ISSN:0271-0749    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Several studies indicate an association between human leukocyte antigens (HLA) and clozapine-induced agranulocytosis. The authors have previously reported a significantly increased frequency of HLA-A1 among patients with schizophrenia who do not respond to conventional drugs, but do respond to clozapine treatment. In this study, the authors addressed the question of whether the same association is found in patients developing granulocytopenia or agranulocytosis. The frequency of the HLA-A1 allele in patients with clozapine-induced agranulocytosis or granulocytopenia was low (11.5%), whereas HLA-A1 was associated with a good therapeutic response to clozapine at an allele frequency of 58%. The frequency of HLA-A1 is 20% in the Finnish population. These results suggest that HLA-A1 may predict a good therapeutic outcome and a low risk of agranulocytosis and, thus, enable defining a subgroup of patients with schizophrenia in whom clozapine treatment could be started early to stop the disease from progressing.

ISSN:0271-0749    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

As part of a prospective clinical study investigating the effects of atypical neuroleptics on autonomic neurocardiac function (ANF), serial standardized recordings of conventional electrocardiograms and computer-calculated measurements of 5-minute resting heart rate variability (HRV) were obtained from 51 medication-free inpatients with schizophrenia (DSM-III-R-diagnosed) before and after an average of 14.1 days of treatment with amisulpride 400 mg/day (N = 12), olanzapine 20 mg/day (N = 13), sertindole 12 mg/day (N = 13), or clozapine 100 mg/day (N = 13). Reference values for the HRV data were obtained from a large group of well-matched healthy controls (N = 70). The most important findings were the following: (1) clozapine, olanzapine, and sertindole all prolonged mean frequency-corrected QTc times, which, in the case of sertindole, proved to be significant (Wilcoxon testp<0.05); (2) sertindole and clozapine significantly increased the mean resting heart rate; and (3) only clozapine significantly reduced the parasympathetic resting tone. The results of the HRV studies are discussed considering thein vitroreceptor profiles of the atypical neuroleptics under study. Potential implications for the cardiac safety and tolerance of these drugs are also discussed.

ISSN:0271-0749    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Olanzapine is an atypical antipsychotic that is effective in the treatment of schizophrenia. Olanzapine plasma concentrations ≥ 9.3 ng/mL (24 hours postdose) have been identified as a predictor of clinical response in acutely ill patients with schizophrenia. The authors report a receiver operating characteristic (ROC) curve analysis of 12-hour olanzapine concentrations and treatment response from the North American Double-Blind Olanzapine Trial. After a 4- to 7-day placebo lead-in, patients meeting DSM-III-R criteria for schizophrenia were randomly assigned to receive olanzapine, haloperidol, or placebo. Patients who were randomly assigned to receive olanzapine were given daily doses ranging from 2.5 to 17.5 mg/day for up to 6 weeks. Blood samples for the determination of olanzapine plasma concentrations were obtained between 10 and 16 hours (11.7 ± 1.7 hours) after the last dose was administered. Therapeutic response data and olanzapine concentrations used for analysis were obtained from the endpoint visit for each patient if the patient had been receiving a fixed olanzapine dose for at least the last 2 weeks of the study. Plasma concentrations from previous visits were used if endpoint concentrations were invalid. Response was defined as a ≥ 20% reduction in Brief Psychiatric Rating Scale (BPRS) scores and a Clinical Global Impression (CGI) Severity scale score of ≤ 3 or a final BPRS score of ≤ 35. The final ROC analysis included data from 84 patients and suggested an olanzapine concentration ≥ 2 3.2 ng/mL to be a predictor of therapeutic response. Fifty-two percent of patients with 12-hour olanzapine concentrations ≥ 23.2 ng/mL responded, whereas only 25% of patients with concentrations <23.2 ng/mL responded. Furthermore, an olanzapine concentration ≥ 23.2 ng/mL was a predictor of response in the Scale for the Assessment of Negative Symptoms (≥ 20% decrease and endpoint CGI ≤ 3). Olanzapine concentrations were found to be a function of olanzapine dose (in milligrams per day) and gender such that prospective olanzapine dosing is feasible. A 12-hour olanzapine plasma concentration of >23.2 ng/mL was a predictor of therapeutic response in acutely ill patients with schizophrenia. Males required a higher olanzapine dose to reach this threshold concentration than their female counterparts.

ISSN:0271-0749    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0271-0749    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Divalproex sodium has been approved for use in treating bipolar disorder. Its usefulness in schizophrenia has yet to be adequately assessed. Three days after initiating haloperidol treatment, patients who were hospitalized for an acute exacerbation of schizophrenia received either valproate augmentation (early-augmentation group) or continued to receive haloperidol alone (no-augmentation group). Patients in the no-augmentation group who failed to respond 14 days after the dose of haloperidol reached 20 mg/day received valproate augmentation (delayed-augmentation group). By day 14, the early-augmentation group improved 32.4% more than the no-augmentation group. Fifty percent of the patients in the no-augmentation group failed to respond to haloperidol alone for 2 weeks. They improved by 29% upon the addition of valproate. Compared with those who received no or delayed augmentation, the early-augmentation group required 44.8% fewer inpatient days from the initiation of haloperidol treatment. Patient response to treatment was particularly noted in suspiciousness, hallucinations, unusual thought content, and emotional withdrawal. Early augmentation with valproate may reduce the length of inpatient stays and provide substantially better therapeutic outcomes. It is, however, premature to recommend changes in the standard clinical management of schizophrenia on the basis of the data provided herein, in view of the small sample and open-label nature of the report.

ISSN:0271-0749    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

This study assessed the efficacy of ziprasidone for the treatment of schizoaffective disorder. Data were taken from subsets of patients with schizoaffective disorder, derived from two separate double-blind, placebo-controlled, parallel-group, multicenter studies. A total of 115 hospitalized patients with an acute episode of schizoaffective disorder were randomly assigned to receive either fixed oral doses of ziprasidone 40 mg/day (N = 16), 80 mg/day (N = 18), 120 mg/day (N = 22), 160 mg/day (N = 25), or placebo (N = 34) for 4 to 6 weeks. Mean baseline-to-endpoint changes in Brief Psychiatric Rating Scale (BPRS) total, BPRS Core, Clinical Global Impressions Severity scale (CGI-S), BPRS Depressive, BPRS Manic, and Montgomery-Åsberg Depression Rating Scale total scores were compared between the placebo and ziprasidone groups. Neurological (Simpson-Angus, Barnes Akathisia, Abnormal Involuntary Movement Scale [AIMS]) and other side effects were also assessed. Significant dose-related improvements on all primary efficacy variables (BPRS total, BPRS Core, CGI-S) and for BPRS Manic items were observed with ziprasidone treatment in a combined analysis of data from both studies (p≤ 0.01). Ziprasidone 160 mg/day was significantly more effective than placebo in improving mean BPRS total, BPRS Core, BPRS Manic, and CGI-S scores (p< 0.05). At 120 mg/day, ziprasidone was significantly more effective than placebo in improving mean CGI-S scores (p< 0.05). The incidence of individual adverse events was generally low in all treatment groups and was not dose-related. In addition, no significant differences were observed between baseline-to-endpoint mean changes in Simpson-Angus and AIMS scores with placebo or ziprasidone 40 to 160 mg/day. These results suggest that ziprasidone may have efficacy in the treatment of affective as well as psychotic symptoms of schizoaffective disorder, with a low side-effect burden.

ISSN:0271-0749    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

In a controlled trial, the β-adrenoceptor/5-hydroxytryptamine-1A (5-HT1A) receptor antagonist pindolol accelerated and enhanced the antidepressant effect of fluoxetine. The median times to sustained response (≥50% reduction of baseline severity maintained until endpoint) were 19 days for fluoxetine plus pindolol (N = 55) and 29 days for fluoxetine plus placebo (N = 56) (p= 0.01). The response rate at endpoint was 16% greater in patients treated with the combination. The plasma concentration of pindolol remained stable between 3 days (first blood sampling) and 6 weeks. Mean values were ∼26 nM, a concentration higher than theKiof (−)pindolol for human 5-HT1Aautoreceptors (11 nM). Plasma fluoxetine and norfluoxetine concentrations increased steadily until the fourth week of treatment. Fluoxetine concentrations were lower in patients receiving the combination (p= 0.043), but there was no significant relationship to the clinical response in either group. A reanalysis of the data using a survival analysis revealed that significant differences in the time to sustained response between both groups would have also been detected (1) in a 2-week trial, (2) without a placebo lead-in phase, and (3) with less frequent visits. However, the use of "response" instead of "sustained response" as measure of clinically relevant change would have greatly diminished the difference between treatment arms (p= 0.08 instead ofp= 0.01). This emphasizes the need of using stringent outcome criteria in antidepressant drug trials. A comparison of the data of all sustained responders (N = 27) in the fluoxetine-plus-placebo group with the first 27 responders in the fluoxetine-plus-pindolol group (of a total of 38) revealed a highly significant difference in the time to sustained response (18 and 10 days, respectively;p= 0.0002). This indicates that the faster response in the fluoxetine-plus-pindolol group is not a result of the greater proportion of responders.

ISSN:0271-0749    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Few controlled studies have evaluated the long-term continuation of pharmacotherapy for relapse prevention in patients with obsessive-compulsive disorder (OCD). This study assessed efficacy and safety of fluoxetine versus placebo in preventing relapse of OCD during a 52-week period in responders to short-term administration of fluoxetine. Patients who met DSM-IV criteria for OCD and had a Yale-Brown Obsessive Compulsive Scale score ≥19 were treated with single-blind fluoxetine 20, 40, or 60 mg/day (based on physician assessment of response and tolerability). After 20 weeks, responders were randomly assigned to receive continued treatment with fluoxetine or placebo and were monitored for relapse for up to 52 weeks. Of 130 patients who entered the study, 71 (55%) were randomly assigned to receive fluoxetine (N = 36) or placebo (N = 35). Patients who received fluoxetine had numerically lower relapse rates compared with those who received placebo, although the difference was not significant (Kaplan-Meier 1-year relapse rates: fluoxetine, 20.6%; placebo, 31.9%; one-tailedpvalue = 0.137). In additional analyses evaluating patients on the basis of fluoxetine dose at randomization, patients who continued treatment with fluoxetine 60 mg/day (N = 52) had significantly lower rates of relapse than those who were switched to placebo (Kaplan-Meier 1-year relapse rates: fluoxetine, 17.5%; placebo, 38.0%; one-tailedpvalue = 0.041). Those who responded to the acute treatment phase with 40 (N = 18) or 20 (N = 1) mg/day had low overall rates of relapse, and the difference between continued fluoxetine and placebo treatment for these patients was not significant. For responders to the 60 mg/day dosage, those patients who continued treatment with fluoxetine were provided greater protection against relapse than those patients switched to placebo.

ISSN:0271-0749    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The changes in aminergic receptors elicited by antidepressant treatments have been extensively examined in the brain of experimental animals using radioligand and molecular techniques. However, there is a very limited direct information regarding the changes effected by such treatments in the human brain, as well as its relationship to clinical improvement. Using positron emission tomography (PET) scanning, the authors examined the cortical 5-Hydroxytryptamine-2A (5-HT2A) receptor binding of [18F]fluoro-ethyl-spiperone after a 4-week treatment with the selective serotonin reuptake inhibitor paroxetine. [18F]fluoro-ethyl-spiperone labels 5-HT2Areceptors in the cortex and dopamine D2receptors in the basal ganglia. A binding index (BI) was calculated in the frontal cortex and the basal ganglia (mostly caudate-putamen) by reference to cerebellum. Thirty-seven inpatients with major depression with a mean ± SD score on the 21-item Hamilton Rating Scale for Depression (HAM-D-21) of 26.3 ±4.3 at admission were treated with paroxetine 40 mg/day. After 4 weeks of treatment, the BI in the frontal cortex of remitted patients (HAM-D-21 score = 4.7 ± 4.0; N = 20) was significantly greater than the score in nonresponder patients (HAM-D-21 score = 21.2 ± 4.0; N = 17) (BI = 0.54 ± 0.15 and 0.41 ± 0.17, respectively;p< 0.02). No such difference was observed in the basal ganglia (5.45 ± 1.11 and 5.39 ± 0.82, respectively;p= 0.85). The significant difference in cortical BI persisted when age was used as covariate (p< 0.016). These data suggest that clinical improvement in patients treated with paroxetine is associated with an increase in the density of 5-HT2Areceptors in the frontal cortex.

ISSN:0271-0749    

出版商:OVID    

年代:2001

数据来源: OVID