Elsevier

The Lancet

Volume 371, Issue 9618, 29 March–4 April 2008, Pages 1085-1097
The Lancet

Articles
Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial

https://doi.org/10.1016/S0140-6736(08)60486-9Get rights and content

Summary

Background

Second-generation antipsychotic drugs were introduced over a decade ago for the treatment of schizophrenia; however, their purported clinical effectiveness compared with first-generation antipsychotic drugs is still debated. We aimed to compare the effectiveness of second-generation antipsychotic drugs with that of a low dose of haloperidol, in first-episode schizophrenia.

Methods

We did an open randomised controlled trial of haloperidol versus second-generation antipsychotic drugs in 50 sites, in 14 countries. Eligible patients were aged 18–40 years, and met diagnostic criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder. 498 patients were randomly assigned by a web-based online system to haloperidol (1–4 mg per day; n=103), amisulpride (200–800 mg per day; n=104), olanzapine (5–20 mg per day; n=105), quetiapine (200–750 mg per day; n=104), or ziprasidone (40–160 mg per day; n=82); follow-up was at 1 year. The primary outcome measure was all-cause treatment discontinuation. Patients and their treating physicians were not blinded to the assigned treatment. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN68736636.

Findings

The number of patients who discontinued treatment for any cause within 12 months was 63 (Kaplan-Meier estimate 72%) for haloperidol, 32 (40%) for amisulpride, 30 (33%) for olanzapine, 51 (53%) for quetiapine, and 31 (45%) for ziprasidone. Comparisons with haloperidol showed lower risks for any-cause discontinuation with amisulpride (hazard ratio [HR] 0·37, [95% CI 0·24–0·57]), olanzapine (HR 0·28 [0·18–0·43]), quetiapine (HR 0·52 [0·35–0·76]), and ziprasidone (HR 0·51 [0·32–0·81]). However, symptom reductions were virtually the same in all the groups, at around 60%.

Interpretation

This pragmatic trial suggests that clinically meaningful antipsychotic treatment of first-episode of schizophrenia is achievable, for at least 1 year. However, we cannot conclude that second-generation drugs are more efficacious than is haloperidol, since discontinuation rates are not necessarily consistent with symptomatic improvement.

Funding

AstraZeneca, Pfizer, Sanofi-Aventis.

Introduction

Second-generation antipsychotic drugs were introduced over a decade ago. They were intended to be more efficacious than were previous drugs for treatment of schizophrenia, and less likely to induce motor side-effects. However, their clinical effectiveness compared with first-generation antipsychotic drugs is still debated.1, 2, 3, 4, 5 Indeed, limited conclusions can be drawn from the studies that have been undertaken so far,6 since most used restrictive inclusion criteria, leading to over-representation of men and under-representation of patients with comorbidities, such as drug abuse. Moreover, treatment response has almost exclusively been defined by use of scales that measure the extent of psychopathology: in most studies, efficacy has been measured, according to narrowly-defined criteria, but not effectiveness, which is a combination of efficacy and tolerability. Some investigators suggest that trials showing that second-generation antipsychotic drugs are better than haloperidol used doses of haloperidol that were too high.2 Finally, study durations have typically been less than 2 months, which is imperfect for an illness potentially lasting a lifetime.6, 7, 8

We7 and others6 have suggested that studies that are not restrictive in the inclusion of patients, have long follow-up periods, and use outcome measures which are clinically meaningful, are urgently needed. The time for which patients continue to use a drug is considered a good measure of effectiveness. Even in short-term studies, fewer than 50–60% of patients continue to take their drugs before the study is complete.9 Pragmatic (open) randomised trials, comparing second-generation drugs with older ones, will arguably provide a better indication of the true value of these drugs in clinical practice than will double-blind trials. Moreover, these trials should include a broad range of patients, so findings have external validity.6

Studies examining effectiveness of second-generation antipsychotic drugs in the early stages of schizophrenia are scarce.7 However, patients in the early stages of schizophrenia might well respond differently to antipsychotic drugs from those who have used them for years or even decades: dopamine-receptor sensitivity is most probably substantially different in patients who have had no previous exposure to the dopamine-antagonistic effects of antipsychotic dugs than in patients who are chronically treated.10 Moreover, trials of drugs in chronic patients often, by definition, include patients who have responded little, or been non-adherent, to previous treatments.

We undertook a pragmatic open randomised-controlled trial to compare the effectiveness of second-generation antipsychotic drugs, with that of a low dose of haloperidol, in first-episode schizophrenia.

Section snippets

Setting and participants

A total of 50 centres, of which 36 were university hospitals, participated; the centres were in 13 European countries and Israel. We selected the centres because of their experience of research in schizophrenia. Between Dec 23, 2002, and Jan 14, 2006 we assessed 1047 patients for eligibility. Eligible patients were aged 18–40 years and met criteria of the diagnostic and statistical manual of mental disorders (fourth edition) for schizophrenia, schizophreniform disorder, or schizoaffective

Results

Figure 1 shows the trial profile. 498 patients were randomly assigned to five treatment groups (figure 1). During follow-up, some enrolled patients appeared not to be eligible: 11 patients (four on haloperidol, two on olanzapine, two on quetiapine, and three on ziprasidone) had another cause for the symptoms than schizophrenia, another patient on quetiapine had positive symptoms exceeding 2 years before randomisation, and two patients on amisulpride had used antipsychotic drugs for more than 2

Discussion

Our study has shown that in patients with first-episode schizophrenia and schizophreniform disorder, treatment discontinuation over 12 months was significantly greater in patients given a low dose of haloperidol than in those assigned to treatment with second-generation antipsychotic drugs, with the lowest discontinuation with olanzapine. However, symptomatic improvement (measured by PANSS) and rates of admission to hospital did not differ significantly between groups. Global improvement as

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