Functional outcomes in schizophrenia: a comparison of olanzapine and haloperidol in a European sample.

The primary aim of this study was to compare functional outcomes between patients with schizophrenia treated with olanzapine or haloperidol in Europe. The sample consisted of European patients from a large, international, double-blind, randomized clinical trial. Patients were randomized to receive either olanzapine (n = 520) or haloperidol (n = 258) for a 6-week acute phase followed by a 46-week maintenance phase for responders. Olanzapine-treated patients experienced superior improvements compared to haloperidol-treated patients on all efficacy measures assessed in both phases. A greater percentage of olanzapine-treated patients had > or = 20% improvement in the Quality of Life Scale total score during both the acute (50.0% versus 31.0%, P = 0.071) and maintenance (69.5% versus 41.7%, P = 0.006) phases compared to haloperidol-treated patients. For patients who entered the maintenance phase as outpatients, olanzapine-treated patients were significantly less likely to require subsequent hospitalization compared to haloperidol-treated patients (P = 0.001). A significantly greater percentage of the olanzapine group compared to the haloperidol group worked part-time or full-time (15.1% versus 5.3%, P = 0.018), participated in useful work > or = 75% of the time (21.0% versus 10.5%, P = 0.038), and socialized more than once a month (53.8% versus 37.9%, P = 0.004) during the maintenance phase. The findings from this study suggest that olanzapine's clinical profile leads to reduced hospitalization and improvements in work and social functioning superior to that achieved with haloperidol treatment.

Clinical and economic outcomes of olanzapine compared with haloperidol for schizophrenia. Results from a randomised clinical trial.

OBJECTIVE: The purpose of this study was to compare, from the payor perspective, the clinical and economic outcomes of olanzapine to those of haloperidol for the treatment of schizophrenia. DESIGN AND SETTING: Clinical, quality-of-life and resource utilisation data were prospectively collected for US-residing patients with schizophrenia who were participating in a multicentre, randomised, double-blind clinical trial comparing olanzapine and haloperidol. Direct medical costs were estimated by assigning standardised prices (1995 values) to the resource utilisation data. PATIENTS AND PARTICIPANTS: 817 patients with schizophrenia who had a baseline Brief Psychiatric Rating Scale score (BPRS) > or = 18 (items scored 0 to 6) and/or were no longer tolerating current antipsychotic therapy. INTERVENTIONS: Olanzapine 5 to 20 mg/day (n = 551) or haloperidol 5 to 20 mg/day (n = 266) for 6 weeks. Patients showing a predefined level of clinical response entered a 46-week maintenance phase. MAIN OUTCOME MEASURES AND RESULTS: After acute treatment, BPRS-based clinical improvements were seen in 38 and 27% of olanzapine and haloperidol patients, respectively (p = 0.002). Clinically important improvements on the Quality of Life Scale were achieved during acute treatment in 33% of olanzapine recipients and 25% of haloperidol recipients (p = 0.094). Olanzapine treatment in the acute phase led to significantly lower inpatient ($US5125 vs $US5795, p = 0.038) and outpatient ($US663 vs $US692, p = 0.001) costs, resulting in a significant overall reduction in mean total medical costs of $US388 (p = 0.033). This significant reduction in total costs was found despite olanzapine mean medication costs being significantly greater than haloperidol medication costs ($US326 vs $US15, p < 0.001). No significant differences in clinical improvement were observed in the maintenance phase. Maintenance phase olanzapine mean total medical costs were $US636 lower than haloperidol total costs (p = 0.128). Although olanzapine medication costs were significantly higher than haloperidol medication costs ($US3461 vs $US95, p < 0.001), this difference was offset by significantly lower inpatient ($US8322 vs $US10,662, p = 0.044) and outpatient ($US3810 vs $US5473, p = 0.038) costs. CONCLUSIONS: In this study, olanzapine treatment was more effective than haloperidol in producing clinical response in the acute phase. In addition, olanzapine treatment led to reductions in inpatient and outpatient costs that more than offset olanzapine's higher medication costs relative to haloperidol.

Olanzapine versus haloperidol in the treatment of schizophrenia and other psychotic disorders: quality of life and clinical outcomes of a randomized clinical trial.

BACKGROUND: Little information is available on the impact of the atypical antipsychotic olanzapine on quality of life (QOL). A 6-week, double-blind randomized multicenter trial, with a long-term extension, was conducted to evaluate the clinical efficacy and QOL of olanzapine and haloperidol in treating schizophrenia and other psychotic disorders. METHODS: A total of 828 outpatients provided QOL data. Study patients were aged greater than 18 years with a DSM-III-R diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder and baseline BPRS (items scored on 0-6 scale) total scores, > or = 18 were randomized to 6 weeks of treatment with olanzapine 5 to 20 mg/day or haloperidol 5 to 20 mg/day. Patients entered a 46-week double-blind extension if they demonstrated minimal clinical response and were tolerant to study medication. The Quality of Life Scale (QLS) and SF-36 Health Survey were used to evaluate QOL. RESULTS: During the 6-week acute phase, olanzapine treatment significantly improved BPRS total (p = 0.004), PANSS total scores (p = 0.043), QLS total (p = 0.005), intrapsychic foundations (p < 0.001) and interpersonal relations scores (p = 0.036), and SF-36 mental component summary scores (p < 0.001) compared with haloperidol. During the extension phase, olanzapine treatment significantly improved PANSS negative scores (p = 0.035) and improved QLS total (p = 0.001), intrapsychic foundations (p < 0.001), and instrumental role category scores (p = 0.015) versus haloperidol treatment. Significantly more haloperidol patients discontinued treatment due to adverse events during the acute and extension phases (p = 0.041 and p = 0.014, respectively). Changes in QLS total and MCS scores were associated with changes in clinical symptoms, depression scores and extrapyramidal symptoms. CONCLUSIONS: Olanzapine was more effective than haloperidol in reducing severity of psychopathology and in improving QOL in patients with schizophrenia and other psychotic disorders. The QOL benefits of olanzapine, although modest, may be important for long-term treatment.

Comparative efficacy of olanzapine and haloperidol for patients with treatment-resistant schizophrenia.

BACKGROUND: There is relatively little information regarding the efficacy of newer atypical antipsychotic drugs for patients with schizophrenia who are treatment-resistant to neuroleptic agents. Several lines of evidence suggest that a clinical trial of olanzapine in this population is warranted. METHODS: A subpopulation of patients (n = 526) meeting treatment-resistant criteria selected from a large, prospective, double-blind, 6-week study assessing the efficacy and safety of olanzapine and haloperidol were examined. Both last-observation-carried-forward (LOCF) and completers (observed cases) analyses were conducted. RESULTS: Olanzapine demonstrated significantly greater mean improvement from baseline in Positive and Negative Syndrome Scale (PANSS) negative symptoms, comorbid depressive symptoms assessed by the Montgomery-Asberg Depression Rating Scale, akathisia as measured by Barnes Akathisia Scale, and extrapyramidal symptoms as measured by Simpson-Angus Extrapyramidal Rating Scale with both LOCF and completers analyses. In addition, olanzapine was significantly superior to haloperidol for Brief Psychiatric Rating Scale total (p = .006), PANSS total (p = .005), and PANSS positive symptoms (p = .017) in completers of the 6-week study. Significantly greater response rates were observed in olanzapine-treated (47%) than haloperidol-treated (35%) patients in the LOCF analysis (p = .008), but significance was not reached in the completers analysis (p = .093). Mean doses (+/- SD) of olanzapine and haloperidol were 11.1 +/- 3.4 mg/day and 10.0 +/- 3.6 mg/day, respectively. CONCLUSIONS: Olanzapine was superior to haloperidol for key symptom domains and parkinsonian side effects. Implications of these data for the therapeutics of this severely ill subgroup are discussed.

A cost-effectiveness clinical decision analysis model for schizophrenia.

A model was developed to estimate the medical costs and effectiveness outcomes of three antipsychotic treatments (olanzapine, haloperidol, and risperidone) for patients with schizophrenia. A decision analytic Markov model was used to determine the cost-effectiveness of treatments and outcomes that patients treated for schizophrenia may experience over a 5-year period. Model parameter estimates were based on clinical trial data, published medical literature, and, when needed, clinician judgment. Direct medical costs were incorporated into the model, and outcomes were expressed by using three effectiveness indicators: the Brief Psychiatric Rating Scale, quality-adjusted life years, and lack of relapse. Over a 5-year period, patients on olanzapine had an additional 6.8 months in a disability-free health state based on Brief Psychiatric Rating Scale scores and more than 2 additional months in a disability-free health state based on quality-adjusted life years, and they experienced 13% fewer relapses compared with patients on haloperidol. The estimated 5-year medical cost associated with olanzapine therapy was $1,539 less than that for haloperidol therapy. Compared with risperidone therapy, olanzapine therapy cost $1,875 less over a 5-year period. Patients on olanzapine had approximately 1.6 weeks more time in a disability-free health state (based on Brief Psychiatric Rating Scale scores) and 2% fewer relapses compared with patients on risperidone. Sensitivity analyses indicated the model was sensitive to changes in drug costs and shortened hospital stay. Compared with both haloperidol and risperidone therapy, olanzapine therapy was less expensive and provided superior effectiveness outcomes even with conservative values for key parameters such as relapse and discontinuation rates.

Olanzapine versus placebo and haloperidol: quality of life and efficacy results of the North American double-blind trial.

This double-blind study evaluated the impact of treatment with olanzapine compared with haloperidol, and placebo on improvements in symptomatology and quality of life in patients with a DSM-III-R diagnosis of schizophrenia. A total of 335 patients was randomized to five treatment groups; olanzapine 5 +/- 2.5 mg/day, olanzapine 10 +/- 2.5 mg/day, olanzapine 15 +/- 2.5 mg/day, haloperidol 15 +/- 5 mg/day, and placebo. Patients responding to treatment during the 6-week acute phase were eligible to enter a 46-week extension. Efficacy measures included the brief psychiatric rating scale total, scale for assessment of negative symptoms summary, and clinical global impressions severity scores. Quality of life was evaluated using the quality of life scale. Data analyzed after 24 weeks of therapy showed that olanzapine was significantly superior to placebo in reducing clinical severity and significantly superior to haloperidol in reducing negative symptoms in patients responding to acute treatment. Furthermore, improvement in quality of life was observed in olanzapine-treated responders.

Fluoxetine in medically stable, depressed geriatric patients: effects on weight.

This study assessed the effect of fluoxetine 20 mg/day on weight loss in older patients treated for major depression in a multicenter, double-blind placebo-controlled, 6-week clinical trial. Thirty U.S. outpatient clinics affiliated with psychiatric programs participated in the study that involved 671 medically stable outpatients at least 60 years old who had normal cognition and met DSM-III-R criteria for major depression. Weight was recorded at weekly visits. As a measure of adiposity, patients were categorized into two groups, high and low/normal body mass index (BMI) groups. Analyses were done for each group. The high BMI group, but not the low/normal BMI group, had a statistically greater proportion of fluoxetine-treated patients who lost at least 5% of their baseline weight. Overall mean weight change for the fluoxetine-treated patients was about 1% compared with essentially no change for placebo-treated patients. Only one patients, who was treated with fluoxetine and in the low/normal BMI group, discontinued from the study because of weight loss. Although 5% weight loss occurred in more fluoxetine-treated than placebo-treated patients, most of the patients who lost weight had higher adiposity at baseline. There was not a statistically significant difference in the proportion of fluoxetine-treated and placebo-treated patients in the low/normal group who had at least 5% weight loss. Medically relevant weight loss in older patients treated with fluoxetine was uncommon.

Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders.

Olanzapine and risperidone, both second-generation antipsychotic agents, represent two different pharmacologic strategies. Although they share some in vitro properties, they differ by virtue of their chemical structure, spectrum of receptor binding affinities, animal neuropharmacology, pharmacokinetics, and in vivo neuroimaging profile. Based on such differences, it was hypothesized that the two compounds would show distinct safety and/or efficacy characteristics. To test this hypothesis, an international, multicenter, double-blind, parallel-group, 28-week prospective study was conducted with 339 patients who met DSM-IV criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder. Results of the study indicated that both olanzapine and risperidone were safe and effective in the management of psychotic symptoms. However, olanzapine demonstrated significantly greater efficacy in negative symptoms (Scale for Assessment of Negative Symptoms summary score), as well as overall response rate (> or = 40% decrease in the Positive and Negative Syndrome Scale total score). Furthermore, a statistically significantly greater proportion of the olanzapine-treated than risperidone-treated patients maintained their response at 28 weeks based on Kaplan-Meier survival curves. The incidence of extrapyramidal side effects, hyperprolactinemia, and sexual dysfunction was statistically significantly lower in olanzapine-treated than risperidone-treated patients. In addition, statistically significantly fewer adverse events were reported by olanzapine-treated patients than by their risperidone-treated counterparts. Thus, the differential preclinical profiles of these two drugs were also evident in a controlled, clinical investigation. Olanzapine seemed to have a risk-versus-benefit advantage.

Olanzapine versus haloperidol: acute phase results of the international double-blind olanzapine trial.

A 6-week acute phase of an international 1-year double-blind study was conducted comparing three dose ranges of olanzapine (5 +/- 2.5 mg/day, 10 +/- 2.5 mg/day, and 15 +/- 2.5 mg/day) with a fixed dose of olanzapine (1.0 mg/day) and with a dose range of haloperidol (15 +/- 5 mg/day) in the treatment of 431 patients with schizophrenia. The purpose was to determine whether olanzapine demonstrated a dose-related ability to decrease overall psychopathology with minimal associated extrapyramidal symptoms in patients with schizophrenia. The high-dose olanzapine group showed statistically significantly greater improvement in overall psychopathology based on mean change in the CGI Severity score and statistically significantly greater improvement in positive psychotic symptoms based on mean change in both the BPRS positive score and the PANSS positive score compared with the 1.0-mg/day olanzapine group. Analyses indicated that an increasing dose-response curve was observed across the range of all olanzapine dose groups. Acute extrapyramidal syndromes were reported less frequently among all olanzapine groups compared with the haloperidol group. Endpoint mean change on both the Simpson-Angus Scale and the Barnes Akathisia Scale reflected improvement for all olanzapine treatment groups compared with worsening for the haloperidol group. Olanzapine was associated with weight gain but did not appear to have any clinically meaningful effect on vital signs. Although olanzapine was associated with some increase in prolactin concentrations, increases were transient, occurred less often, and were of lesser magnitude than those observed with haloperidol.

Estrogen replacement and response to fluoxetine in a multicenter geriatric depression trial. Fluoxetine Collaborative Study Group.

The estrogen decrease of the postmenopausal state may be a factor in both the pathogenesis of late-life depression and in therapeutic response. Studies of nondepressed women over 60 given estrogen replacement therapy (ERT) suggest improvement in mood. The authors compared clinical response of elderly depressed women outpatients entering a 6-week, randomized, placebo-controlled, double-blind, multicenter trial of fluoxetine (20 mg/day); 72 patients received ERT, and 286 did not. There was a significant interaction between ERT status and treatment effect (P = 0.015). Patients on ERT who received fluoxetine had substantially greater mean Ham-D percentage improvement than patients on ERT who received placebo (40.1% vs. 17.0%, respectively); fluoxetine-treated patients not on ERT did not show benefit significantly greater than placebo-treated patients not on ERT. ERT use may augment fluoxetine response in elderly depressed outpatients and should be considered as a factor in clinical trials in elderly women.

Predicting response to fluoxetine in geriatric patients with major depression.

No consensus exists regarding whether early response to an antidepressant strongly predicts a good outcome, what is the criterion for early response, or when to measure it. We hypothesized that early response (> or = 20% decrease in HAM-d21) after any of weeks 1, 2, or 3 of fluoxetine treatment of major depression in geriatric outpatients would predict a favorable outcome by week 6 or an earlier endpoint accurately enough for clinical use. We also hypothesized that the week 1, 2, and 3 percent changes in 21-item Hamilton Rating Scale for Depression (HAM-D21) would predict the percent change at week 6 (or endpoint) accurately enough for clinical use. We enrolled 671 elderly outpatients with unipolar DSM-III-R major depression in a double-blind, placebo-controlled trial of fluoxetine, 20 mg/day. For analysis, fluoxetine-treated patients were randomly divided into a development set (N = 154) for a preliminary test of our criteria and a validation set (N = 181) to validate the development data set's results. Early responders at weeks 1, 2, and 3 were statistically significantly more likely to experience marked improvement or remission than those lacking early response. However, at week 3, this criterion correctly classified only about three-fourths of patients with regard to marked improvement and only about two-thirds with regard to remission. Moreover, about one-third of patients predicted to experience marked improvement and about three-fifths of those predicted to remit did not. The continuous variable, percent change in HAM-D21, did not produce predictive results of any greater clinical utility. We believe that the sensitivity, specificity, false-positive rate, false-negative rate, and kappa of outcome predictions all should be reported in future studies. Without a full set of descriptive statistics, clinicians can be misled by statistically significant results.

Efficacy and safety of long-term fluoxetine treatment of obesity--maximizing success.

Obesity is a major health care concern because of its associated medical complications and increased mortality. Despite a myriad of short-term weight loss strategies and the motivation of improving health, patients have difficulty maintaining reduced weight. Pharmacologic agents, such as fluoxetine, a selective serotonin uptake inhibitor, have been investigated as adjunctive therapy to standard weight management programs. Extended therapy with fluoxetine has demonstrated clinically meaningful benefits on weight loss and obesity-associated medical conditions in double-blind placebo-controlled studies. However, the magnitude of these benefits for individuals vary. Such findings are consistent with the belief that the obesity syndrome has differing etiologies. Accordingly not all patients are likely to benefit from a particular therapy. Studies should identify patient subgroups that are more likely to respond to a specific therapy. In this study of 719 fluoxetine-treated and 722 placebo treated patients in four multicenter, randomized, double-blind, long-term clinical trials, we investigated possible predictors of a beneficial long-term outcome from fluoxetine therapy. Patients' age, current smoking activity, and baseline uric acid concentration were predictors of a meaningful long-term treatment effect. Further review of the weight loss patterns of patients achieving long-term success provided the basis for a treatment monitor. Use of the predictors and the treatment monitor are strategies to maximize the benefits of therapy through improved patient selection and monitoring during a therapeutic program.

Clinical response predictors in a double-blind, placebo-controlled trial of fluoxetine for geriatric major depression. Fluoxetine Collaborative Study Group.

BACKGROUND: We attempted to determine baseline characteristics predicting response in a 6-week, double-blind, geriatric depression trial, which showed a significantly higher remission rate for fluoxetine (20 mg daily) than for placebo (31.6% vs. 18.6%, p < .001). METHODS: Outpatients (N = 671) were 60 years or older (mean +/- SD = 67.7 +/- 5.7), met Diagnostic and Statistical Manual of Mental Disorders (3rd ed., rev., American Psychiatric Association, 1987) criteria for unipolar major depression, had baseline scores on the 17-item Hamilton Depression Rating Scale (HAMD17) of 16 or more, and were randomized after a 1-week placebo lead-in. Potential baseline predictors of percentage change in last-visit-carried-forward HAMD21 total scores were entered into a stepwise regression model. The sample was randomly divided into two groups (development and validation data sets) so that potential predictors could be confirmed in a second analysis. RESULTS: Of the 266 variables considered for their prognostic ability, 13 were found to be significant predictors using the development data set, including (a) presence of somatic complaints, absence of agitation, and presence of previous accidental injury for fluoxetine response; and (b) reported feelings of emptiness, absence of somatic complaints, and absence of early insomnia for placebo response. The second analysis using the validation data set failed to confirm statistical significance of predictors identified in the development data set. CONCLUSIONS: Although potentially useful baseline characteristics were initially identified as response predictors, conservative statistical methods failed to confirm any significant predictors of differential responses between fluoxetine and placebo in this double-blind, placebo-controlled trial. These results suggest that response predictor analyses require confirmation before conclusions can be generalized.

Loss of genes on the short arm of chromosome 11 in bladder cancer.

Recent studies have shown that normal cellular sequences on chromosome 13 are lost during the development of retinoblastomas and that sequences on chromosome 11 are similarly lost during the development of Wilms' kidney tumours and embryonal tumours. Cells from these tumors have been found to contain either the paternal or maternal copies of loci on the affected chromosome, but not both. Thus, the somatic loss of heterozygosity for sequences on chromosome 13 or 11 is hypothesized to result in homozygosity for a recessive mutant allele on these chromosomes, and in this way the chromosomal loss may contribute to the development of these tumours. We sought to investigate whether similar losses of heterozygosity for chromosome 11 sequences occurred in a common adult tumour. We chose to analyse bladder cancers, since such cancers are common in the adult population and are derived from urogenital tissue, as are Wilms' tumours. We examined constitutional and tumour genotypes at loci on the short arm of chromosome 11 (11p) in 12 patients with transitional cell carcinomas. In five tumours, we observed the somatic loss of genes on 11p resulting in homozygosity or hemizygosity of the non-deleted alleles in the tumour cells. Our results show that the frequency of loss of 11p sequences in bladder cancer approaches that seen in Wilms' tumour (42% compared with 55%), and suggest that recessive genetic changes involving sequences on 11p may contribute to the development of bladder neoplasms.