The effectiveness of olanzapine in treatment-refractory schizophrenia when patients are nonresponsive to or unable to tolerate clozapine.

OBJECTIVE: This multicenter, open-label study was designed to assess the efficacy and tolerability of olanzapine in patients with chronic schizophrenia who are resistant to therapy with classic neuroleptic agents and are either not responsive to or unable to tolerate clozapine. METHODS: Patients received olanzapine orally once daily for 18 weeks at doses ranging from 5 to 25 mg. The primary efficacy measure was change in the total score on the Positive and Negative Syndrome Scale (PANSS) from baseline to end point. Secondary efficacy measures were the total score on the Brief Psychiatric Rating Scale (BPRS); the PANSS positive, negative, general psychopathology, and mood subscores; and the Clinical Global Impression improvement score. Also recorded were spontaneously reported adverse events; extrapyramidal symptoms (assessed by the Abnormal Involuntary Movement Scale, Simpson-Angus Scale, and Barnes Akathisia Scale); vital signs; and clinical laboratory test results. RESULTS: Forty-eight patients were treated with olanzapine; of these, 45 were assessable over the full 18-week study period. Total scores on the PANSS and BPRS were reduced from baseline by an average of 17.7 (14.2%) and 9.8 points (20.2%), respectively. Eighteen patients (40.0%) experienced a treatment response, defined as a reduction in PANSS total score of > or = 20%. A total of 25 patients (55.6%) achieved a similar reduction in BPRS total score. Significant reductions were seen in both the positive and negative symptom scores on the PANSS (P < 0.001). Olanzapine was well tolerated, with minimal treatment-emergent adverse events or clinically relevant changes in vital signs or clinical laboratory test results. No clinically significant blood dyscrasias were observed in olanzapine-treated patients, including those who had discontinued clozapine because of treatment-associated leukopenia or neutropenia. CONCLUSION: The results of this study suggest that olanzapine may be of benefit in patients who are refractory to or unable to tolerate clozapine.

A comparison of the effects of olanzapine, haloperidol and placebo on cognitive and psychomotor functions in healthy elderly volunteers.

The cognitive and psychomotor effects of olanzapine (3 mg) were compared with haloperidol (3 mg) and placebo in a double-blind, cross-over study. Fourteen healthy elderly volunteers (>65 years) were randomized to receive once daily medication for 4 days with a 16-day interval between treatment periods. Assessments of attention, memory and motor control were made prior to dosing on each day, at 2, 4, 6 and 8 h after dosing on days 1 and 4, and at 24 and 48 h following the last dose. On day 1, detectable impairment was observed at all time points in both groups. On day 4, haloperidol treated subjects showed increased impairment compared with day 1 and this was sustained throughout the 48 h of testing. Olanzapine treated subjects showed reduced day 4 deficit (compared with day 1), with no significant difference from placebo beyond 6 h post dose. These results suggest that both haloperidol and olanzapine have a measurable initial effect on cognitive and psychomotor function in elderly volunteers. However, acute effects associated with olanzapine decrease with repeated dosing and show substantial adaptation within 4 days. In contrast, effects seen with haloperidol are sustained and increase with repeated dosing over the same period.

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.

[Current methodologies and clinical research]. / Méthodologies actuelles et recherche clinique.

Clinical research is like health, which although is said to be priceless, has a cost however. This cost is currently reaching record levels which will be, without any doubt, broken in years to come. Providing patients with more effective molecules, better tolerated or likely to save more lives, is definitely a priority. Everything should be undertaken in order to save time and money. By interrupting the development of a compound proven to be useless, the subsequent savings may be reinvested in the development of another promising drug. This is the reason why Ethical Committees, Regulatory Agencies, clinicians and statisticians are carefully looking at the way to sort out the issue of the right balance between the most exhaustive evaluation of a new substance, in order to minimize potential risks, and the expeditious launch unto markets of supposedly effective drugs in severe or fatal diseases which currently lack truly adequate treatments. These two pitfalls can be named "too early" or "too late". New methodologies are now in the process of seeing the light of day. They tend to reconcile different constraints, either by reducing the clinical trial length or by decreasing the calculated number of enrolled patients, or even by dealing with both parameters. They call more for " bayesian " or " frequentist " methods than for traditional statistics. Several approaches are currently used, namely adaptive strategy.

The cost of treatment dropout in depression. A cost-benefit analysis of fluoxetine vs. tricyclics.

In this study, we tried to estimate the economic potential benefit of the use of fluoxetine (PROZACR 20 mg, Lilly) versus tricyclic antidepressants (TCAs) in depression of mild to moderate intensity. Fluoxetine has demonstrated, in controlled studies, significantly lower rates of side-effects and treatment dropout than TCAs while showing similar efficacy. Treatment dropout, especially at an early stage of the therapy, can have profound consequences, including excessive lengthening of the depressive episode, symptomatic relapse, increase of repeated days out of work, even suicides or suicide attempts. We estimated the expected cost of treatment dropout using a Delphi expert panel. We then computed the economic benefit of fluoxetine by combining the dropout cost and the differential rate of total treatment dropout between fluoxetine and TCAs, as found in clinical trials. We thus showed that a 8 week fluoxetine could be beneficial to society provided society values a year of human life above a threshold varying from French Francs 23.800 to FF8.600 (respectively, about US$4500 and 1600) depending on the type of depression. As these values are extremely low compared to those found in the literature, we concluded that an apparently costly innovation such as fluoxetine may induce short-term financial savings for society.

[Work loss and depression. Impact of fluoxetine]. / Arrêt de travail et dépression. Impact de la fluoxétine.

The goal of our study was to explore the impact of various antidepressant drugs on the relative risk of work loss in depressed patients. 1,852 depressed patients (DSM III-R) were observed using a "cross-sectional" design. Patients were included into five groups: patients without antidepressant treatment, patients treated with one of the main antidepressant drugs in France (amineptine amitriptyline, clomipramine and fluoxetine). Primary variables were the depression intensity (Hamilton scores) and job status (work loss). The other parameters (clinical, demographic, economic, therapeutic) were used as potentially predicting variables. Data have been collected through a network of 295 physicians (GP, Psychiatrists). The main socio-demographic characteristics of treated and untreated depressive patients, either working or absent from work, were predominantly female and city dwellers. A significant difference was found between working patients and work loss in terms of professional characteristics, i.e. type of employment (p < 0.001), type of employer (p < 0.05), level of responsibility (p < 0.01) and type of remuneration (p < 0.01). We found a positive correlation between depression severity and the risk of work loss (R2 = 0.86, p < 0.001). This risk was significantly lower with fluoxetine compared to other treatments. Pooling these data with data from clinical trials led to a saving of 2.4 days (vs clomipramine) to 4.7 days (vs amitriptyline) (p < 0.05, respectively) of work loss per patient for a 8-week treatment period.