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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The clinical profile of clozapine (CAS 5786-21-0) is characterized by superior efficacy in reducing the positive and negative symptoms of schizophrenia and a greatly reduced propensity to elicit acute extrapyramidal symptoms (e.g., Parkinsonian symptoms), long-term effects (e.g., tardive dyskinesia) and hyperprolactinemia. For these reasons clozapine is considered the prototypic atypical antipsychotic. The failure of clozapine to elevate serum prolactin concentrations may be related to the stimulatory effect of clozapine on tuberoinfundibular dopamine neurons and/or the failure of clozapine to achieve effective blockade of pituitary dopamine D2 receptors. The lack of acute blockade of striatal D2 receptors by clozapine and the failure of chronic clozapine treatment to suppress striatal dopamine release, relative to that produced by typical antipsychotic agents, may account for the lack of acute extrapyramidal symptoms and tardive dyskinesia, respectively, associated with the use of clozapine. Although the neurochemical substrates that subserve the unique preclinical and clinical profile of clozapine have not been determined unequivocally, clozapine and other purported atypical antipsychotic agents produce a greater antagonism of 5-HT2 receptors relative to D2 receptors than is the case for typical antipsychotics. Clozapine also exerts antagonism of D1 receptors. It is proposed that the selective interaction of clozapine among D2, D1, D4 and 5-HT2 receptors results in a distinctive alteration in the function of pre- and post-synaptic dopamine elements.
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PMID:Dopaminergic and serotonergic effects of clozapine. Implications for a unique clinical profile. 158 97

Twelve patients with schizophrenia received positron emission tomography scans with 18F-deoxyglucose before and after 4 to 6 weeks of treatment with clozapine or thiothixene. Both stereotaxic and magnetic resonance image template methods were used to position regions of interest for metabolic rate analysis. Clozapine increased and thiothixene decreased metabolic rates in the basal ganglia; these effects were most marked on the right side. Within the basal ganglia, a superior to inferior gradient in drug effect was found for thiothixene but not clozapine. This gradient resembled in some respects observations on regional differences in D2 receptors in human autoradiography. Baseline metabolic rates also predicted clinical medication response, with right inferior caudate metabolic rates differentiating clozapine and thiothixene responders. Larger sample studies are needed to replicate and extend these initial findings.
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PMID:Effects of clozapine and thiothixene on glucose metabolic rate in schizophrenia. 159 6

The authors review recent research findings on the drug treatment of schizophrenia. A number of studies emphasize that neuroleptic medications are severely limited by neurological side effects that include acute extrapyramidal syndromes and tardive dyskinesia. Studies comparing neuroleptic doses in both acute and maintenance therapy have encouraged clinicians to evaluate methods for treating patients with the lowest effective dose. Other studies, but not all, indicate that plasma level measurement may be helpful in decision making about drug dosage. The management of schizophrenic patients with illnesses that are refractory to conventional neuroleptics is also discussed. Clozapine, an atypical neuroleptic, may be more effective than other available neuroleptics for severely ill, treatment refractory patients or patients who are unable to tolerate the neurological side effects of typical neuroleptics.
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PMID:Drug treatment of schizophrenia. Overview of recent research. 167 83

The epidemiology, etiology, diagnosis, and treatment of schizophrenia are reviewed. In the United States, at least 1 in every 100 persons is afflicted with schizophrenia. The theory that schizophrenia is a biochemical disorder has gained wide acceptance, although none of the etiological theories are conclusive. Criteria contained in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, are most commonly used to diagnose schizophrenia. Accuracy in diagnosing schizophrenia is critical because the treatments and prognoses for different types of psychoses can vary considerably. Treatment primarily involves the use of antipsychotic drugs, which are thought to act by blocking central dopamine receptors. The classical antipsychotics are the phenothiazines; of these, the prototype is chlorpromazine. Other classes of antipsychotics are the thioxanthenes, butyrophenones, dihydroindolones, dibenzoxazepines, diphenylbutylpiperidines, and dibenzodiazepines. Selecting an appropriate agent involves consideration of adverse effects, dosage forms, and the agent's ability to relieve target symptoms. Adverse effects of these agents include sedation, extrapyramidal effects, and anticholinergic effects. Tardive dyskinesia is a serious, irreversible condition associated with long-term antipsychotic therapy. Clozapine, a newer atypical antipsychotic, has been shown to be more effective than chlorpromazine and haloperidol and seems to cause few neurological adverse effects. Treatment of schizophrenia has not changed much since the advent of antipsychotic drug use nearly 30 years ago. Newer atypical antipsychotics show promise in improving target symptoms while causing fewer adverse effects.
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PMID:Epidemiology, etiology, diagnosis, and treatment of schizophrenia. 167 28

Clozapine is a neuroleptic agent whose structure consists of a dibenzodiazepine derivative with a piperazinyl side chain. It has been classified as an atypical neuroleptic drug due to its unique neuropharmacologic profile. Clozapine has a weak binding affinity for dopamine D-1 and D-2 receptors by its slightly greater preference for D-1 receptors, as noted with a D-1:D-2 receptor binding ratio of 1.3. Other neuroreceptors are involved, as the drug has potent binding affinity for serotonin receptors 5-HT1A and 5-HT2. Clozapine also has antihistaminic, anticholinergic, and alpha-adrenergic antagonistic properties. Electrophysiologic studies show that it differs from other typical neuroleptics in that its actions appear to be specific for the cortical-limbic dopamine A-10 tract. In animal paradigms, in contrast to typical neuroleptics, clozapine did not produce catalepsy and had only transient effects in antagonizing other dopamine agonists. The drug is rapidly absorbed orally with a bioavailability of 0.27. After a single oral dose the elimination half-life was approximately 8-10 hours, but with several doses it increased to 14.1 hours. The agent is extensively metabolized by hepatic microsomal enzymes that forms the N-desmethyl and N-oxide metabolites. It is an effective neuroleptic that has been studied in short-term and long-term clinical trials, and multicenter trials. Clozapine was superior to chlorpromazine in the treatment of refractory schizophrenia that failed to respond to previous neuroleptic therapy. Reports of extrapyramidal side effects are minimal, and no case reports of tardive dyskinesia have been published. Indeed, clozapine has been used to treat tardive dyskinesia and other movement disorders. Agranulocytosis is the major adverse effect and its prevalence appears to differ among various ethnic groups. Other adverse effects that have been reported include hypersalivation, orthostatic hypotension, and constipation. Clozapine can lower the seizure threshold in a dose-dependent manner. The drug represents a significant advancement in the treatment of mental illness.
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PMID:Clozapine. 167 65

Clinical studies have shown clozapine to be effective in the treatment of schizophrenia and associated with an extremely low incidence of extrapiramidal side effects. Diverse studies indicate that clozapine is an atypical neuroleptic with a preferential activity on the mesolimbic structures and a lower affinity for striatal D2 receptors than the classical antipsychotics. The purpose of this study was to assess the behavioral properties of clozapine, especially its effects on aggressive and motor behaviors. Individually housed male mice of the OF1 strain were exposed to anosmic "standard opponents" 30 minutes after the last drug administration. One category of animals received a single IP dose of the compound (0.2, 0.5, 1 or 1.5 mg/kg). Another category received daily doses (0.5, 1 or 1.5 mg/kg) for 21 days. Encounters were videotaped and behavior evaluated using an ethologically based analysis. Clozapine, in the acute treatment condition, produced a significant decrease in "attack" and "threat" behaviors without "immobility" being significantly increased. These results suggest a rather specific antiaggressive action of the compound with little motor impairment. In the chronic administration, no significant change in aggressive behavior was observed which may be attributed to the development of some degree of tolerance.
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PMID:Clozapine: strong antiaggressive effects with minimal motor impairment. 174 50

Dopamine receptors belong to the family of G protein-coupled receptors. On the basis of the homology between these receptors, three different dopamine receptors (D1, D2, D3) have been cloned. Dopamine receptors are primary targets for drugs used in the treatment of psychomotor disorders such as Parkinson's disease and schizophrenia. In the management of socially withdrawn and treatment-resistant schizophrenics, clozapine is one of the most favoured antipsychotics because it does not cause tardive dyskinesia. Clozapine, however, has dissociation constants for binding to D2 and D3 that are 4 to 30 times the therapeutic free concentration of clozapine in plasma water. This observation suggests the existence of other types of dopamine receptors which are more sensitive to clozapine. Here we report the cloning of a gene that encodes such a receptor (D4). The D4 receptor gene has high homology to the human dopamine D2 and D3 receptor genes. The pharmacological characteristics of this receptor resembles that of the D2 and D3 receptors, but its affinity for clozapine is one order of magnitude higher. Recognition and characterization of this clozapine neuroleptic site may prove useful in the design of new types of drugs.
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PMID:Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. 184 Jun 45

Clozapine (CLOZ) is an atypical antipsychotic drug being used with increasing frequency throughout the world and has recently been commercially marketed in the United States. Its unique properties make it a promising but challenging drug to use in the treatment of schizophrenia. In order to use CLOZ most effectively and efficiently, clinicians must be aware of its potential benefits and risks. This report is a review and critical evaluation of current knowledge regarding the clinical efficacy and side effects of CLOZ. Although CLOZ has proven to be effective in some treatment-refractory schizophrenic patients and to produce relatively few extrapyramidal side effects compared to classical neuroleptic drugs, several issues require further investigation including what defines neuroleptic intolerance, the optimal dose range, and the appropriate duration of a CLOZ treatment trial. Similarly, studies are needed to determine what role CLOZ should have in the treatment of patients with predominantly negative symptoms and those patients who are only partially responsive to standard neuroleptics. In addition, important questions remain as to what other conditions might be indications for CLOZ, for example, schizoaffective disorder, affective psychoses, and idiopathic Parkinson's disease.
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PMID:Update on the clinical efficacy and side effects of clozapine. 188 9

Most of the experience with the atypical neuroleptic of Clozapine (Leponex, Sandoz) pertains to active treatment. In conjunction with possible risks, at present its administration in selected groups of patients is recommended. The authors describe the results of an intraindividual comparison of Clozapine in 11 patients with the diagnosis of schizophrenia (according to ICD-9), 7 men, mean age 30.5 years with previous neuroleptic treatment. The average period for comparison was 2.3 years (1.5-4 years), the mean daily dose of Clozapine was 200 mg (50-400 mg). During Clozapine treatment the hospitalization period was significantly shorter and the number of hospital admissions was lower. The frequency of undesirable effects was equal during both periods. During Clozapine treatment morning sleepiness and hypersalivation were more frequent and during treatment with neuroleptics extrapyramidal undesirable effects. In none of the patients they caused discontinuation of treatment. Transient leukopenia after Clozapine in one patient was improved after reduction of the dose. The paper is supplemented by the case-history of female patient treated by Clozapine monotherapy during 17 years.
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PMID:[Maintenance therapy in schizophrenia using clozapine]. 191 53

Clozapine is an effective antipsychotic agent with atypical neuroleptic and side effects. The risk of pathological changes in the EEG and of seizures is correlated to the dosage administered. With dosages of 300 mg/day or higher the EEG should be monitored regularly. The neurophysiological effects of this drug, known only in adults up till now, were also found in adolescents suffering from schizophrenia.
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PMID:[EEG changes and seizures with clozapine medication in schizophrenic adolescents]. 196 11


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