Olanzapine and haloperidol in first episode psychosis: Two-year data

Abstract

Few studies have assessed the comparative efficacy and safety of atypical and typical antipsychotic medications in patients within their first episode of psychosis. This study examined the effectiveness of the atypical antipsychotic olanzapine and the typical antipsychotic haloperidol in patients experiencing their first episode of a schizophrenia-related psychotic disorder over a 2-year treatment period.

Two hundred and sixty-three patients were randomized to olanzapine or haloperidol in a doubleblind, multisite, international 2-year study. Clinical symptoms and side effects were assessed at baseline and longitudinally following randomization for the duration of the study.

Olanzapine and haloperidol treatment were both associated with substantial and comparable reductions in symptom severity (the primary outcome measure) over the course of the study. However, the treatment groups differed on two secondary efficacy measures. Patients were less likely to discontinue treatment with olanzapine than with haloperidol: mean time (in days) in the study was significantly greater for those treated with olanzapine compared to haloperidol (322.09 vs. 230.38, p < 0.0085). Moreover, remission rates were greater in patients treated with olanzapine as compared to those treated with haloperidol (57.25% vs. 43.94%, p < 0.036). While extrapyramidal side effects were greater in those treated with haloperidol, weight gain, cholesterol level and liver function values were greater in patients treated with olanzapine.

The data from this study suggest some clinical benefits for olanzapine as compared to haloperidol in first episode patients, which must be weighed against those adverse effects that are more likely with olanzapine.

Introduction

Schizophrenia is a severe and complex psychiatric disorder. After an initial onset of often florid symptoms in late adolescence or early adulthood, many patients experience fluctuating levels of symptoms and a decline of overall functioning over the ensuing years (McGlashen and Fenton, 1993). A growing body of data (Wyatt, 1991, Olney and Farber, 1995, Lieberman et al., 1998), however, suggests that intensive intervention during the early years of psychosis may have a beneficial effect on functioning and improve the long-term course of the disorder (Waddington et al., 1998, Loebel et al., 1992, Haas et al., 1998, Birchwood et al., 1998).

Until the past decade, typical antipsychotic drugs, introduced in the 1950s, were the mainstay of psychopharmacologic treatment for patients with schizophrenia, including those early in the course of illness. Response of first episode patients to treatment with such medications is usually quite good, with improvement of florid symptoms, although for many patients some symptoms, particularly negative symptoms, remain, and for many others exacerbation of positive symptoms (e.g., the development of the second episode) is quite common after an initial response (Robinson et al., 1999). Such symptom exacerbations producing a second episode is made dramatically more likely if patients do not take their medication continuously following initial symptomatic improvement (Robinson et al., 1999).

The recent availability of the new atypical or “novel” antipsychotic drugs has further sparked research in the early phases of schizophrenia. The introduction of these agents–clozapine and the medications introduced after it–has provided clinicians with a group of medications that are at least as efficacious for symptoms of schizophrenia, are generally better tolerated and may be associated with fewer exacerbations during chronic treatment (Geddes et al., 2000, Davis et al., 2003, Czernansky et al., 2002). Clinical trials of these new agents in first episode populations are underway and preliminary reports are beginning to appear (Lieberman et al., 2003a, Lieberman et al., 2003b, Emsley, 1999, Woerner et al., 2003). If these medications are in fact more efficacious in first episode patients (Sanger et al., 1999, Lieberman et al., 2003a, Lieberman et al., 2003b), or if they are associated with fewer relapses than the first generation agents (Czernansky et al., 2002, Lieberman et al., 2003a), they may produce a better long-term outcome in patients when used early in the course of the disorder (Green and Schildkraut, 1995). But, even these medications need to be taken on a chronic basis to have their effect.

We report on a study designed to compare the efficacy of the novel antipsychotic olanzapine and the typical antipsychotic haloperidol in patients experiencing their first episode of a schizophrenia-related psychosis. The study was designed to evaluate treatment effects over short- and long-term periods by using three outcome domains: clinical measures of treatment response based on psychopathology, side effects and treatment adherence; cognitive function as measured by neuropsychological test performance; and biomarkers of treatment effects measured by neuroimaging. We have previously reported on the results of the clinical measures and neuropsychological test performance over the initial 12 weeks of treatment (Lieberman et al., 2003b, Keefe et al., 2004), and initial neuroimaging data over the first year of treatment have been presented (Lieberman et al., 2005). In these reports, olanzapine demonstrated some advantages in acute therapeutic response and neurological side effects compared to haloperidol over 12 weeks of treatment, while it was associated with more weight gain during this period, and there was evidence that one year of olanzapine treatment was associated with some possible protective effect as noted by structural imaging measures. Here we report on clinical measures of treatment response over the course of the entire 2-year study.