Clozapine for the Treatment-Resistant Schizophrenic

TLDR

Treating schizophrenia patients who fail adequate neuroleptic trials is a major challenge, and clozapine, though promising, has been delayed due to its agranulocytosis risk. The study evaluates clozapine’s efficacy in patients with treatment‑resistant schizophrenia. In a double‑blind, multicenter trial, 268 patients were randomized to receive clozapine (up to 900 mg/d) or chlorpromazine (up to 1800 mg/d) for six weeks. Clozapine yielded a 30 % response rate versus 4 % for chlorpromazine, significantly improving BPRS, CGI, and Nurses’ Observation Scale scores—including negative symptoms—yet no agranulocytosis occurred, indicating a higher comparative risk that limits its use to selected patients.

Abstract

• The treatment of schizophrenic patients who fail to respond to adequate trials of neuroleptics is a major challenge. Clozapine, an atypical antipsychotic drug, has long been of scientific interest, but its clinical development has been delayed because of an associated risk of agranulocytosis. This report describes a multicenter clinical trial to assess clozapine's efficacy in the treatment of patients who are refractory to neuroleptics.<i>DSM-III</i>schizophrenics who had failed to respond to at least three different neuroleptics underwent a prospective, single-blind trial of haloperidol (mean dosage, 61 ±14 mg/d) for six weeks. Patients whose condition remained unimproved were then randomly assigned, in a double-blind manner, to clozapine (up to 900 mg/d) or chlorpromazine (up to 1800 mg/d) for six weeks. Two hundred sixty-eight patients were entered in the doubleblind comparison. When a priori criteria were used, 30% of the clozapine-treated patients were categorized as responders compared with 4% of chlorpromazine-treated patients. Clozapine produced significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale, and Nurses' Observation Scale for Inpatient Evaluation; this improvement included "negative" as well as positive symptom areas. Although no cases of agranulocytosis occurred during this relatively brief study, in our view, the apparently increased comparative risk requires that the use of clozapine be limited to selected treatment-resistant patients.