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)

1. Progress in 25 years' history of the neuroleptics is briefly reviewed. 2. Development of certain butyrophenones more directly effective in "minus" symptoms of schizophrenia and introduction of depot neuroleptics is discussed. 3. Extrapyramidal motor side effects (EPMS) are still a serious problem in the treatment. 4. Clozapine does not have EPMS. This drug could therefore become the starting point of a series of less hazardous antipsychotic drugs. 5. The neuroleptics can be used as tools for exploration of the etiopathogenesis of schizophrenia. Some important pharmacological mechanisms, i.e. their antidopaminergic activity, are briefly outlined.
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PMID:Treatment of schizophrenia. 4 64

The mechanisms by which the atypical neuroleptic clozapine produces its therapeutic effects in the treatment of schizophrenia without causing the extrapyramidal side effects that are characteristic of most antipsychotic drugs remain unclear. Recently, a single injection of the typical antipsychotic haloperidol has been shown to increase c-fos expression in the striatum [Dragunow et al. (1990) Neuroscience 37, 287-294]. C-fos is a proto-oncogene that encodes a 55,000 mol. wt phosphoprotein, Fos, which is thought to assist in the regulation of "target genes" containing an AP-1 binding site. Because a wide variety of physiological and pharmacological stimuli increase c-fos expression, it has been proposed that Fos immunohistochemistry might be useful in mapping functional pathways in the central nervous system. The present experiments examined some potential neuroanatomical differences in the actions of clozapine and haloperidol by comparing their effects on c-fos expression in the medial prefrontal cortex, nucleus accumbens, striatum and lateral septum. The effects of the selective dopamine receptor antagonists SCH 23390 (D1) and raclopride (D2) were also examined. Haloperidol (0.5, 1 mg/kg) and raclopride (1, 2 mg/kg) produced large increases in the number of Fos-containing neurons in the striatum and nucleus accumbens. SCH 23390 (0.5, 1 mg/kg) reduced the number of Fos-positive neurons in the nucleus accumbens and striatum, and had no effect in the other regions. Neither haloperidol nor raclopride increased the number of Fos-positive neurons in the medial prefrontal cortex. Haloperidol, but not raclopride, produced a modest increase in c-fos expression in the lateral septal nucleus. Clozapine (10, 20 mg/kg) was without effect in the striatum; however, it significantly increased the number of Fos-positive neurons in the nucleus accumbens, medial prefrontal cortex and lateral septal nucleus. Destruction of mesotelencephalic dopaminergic neurons with 6-hydroxydopamine abolished the increase in Fos expression in the nucleus accumbens and striatum produced by haloperidol and raclopride, and also blocked the clozapine-induced increase in the nucleus accumbens. However, the inductive effects of clozapine and haloperidol on c-fos expression in the lateral septal nucleus and of clozapine in the medial prefrontal cortex were not affected by the 6-hydroxydopamine lesions. These results suggest that clozapine's unique therapeutic profile may be related to its failure to induce Fos in the striatum as well as its idiosyncratic actions in the lateral septum and medial prefrontal cortex. The effects of clozapine in these latter regions do not appear to be mediated by dopaminergic mechanisms.
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PMID:Neuroleptics increase c-fos expression in the forebrain: contrasting effects of haloperidol and clozapine. 134 6

The ability to use pharmacological treatment for schizophrenia is progressing in a most efficacious fashion, while the risk of adverse effects is declining. An important reevaluation of minimal effective antipsychotic drug dosages for both acute and extended treatment has taken place. Clozapine has provided clinical practitioners with a useful new alternative for treatment-refractory patients, and new research has helped clarify the role of different maintenance and prophylactic medication strategies. The author summarizes recent progress in these areas.
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PMID:New developments in the pharmacological treatment of schizophrenia. 134 97

It was measured for clozapine saliva level in 62 patients with schizophrenia taking clozapine, the study have found that therapeutic window was at the range from 550 ng/ml to 920 ng/ml in 34 patients with duration more than two years and was at the range from 400 ng/ml to 510 ng/ml in 28 patients with duration less than two years. Clozapine saliva concentration has positively correlated with improvement of though disorders and hostility & suspiciousness in 30 patients with duration more than two years and with improvement of activation in 12 patients with duration less than two years and with anti-adrenergic side effect in 62 patients, the latter effect was significant increased when clozapine saliva level was more than 380 ng/ml.
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PMID:[The correlation between clozapine saliva level and clinical response as well as side effect in patient with schizophrenia]. 135 17

Clozapine, a dibenzodiazepine derivative, has potent antipsychotic activity; but bone marrow suppression resulting in agranulocytosis has been associated with clozapine treatment and has restricted the administration of this drug to treatment-resistant schizophrenic patients. This report describes preliminary results of an open prospective study of the effects of clozapine on symptomatology and social function in 16 treatment-resistant schizophrenic patients. Authors prospectively followed up for 18 months 16 DSM III-R schizophrenic patients who had failed to respond to various neuroleptics (n: 7.2 +/- 2.8); when clozapine treatment was initiated, the mean duration of the illness was 14.2 (+/- 6.7) years. Total BPRS, BPRS "positive" and "negative" symptoms scores were used for evaluation. Social integration and side effects were also studied. 14 of 16 patients are still receiving clozapine; 1 out of 14 patients has a more than 60% decrease in total BPRS, 11 out of 14 have 30 to 60% decrease in total BPRS and 2 out of 14 have less than 30% decrease in total BPRS. Improvements in both total and positive symptoms BPRS scores were observed within the first month of treatment (p < 0.001); improvement in negative symptoms was noted within the third month (p < 0.02). At the end of the follow up period, 43% of patients showed marked improvement in family life and 21% found a job during the study. Beyond noteworthy improvement of clinical symptoms in these patients who presented with severe schizophrenia, clozapine also significantly reduced the use of concomitant medication. Side effects are studied but none required treatment disruption; neurological side effects were less reported than with usual neuroleptics. It is concluded that clozapine offers particular benefits for some treatment-resistant schizophrenic patients; however the increased comparative risk requires a restricted use of clozapine to selected patients.
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PMID:[A new therapeutic approach tp drug-resistant schizophrenia: clozapine. Long-term prospective study in 16 patients]. 136 81

Twenty-one patients with schizophrenia who met criteria for neuroleptic treatment resistance or intolerance participated in a crossover, placebo-controlled, double-blind comparison of long-term typical neuroleptic and clozapine treatment. Clozapine significantly reduced total as well as positive and negative symptoms in comparison with both fluphenazine and placebo. Of the 21 patients, eight (38%) showed clozapine superiority on the basis of prospective response criteria. High levels of extrapyramidal side effects during fluphenazine treatment and later onset of illness were clinical predictors of clozapine superiority. Clozapine and fluphenazine equally reduced plasma homovanillic acid levels in comparison with placebo, although fluphenazine but not clozapine increased plasma prolactin level. A striking biologic difference between clozapine and fluphenazine was clozapine's enhancement of indexes of noradrenergic activity. Superior clozapine response was predicted by low ratios of cerebrospinal fluid homovanillic acid to 5-hydroxyindoleacetic acid, consistent with the notion that balance between dopaminergic and serotoninergic systems is important for clozapine's mechanism of action.
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PMID:Clinical and biologic response to clozapine in patients with schizophrenia. Crossover comparison with fluphenazine. 768 12

The treatment of patients with schizophrenia who fail to respond to antipsychotic medications remains a challenge. Despite numerous attempts to establish effective somatic treatment approaches for this population, clozapine appears to be the only well established alternative. Depending upon trial duration and response criteria, between 30% and 60% of previously unresponsive patients appear to derive clinically significant benefit from clozapine. Clozapine also has important advantages in terms of its reduced propensity to produce extrapyramidal side-effects. Agranulocytosis remains an important risk, so strategies to improve the benefit-to-risk ratio should be explored. Issues such as trial duration, dosage, blood levels and predictors of response require additional study.
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PMID:Clinical efficacy of clozapine in treatment-refractory schizophrenia: an overview. 141 88

Clozapine is an atypical neuroleptic agent that has recently become available in Canada with potential clinical efficacy in the treatment of refractory schizophrenia, and in patients with schizophrenia neurologically intolerant to conventional neuroleptics. Although it causes few extra-pyramidal symptoms, the drug has a number of other adverse effects including a risk of agranulocytosis in one to two percent of all patients. Because of this, the use of the drug is permitted only if the white blood count is monitored weekly. The monitoring system, outlined in this article, requires a coordinated effort between clinical staff, pharmacy, laboratory and the Clozaril Support and Assistance Network. Clinical guidelines are proposed, detailing the indications and contraindications for treatment and the pharmacokinetics, dosing, adverse effects, and drug interactions with clozapine. In addition, the economics, government policies and implications for future research are considered. Although there are administrative and clinical difficulties associated with its use, clozapine represents an advance in therapeutic research. Patients and family members will be inquiring about the drug and may deserve a trial. This article aims to inform Canadian mental health professionals about the safe and beneficial use of clozapine.
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PMID:Clozapine in the treatment of refractory schizophrenia: Canadian policies and clinical guidelines. 142 46

The affinities of a range of antipsychotic drugs at human hippocampal 5-HT1A receptors, defined by specific [3H]8-OH-DPAT binding, were determined. Clozapine demonstrated the highest affinity; all other antipsychotics studied demonstrated pK(i) values below 6.0 5-HT1A receptors are found on cortical glutamatergic neurons, a dysfunction of which may occur in schizophrenia. Binding at this site indicates a possible mechanism contributing to the unique efficacy of clozapine in the treatment of some schizophrenic patients.
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PMID:Clozapine has sub-micromolar affinity for 5-HT1A receptors in human brain tissue. 142 17

Medical records of the first 37 patients to begin clozapine treatment at a state hospital in Oregon were reviewed for six months before clozapine treatment and six months after. Patients had a long history of schizophrenia and had responded poorly to antipsychotic medication. Clozapine treatment was generally well tolerated, although the rate of seizures (8 percent) was slightly higher than expected. Psychotic symptoms decreased as measured by the Brief Psychiatric Rating Scale, as did symptoms of tardive dyskinesia as measured by the Abnormal Involuntary Movement Scale. Thirty-four patients remained hospitalized after six months of treatment. However, indicators of social function (hospital privilege level, community passes, violent episodes, and episodes of seclusion and restraint) all showed that patients improved markedly after receiving clozapine.
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PMID:Clinical review of clozapine treatment in a state hospital. 151


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