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Ziprasidone Has Comparative Efficacy and Safety With Clozapine in Treatment-Refractory Schizophrenic Patients: Presented at ECNP

By Chris Berrie

PARIS, FRANCE -- September 22, 2006 -- The second generation antipsychotic ziprasidone has comparable efficacy to the current gold standard, clozapine, while showing improved tolerability and metabolic safety, for patients with schizophrenia who are refractory or intolerant, or both, to antipsychotic treatment.

Study coordinator Fabio Romeo, MD, medical advisor, CNS Team, Medical Affairs, Medical Department, Pfizer Italia, Rome, Italy, presented this 18-week, equivalence (non-inferiority), randomised, double-blind, parallel-group study on behalf of the MOZART Study Group.

Among schizophrenic patients, about 20% to 30% do not respond adequately to their current treatment due to inefficacy or tolerability problems, represents a major public health issue, said Dr. Romeo here on September 18^th at the 19^th Congress of the European College of Neuropsychopharmacology (ECNP).

Dr. Romeo and colleagues therefore designed a study to compare the efficacy of ziprasidone versus that of clozapine for treatment of patients with treatment-resistant schizophrenia. A secondary objective was to compare the tolerability and safety of clozapine and ziprasidone.

The key inclusion criteria were adults (>/=18 years old; female patients had to be non-fertile or on approved contraception).

Patients had a Diagnostic and Statistical Manual of Mental Disorders, Revision IV (DSM-IV) diagnosis of schizophrenia, with a documented history of refractory or intolerant antipsychotic treatment, specifically defined as: refractory, lack of adequate therapeutic response after >/=3 adequate (>/=6 week) trials in the previous 5 years; intolerant, unable to achieve adequate therapeutic doses due to severe or persistent side effects of a therapeutic dose. The patients also had a Clinical Global Impression of Severity (CGI-S) >/=4, and a Positive and Negative Syndrome Scale (PANSS) total >/=80.

The main exclusion criteria were for clozapine or ziprasidone treatment within the previous 3 months, along with a range of clinical exclusions.

For drug dosing, Dr. Romeo stressed, "The dosing in this trial was quite high, which is important for ziprasidone, as it was about 140 mg/day." A starting dose of clozapine 25 mg/day was titrated up 25 mg/day to 300 mg/day for 1 week from day 10, with flexible dosing thereafter between 250 and 600 mg/day. The ziprasidone starting dose was 80 mg/day, increased to 120 mg/day from days 4 to 10, with flexible dosing thereafter between 80 and 160 mg/day.

In all, 73 patients were randomised to clozapine and 73 to ziprasidone. There were no significant differences in their clinical characteristics, including (clozapine vs ziprasidone). Patients were 38.3 and 41.6 years, respectively; 67.1% and 71.2% were male, respectively.

The study used an analysis of covariance (ANCOVA) model.

The 4 most common antipsychotic treatments previously received were: haloperidol (24.0% vs 24.6%); olanzapine (19.3% vs 18.1%); risperidone (18.8% vs 17.5%); and quetiapine (10.9% vs 7.0%).

Both groups had significant reductions from baseline in PANSS total score at the study end of day 11, the study's primary outcome, in the intention-to-treat population as last observation carried forward. The benefits of ziprasidone fell entirely within the prespecified +/=13.5 limit (95% unilateral confidence interval [CI] 6.45 and bilateral 95% CI -6.42 to 7.59). Thus, ziprasidone was shown to be clinically equivalent to clozapine.

Similarly, significant and equivalent improvements versus baseline were seen for clozapine and ziprasidone for the full PANSS subscales considered: positive, -7.0 versus -6.0; negative, -6.1 versus -7.6; and general psychopathology, -11.4 versus -11.3, respectively.

Clozapine and ziprasidone showed significant reductions from baseline for CGI-S scores, from day 18 for clozapine and day 11 for ziprasidone, to study endpoint, and significant improvements from baseline in depressive symptoms, according to decrease in Calgary Depression Scale for Schizophrenia (clozapine, 2.1; ziprasidone, 3.1, P < .001).

The most frequently reported treatment-related adverse events generally favoured ziprasidone. Specific analyses were made for movement disorders in particular, for clozapine versus ziprasidone, where greater and more significant improvements from baseline were seen for ziprasidone: Simpson-Angus Scale (P < .001), Barnes Akathisia Scale (P < .05); Abnormal Involuntary Movement Scale (P < .001).

Ziprasidone-treated patients had no electrocardiogram abnormalities, significantly more favourable lipid profiles, and significant reduction in weight compared with clozapine. Clozapine was also associated with significant increase over baseline in fasting glucose levels.

Dr. Romeo stressed the need to use agents like ziprasidone at the right doses. "If ziprasidone is used at these doses, it is as effective as clozapine in this very difficult to treat subgroup of patients, while it also showed better tolerability and safety," he said.

This study was supported by funding from Pfizer Italia.


[Presentation title: Comparative Efficacy and Safety of Ziprasidone and Clozapine in Treatment-Refractory Schizophrenic Patients: Results of a Randomised, Double-Blind, 18-Week Trial. Abstract P.3.a.019]

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