Comparative efficacy of risperidone and clozapine in the treatment of patients with refractory schizophrenia or schizoaffective disorder: a retrospective analysis.

BACKGROUND: Clozapine is effective in up to 60% of patients with refractory schizophrenia, whereas the efficacy of risperidone remains unknown. This retrospective study examined the relative efficacy of these drugs in chronically institutionalized patients refractory to conventional antipsychotic agents. METHOD: A total of 24 patients who at different time periods had received adequate trials of both clozapine and risperidone and met our inclusion criteria for minimum dose and duration of each trial were included; for clozapine, a minimum dose of 300 mg/day had to be maintained for at least 12 weeks, and for risperidone, a minimum dose of 6 mg/day for at least 6 weeks. Information obtained from systematic retrospective chart review was blindly rated by 2 psychiatrists using the 7-point Clinical Global Impressions-Improvement (CGI-I) scale on overall clinical state and along specific symptom domains of positive symptoms, negative symptoms, and aggressive behavior. RESULTS: The mean +/- SD dose was 520+/-94 mg/day for clozapine and 7.5+/-2.2 mg/day for risperidone. Fourteen patients (58%) were classified as responders to clozapine, while 6 (25%) responded to risperidone (CGI-I score of 1 or 2); on specific symptom domains, response rates to clozapine were 38% (9/24) on positive symptoms, 29% (7/24) on negative symptoms, and 71% (12/17) on aggressive behavior. For risperidone, response rates were 17% (4/24) on positive symptoms, 8% (2/24) on negative symptoms, and 41% (7/17) on aggressive behavior. CONCLUSION: The results of this study support the utility of first giving a risperidone trial in a treatment algorithm for refractory patients because of its better risk/benefit profile compared with clozapine. Clozapine, however, remains our gold standard in the management of these patients.

Common treatment goals of antipsychotics: acute treatment.

When a patient with an acute exacerbation of schizophrenia is admitted into the hospital, the target symptoms include pathologic excitement/agitation and exacerbated psychotic symptoms. The goal of hospitalization becomes attenuation of these symptoms to a level compatible with safe discharge. The mainstay of stabilization is antipsychotic treatment. A risk/benefit analysis of the conventional versus the newer antipsychotics favors the use of the newer agents as first-line drugs. These newer antipsychotic agents represent the first significant advance in the pharmacologic treatment of schizophrenia in the past four decades. They are at least as effective as conventional agents and are clearly superior from a safety perspective. Because of short inpatient stays, the challenge for clinicians is to provide an adequate treatment period without aggressively escalating the dose.

Treatment refractory schizophrenia: how should we proceed?

A substantial portion of schizophrenic patients demonstrate suboptimal response to conventional antipsychotics. These agents are primarily effective in the treatment of psychotic symptoms; their efficacy in other domains of psychopathology such as negative symptoms, chronic aggressive behavior, and cognitive deficits, is limited or non-existent. In this group of refractory patients, the novel atypical antipsychotic clozapine has demonstrated robust efficacy, with response rates approaching 60% after twelve weeks of treatment. Efficacy of clozapine extends to symptom domains other than psychosis, including negative symptoms, mood stabilization, aggressive behavior and compulsive water drinking. Several novel agents, each of which shares some, but not all, of the preclinical and clinical characteristics that make clozapine so unique, have been introduced in the last 4 years. These agents demonstrate a broader spectrum of efficacy and an improved side effect profile in non-refractory patients. Initial data on their efficacy in refractory patients suggests that olanzapine does not achieve overall superior efficacy in this patient population compared to conventional agents although there is some evidence of relatively greater efficacy in negative symptoms and aggressivity. Several studies suggest that the efficacy of risperidone is superior to that of conventional agents in refractory patients. Preliminary conclusions are not possible for quetiapine because of a paucity of data in the literature. The literature supports a risperidone trial prior to a clozapine trial in a treatment algorithm for refractory patients because of its more favorable risk/benefit profile.