Olanzapine versus haloperidol: acute phase results of the international double-blind olanzapine trial

Abstract

A 6-week acute phase of an international 1-year double-blind study was conducted comparing three dose ranges of olanzapine (5±2.5 mg/day, 10±2.5 mg/day, and 15±2.5 mg/day) with a fixed dose of olanzapine (1.0 mg/day) and with a dose range of haloperidol (15±5 mg/day) in the treatment of 431 patients with schizophrenia. The purpose was to determine whether olanzapine demonstrated a dose-related ability to decrease overall psychopathology with minimal associated extrapyramidal symptoms in patients with schizophrenia. The high-dose olanzapine group showed statistically significantly greater improvement in overall psychopathology based on mean change in the CGI Severity score and statistically significantly greater improvement in positive psychotic symptoms based on mean change in both the BPRS positive score and the PANSS positive score compared with the 1.0-mg/day olanzapine group. Analyses indicated that an increasing dose–response curve was observed across the range of all olanzapine dose groups. Acute extrapyramidal syndromes were reported less frequently among all olanzapine groups compared with the haloperidol group. Endpoint mean change on both the Simpson-Angus Scale and the Barnes Akathisia Scale reflected improvement for all olanzapine treatment groups compared with worsening for the haloperidol group. Olanzapine was associated with weight gain but did not appear to have any clinically meaningful effect on vital signs. Although olanzapine was associated with some increase in prolactin concentrations, increases were transient, occurred less often, and were of lesser magnitude than those observed with haloperidol.

Introduction

Schizophrenia is one of the most expensive psychiatric illnesses worldwide. In the United Kingdom alone, schizophrenia incurs estimated annual direct treatment costs of £397 million and indirect lost productivity costs of £1.7 billion (Davies and Drummond, 1994). Although typical antipsychotics, such as haloperidol, have been available since the 1950s, their effectiveness in the management of schizophrenia has been compromised by extrapyramidal syndromes (EPS) that often lead to lack of compliance and drug discontinuation. In addition, although the typical antipsychotics can be effective in the control of the positive symptoms of schizophrenia, which most often lead to institutionalization, they have little effect or actually may worsen negative symptoms, which generally constrain social relations, work capacity and a more functional lifestyle.

Over the past decade, a substantial amount of research has been directed to the search for an atypical antipsychotic, ie, an agent associated with fewer EPS and a greater therapeutic impact on negative symptoms. Interest in the development of such compounds was intensified when the atypical properties of clozapine were demonstrated (Kane et al., 1988). However, the use of clozapine has been limited by a substantial risk of agranulocytosis (1.3%), necessitating costly weekly blood monitoring (Alvir et al., 1993).

Several possible defintions of atypical antipsychotics have proposed that, in addition to producing fewer EPS, atypical antipsychotics have the following clinical characteristics: (1) greater efficacy in the treatment of overall schizophrenic psychopathology among those nonresponsive to typical antipsychotics (Kane et al., 1988), (2) greater negative symptom efficacy (Kane et al., 1988), and (3) less perturbation of serum prolactin (Meltzer et al., 1979, Kane et al., 1981).

The distinct receptor-binding profile exhibited by clozapine may explain its atypical characteristics. Whereas conventional agents have their highest affinity for dopamine receptors, particularly the D₂ class, clozapine demonstrates preferential affinity for serotonergic (5-HT₂), histaminergic (H₁), adrenergic (α₁ and α₂), and muscarinic receptors (Tye et al., 1992, Moore et al., 1993, Wong et al., 1993). Within its dopaminergic profile, clozapine exhibits greater activity at D₁ than D₂ receptors (Tye et al., 1992, Moore et al., 1993, Wong et al., 1993) and also significant D₄ affinity (Seeman and Van Thol, 1993). Accordingly, clozapine differs from typical agents in its effects on dopamine-mediated behaviors, eg, induction of catalepsy in rodents (Tye et al., 1992, Moore et al., 1992, Moore et al., 1993, Wong et al., 1993).

Biochemical studies have demonstrated that olanzapine has a broad pharmacologic profile similar to that of clozapine. Olanzapine shows a relatively higher affinity for the serotonin 5-HT_2A receptor than for the dopamine D₂ receptor as well as a relatively high affinity for the D₄, D₁, 5-HT_2C, muscarinic (especially m₁), α₁-adrenergic, and histamine H₁ receptors (Tye et al., 1992, Moore et al., 1993, Seeman and Van Thol, 1993, Wong et al., 1993, Hemrick-Luecke et al., 1993). Electrophysiologic studies have shown that chronic administration of olanzapine decreases the firing of A10 neurons while increasing the number of spontaneously active A9 neurons in a dose-dependent fashion (Stockton and Rasmussen, 1996). These effects resemble those exhibited by clozapine (Stockton and Rasmussen, 1996).

Behavioral studies with olanzapine are consistent with the in vitro affinity profile and suggest potential atypicality (Tye et al., 1992, Moore et al., 1992, Moore et al., 1993, Wong et al., 1993). Similar to clozapine, olanzapine blocks conditioned avoidance in rats at doses much lower than those required to induce catalepsy (Tye et al., 1992, Moore et al., 1992, Moore et al., 1993, Wong et al., 1993), suggesting that the therapeutic dose range of olanzapine would exhibit minimal acute EPS potential. Olanzapine also increases punished responding in rats in a conflict model similar to clozapine but not seen with haloperidol, remoxipride or risperidone (Tye et al., 1992, Moore et al., 1993, Moore et al., 1994, Wong et al., 1993). Demonstration that olanzapine substitutes for clozapine in animals trained to discriminate clozapine from test vehicle (Tye et al., 1992, Moore et al., 1992, Moore et al., 1993, Wong et al., 1993) further underscores their pharmacologic similarity.

Evidence from patient studies also suggests that olanzapine has an atypical profile. A recent open-label study suggested that olanzapine (5 to 20 mg/day) had significant antipsychotic activity against both positive and negative symptoms. In addition, minimal EPS were observed, and by study endpoint serum prolactin concentrations were not elevated above baseline (Baldwin and Montgomery, 1995).

In a large (N=335), double-blind, placebo- and comparator-controlled trial in schizophrenia, olanzapine was significantly superior to placebo in the treatment of overall psychopathology, including both positive and negative symptoms. Furthermore, olanzapine was also significantly superior to haloperidol in the treatment of negative symptoms (Beasley et al., 1996). There were no dystonic reactions observed with olanzapine in that study. In contrast to haloperidol, olanzapine was associated with a significantly lower incidence of parkinsonism and akathisia at all dosages. Prolactin elevations with olanzapine occurred significantly less often and were of lesser magnitude compared with haloperidol.

The study presented here sought to evaluate the safety, tolerability (including treatment-emergent EPS), and dose-response efficacy of olanzapine in hospitalized patients with chronic schizophrenia in an acute exacerbation.