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)

Clozapine, an antipsychotic agent of the dibenzodiazepine class, is characterised by relatively weak central dopaminergic activity and displays atypical pharmacological and clinical properties in relation to the classic antipsychotics. Clinical studies have shown clozapine to be effective in suppressing both the positive and negative symptoms of schizophrenia and to be associated with an extremely low incidence of extrapyramidal side effects. Clozapine has been shown to be of comparable, or on some criteria superior, therapeutic efficacy to perphenazine, levomepromazine, haloperidol and chlorpromazine in several short term comparative studies in patients with schizophrenia of predominantly acute symptomatology. Moreover, clozapine is effective in a substantial proportion (30 to 50%) of schizophrenic patients who are refractory to or intolerant of classic antipsychotic therapy. Despite its promising therapeutic potential, the relatively high incidence of clozapine-induced agranulocytosis (1 to 2% of patients) is a major factor restricting the drug's wider use in psychiatric practice. In accordance with current guidelines, clozapine therapy, performed in conjunction with close haematological monitoring, is indicated for the management of severe and chronic schizophrenia refractory to classic antipsychotic therapy, and in those unable to tolerate such therapy. In such appropriately selected patients, clozapine represents an important alternative to the classic antipsychotics.
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PMID:Clozapine. A review of its pharmacological properties, and therapeutic use in schizophrenia. 229 34

Clozapine, a new drug for schizophrenia, was recently released for use. We have described the drug and nursing care involved for patients who are on acute inpatient unit for a trial of the drug. From our early observations, clozapine appears to be a promising drug for patients who have not responded to standard neuroleptics.
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PMID:Clozapine: a new drug for schizophrenia. 240 37

Clozapine can produce greater clinical improvement in both positive and negative symptoms than typical antipsychotic drugs in neuroleptic-resistant schizophrenic patients. The clinical response may occur rapidly in some patients but is delayed in others. Clozapine has also been reported to produce fewer parkinsonian symptoms, to involve a lower risk of producing tardive dyskinesia, and to produce no serum prolactin elevations in man. It seems likely that these effects are the result of a common biological mechanism or related mechanisms, rather than unrelated effects. Other atypical antipsychotic drugs, such as melperone and fluperlapine, share at least some of these properties. A relatively low affinity for the D-2 dopamine (DA) receptor and high affinity for the 5-HT2 receptor, producing a high 5-HT2/D-2 ratio, best distinguishes atypical antipsychotics like clozapine from typical antipsychotic drugs. Through its weak antagonist action on D-2DA receptors and a potent inhibitory effect on 5-HT2 receptors, as well as its ability to increase DA and 5-HT2 release, clozapine may be able to permit more normal dopaminergic function in the anterior pituitary, the mesostriatal, mesolimbic and mesocortical regions. The numerous advantages of clozapine over typical neuroleptics are consistent with the primary importance of DA to the pathophysiology of schizophrenia. The secondary but still significant role of 5-HT in the action of clozapine may either be direct or via the effect of 5-HT on dopaminergic mechanisms. Some aspects of schizophrenia could be due to a dysregulation of the interaction between serotonergic and dopaminergic neurotransmission.
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PMID:Clozapine: new research on efficacy and mechanism of action. 256 75

Clozapine is a novel antipsychotic agent that selectively blocks mesolimbic--rather than nigrostriatal--dopamine receptors, causes fewer extrapyramidal symptoms than do other neuroleptics, and has superior antipsychotic efficacy in some patients. However, clozapine also causes agranulocytosis more frequently than do other neuroleptics. The evidence documenting the superior benefits obtained with clozapine has primarily involved short-term (4-6 weeks) trials, and the systematic evaluation of long-term clozapine use has been limited. In this study, 14 patients with refractory chronic schizophrenia were treated openly with clozapine up to 2 years; 8 did substantially better when given clozapine than they had when given other neuroleptics. That finding suggests that clozapine may provide a useful addition to the therapeutic armamentarium for the long-term treatment of schizophrenia, despite the increased risks and the need for frequent blood tests.
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PMID:Clozapine for refractory schizophrenia: an open study of 14 patients treated up to 2 years. 257 12

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, dosage, and cost of the atypical antipsychotic drug clozapine are reviewed. Clozapine is a dibenzazepine compound chemically similar to loxapine but with a distinct pharmacologic profile. Unlike currently available medications, clozapine has a low potential for causing extrapyramidal symptoms and does not induce dopamine type 2 receptor hypersensitivity. It shows affinity in vitro not only for dopamine type 1 and 2 receptors but also for histamine type 1, alpha-adrenergic type 1 and 2, serotonin type 2, and muscarinic receptors. Clozapine given orally is nearly completely absorbed and readily metabolized. Urinary excretion is the major route of metabolite elimination. Clozapine has been used to treat schizophrenia, nonschizophrenic psychotic states, depression, neuroses, and behavioral disorders. Double-blind comparative studies have shown clozapine to be superior to haloperidol, chlorpromazine, and placebo in treating the symptoms of schizophrenia, as measured with validated psychiatric rating scales. Adverse effects include orthostatic hypotension, tachycardia, benign hyperthermia, hypertension, seizures, and sedation. Many of these effects are transient. Because of the risk of agranulocytosis, a comprehensive case-management system has been developed. In treating acute psychosis, the optimum dosage of clozapine is 300-450 mg/day given orally in divided doses. The high cost of clozapine may be offset by improved patient response and reduced hospital costs. Clozapine may be superior to other agents in the treatment of refractory schizophrenia and is associated with a negligible incidence of extrapyramidal symptoms.
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PMID:Clozapine: an atypical antipsychotic agent. 257 73

Clozapine is an antipsychotic without the extra-pyramidal adverse effects associated with currently marketed antipsychotics. In animals, this drug has not been shown to induce catalepsy and only weakly antagonizes the stereotypic movements induced by apomorphine and the amphetamines. Clozapine is rapidly absorbed after both single and repeated oral doses, with steady-state concentrations attained within eight to ten days after beginning therapy. It is metabolized to N-oxideclozapine and N-desmethylclozapine, which have less pharmacological activity than the parent compound and are excreted in the urine and, to a lesser extent, in the feces. Clozapine has overall therapeutic efficacy and/or superiority to currently marketed antipsychotics in the treatment of refractory schizophrenia. Usual doses (25-900 mg/d) of clozapine cause fewer extrapyramidal adverse reactions than available antipsychotics. Hypotension, dizziness, salivation, and sedation are the most frequently reported adverse effects and tend to subside over time. Agranulocytosis is the most serious adverse reaction, and those receiving clozapine should undergo weekly white blood cell count determinations. Clozapine is useful for those treatment-resistant patients who have not responded to adequate trials of other antipsychotics.
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PMID:Clozapine: a novel antipsychotic agent. 265 70

Clozapine administration to schizophrenic patients was found to produce dopamine2 (D-2) and serotonin2 (5-HT2) receptor blockade, as evidenced by the ability to block the increases in growth hormone and cortisol secretion produced by apomorphine and MK-212, respectively, direct acting dopamine (DA) and 5-HT2 agonists. Clozapine did not increase plasma prolactin (PRL) levels nor did it block the apomorphine-induced decrease in plasma PRL concentration, as would be expected from a D-2 receptor antagonist. These PRL results are consistent with the observation that clozapine may increase DA release. Clozapine also decreased plasma tryptophan, plasma homovanillac acid (HVA) and basal plasma cortisol levels. Rodent studies suggest clozapine also increases 5-HT release. We hypothesize that antagonism of D-2 and 5-HT2 receptors and enhancement of DA and 5-HT release are critical elements in the action of clozapine to minimize both positive and negative symptoms without producing significant extrapyramidal symptoms or plasma PRL increases. It is proposed that schizophrenia may also involve a dysregulation of 5-HT2- and D-2-mediated neurotransmission, and that a more normal balance in serotonergic and dopaminergic neurotransmission is at least partially restored by clozapine.
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PMID:Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia. 268 29

Tolerability of long term clozapine treatment (7-8 years) was investigated in 27 female patients (age 34-77 years). Diagnosis according to ICD 9 was schizophrenia in 21 patients, severe psychomotor agitation with mental deficiency in 4 patients and an "endogenous" depression in 2 patients. All patients had previously been treated with different neuroleptics but with inadequate response or distressing side effects. The duration of the disorder was 10-36 years, duration of hospitalisation 10-36 years. At the day of investigation the total dose of clozapine ranged from 52-826 g, the average total dose being 385 g. The daily dose of clozapine ranged from 75 to 600 mg, the average daily dose being 225 mg. Only 2 patients were treated exclusively with clozapine, the other 25 patients were also receiving other neuroleptics. Seventy eight per cent of the investigated patients complained about hypersalivation and 63% showed overweight. In 37% of the patients the EEG demonstrated abnormalities. Mild parkinsonism was reported in 15% and akathisia in 11% of the patients, all these patients being on combined treatment. Clozapine did not induce tardive dysakinesia (TD) in any of the patients within a treatment period of 7-8 years. It is concluded that a potential benefit of clozapine includes a low incidence of neurological side effects even after long term administration.
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PMID:Tolerability of long term clozapine treatment. 281 63

Medical charts of 387 in-patients (schizophrenia n = 284, tardive dyskinesia, TD, n = 48), were analyzed to evaluate efficacy and adverse effects of clozapine. These patients were previously treated with between two and four other neuroleptics and were either therapy resistant or had severe side effects. Schizophrenic patients were treated with clozapine for 48 +/- 35 (TD 49 +/- 40) days, dosage was 189 +/- 119 (TD 220 +/- 176) mg. Four per cent showed worsening, 13% no change, 38% slight improvement, 42% marked improvement and 3% nearly total reduction of symptoms. In TD, 44% showed marked improvement, but only in 17% the drug was superior to previous neuroleptics. Adverse effects occurred in 56% of patients. Most frequent were sedation (17%), EEG alterations (16%), increase of liver enzymes (8%), hypotension (7%), hypersalivation (5%), fever (5%), ECG alterations (4%), tachycardia (3%), gastro-intestinal (3%) and delirious states (2%). A gradual increase in dosage seems to considerably reduce the incidence of some side effects. Clozapine treatment had to be discontinued because of severe side effects in 5.9%. In none of these patients did serious complications such as agranulocytosis occur. Only EEG alterations were significantly related to clozapine dosage (P less than 0.0005). At dismissal, most patients continued to receive clozapine; only in 22% (TD 20%) was it replaced by another neuroleptic. Thus, the ratio benefit/risk of clozapine treatment seems to be satisfactory in most of the negatively selected patients. Nevertheless, a gradual increase in dosage and careful control of hematological and other variables is highly recommended.
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PMID:Efficacy and adverse effects of clozapine in the treatment of schizophrenia and tardive dyskinesia--a retrospective study of 387 patients. 281 68

Risperidone (Risperdal) is a novel antipsychotic drug, with beneficial effects on both positive and negative symptoms of schizophrenia, and with a low incidence of extrapyramidal side effects (EPS). These particular properties have been attributed to the predominant and very potent serotonin 5-HT2 receptor antagonism of the drug combined with less potent dopamine D2 antagonism. In order to provide data on the degree to which various central neurotransmitter receptors are occupied in vivo, we performed ex vivo receptor occupancy studies with risperidone in comparison with clozapine and haloperidol in rats and guinea pigs. Various types of receptors, to which the compounds were known to bind to in vitro, were investigated precisely using receptor autoradiography in sections of the same rat brain except for histamine H1 receptors that were measured in the guinea-pig cerebellum. Risperidone (2 h after s.c. treatment) occupied 5-HT2 receptors at very low doses (ED50 = 0.067 mg/kg). Nearly full occupancy (> 80%) was achieved before H1, D2, alpha 1 and alpha 2 receptors became occupied (ED50 = 0.45, 0.66, 0.75 and 3.7 mg/kg, respectively). Clozapine displayed occupancy of H1 and alpha 1 receptors at low doses (ED50 = 0.15 and 0.58 mg/kg, respectively) and of 5-HT2, 5-HT1C, D2, alpha 2, cholinergic muscarinic and 5-HT1A receptors at higher doses (ED50 = 1.3, 1.8, 9.0, 9.5, 11 and 15 mg/kg, respectively). Haloperidol occupied D2 and alpha 1 receptors at low doses (ED50 = 0.13 and 0.42 mg/kg, respectively) and 5-HT2 receptors at a higher dose (ED50 = 2.6 mg/kg). Occupancy of receptor types occurred with similar ED50-values in various brain areas, e.g. D2 receptors in striatum and mesolimbic areas. The ED50-values for the ex vivo measured occupancy of 5-HT2 and D2 receptors were in good agreement with ED50-values for functional effects putatively mediated by these central receptors. The dose-dependent occupancy of D2 receptors proceeded more gradually with risperidone (slope in the caudate-putamen: 0.85) than with clozapine (slope: 1.44) or haloperidol (slope: 1.51). It has previously been suggested that partial D2 receptor occupancy may suffice to control the positive symptoms of schizophrenia, whereas higher D2 receptor occupancy would induce extrapyramidal symptoms (EPS). The dose ratio for high (75%) vs. low (25%) D2 receptor occupancy in the caudate-putamen, was 37.3 for risperidone, 8.4 for clozapine, and 7.9 for haloperidol.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Occupancy of central neurotransmitter receptors by risperidone, clozapine and haloperidol, measured ex vivo by quantitative autoradiography. 751 May 74


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