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.