ISSN:0271-0749    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The aim of this study was to compare the disposition of the tricyclic antidepressant clomipramine (C) in Japanese and Swedish patients receiving continuous treatment. Therapeutic drug monitoring data for C and the active metaboliteN-desmethylclomipramine (DC) in Japanese patients receiving monotherapy (N = 12) and in those receiving C plus benzodiazepines (BZDs) (N = 96) as well as in Swedes receiving C monotherapy (N = 131) and in those receiving C plus BZDs (N = 43) were used. A population kinetic approach with Bayesian feedback was used to estimate the individual clearance values for C. The relationships between kinetic variables and covariates were evaluated by linear multiple regression. The median (25% and 75% quartiles, respectively) oral clearance of C was 12.7 L/hr (11.6, 30.6) in Japanese patients receiving C monotherapy, 18.1 L/hr (5.6, 31.8) in Japanese patients receiving C plus BZDs, 62.7 L/hr (40.0, 90.6) in Swedish patients receiving C monotherapy, and 56.5 L/hr (34.3, 74.1) in Swedish patients receiving C plus BZDs. When combining all populations in a linear multiple regression, clearance was correlated with ethnic group (p< 0.00001) and age (p< 0.0005), but it was uncorrelated with gender, body weight, and administration of BZDs. The C/DC plasma concentration ratios were 1.08 in Japanese patients receiving C monotherapy, 0.90 in Japanese patients receiving C plus BZDs, 0.51 in Swedish patients receiving C monotherapy, and 0.49 in Swedish patients receiving C plus BZDs. Thus, the lower oral clearance of C in Japanese patients compared with that in Swedish patients is not accounted for by the lower body weight in Japanese patients or by concomitant treatment with BZDs and is therefore likely to be a true ethnic difference. The higher C/DC ratio implicates a more pronounced serotonergic than noradrenergic effect in Japanese patients than in Swedish patients.

ISSN:0271-0749    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

This was an 8-week, multicenter, open-label study of the efficacy and tolerability of venlafaxine in patients with treatment-resistant depression conducted in Canada. Inpatients or outpatients aged 18 to 70 years with major depression were eligible if they had a 21-item Hamilton Rating Scale for Depression (HAM-D-21) score of ≥18 and a documented history of unsatisfactory improvement after a minimum of 8 weeks of treatment with an adequate dose of an antidepressant. Treatment with venlafaxine was started at 37.5 mg twice daily, and the dose could be titrated upward to a maximum of 375 mg/day during the first 4 weeks on the basis of the investigator's assessment of clinical response and tolerability. Of the 159 patients enrolled, 152 were evaluable for efficacy. The mean daily venlafaxine dose was 260 mg/day. The mean HAM-D-21 score decreased by 52%, and the mean Montgomery-Åsberg Depression Rating Scale score decreased by 50% from baseline to day 56. A response (50% improvement from baseline) was achieved by 58% of patients on the HAM-D-21, and a remission (≥75% improvement in the HAM-D-21) was observed in 28% at day 56. By day 56, 88% of patients had improved from baseline on the Clinical Global Impression Improvement scale. Only 8% of the patients discontinued for adverse events. The most common adverse events were headache, insomnia, nausea, constipation, diaphoresis, and xerostomia. In conclusion, these results suggest that venlafaxine is effective and well tolerated for the management of patients with treatment-resistant major depression.

ISSN:0271-0749    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The selective serotonin reuptake inhibitors (SSRIs) are believed to have a more benign cardiovascular safety profile than do the tricyclic antidepressants. The effects of the SSRI citalopram on cardiac conduction and repolarization have been extensively evaluated, both in prospective studies in volunteers and patients and in retrospective evaluations of all electrocardiographic (ECG) data from all clinical trials conducted from 1978 through 1996 (a total of 40 studies). A randomized, double-blind, placebo-controlled study was conducted in healthy volunteers (N = 23) to assess intraindividual variability of the QTcinterval, as well as possible changes during treatment with placebo or citalopram, and its correlation to plasma drug levels. To document any dose-related changes, ECGs were performed at baseline and at the end of study in three randomized, double-blind, placebo- or active-controlled, fixed-dose trials in adult and elderly patients (N = 1,460) with major depression and/or dementia. Finally, more than 6,000 ECGs (N = 1,789 citalopram-treated patients) collected from all clinical trials conducted from 1978 through 1996 were reassessed in a standardized manner to identify any effects of citalopram on ECG parameters. Results of both prospective and retrospective analyses showed that the only effect of citalopram on ECG findings is a small reduction in heart rate (≤8 beats per minute). There were no significant effects on PQ, QRS, or QTcintervals, indicating that citalopram has no effect on cardiac conduction and repolarization during short- or long-term treatment.

ISSN:0271-0749    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Due to the scarcity of clinical trials (CTs) directly comparing newer antidepressants, clinicians and reviewers often compare drugs on the basis of active drug and placebo-subtracted adverse event rates (AERs) published in references such as the Physician's Desk Reference in the United States, the Compendium of Pharmaceutical Specialities in Canada, and product monographs. This study examined the suitability of the above data and methods for comparing AERs of nine newer antidepressants: bupropion, citalopram, fluoxetine, fluvoxamine, moclobemide, nefazodone, paroxetine, sertraline, and venlafaxine.First, the authors examined data precision and comparability across drugs by analyzing placeboarm AERs and their 95% confidence limits for each drug and by testing the homogeneity of placebo-arm AERs across drugs. The rationale was that placebo AER heterogeneity is likely a reflection of heterogeneity of nonpharmacologic factors among CTs. For all 16 adverse events examined, placebo AERs were found to be significantly heterogenous, suggesting significant nonpharmacologic heterogeneity across drugs. Second, using placebo AER heterogeneity as a measure of non-pharmacologic heterogeneity, the authors estimated the degree to which active drug and placebo-subtracted AERs were related to nonpharmacologic heterogeneity by estimating the degree of association between active drug and placebo AERs and between placebo-subtracted and placebo AERs. Also, 95% confidence limits for placebo-subtracted AERs were calculated. It was found that most active drug AERs and some placebo-subtracted AERs were significantly correlated with placebo AERs, suggesting a relationship with nonpharmacologic heterogeneity. Placebo-subtracted AERs were less strongly related than were active drug AERs. Finally, the authors discuss factors that may be associated with the observed heterogeneity and offer suggestions that may improve the methodology and reporting of CTs.

ISSN:0271-0749    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The addition of lithium to the treatment regimens of previously nonresponding depressed patients has been repeatedly investigated in controlled studies. The authors undertook this meta-analysis to investigate the efficacy of lithium augmentation of conventional antidepressants. An attempt was made to identify all placebo-controlled trials of lithium augmentation in refractory depression. Only double-blind studies that involved participants who had been treated with lithium or placebo addition after not responding to conventional antidepressants were to be included in the meta-analysis. Further inclusion criteria were the use of accepted diagnostic criteria for depression and the use of response criteria based on the acceptable measurement of depression as an outcome variable. Studies were located by a search of the MEDLINE database, a search in the Cochrane Library, and an intensive search by hand of reviews on lithium augmentation. Nine of 11 placebo-controlled, double-blind studies were included in this meta-analysis. Aggregating three studies with a total of 110 patients that used a minimum lithium dose of 800 mg/day, or a dose sufficient to reach lithium serum levels of ≥0.5 mEq/L, and a minimum treatment duration of 2 weeks, the authors found that the pooled odds ratio of response during lithium augmentation compared with the response during placebo treatment was 3.31 (95% confidence interval, 1.46-7.53). The corresponding relative response rate was 2.14 (95% confidence interval, 1.23-3.70), the absolute improvement in response rate was 27% (95% confidence interval, 9.8%-44.2%), and the number of patients needed to be treated to obtain one more responder was 3.7. Inclusion of six more studies that fulfilled inclusion criteria but which treated subjects with additional lithium for less than 2 weeks or with a lower lithium dose (total, 234 patients) resulted in even higher estimates. Lithium augmentation seems to be the treatment strategy in refractory depression that has been investigated most frequently in placebo-controlled, double-blind studies. The authors conclude from this meta-analysis that with respect to efficacy, lithium augmentation is the first-choice treatment procedure for depressed patients who fail to respond to antidepressant monotherapy.

ISSN:0271-0749    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The abrupt appearance of clozapine discontinuation symptoms represents a particularly unique situation that has not been characterized in a double-blind, placebo-controlled trial. A randomized, double-blind comparison of placebo (N = 53) and olanzapine 10 mg (N = 53) for 3 to 5 days following the abrupt discontinuation of clozapine (≤300 mg/day) was carried out. Subjects were assessed with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale of Severity, the Montgomery-Åsberg Depression Rating Scale (MADRS), and the Mini-Mental State Evaluation. Subsequently both groups received open-label olanzapine (10-25 mg/day) for an additional 9 weeks. Statistically significantly more placebo-treated (24.5%) than olanzapine-treated (7.5%) patients experienced clozapine discontinuation symptoms (p= 0.017). Core symptoms included delusions, hallucinations, hostility, and paranoid reaction and translated into a significantly higher worsening from baseline on the PANSS total, PANSS General Psychopathology subscale, and MADRS among subjects randomly assigned to receive placebo. After open-label treatment with olanzapine for 9 weeks, both groups were clinically stable, suggesting that the discontinuation symptoms were transient. However, subjects who had been randomly assigned to the 3- to 5-day placebo discontinuation segment achieved somewhat less global clinical improvement. Although a pharmacologic interpretation is speculative, evidence of a clozapine discontinuation syndrome was apparent. In most cases, the direct substitution of a pharmacologically similar agent (olanzapine) prevented the syndrome. Clozapine discontinuation or noncompliance should be considered in the differential assessment of an acutely emergent psychosis. The possibility that subjects who experience a clozapine discontinuation syndrome may take longer or are less likely to clinically restabilize warrants further investigation.

ISSN:0271-0749    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The loss of dopaminergic cells during Parkinson's disease (PD) produces "frontal"-like impairment in spatial working memory (SWM) and planning functions. This study investigated whether an α2-adrenergic agonist, clonidine (0.5 or 2 μg/kg, orally), improves SWM, spatial short-term or spatial recognition memory, and planning functions in PD patients. Clonidine 2 μg/kg decreased errors in SWM, but a lower dose, 0.5 μg/kg, had no effect on performance. Clonidine 0.5 and 2 μg/kg failed to improve the strategy used to solve the SWM test. Clonidine 0.5 and 2 μg/kg had no effect on accuracy of performance in the other tests. These results showed that clonidine improves performance in a test of SWM and that this is not due to improved spatial short-term or spatial recognition memory or planning functions. The authors suggest that stimulation of α2-adrenoceptors improves the mnemonic processing required for accurate SWM performance in PD patients.

ISSN:0271-0749    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

This study investigated the subjective and behavioral effects of a commonly used benzodiazepine, triazolam, in healthy women at three phases of the menstrual cycle: follicular, periovulatory, and luteal. Ovarian hormones or their metabolites have direct and indirect actions on neuronal receptors, which may affect responses to psychoactive drugs acting on the same central nervous system receptors. This study explored the effect of menstrual cycle phase on the mood-altering and performance effects of a single oral dose of the benzodiazepine triazolam. Twenty women received triazolam (0.25 mg orally) or placebo at the follicular, periovulatory, and luteal phases of their menstrual cycles in a within-subject design. Dependent measures included self-reported mood states, psychomotor performance, and plasma levels of triazolam, estradiol, progesterone, and allopregnanolone. After administration of triazolam, most subjects reported the expected increases in fatigue and decreases in arousal and psychomotor performance. Neither plasma levels nor mood and performance effects of triazolam differed across the three phases. This study illustrates a useful methodology for assessing responses to psychoactive drugs in normally cycling women and shows that the effects of this drug were highly stable across the cycle.

ISSN:0271-0749    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Differences between the side effect profiles of clomipramine (CMI) and the selective serotonin reuptake inhibitors may be important factors in both treatment outcome and patient selection in obsessive-compulsive disorder (OCD). Safety and efficacy data from an industry-sponsored, multicenter clinical trial of CMI were analyzed previously using tabular and multiple regression methods. Good response, defined as at least a 35% drop in final scores on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), was associated with a later age of OCD onset and certain early side effects that may reflect a sensitivity of responders to CMI's serotonergic actions. The authors conducted a similar analysis of data from an industry-sponsored clinical trial of fluoxetine in OCD. Fluoxetine response did not seem to be associated with age of OCD onset. Good response to both drugs was associated with initial nervousness and sexual complaints. The common side effects of fluoxetine (headache, nausea, and gastrointestinal complaints) did not seem to be associated with treatment response. Slight differences in the protocols of the two clinical trials yielded patient populations that were different in factors found to be associated with treatment outcome: subjects in the fluoxetine study had lower scores on the Y-BOCS, higher scores on the Hamilton Rating Scale for Depression, and an earlier age of OCD onset.

ISSN:0271-0749    

出版商:OVID    

年代:1999

数据来源: OVID