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Ziprasidone Has Long-Term Effectiveness and Favourable Metabolic Profile in Schizophrenia: ECNP

By Chris Berrie

PARIS, FRANCE -- September 21, 2006 -- The serotonin receptor inhibitor and novel second-generation antipsychotic ziprasidone shows higher long-term remission rates and more persistent improvements in quality-of-life outcome than haloperidol for patients with chronic or subchronic schizophrenia or schizoaffective disorder, shows research presented here at the 19^th Congress of the European College of Neuropsychopharmacology (ECNP).

The 3-year, double-blind, continuation study followed a 40-week, randomised, double-blind, trial, and its results highlight the validity and clinical relevance of consensus-based remission criteria to facilitate the detection of differential long-term effects of treatments.

Ziprasidone is a novel antipsychotic agent that has proven effective and well tolerated in both short-term and long-term clinical trials. However, most studies have shown only modest advantages between the second-generation antipsychotics over the short term, with long-term data lacking on their full potential for overall outcome.

In a presentation on September 18^th, primary study statistician Cynthia Siu, PhD, statistician, quantitative methodology, Data Power Inc., Ringoes, New Jersey, stressed that the study used Andreasen remission criteria (2005, Am. J. Psychiatry, 162, 441-449), which use an absolute threshold for severity of symptoms, rather than using improvement from baseline, because the study had a 4-year double-blind design and the baseline values could be variable.

This consensus-based operational criteria for symptom remission in schizophrenia requires a 6-month period of maintenance of ratings of mild or less (</=3) on 8 Positive and Negative Syndrome Scale (PANSS) items to facilitates the assessment of long-term treatment effectiveness.

The objective was to compare long-term effectiveness of 2 dose regimens of ziprasidone with haloperidol based on these recently the Andreasen remission criteria, and within the confines of a 3-year continuation study following an initial 40-week randomised trial.

The dose regimens were ziprasidone 80 to 160 mg/day BID and ziprasidone 80 to 120 mg/day, with haloperidol at 5 to 20 mg/day.

Initial entry requirements were a primary diagnosis of chronic or subchronic schizophrenia or schizoaffective disorder according to Diagnostic and Statistical Manual of Mental Disorders, Revision III-R (DSM-III-R) criteria, with: PANSS negative, >=-10; PANSS hostility and cooperativeness item, <4 (moderate); Clinical Global Impression for Improvement, <6 (much worse) at baseline (compared to screening); Global Assessment of Functioning Scale (GAF), >30. For the extension trial, completion of the 40-week trial was needed, with GAF >30.

Of the original 599 patients randomised in the study, completion and continuation into the extended phase was seen for 72 of 227 ziprasidone-BID patients, 67 of 221 ziprasidone-QD and 61 of 151 haloperidol, with 35%, 42% and 34% of these, respectively, completing this 3-year extension.

The demographics and patient characteristics were similar across the treatment groups at the baseline treatment assignment visit for initial randomisation trial (40.2, 41.1 and 40.7 years; male, 65%, 63%, and 62%). Mean PANSS was 71.6 for ziprasidone-BID, 71.3 for ziprasidone-QD, and 70.0 for haloperidol.

For the analysis, remission was defined as attainment of a score of mild or less for at least 6 months for these PANSS items: delusion P1; unusual thought content G9; hallucinatory behaviour P3; conceptual disorganisation P2; mannerisms/posturing G5; blunted effect N1; social withdrawal N4; and lack of spontaneity N6. Cross-sectional remission was defined as meeting the symptom-severity component of the remission criteria (excluding the time component).

Generalised estimating equations were applied to analyse rates of longitudinal cross-sectional remission and quality of life scores with adjustments for drop-out time, and mediator analyses evaluated if the differential effect of ziprasidone versus haloperidol on remission mediated improvements in quality of life.

Rates of full remission for the final 6 months of trial participation was significantly higher with ziprasidone-BID (about 40% patient remission; alone and in combination with ziprasidone-QD), as compared with haloperidol (about 20%, P < .05).

This benefit of the ziprasidone protocols was further seen in the longitudinal analysis of cross-sectional remission rates (as severity-symptom component), with significant benefits of ziprasidone over haloperidol from week 84 of the extension phase (P < .05). Similarly, significance was reached for the ziprasidone protocols versus haloperidol for the longitudinal analysis of quality of life total scores over the same period (P < .001).

Thus, ziprasidone was associated with a greater likelihood of attaining cross-sectional remission than haloperidol, and with a better quality of life total score over the 3-year continuation period. This superior remission rate favouring ziprasidone was strongly associated with the longitudinal quality of life scale score (P < .001, for mediator effect).

Treatment tolerability rates indicated a significantly higher Barnes Akathisia Rating Scale score for haloperidol versus ziprasidone (P = .02), although in general the overall incidences of treatment-emergent adverse events and clinical laboratory test abnormalities were comparable across treatment groups.

While Dr. Siu emphasised this particular methodological approach for the assessment of the efficacy and quality of life effects in comparisons between such treatment groups over the long-term, she also said, "What this tells us is that ziprasidone has now demonstrated long-term effectiveness in treating schizophrenia, and its very neutral profile and favourable metabolic profile will be particularly helpful for patients."

This study was supported by Pfizer Inc.


[Presentation title: Remission in Schizophrenia: A Comparison of Two Dose Regimens of Ziprasidone Versus Haloperidol Treatment in a 3-Year, Double-Blind Extension Study. Abstract P.3.a.047]

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