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N Engl J Med. 1997 Sep 18;337(12):809-15.

A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia.

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Veterans Affairs Connecticut Healthcare System, West Haven 06516, USA.



Clozapine, a relatively expensive antipsychotic drug, is widely used to treat patients with refractory schizophrenia. It has a low incidence of extrapyramidal side effects but may cause agranulocytosis. There have been no long-term assessments of its effect on symptoms, social functioning, and the use and cost of health care.


We conducted a randomized, one-year, double-blind comparative study of clozapine (in 205 patients) and haloperidol (in 218 patients) at 15 Veterans Affairs medical centers. All participants had refractory schizophrenia and had been hospitalized for the disease for 30 to 364 days in the previous year. All patients received case-management and social-rehabilitation services, as clinically indicated.


In the clozapine group, 117 patients (57 percent) continued their assigned treatment for the entire year, as compared with 61 (28 percent) of the patients in the haloperidol group (P<0.001). As judged according to the Positive and Negative Syndrome Scale of Schizophrenia, patients in the clozapine group had 5.4 percent lower symptom levels than those in the haloperidol group at all follow-up evaluations (mean score, 79.1 vs. 83.6; P=0.02). The differences on a quality-of-life scale were not significant in the intention-to-treat analysis, but they were significant among patients who did not cross over to the other treatment (P=0.003). Over a one-year period, patients assigned to clozapine had fewer mean days of hospitalization for psychiatric reasons than patients assigned to haloperidol (143.8 vs. 168.1 days, P=0.03) and used more outpatient services (133.6 vs. 97.9 units of service, P=0.03). The total per capita costs to society were high -- $58,151 in the clozapine group and $60,885 in the haloperidol group (P=0.41). The per capita costs of antipsychotic drugs were $3,199 in the clozapine group and $367 in the haloperidol group (P<0.001). Patients assigned to clozapine had less tardive dyskinesia and fewer extrapyramidal side effects. Agranulocytosis developed in three patients in the clozapine group; all recovered fully.


For patients with refractory schizophrenia and high levels of hospital use, clozapine was somewhat more effective than haloperidol and had fewer side effects and similar overall costs.

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