PHARMACOEPIDEMIOLOGY OF CLOZAPINE IN 202 INPATIENTS WITH SCHIZOPHRENIA

OBJECTIVE: To evaluate clozapine in a field trial for hosPitalized pat ients with treatment-resistant schizophrenia. METHOD: The setting cons isted of a large, state-operated, public psychiatric system. The proto col called for the treating psychiatrist to provide symptom- and adver se-effect ratings at four times following the start of drug therapy- T he outcome criteria included the Sandoz study outcome measure of sympt om improvement as well as discharge status for One Year of follow-up. To assess the validity of the ratings, several measures of internal co nsistency were determined. Clozapine therapy was started in 227 patien ts, and symptom data are available for 202. RESULTS: Overall, 33 perce nt (n = 66) of the Patients were improved at the end of one year of tr eatment; 12 percent (n = 24) maintained symptom improvement at all thr ee evaluation times. Modest, statistically significant improvement aft er 12 weeks compared with baseline Brief Psychiatric Rating Scale (BPR S) total scores was observed for the patients continuing medication (n = 152); the emergence of a previously unimProved group (n = 26) expla ins this modest improvement. However, in the analysis of all patients (n = 202), (including dropouts), there was no significant symptom impr ovement after 12 weeks. Lower baseline BPRS scores predicted significa nt symptom improvement after 12 weeks of treatment. Among those medica ted for one Year, the pattern of symptom improvement showed that the p robability of late improvement was 0.26 for those previously unimprove d, and the probability of a 12-week responder losing improvement was 0 .23, resulting in a net group gain of 3 cases in 100. By the end of on e year, 8 percent (n = 17) of the cohort was discharged, and 3 percent (n = 7) was transferred to another facility while continuing to recei ve clozapine. Of the 227 original patients started on clozapine therap y, medication was discontinued for adverse effects in 11 percent (n = 25): white blood cell count (WBC) decrease (but no agranulocytosis) in 5 percent (n = 12), seizures in 1 percent (n = 3), one patient with s eizures and decreased WBC count, and other events (e.g., cardiovascula r changes, fever, or possible neuroleptic malignant syndrome) in 4 per cent (n = 9). Patient refusal was reported for 6 percent (n = 13) of t hose starting treatment. CONCLUSIONS: Although only 19 percent of the patients exhibited improvement at 6 weeks, the response rate at 12 wee ks (29 percent) for this naturalistic study cohort was similar to that in the major, double-blind, six-week, controlled, clinical trial of c lozapine. The impersistence of response as symptoms were followed for up to one year is a finding that deserves rigorous evaluation.