Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sertindole is a non-sedating atypical antipsychotic agent with high selectivity for dopaminergic neurons in the mesolimbic system. In pivotal clinical trials, sertindole has demonstrated significantly greater efficacy than placebo against both the positive and negative symptoms of schizophrenia. In addition, sertindole has had at least similar efficacy to haloperidol and risperidone against positive symptoms, and significantly greater efficacy than haloperidol and risperidone against negative symptoms. The incidence of extrapyramidal symptom (EPS)-related adverse events and the rate of medication used to treat EPS in patients receiving clinically effective doses of sertindole in clinical trials were similar to those observed in placebo recipients and significantly less than those in haloperidol recipients. The incidence of QTc interval prolongation of 500 ms or greater with therapeutic dosages of sertindole has also been low. In general, sertindole has been well tolerated in clinical trials. Unlike other antipsychotic agents, sertindole has not been associated with cognitive impairment, and can actually improve cognitive function. Observational studies have shown that the efficacy and tolerability of sertindole observed in the clinical trial situation are emulated in a naturalistic setting. Large cohort analyses (N > 8000) have shown that all-cause and cardiovascular mortality is no greater with sertindole than with risperidone or olanzapine.
 ...
PMID:A review of the efficacy, tolerability and safety of sertindole in clinical trials. 1546 13

This review first describes the preclinical findings with sertindole, a novel phenyl indole derivative antipsychotic agent. Second, a summary is provided of the major clinical trials conducted to date. Based on these findings, sertindole appears to be an effective antipsychotic agent for the treatment of positive and negative symptoms of schizophrenia, with efficacy that is clearly superior to placebo. Sertindole is as effective as haloperidol, however, is much better tolerated with significantly fewer adverse neurologic effects across a wide dosage range of both drugs. Sertindole is associated with a significant mean prolongation of the QT and QTc intervals of 3 - 6% from baseline in placebo-controlled studies. This potential adverse effect should be taken into account when treating specific patients with known risk factors for ventricular arrhythmias. Sertindole should prove to be a very useful addition to the therapeutic options available for the treatment of psychotic disorders.
 ...
PMID:Sertindole (Serdolect): preclinical and clinical findings of a new atypical antipsychotic. 1598 77

Sertindole is a non-sedating atypical antipsychotic effective in the management of schizophrenia and is associated with placebo-level incidence of extrapyramidal symptoms (EPS). In this randomized, double-blind, parallel-group, flexible-dose, multi-centre study, the efficacy and tolerability of sertindole was directly compared with another atypical antipsychotic in patients with schizophrenia. A total of 187 patients were randomly assigned to treatment with sertindole (12-24 mg/day, n=98) or risperidone (4-10 mg/day, n=89) for 12 weeks. Although early termination reduced the power of the study, some significant between-group differences were evident. Sertindole reduced the mean Positive and Negative Syndrome Scale total scores to a greater extent than risperidone, and the difference reached statistical significance at endpoint for the Observed Cases (OC) dataset. Moreover, sertindole was superior for the treatment of negative symptoms compared to risperidone (P<0.05, Last Observation Carried Forward and OC). Both treatment groups were similarly effective in improving Clinical Global Impression (Severity and Improvement), the Drug Attitude Inventory and Global Assessment of Functioning scores. Sertindole and risperidone were both well tolerated. Numerically, fewer patients in the sertindole group (19%) reported EPS-related adverse events than in the risperidone group (28%), although significantly more sertindole-treated patients reported QT prolongation and abnormal ejaculation volume (P<0.05). In conclusion, sertindole was well tolerated and demonstrated clinically relevant efficacy advantages over risperidone.
 ...
PMID:A double-blind, controlled study of sertindole versus risperidone in the treatment of moderate-to-severe schizophrenia. 1631 17

Oral sertindole (Serdolect) is an atypical antipsychotic approved in the EU for once-daily use in patients with schizophrenia who are intolerant to at least one other antipsychotic agent. Extensive data from post-marketing studies do not indicate an excess of overall mortality with sertindole. Sertindole is at least as effective as haloperidol and risperidone in the treatment of neuroleptic-responsive schizophrenia. Sertindole improves negative symptoms, and is also effective for the treatment of neuroleptic-resistant schizophrenia. Sertindole is generally well tolerated and is associated with a low rate of extrapyramidal symptoms (EPS). Thus, sertindole is a useful option in the treatment of patients with schizophrenia.
 ...
PMID:Sertindole : a review of its use in schizophrenia. 1652 28

Cognitive deficits in schizophrenia are associated with poor functional outcome, and may be further aggravated by treatment with antipsychotics. In the present study the acute and chronic (3 weeks of treatment) effects of clozapine, olanzapine, and sertindole on performance in the Morris water maze in rats was compared, using pharmacologically and/or clinically relevant dose regimens. An experimental design consisting of three trials/day over 3 days was used. Performance was expressed as the distance and latency to find a submerged platform, as well as the percentage of "non-finders", i.e. percentage of trials where the rat was unable to find the platform within the total trial time of 60 s. Clozapine (40 mg/kg, p.o.) and olanzapine (2.5 mg/kg, s.c.) impaired water maze performance when given acutely. However, tolerance developed to the deficit induced by clozapine, whereas the olanzapine-mediated impairment was enhanced after chronic treatment. Sertindole (2.5 mg/kg, p.o.) had no disruptive effect on performance after either acute or chronic treatment. Exposure measurements confirmed that all three compounds were present in the serum at least at clinically effective concentrations. Thus, the three antipsychotics tested differentially affected rodent cognition, whereby sertindole appeared to have a lower potential than either clozapine or olanzapine to induce cognitive impairment. The hypothesis that the low potency of sertindole in inducing dopamine D2 receptor blockade, combined with lack of antimuscarinic and histamine H1 antagonist activity in vivo is discussed. Clearly further studies are needed to assess the potential cognition-enhancing effects of sertindole vs. other antipsychotics in a relevant animal model of schizophrenia.
 ...
PMID:Sertindole, in contrast to clozapine and olanzapine, does not disrupt water maze performance after acute or chronic treatment. 1680 67

Sertindole is an antipsychotic drug with affinity for dopamine D2, serotonin 5-HT2A and 5-HT2C, and alpha1-adrenoreceptors. Preclinical studies suggest that sertindole acts preferentially on limbic and cortical dopaminergic neurons and clinical trials have confirmed that sertindole is effective at a low dopamine D2 occupancy level. The active substance has a long half-life. Oral administration once daily yields highly stable plasma levels. These features may explain the clinically observed low frequency of extrapyramidal side effects, including tardive dyskinesia. In contrast to most antipsychotics, sertindole seems to be void of sedative effects. However, although not strictly proven by objective neuropsychological tests, this asset of sertindole does not add to the cognitive problems inherent in schizophrenia. Administration of sertindole is more often associated with prolongation of QTc compared with most other currently used antipsychotics. However, large cohort analyses do not suggest that all-cause mortality is higher with sertindole than with, for example, risperidone or olanzapine. The effective antipsychotic dose range of sertindole is 12-20 mg/day, with small variations among patients. The frequency of most adverse events, for example extrapyramidal symptoms and somnolence, with such a dose does not differ from placebo. Three side effects have been more common than with placebo/haloperidol in short-term studies: weight gain, rhinitis and a decreased ejaculation volume. Two head-to-head comparisons (one in treatment-resistant patients) of sertindole and risperidone showed equivalent effects on positive symptoms. For negative symptoms, one study obtained equivalent effects and one a superior effect of sertindole. Sertindole should not be used as first-line treatment for first-episode patients with schizophrenia because of the QTc prolongation. It has a side-effect profile that makes it an interesting alternative for many patients who do not respond well to the initial choice of antipsychotic drug.
 ...
PMID:Sertindole: efficacy and safety in schizophrenia. 1692 8

(1) The first-line drug for the treatment of schizophrenic disorders is a neuroleptic such as haloperidol. Amisulpride may be preferable when haloperidol causes unacceptable neurological reactions. Overall, the risk-benefit balance of more recent, so-called atypical neuroleptics is no better. (2) Sertindole, a neuroleptic, was first marketed in 1996 in several European countries before being withdrawn two years later because of numerous cardiac adverse effects. It has once again been approved and should soon be available on the French market. (3) Two comparative double-blind trials suggest that a daily sertindole dose of 24 mg is about as effective as 10 mg of haloperidol. Sertindole was no more effective than risperidone in a trial comparing these two drugs. (4) Like other 'atypical' neuroleptics, sertindole has few short-term neurological adverse effects (extrapyramidal syndrome) at the doses used in clinical trials. However, it causes weight gain. Sertindole also has alpha blocking properties, which can cause postural hypotension and reduce ejaculate volume; it also has atropinic effects (constipation, dry mouth, etc.). (5) Sertindole provokes a dose-dependent increase in the QT interval more frequently than haloperidol in comparative trials, and apparently more frequently than other 'atypical' neuroleptics such as risperidone and olanzapine. Sertindole has been suspected of increasing cardiovascular mortality but this has not been established. (6) Sertindole is metabolised by cytochrome P450 isoenzymes CYP 2D6 and CYP 3A4, hence a high risk of pharmacokinetic interactions. (7) In practice, when haloperidol has to be withdrawn because of adverse effects, especially neurological reactions, it is better to continue to resort to amisulpride, for example, with close monitoring of adverse effects, rather than expose patients to the potential dangers of sertindole.
 ...
PMID:Sertindole: new drug. Another "atypical" neuroleptic; QT prolongation. 1745 45

Atypical antipsychotics were a great advance in the treatment of schizophrenia. But, there is still no atypical antipsychotic with an exceptional efficacy and safety profile for all patients. Clinicians are required to draw on their experiential knowledge to examine suitable options for individual patients. Following its suspension in 1998, the safety and efficacy of sertindole have been investigated in several post-marketing studies based in clinical settings. These have provided the safety data to support the reintroduction of sertindole, as well as specific examples demonstrating that certain patients, in particular, may benefit from a switch from other atypical antipsychotics to sertindole. Sertindole's individual and mostly favourable profile of treatment-emergent effects and safety allows for flexibility in treating patients. The propensity of sertindole to cause anticholinergic effects, which can be particularly troublesome, is small and, more recently, there have been suggestions that sertindole may have beneficial effects on cognition.
 ...
PMID:Do we need another atypical antipsychotic? 1851 Dec 42

Sertindole has been marketed and offered daily clinical practice only for 9 months in our country, so no data has been its QTc prolongation potential. In the present study, we performed a clinical trial to investigate the effects of sertindole on QTc in patients with schizophrenia. The study comprised 21 patients with schizophrenia. Sertindole was administered in the following dosing regime: treatment was initiated with 4 mg/day sertindole. From day 3 to day 6, the dose was increased to 8 mg/day, and up to day 9, it was raised to 12 mg/day. The protocol allowed up to dose of 20mg/day according to effectiveness and tolerability. QTc values were determined at beginning, months 3 and 6. In addition, Positive and Negative Syndrome Scale (PANSS) were scored concomitantly. At the beginning of 6-month period, the mean QTc interval of patients was 391.7+/-19.2 ms. At the end of this period, it was 402.8+/-23.8 ms. Although the mean QTc interval changing was significant throughout 6-month period, of the patients, at any evaluation point, only 1 female (451 ms) and 1 male (433 ms) had borderline prolongation at month 3 for both, without any exceeding the dangerous limits. In summary, our results suggest that sertindole is tolerable and despite dose-related QT prolongation, sertindole had not the proarrhythmic profile. Future studies with larger sample evaluating the effects of treatment are required.
 ...
PMID:Effect of sertindole on QTc interval in patients with schizophrenia. 1863 80

The objective of the European Post-marketing Observational Serdolect((R)) (EPOS) Study was to compare the safety of treatment with Serdolect (sertindole) with that of usual treatment in patients with schizophrenia, in normal European clinical practice. The EPOS was a multicentre, multinational, referenced, cohort study. Patients were enrolled at 226 centres in ten European countries. The study was prematurely terminated in 1998 as a result of the temporary market suspension of sertindole. Termination of the study reduced the number of patients recruited from the planned 12,000 to 2,321. While the power of the study was weakened, it did provide useful mortality information, which may be useful for future long-term studies. Crude mortality in the sertindole and non-sertindole groups was 1.45 (95% confidence interval, CI 0.53-3.16) and 1.50 (CI 0.72-2.76) deaths/100 patient-years exposed, respectively. There were no more cardiac deaths in the sertindole group than in the non-sertindole group. QT interval prolongation did not translate into an increased risk of death. Sertindole was well tolerated and caused few extrapyramidal symptoms. Although CIs remained large, this post-marketing study does not provide any evidence against the use of sertindole under normal conditions. Sertindole was well tolerated and posed no significant safety problems.
 ...
PMID:The European post-marketing observational sertindole study: an investigation of the safety of antipsychotic drug treatment. 1945 75


<< Previous 1 2 3 4 Next >>