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)

New neuroleptic drugs are being developed for the treatment of schizophrenia and other psychoses. Clozapine and risperidone are available for general use. Sertindole and olanzapine are nearing release. Seroquel and ziprazidone are in the final stages of study. This generation of drugs will provide advantages in the area of lower motor side effects and probably in improved negative symptom treatment.
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PMID:The new generation of antipsychotic drugs. 880 64

Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT2A receptors and D2-type receptors. Predominant 5HT2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D2 antagonism is required the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D3 and in particular D4 receptors has been proposed. In vitro, all compounds, except the 'typical' antipsychotics haloperidol and fluspirilene, showed higher affinity for 5HT2A than for D2 receptors. Subnanomolar affinity for human 5HT2A receptors was observed for ORG-5222, sertindole, risperidone, 9-OH-risperidone and ziprasidone. Fluspirilene, ORG-5222, haloperidol, ziprasidone, risperidone, 9-OH-risperidone and zotepine displayed nanomolar affinity for human D2 receptors. Sertindole and olanzapine were slightly less potent. Pipamperone, clozapine and seroquel showed 2 orders of magnitude lower D2 affinity in vitro. Clozapine, but even more so pipamperone, displayed higher affinity for D4 than for D2 receptors. For most other compounds, D4 affinity was only slightly lower than their D2 affinity. Seroquel was totally devoid of D4 affinity. None of the compounds had nanomolar affinity for D1 receptors; their affinity for D3 receptors was usually slightly lower than for D2 receptors. In vivo, ORG-5222, risperidone, pipamperone, 9-OH-risperidone, sertindole, olanzapine, zotepine and clozapine maintained a higher potency for occupying 5HT2A than D2 receptors. Risperidone and ORG-5222 had 5HT2A versus D2 potency ratio of about 20. Highest potency for 5HT2A receptor occupancy was observed for ORG-5222 followed by risperidone and olanzapine. Ziprasidone exclusively occupied 5HT2A receptors. ORG-5222, haloperidol, fluspirilene and olanzapine showed the highest potency for occupying D2 receptors. No regional selectivity for D2 receptor occupancy in mesolimbic versus nigrostriatal areas was detected for any of the test compounds. Risperidone was conspicuous because of its more gradual occupancy of D2 receptors; none of the other compounds showed this property. The various compounds also displayed high to moderate occupancy of adrenergic alpha 1 receptors, except fluspirilene and ziprasidone. Clozapine, zotepine, ORG-5222 and sertindole occupied even more alpha 1 than D2 receptors. Clozapine showed predominant occupancy of H1 receptors and occupied cholinergic receptors with equivalent potency to D2 receptors. A stronger predominance of 5HT2A versus D2 receptor occupancy combined with a more gradual occupancy of D2 receptors differentiates risperidone and its 9-OH-metabolite from the other antipsychotic compounds in this study. The predominant 5HT2A receptor occupancy probably plays a role in the beneficial action of risperidone on the negative symptoms of schizophrenia, whereas maintenance of a moderate occupancy of D2 receptors seems adequate for treating the positive symptoms of schizophrenia. A combined 5HT2A and D2 occupancy and the avoidance of D2 receptor overblockade are believed to reduce the risk for extrapyra
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PMID:Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. 893 1

Advances in our understanding of schizophrenia have led to a new generation of antipsychotic agents. These medications not only demonstrate reduced extrapyramidal symptoms but also possess pharmacologic profiles that can be especially advantageous in treating the negative symptoms of schizophrenia. The pharmacokinetics of many of the newer agents are compared and contrasted with typical neuroleptics. Changes in the pharmacokinetics and dosage of the newer agents are also reviewed. A particular emphasis is placed on the metabolism of the newer agents and their potential for drug-drug pharmacokinetic interactions. Clozapine, the archetypal atypical agent, has a complex pharmacokinetic profile with extremely large interpatient variability and many well-documented drug-drug interactions. Thus, clozapine presents special challenges in dose optimization and requires vigilant clinical monitoring for cardiovascular, neurologic, and hematologic adverse effects. Olanzapine demonstrates a very low potential for drug-drug interactions; it requires extremely high inhibitory concentrations at cytrochrome P450 (CYP) systems, typically 30-fold above the usual concentrations observed at steady-state oral high-dose therapy. The metabolic pathways of olanzapine include N-glucuronidation, reducing its overall sensitivity to drugs that might induce or inhibit its own metabolism via CYP or flavin-containing monooxygenase (FMO) systems. Plasma olanzapine concentrations at steady state typically demonstrate only a fourfold to fivefold variability among patients at a standard dose of medications. Sertindole and risperidone demonstrate polymorphic metabolism characteristics mirroring the CYP 2D6 phenotype. The inhibitory potentials of sertindole at CYP 2D6 and CYP 3A are modest and not likely to be of clinical significance. However, in those patients taking CYP 2D6 inhibitors or in those who are genotypic poor metabolizers, concentrations achieved by sertindole and its metabolites might result in moderate inhibition of CYP 3A.
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PMID:Pharmacokinetics and drug interactions: update for new antipsychotics. 937 97

New, so-called atypical antipsychotic medications will no doubt supplant the traditional, or "typical," antipsychotic medications, just as the new generation of antidepressant agents has replaced the older tricyclic drugs. At issue with most of the new drugs is not acute efficacy, but long-term tolerability. Side effects must be minimized to enhance compliance and prevent relapse. It appears that many of the new antipsychotic drugs have fewer or less troublesome side effects than the older agents. In addition, the "atypical" antipsychotic agents hold promise for treating refractory schizophrenia. At present, only clozapine, with its risks for agranulocytosis and seizures, is clearly established as a treatment for refractory illness. Risperidone may be an alternative for treatment-resistant schizophrenia, but this has not yet been clearly proved. Olanzapine has recently been introduced. Sertindole should be available soon, and quetiapine and ziprasidone should quickly follow. Safety, efficacy, and cost will guide their use. None of these newer agents have been compared head-to-head with clozapine. More research is needed to place these new drugs into clinical perspective.
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PMID:New antipsychotic medications: what advantages do they offer? 904 36

Forty percent of all long-term care hospitalization days are accounted for by patients with schizophrenia. New approaches to managing this disorder are needed, including improved efficacy and better tolerability to enhance compliance with treatment. Sertindole hydrochloride is a novel antipsychotic medication soon to be available in the United States and Canada. As part of multisite phase II and III studies, we studied effects of this medication in five patients with chronic schizophrenia and examined the side effect profile. With more than 30 patient-months of exposure, sertindole treatment was not associated with neurologic side effects and was well tolerated in all patients studied. No evidence of hematologic abnormalities was found. Serial electrocardiograms revealed slight increases in QTc that were not considered clinically significant and did not lead to discontinuance of treatment. While data from larger samples are needed, in this small population sertindol hydrochloride was tolerated well with no evidence of acute neurologic side effects associated with traditional treatments for schizophrenia. Individuals with schizophrenia may benefit from enhanced compliance with treatment and a possible reduction in hospitalizations in the future.
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PMID:Sertindole hydrochloride: a novel antipsychotic medication with a favorable side effect profile. 922 89

The introduction of antipsychotics for the management of schizophrenia greatly improved the quality of life of many patients suffering from this debilitating disease. Although typical antipsychotic drugs represent a significant advancement in psychopharmacology, they carry a heavy side effect burden, have little efficacy in the management of negative symptoms, and are ineffective in about one-third of patients with schizophrenia. Atypical antipsychotic agents characterized the next major advancement in pharmacotherapy. They differ from typical antipsychotics in their mechanism of action, side effect profiles, and clinical efficacy. Sertindole is a new atypical antipsychotic.
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PMID:Sertindole, a new atypical antipsychotic for the treatment of schizophrenia. 946 84

Sertindole is an atypical antipsychotic that is efficacious in schizophrenia and is associated infrequently with extrapyramidal symptoms (EPS). This study assessed time to treatment failure with 24 mg/day sertindole or 10 mg/day haloperidol in 282 clinically stable neuroleptic-responsive outpatients with schizophrenia. During a 5-week transition period, patients were randomized to treatment with sertindole or haloperidol; other treatments were gradually discontinued. Patients then received treatment through Day 365. Time to treatment failure was numerically superior in sertindole-treated patients compared with haloperidol-treated patients, although this difference was not statistically significant. Sertindole-treated patients, however, remained free of hospitalization for exacerbation of schizophrenia and remained medically compliant significantly longer than did haloperidol-treated patients. In addition, there were significantly fewer reports of EPS in sertindole-treated patients and sertindole therapy was generally well tolerated. Patients transitioned well from other antipsychotic agents to sertindole. Sertindole appears to be an effective long-term treatment for schizophrenia.
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PMID:Long-term efficacy and safety comparison of sertindole and haloperidol in the treatment of schizophrenia. The Sertindole Study Group. 956

Well-controlled clinical trials, although essential for registration purposes, often fail to reflect the real-life usage of a drug. Ultimately, it is how a new medicinal product is used in clinical practice, how it performs in everyday life and how the patient who takes it feels and functions that determine the real benefit: risk ratio of the drug. Such a prospective, referenced, cohort study of sertindole (Serdolect, H. Lundbeck A/S, Copenhagen, Denmark) in schizophrenia was initiated in 1997. Sertindole is a new limbic-selective antipsychotic agent which has recently received marketing authorization in several countries across Europe for the treatment of schizophrenia. The experience gained in around 2200 sertindole-treated patients in controlled clinical trials has enabled an optimal targeting of sertindole to those patient groups who will benefit most and who are least likely to experience adverse effects. The European Post-marketing Observational Serdolect (EPOS) project plans to recruit over 12000 patients in two cohorts in centres throughout Europe. The aims are to provide a full safety evaluation of sertindole under marketed conditions at the relevant clinical dosage and, further, to provide epidemiological data on the treatment of schizophrenia in Europe under usual clinical conditions. The study is currently the only one of its kind to be undertaken in schizophrenia, and will provide important new data for psychiatrists around the world.
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PMID:The European Post-marketing Observational Serdolect (EPOS) Project: increasing our understanding of schizophrenia therapy. 969 Sep 67

Schizophrenia is the most serious and disabling form of psychiatric disorder, and affects 1% of people worldwide. Until recently, treatment has relied heavily on the use of conventional antipsychotic drugs. These drugs do help schizophrenic patients, but have severe limitations. Conventional antipsychotic drugs are not effective in all patients, and even in patients who respond to treatment, the improvement in negative symptoms is often minimal. In fact, these drugs can increase negative symptoms through the production of severe neurological side effects. In recent years, novel antipsychotics have been developed which have superior efficacy and safety profiles. Sertindole is a novel antipsychotic which has been tested in large clinical trials in North America and Europe; the results showed that this drug has efficacy against both the positive and negative symptoms of schizophrenia, while causing adverse neurological events at a similar level to that observed in patients taking placebo. The Positive and Negative Symptom Scale used in these trials showed that sertindole was as effective as haloperidol in controlling positive symptoms, and was superior to placebo in reducing negative symptoms, whereas haloperidol was not. These trials also confirmed that sertindole does not cause the neurological side effects common to the conventional antipsychotics.
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PMID:Sertindole: a review of clinical efficacy. 969 Sep 72

Sertindole is a novel atypical antipsychotic, which has shown efficacy in the treatment of positive and negative symptoms of schizophrenia in phase II and III studies. Furthermore, these studies have demonstrated tolerability and a favourable side-effect profile. In contrast to classical antipsychotics, sertindole was not associated with extrapyramidal symptoms (EPS). We report drug surveillance data in 34 comorbid and comedicated sertindole treated patients suffering from different psychotic disorders. The drug surveillance consisted of two distinct phases: inpatient treatment and outpatient follow-up. Clinical global impression (severity and improvement of illness), psychotic symptoms, side-effects, and blood parameters have been carefully documented. With special respect to cardiac safety electrocardiograms (ECGs) have been recorded twice (during sertindole treatment and during treatment with an antipsychotic different from sertindole). Recommended ECG-parameters for assessment of the proarrhythmic risk of a drug have been calculated (QTc-, QTc2-interval; QT-, QTc-dispersion). The majority of patients (n = 29) have been treated previously with several typical and/or atypical antipsychotics. We observed a clinical response to sertindole treatment in 29 patients (85%). Both positive and negative symptoms improved with sertindole and no severe side-effects have been documented. EPS occurred at placebo level. A mean QTc-interval prolongation of 19.7 ms (4.7%) has been detected. None of the patients developed clinical or electrocardiographic evidence of cardiac dysrhythmia during sertindole treatment, or other clinical evidence of cardiac abnormalities. In summary, sertindole did show efficacy for positive and negative symptoms together with a favourable side-effect profile. No evidence for an increased proarrhythmic risk has been found.
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PMID:Efficacy, cardiac safety and tolerability of sertindole: a drug surveillance. 1095 60


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