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)

Changes in cholinergic neurons have been implicated in the pathology of schizophrenia. Clozapine, an atypical anti-psychotic drug, has been shown to bind with high affinity to the muscarinic1 (M1) receptor suggesting this receptor could be involved in the therapeutic efficacy of the drug. Because of this we measured the density of M1 receptors in the caudate-putamen, obtained at autopsy, from 19 schizophrenic subjects and 19 non-schizophrenic subjects. The density of M1 receptors was decreased in the caudate-putamen from the schizophrenic subjects (181 +/- 20 vs 287 +/- 10 fmol mg-1 TE; mean +/- s.e.m.; P < 0.001). Furthermore, preliminary studies would not suggest that the change in the density of M1 receptors in the tissue from the schizophrenic subjects had resulted from drug treatment prior to death. These data raise the possibility that changes in muscarinic receptors may be involved in the pathology of schizophrenia.
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PMID:The density of muscarinic M1 receptors is decreased in the caudate-putamen of subjects with schizophrenia. 915 28

Clozapine is an antipsychotic drug with few extra-pyramidal motor side-effects, used to treat schizophrenia which is resistant to classical neuroleptic therapy. This report shows that norclozapine but not clozapine-N-oxide has the same D2 receptor affinity as clozapine. Assay results suggest a bimodal distribution which may be explained by CYP1A2 polymorphism. Extensive metabolizers could produce other active metabolites, probably other hydroxy-clozapine derivatives.
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PMID:Determination of clozapine in serum by radioreceptor assay versus high-performance liquid chromatography: possible detection of hydroxy-metabolites. 911 16

This study examined the cognitive functioning of 10 treatment-resistant schizophrenic patients after a minimum of a 1-year trial on clozapine. Results indicated significant improvements on prorated Wechsler Adult Intelligence Scale-Revised (WAIS-R) Full Scale, Verbal, and Performance IQs and on the WAIS-R Similarities and Digit Symbol subtests. A trend was also found for improvement on the Wisconsin Card Sorting Test. It was concluded that clozapine treatment is associated with global cognitive improvements in patients with treatment-resistant schizophrenia. Clozapine treatment may also improve performance on the Wisconsin Card Sorting Test in a subset of patients. Improvement did not appear to be related to the reduction of any cognitive effects of the typical neuroleptics upon their discontinuation.
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PMID:The effects of clozapine on cognitive functioning in treatment-resistant schizophrenic patients. 914 3

During the past 5 years unprecedented advances have taken place in the psychopharmacology of schizophrenia and related psychoses. Clozapine and risperidone, two prototypic novel antipsychotic drugs, have had a significant impact on the treatment of psychotic disorders. Additionally, they have ushered in another generation of antipsychotic drugs with complex pharmacologic profiles, potentially enhanced efficacy, and more benign side-effect profiles than previously associated with conventional antipsychotic medications. This review highlights these developments, implications for the management of psychotic disorders, and the use of novel antipsychotic drugs in specific clinical subgroups.
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PMID:New dimensions in the pharmacologic treatment of schizophrenia and related psychoses. 915 69

The atypical neuroleptic, clozapine, has been shown to have encouraging, but mixed, effects on prefrontal cortical (PFC) cognitive deficits in schizophrenia, a stress-exacerbated disorder involving dopamine (DA) dysregulation. The current study examined the effects of acute clozapine pretreatment on the spatial working memory deficits induced by the pharmacological stressor, FG7142, in monkeys. Previous research has shown that FG7142 impairs spatial working memory in rats and monkeys through excessive DA receptor stimulation in the PFC (Murphy et al. 1996). Lower clozapine doses (1-3 mg/kg p.o.) reversed the FG7142-induced spatial working memory deficits, whereas doses in the clinical range (e.g., 6 mg/kg, p.o.) did not improve cognitive function in most animals. Clozapine alone produced a dose-related impairment in delayed response performance. These results from nonhuman primates suggest that the clozapine doses commonly used to treat schizophrenia may not be optimal for treating the PFC cognitive deficits associated with this illness.
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PMID:Clozapine reverses the spatial working memory deficits induced by FG7142 in monkeys. 916 99

Schizophrenia is a serious and often debilitating neuropsychiatric disease of worldwide importance. Current therapy relies on the use of typical antipsychotic medications, which specifically inhibit binding of ligand at the D2 dopamine receptor, and atypical medications which display little activity for this receptor interaction. While atypical antipsychotic agents have been shown to variably inhibit other neuroreceptor-ligand interactions, the exact mechanisms for the therapeutic efficacy of these medications have not been completely defined. Clozapine, an atypical antipsychotic, and nine of its metabolites were studied in vitro for possible antiviral activity against a model of a human neurotropic virus, human immunodeficiency virus type 1 (HIV-1). In an assay for inhibition of virus-induced cytopathic effect (CPE) two metabolites demonstrated antiviral activity (ID50 = 37-85 micrograms/ml) (119-289 microM), while other atypical or novel antipsychotics as well as typical medications had no effect. Based on an ELISA, four chemically similar metabolites inhibited the production of p24, the major internal antigen of HIV (ID50 = 11.6-15.7 micrograms/ml) (38-51 microM). These data suggest that the therapeutic efficacy of some antipsychotics may be due in part to an ability to inhibit viral replication. Antiviral agents may prove to be effective adjuncts in the treatment of schizophrenia.
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PMID:Metabolites of the antipsychotic agent clozapine inhibit the replication of human immunodeficiency virus type 1. 917 28

1. The atypical antipsychotic profile of (R)-(+)-2-amino-4-(4-fluorophenyl)-5-[1-[4-(4-fluorophenyl)-4-oxobutyl] pyrrolidin-3-yl] thiazole (NRA0045), a potent dopamine D4 and 5-hydroxytryptamine (5-HT)2A receptor antagonist, was examined in rats. 2. Spontaneous locomotor activity was decreased dose-dependently with i.p. administration of clozapine (ED50 3.7 mg kg-1), haloperidol (ED50 0.1 mg kg-1) and chlorpromazine (ED50 0.9 mg kg-1), whereas inhibition of this type of behaviour induced by i.p. administration of NRA0045, at doses up to 10 mg kg-1, did not exceed 50%. 3. Locomotor hyperactivity induced by methamphetamine (MAP, 2 mg kg-1, i.p.) in rats (a model of antipsychotic activity) was dose-dependently antagonized by NRA0045 (ED50 0.4 mg kg-1, i.p., and 0.3 mg kg-1, p.o., respectively), clozapine (ED50 0.3 mg kg-1, i.p. and 0.8 mg kg-1, p.o., respectively), haloperidol (ED50 0.02 mg kg-1, i.p. and 0.1 mg kg-1, p.o., respectively), chlorpromazine (ED50 0.3 mg kg-1, i.p. and 3.3 mg kg-1, p.o., respectively). In contrast, the MAP (3 mg kg-1, i.v.)-induced stereotyped behaviour in rats (a model of extrapyramidal symptoms) was not affected by NRA0045 or clozapine, at the highest dose given (30 mg kg-1, i.p.). Haloperidol (ED50 0.3 mg kg-1, i.p.) and chlorpromazine (ED50 4.8 mg kg-1, i.p.) strongly blocked the MAP-induced stereotyped behaviour. NRA0045 and clozapine selectively blocked behaviour associated with activation of the mesolimbic/mesocortical dopamine neurones rather than nigrostriatal dopamine neurones. 4. Extracellular single-unit recording studies demonstrated that MAP (1 mg kg-1, i.v.) decreased the firing rate in the substantia nigra (A9) and ventral tegmental area (A10) dopamine neurones in anaesthetized rats. NRA0045 completely reversed the inhibitory effects of MAP on A10 dopamine neurones (ED50 0.1 mg kg-1, i.v.), whereas the inhibitory effects of MAP on A9 dopamine neurones were not affected by NRA0045, in doses up to 1 mg kg-1 (i.v.). Clozapine completely reversed the inhibitory effects of MAP on A10 dopamine neurones (ED50 1.9 mg kg-1, i.v.) and on A9 dopamine neurones (ED50 2.5 mg kg-1, i.v.). Haloperidol completely reversed the inhibitory effects of MAP on A10 (ED50 0.03 mg kg-1, i.v.) and on A9 dopamine neurones (0.02 mg kg-1, i.v.). NRA0045, like clozapine, was more potent in reversing the effects of MAP on A10 than A9 dopamine neurones. 5. Prepulse inhibition (PPI) is impaired markedly in humans with schizophrenia. The disruption of PPI in rats by apomorphine (0.5 mg kg-1, s.c.) was reversed significantly by NRA0045 (3 mg kg-1, i.p.), clozapine (3 mg kg-1, i.p.) and haloperidol (0.3 mg kg-1, i.p.). 6. Phencyclidine (PCP) elicits predominantly psychotic symptoms in normal humans and in schizophrenics. NRA0045 (0.03-0.3 mg kg-1, i.p.) and clozapine (0.1-1 mg kg-1, i.p.) significantly and dose-dependently shortened the PCP(1.25 mg kg-1, i.p.)-induced prolonged swimming latency in rats in a water maze task, whereas haloperidol (0.01-0.1 mg kg-1, i.p.) did not significantly alter swimming latency. 7. These findings suggest that NRA0045 may have unique antipsychotic activities without the liability of motor side effects typical of classical antipsychotics.
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PMID:The atypical antipsychotic profile of NRA0045, a novel dopamine D4 and 5-hydroxytryptamine2A receptor antagonist, in rats. 917 95

Clozapine has been shown to have superior effectiveness compared with classic neuroleptics in treating refractory schizophrenia in Caucasians, but its efficacy and safety in Chinese have not been adequately studied. Forty Chinese schizophrenic patients were recruited in a 12-week, double-blind, comparative trial. Twenty-one patients were randomly assigned to clozapine treatment and 19 to chlorpromazine treatment. The average dose was 543 +/- 157 and 1163 +/- 228 mg/day for clozapine and chlorpromazine, respectively. The results showed that six clozapine-treated patients (28.6%) had more than 20% improvement in Brief Psychiatric Rating Scale score and were classified as responders, whereas none of the chlorpromazine-treated patients was classified as a responder. The degree of improvement in positive symptoms, negative symptoms and Brief Psychiatric Rating Scale scores in the clozapine group was inversely correlated with the severity of negative symptoms at entry into the trial. Two clozapine-treated patients were withdrawn from the study, one because of leukopenia and nausea, and the other because of vomiting and hypotension. Chlorpromazine treatment was prematurely discontinued in two patients, because of jaundice and over sedation in one, and because of severe weight loss in the other (9 kg). The rate of moderate-to-severe sialorrhea was high in clozapine-treated patients (28.6%). Two clozapine-treated patients and two chlorpromazine-treated patients showed significant improvement in previously existing tardive dyskinesia and one chlorpromazine-treated patient exhibited aggravation of tardive dyskinesia. The results of this study indicate that clozapine treatment might have advantages over chlorpromazine for Chinese schizophrenic patients who are refractory to typical neuroleptic treatment.
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PMID:A double-blind comparative study of clozapine versus chlorpromazine on Chinese patients with treatment-refractory schizophrenia. 924 67

Clozapine is increasingly being used for clinical indications in addition to treatment-resistant schizophrenia; this article reviews the relevant literature. The first section reassesses the risks associated with clozapine treatment, particularly agranulocytosis. The next section discusses its use for schizophrenia in patients who are treatment resistant, not treatment resistant, and intolerant of traditional drug treatments. Subsequent sections address its use in mood disorders, neurologic conditions, comorbid substance abuse, aggressive behavior, and childhood schizophrenia. Each includes the initial rationale for the use of clozapine in the disorder, a critical evaluation of the relevant literature, and theories as to why clozapine's unique pharmacodynamic profile may be efficacious for the specific condition. This body of literature suggests clozapine may be an effective treatment for a wide range of disorders.
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PMID:The expanding indications for clozapine. 926 69

Clozapine was approved by the U.S. Food and Drug Administration in 1989 for treatment of severely ill schizophrenic patients. It has activity against both the positive and negative symptoms of schizophrenia, which has made it an alternative to traditional antipsychotic medications such as haloperidol. However, clozapine must be used cautiously due to its side effect profile. These side effects include agranulocytosis, seizures, and cardiorespiratory symptoms. We report the case of a patient who developed polyserositis (pericardial effusion, pleural effusion, and pericarditis) after being started on clozapine, and whose symptoms remitted upon discontinuation of clozapine. The literature is reviewed and the treatment implications are discussed.
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PMID:Clozapine induced polyserositis. 926 Jul 33


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