Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine.
This multi-center randomized controlled trial, published in 1988, demonstrated clozapine’s superiority in treatment-resistant schizophrenia. Response was seen in 30% of clozapine-treated patients, compared with 4% of chlorpromazine-treated patients.
- Randomized controlled trial.
- N=268 patients with DSM-III schizophrenia, with no response to at least 3 neuroleptics, plus a six-week single-blinded trial of haloperidol, were randomized (double-blinded) to:
- Clozapine (n=126)
- Chlorpromazine and benztropine mesylate (n=139)
- The chlorpromazine group received prophylactic benztropine to enhance blinding, as clozapine has been previously established to reduce extrapyramidal symptoms.
- Subjects had a mean age of 35.7 (range 20-59), were 80% male (a high proportion of participating centers were VA medical centers), 65% white, 84% undifferentiated/paranoid subtypes, mean duration of current hospitalization approximately 2 years.
- Setting: 16 medical centers.
- Primary outcome: a priori response criteria required both:
- Brief Psychiatric Rating Scale (BPRS) total score reduction >20% from baseline.
- Clinical Global Improvements (CGI) Scale score ≤3 (mild) or posttreatment BPRS total score ≤35.
- Secondary outcome: Nurses’ Observation Scale for Inpatient Evaluation (NOSIE-30), a 30-item evaluation of ward behavior completed by nursing staff who were blind to treatment assignment.
- Response (based on a priori criteria) was achieved in 30% of clozapine-treated patients compared with 4% of chlorpromazine-treated patients (P<0.001).
- BPRS total score at end of study (baseline was 61 for both groups) was significantly lower in clozapine group (P<0.001):
- Clozapine: 45 (SD=13)
- Chlorpromazine: 56 (SD=12)
- Clozapine was associated with significant improvement in BPRS negative symptoms, while chlorpromazine was not.
- Clozapine, compared with chlorpromazine, was associated with significantly greater improvement in all six factors of the NOSIE-30: social competence, social interest, personal neatness, irritability, manifest psychosis, and retardation.
- For the majority of BPRS symptoms, NOSIE-30 factors, and CGI Scale, clozapine was associated with significant improvement compared with chlorpromazine, in as little as 1-2 weeks.
- Adverse Events:
- Salivation occurred significantly more frequently in the clozapine group (13% vs 1%)
- Dry mouth occurred significantly more frequently in the chlorpromazine group (20% vs 5%)
- Hypotension occurred significantly more frequently in the chlorpromazine group (38% vs 13%)
- Adverse events that did not differ significantly between the groups included: drowsiness, tachycardia, constipation, dizziness, fever, hypertension, headache, nausea/vomiting.
- Extrapyramidal side effects were rated weekly with the Simpson-Angus Scale for Extrapyramidal Side Effects. Patients receiving clozapine had significantly greater improvement in EPS compared with chlorpromazine in weeks 4-6 of the study.
- None of the patients in this study were reported to have agranulocytosis.
Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45(9):789-796.