Effectiveness of clozapine in neuroleptic-resistant schizophrenia: clinical response and plasma concentrations

OBJECTIVE: To assess the relation between plasma concentrations of clozapine and its 2 main metabolites desmethyl clozapine and clozapine N-oxide, and clinical change in a sample of inpatients with schizophrenia who were resistant to conventional neuroleptics. METHOD: Thirty-seven patients (27 men and 10 women, mean age 34.8 yr) with treatment-resistant schizophrenia were treated with clozapine for 18 weeks; dosage was adjusted according to clinical response, and plasma concentrations of clozapine and of its metabolites were measured weekly by high-performance liquid chromatography. Clinical status was also assessed weekly with the Positive and Negative Syndrome Scale (PANSS). Patients were considered "responsive" if they showed at least a 20% improvement over their baseline PANSS ratings. RESULTS: The mean endpoint clozapine dosage was 486.5 mg/day. There was a significant correlation between the daily dosage of clozapine and the plasma levels of clozapine and of its metabolites (p < 0.05). There was no correlation between the clozapine plasma level and the percent improvement on the PANSS. Clozapine plasma levels were not significantly different between those who responded to clozapine (n = 19) and those who did not (n = 18) and were not significantly different between patients who smoked (n = 28) and those who did not (n = 9). Receiver operating characteristic (ROC) curve analysis determined the plasma level threshold (above which a better clinical response was obtained) to be 550 ng/mL. Using the total of plasma levels of clozapine and its metabolites did not lead to a better sensitivity and specificity. CONCLUSIONS: Our calculated plasma clozapine threshold was higher than that reported by others, but this may be related to the severity of symptoms of our patient sample. Monitoring plasma rates remains a useful tool, together with clinical evaluation, to establish the clozapine dosage for an optimum benefit-risk ratio.