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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 19th 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 18th, 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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