various criteria used to define atypical antipsychotic drugs include: 1) decrease, or absence, of the capacity to cause acute extrapyramidal motor side effects (acute EPSE) and tardive dyskinesia (TD); 2) increased therapeutic efficacy reflected by improvement in positive, negative, or cognitive symptoms; 3) and a decrease, or absence, of the capacity to increase prolactin levels. The pharmacologic basis of atypical antipsychotic drug activity has been the target of intensive study since the significance of clozapine was first appreciated. Three notions have been utilized conceptually to explain the distinction between atypical versus typical antipsychotic drugs: 1) dose-response separation between particular pharmacologic functions; 2) anatomic specificity of particular pharmacologic activities; 3) neurotransmitter receptor interactions and pharmacodynamics. These conceptual bases are not mutually exclusive, and the demonstration of limbic versus extrapyramidal motor functional selectivity is apparent within each arbitrary theoretical base. This review discusses salient distinctions predominantly between prototypic atypical and typical antipsychotic drugs such as clozapine and haloperidol, respectively. In addition, areas of common function between atypical and typical antipsychotic drug action may also be crucial to our identification of pathophysiological foci of the different dimensions of schizophrenia, including positive symptoms, negative symptoms, and neurocognitive deficits.
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PMID:Mechanisms of action of atypical antipsychotic drugs: a critical analysis. 893 97


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