Olanzapine plasma concentrations and clinical response: Acute phase results of the North American Olanzapine Trial

Olanzapine is an atypical antipsychotic that is effective in the treatment of schizophrenia. Olanzapine plasma concentrations greater than or equal to9.3 ng/mL, (24 hours postdose) have been identified as a predictor of clinical response in acutely ill patients with schizophrenia. The authors report a receiver operating characteristic (ROC) curve analysis of 12-hour olanzapine concentrations and treatment response from the North American Double-Blind Olanzapine Trial. After a 4- to 7-day placebo lead-in, patients meeting DSM-III-R criteria for schizophrenia were randomly assigned to receive olanzapine, haloperidol, or placebo. Patients who were randomly assigned to receive olanzapine were given daily doses ranging hom 2.5 to 17.5 mg/day for up to 6 weeks. Blood samples for the determination of olanzapine plasma concentrations mere obtained between 10 and 16 hours (11.7 +/- 1.7 hours) after the last dose was administered, Therapeutic response data and olanzapine concentrations used for analysis were obtained from the endpoint visit for each patient if the patient had been receiving a fixed olanzapine dose for at least the last 2 weeks of the study, Plasma concentrations from previous visits were used if endpoint concentrations were invalid. Response was defined as a greater than or equal to 20%, reduction in Brief Psychiatric Rating Scale (BPRS) scores and a Clinical Global Impression (CGI) Severity scale score of less than or equal to3 or a final BPRS score of less than or equal to 35, The final ROC analysis included data from 84 patients and suggested an olanzapine concentration greater than or equal to 23.2 ng/mL to be a predictor of therapeutic response, Fifty-two percent of patients with 12-hour olanzapine concentrations greater than or equal to 23.2 ng/mL responded, whereas only 25% of patients with concentrations <23.2 ng/mL responded. Furthermore, an olanzapine concentration <greater than or equal to>23.2 ng/mL was a predictor of response in the Scale for the Assessment of Negative Symptoms (greater than or equal to 20% decrease and endpoint CGI less than or equal to3), Olanzapine concentrations were found to be a function of olanzapine dose (in milligrams per day) and gender such that prospective olanzapine dosing is feasible. A 12-hour olanzapine plasma concentration of >23.2 ng/mL was a predictor of therapeutic response in acutely ill patients with schizophrenia. Males required a higher olanzapine dose to reach this threshold concentration than their female counterparts.