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Study Questions Advantages of Newer Antipsychotics for Early Schizophrenia

1 April 2008. An open-label study comparing first- and second-generation antipsychotic drugs in first-episode psychosis finds that patients continued to take the newer drugs for significantly longer, even though psychopathological symptoms, as measured by a standard rating scale, indicated no differences between drugs. The report, published in the March 29 Lancet, notes that extrapyramidal symptoms were more common with the first-generation drug haloperidol, but also raises the question of whether physician bias against the older drug may be at play.

René S. Kahn of University Medical Centre in Utrecht, the Netherlands, and W. Wolfgang Fleischhacker of Medical University Innsbruck in Austria, who led the European First-Episode Schizophrenia Trial (EUFEST), and colleagues write that “Studies examining effectiveness of second-generation antipsychotic drugs in the early stages of schizophrenia are scarce.” They also note that most comparisons of first- and second-generation antipsychotics have tested efficacy—reductions on symptom scales in short trials—but not effectiveness, the fusion of efficacy and tolerability. In addition, they write, previous trials have included too few women and subjects with comorbid conditions. EUFEST was designed to overcome these drawbacks.

In the spirit of the American CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness; see SRF related news story) and British CUtLASS (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study; see SRF related news story), the latest prizefight between first-generation (or "typical") and second-generation (or "atypical") antipsychotic drugs sought to mirror the real world. Unlike CATIE (for overview, see Lewis and Lieberman, 2008), it did so via an open-label design. Like CATIE, EUFEST used treatment discontinuation to measure effectiveness. It randomly assigned 498 subjects, in 13 European countries and Israel, to receive either haloperidol, at a low dose, or one of four atypical antipsychotic drugs: amisulpride, olanzapine, quetiapine, or ziprasidone. The low dose of haloperidol was a response to charges that head-to-head comparisons of the drug to demonstrate the efficacy of atypicals have used doses that were too high and likely to decrease tolerability, particularly by increasing the likelihood of extrapyramidal symptoms.

Over the one-year follow-up, Kahn and colleagues found significant advantages for all the newer antipsychotics over haloperidol in the primary outcome variable, which was rate of treatment discontinuation (72 percent, versus 40 percent for amisulpride, 33 percent for olanzapine, 53 percent for quetiapine and 45 percent for ziprasidone; by Kaplan-Meier estimates). Prescriber dissatisfaction with efficacy and concern about side effects, rather than patient nonadherence, seemed to drive the additional departures from the haloperidol regimen. Yet all of the medications curbed symptoms by the same 60 percent, as measured by the postitive and negative symptom scale (PANSS), one of the secondary outcomes. None outshone the others in enhancing quality of life. These findings partly echo those of CATIE and CUtLASS, and they extend them beyond chronic or treatment-resistant schizophrenia to early in the disease.

Since haloperidol’s efficacy with regard to psychopathology matches that of the newer treatments, Kahn and colleagues speculate that prescriber bias against the drug might have influenced decisions to stop treatment with it. Despite seeing a positive in “the high continuation rates” seen with some of the atypicals, the researchers write, “We cannot conclude that second-generation drugs are more efficacious than is haloperidol, since discontinuation rates are not necessarily consistent with symptomatic improvement.”

In an email interview with SRF, Kahn and Fleishhacker added, "We feel it is important to reiterate that there is a difference between efficacious (which refers to efficacy against symptoms) and effective (efficacy plus tolerability). Our study was positive on the primary effectiveness outcome but failed to differentiate between drugs on efficacy. This is a highly important differentiation both with regard to our findings and also their clinical relevance."

In a related commentary, Robert A. Rosenheck of the VA Connecticut Health Care System in West Haven notes, "When this study began in 2002, enthusiasm for the new drugs was at a peak, and conscientious doctors, believing their patients had been assigned to an older, inferior drug, would have felt urgency, even in the context of a clinical trial, to switch their patients to newer, purportedly superior, treatments…. There clearly seems to be much less, if any, ground for enthusiasm about these costly drugs now than in 2002.” He writes that the time has come to face “head-on” the question of whether clinicians should reserve atypical antipsychotics for narrow indications, such as the presence of akathisia or pseudoparkinsonism, in chronic as well as first-episode schizophrenia.—Victoria L. Wilcox.

Kahn RS, Fleischhacker WW, Boter H, Davidson M, Verguowe Y, Keet IPM, Gheorghe MD, Rybakowski JK, Galderisi S, Libiger J, Hummer M, Dollfus S, López-Ibar JJ, Hranov LG, Gaebel W, Peuskens J, Lindefors N, Reicher-Rössler A, Grobbee DE, for the EUFEST study group. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet. 2008 Mar 29; 371:1085-1097. Abstract

Rosenheck RA. Pharmacotherapy of first-episode schizophrenia. Lancet. 2008 Mar 29; 371:1048-1049. Abstract

Comments on News and Primary Papers
Comment by:  Jan Volavka
Submitted 2 April 2008 Posted 3 April 2008
  I recommend the Primary Papers

The EUFEST study found that haloperidol, in comparison with several SGAs, was associated with a higher rate of overall treatment discontinuation, a higher rate of discontinuation because of lack of efficacy, a higher rate of discontinuation because of side effects, and worse outcome on the CGI and the GAF. Surprisingly, the authors’ last sentence reads: “It cannot be concluded that SGAs are more efficacious than is haloperidol….” Although restraint in scientific conclusions is generally admirable, I think that these authors are being too conservative in the interpretation of their important findings.

The reason for their hesitancy, it appears, is that the PANSS and the rehospitalization rates have not shown significant differences among drugs. Furthermore, they are concerned about the possibility of provider expectation biasing the results against haloperidol: if the psychiatrists expected haloperidol to do poorly, perhaps they were more likely to discontinue it than another treatment in which they believed. But the lack of difference on the PANSS total can have many...  Read more

View all comments by Jan Volavka

Comment by:  Peter F. Buckley
Submitted 11 April 2008 Posted 11 April 2008

This timely study, conducted by a stellar group of European investigators, adds to the continued debate about choice of medications for schizophrenia, informed by other similarly impressive pragmatic trials such as CATIE and CUTlass. Unlike the other recently published first-episode treatment study—the CAFE study (McEvoy et al., 2007)—which was double blind and compared SGAs only (risperidone versus olanzapine versus quetiapine), EUFEST better fits the model of a pragmatic trial and also included a FGA comparator. Although readers, particularly policy makers, will inevitably be drawn to the “Should I choose an FGA or SGA” content of this study, it seems to me that the most striking finding is (yet again) how frequently patients stop their medications. The 72 percent overall “All Cause” Discontinuation rate bears an uncanny resemblance to the 74 percent in CATIE and to the similar rate in the one-year CAFE first-episode study. Thus, medication non-adherence is a major treatment...  Read more

View all comments by Peter F. Buckley

Comment by:  Leslie Citrome
Submitted 18 April 2008 Posted 19 April 2008
  I recommend the Primary Papers

Although in EUFEST, psychopathology improved to a similar extent among the different groups, durability of the medication was quite different. This is of the utmost importance when it comes to treating patients—no one would disagree that continuation on medication is crucial in the successful treatment of patients with schizophrenia. If my goal is to pick the antipsychotic that my first-episode patient will stick with the longest, olanzapine or amisulpride appears to be what the data recommend. The alternative is to prescribe something else and then switch if necessary. Curiously, amisulpride and olanzapine (and risperidone) appeared to perform better than haloperidol in the Davis meta-analysis published when EUFEST was being launched (Davis et al., 2003).

As an exercise in looking at EUFEST through the lens of evidence-based medicine, I calculated the number needed to treat (NNT) for all-cause discontinuation (Citrome, 2008). NNT yields statistically significant pair-wise...  Read more

View all comments by Leslie Citrome

Comment by:  Herbert Meltzer (Disclosure)
Submitted 29 April 2008 Posted 29 April 2008

EUFEST, CATIE, and CUtLASS: Should Atypical Antipsychotic Drugs Remain the Most Prescribed Treatment for Schizophrenia?
The EUFEST (Kahn et al., 2008) study is the third major effectiveness-style study published in the last three years whose goal has been to compare typical and atypical antipsychotic drugs in the treatment of specified subgroups of patients with schizophrenia, the others being CATIE (Lieberman et al., 2005) and CUtLASS (Jones et al., 2006). The authors of EUFEST close their report with: “…it cannot be concluded that second-generation antipsychotic drugs are more efficacious than is haloperidol in the treatment of these (first-episode schizophrenia) patients” despite the fact that the discontinuation rate was the primary endpoint, and there was a significantly lower rate of discontinuation of the atypical drugs: 40 percent for amisulpride, 33 percent for olanzapine, 53 percent for quetiapine, and 45 percent for...  Read more

View all comments by Herbert Meltzer

Comment by:  Erik JohnsenHugo A. Jorgensen
Submitted 12 May 2008 Posted 14 May 2008

In our recently published systematic review of randomized effectiveness trials on SGAs (Johnsen and Jorgensen, 2008), the main findings were that chronically ill patients treated with olanzapine had longer time until treatment discontinuation and/or better drug compliance compared to those treated with the other SGAs, as well as the FGAs in those studies that had an FGA arm. The SGAs and FGAs did not differ on efficacy measures, and there were surprisingly few differences among SGAs on tolerability outcomes. The most consistent tolerability difference among the SGAs was in the area of metabolic adverse effects, where olanzapine-treated patients had more weight gain and adverse influence on cholesterol and triglyceride levels. The most pronounced difference between FGAs and SGAs on tolerability outcomes was that the FGAs were associated with significantly more extrapyramidal side effects (EPS) or discontinuation owing to EPS in the majority of studies. We noticed that this finding was also replicated in the EUFEST.

In summary,...  Read more

View all comments by Erik Johnsen
View all comments by Hugo A. Jorgensen
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