Effectiveness of antipsychotics in first-episode schizophrenia and schizophreniform disorder on response and remission: An open randomized clinical trial (EUFEST)
Introduction
The Positive and Negative Syndrome Scale (PANSS) is often used to assess the severity of psychopathology in psychotic disorders (Andreasen et al., 2005, Leucht et al., 2008). Although changes in mean values of the PANSS may be significant, the clinical relevance of such changes is often less clear. Dichotomized outcomes like response and remission may be more useful in this regard. Previously, investigators evaluating dichotomized outcomes have used a wide range of cutoff scores. Fortunately, criteria for response and remission have been introduced recently. For acutely ill, nonrefractory patients with schizophrenia – such as most first-episode patients who generally respond well to antipsychotics – a cutoff of at least 50% PANSS reduction may be informative, corresponding to ‘much improvement’ on the Clinical Global Impression scale (CGI; Leucht et al., 2008). Other cutoffs may provide meaningful additional information, i.e. symptom reductions of ≤ 0%, 0–24%, 25–49%, 50–74%, and 75–100% (Leucht et al., 2008). Since ‘responders’ can still experience significant symptoms at endpoint (van Os et al., 2006), criteria for remission have been introduced that reflect a sustained relative absence of core symptoms of schizophrenia (Andreasen et al., 2005). According to these criteria patients are in remission if eight specific PANSS items are only mildly present for at least 6 months.
In the European First-Episode Schizophrenia Trial (EUFEST), an open-treatment randomized clinical trial, we recruited first-episode schizophrenia patients with broad inclusion criteria to compare the effectiveness of low doses of haloperidol versus regular doses of the second generation antipsychotics (SGAs): amisulpride, quetiapine, olanzapine, and ziprasidone on treatment discontinuation during 12 months of follow-up (Kahn et al., 2008). Though we found higher discontinuation rates on haloperidol (72%) as compared with the SGAs (33–53%), mean PANSS total scores did not differ between treatment arms. For the present study we have analyzed the effect of these study drugs on dichotomized PANSS total scores: ≥ 50% response within 12 months and remission within 12 months.
Section snippets
Setting, participants, and recruitment
The study′s design has been published previously in more detail but will be described here briefly (Fleischhacker et al., 2005, Kahn et al., 2008). A total of 50 centers participated in 13 European countries and Israel. Eligible patients were 18–40 years of age and met DSM-IV criteria for schizophrenia, schizophreniform, or schizoaffective disorder confirmed by the Mini International Neuropsychiatric Interview Plus (MINI+; Sheehan et al., 1998). In this article we use the word ‘schizophrenia’ as
Results
Between December 2002 and January 2006 498 patients were randomized (Fig. 1). In a few patients no baseline PANSS total scores were assessed and a substantial number of patients discontinued treatment or dropped out within 6 months and, therefore, could not meet the time component of remission. We included in the analyses four patients who did not take any dose of the assigned study drug (one patient on haloperidol, one on olanzapine, and two on quetiapine) and 14 patients who, during follow-up,
Discussion
The results show that a substantial proportion of unselected first-episode patients met criteria for ≥ 50% response or remission within 12 months. Patients on a low dose of haloperidol were less likely to respond or remit within 12 months when compared with patients on amisulpride, olanzapine, or ziprasidone. The most important predictor of ≥ 50% response and remission was the use of amisulpride.
To our knowledge this is the first open randomized clinical trial that included high numbers of
Role of funding sources
This study was funded by the European Group for Research in Schizophrenia (EGRIS) with grants from AstraZeneca, Pfizer, and Sanofi-Aventis. The sponsors had no role in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit the paper for publication. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Contributors
RSK and WWF designed, obtained funding and supervised the EUFEST study. HB analyzed the data. HB and RSK interpreted the data and HB drafted the manuscript. All authors participated in the critical revision of the manuscript and approved the final report.
Conflict of interest
HB declares no conflict of interests.
JP received consultancy fees and research grants from and participated in clinical trials sponsored by AstraZeneca, Sanofi-Aventis, Eli Lilly, Pfizer, and Janssen-Cilag.
JL has received speaker′s honoraria, travel grants or consultancy fees from Eli Lilly, Bristol-Myers Squibb, Lundbeck and Servier. JL was a member of the advisory boards of Eli Lilly and Bristol-Myers Squibb and he is a faculty member of the Lundbeck Institute (Lundbeck Neuroscience
Acknowledgements
We thank all patients who participated in the study.
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