Relationship between plasma concentrations of clozapine and norclozapine and therapeutic response in patients with schizophrenia resistant to conventional neuroleptics

Rationale: Monitoring plasma clozapine concentrations may play a useful rol e in the management of patients with schizophrenia, but information on the relationship between the plasma levels of the drug and response is still co ntroversial. Objective: The purpose of this study was to assess the relatio nship between plasma concentrations of clozapine and its weakly active meta bolite norclozapine and clinical response in patients with schizophrenia re sistant to conventional neuroleptics. Methods: Forty-five patients, 35 male s and ten females, aged 19-65 years, were given clozapine at a dosage up to 500 mg/day for 12 weeks. Steady-state plasma concentrations of clozapine a nd norclozapine were measured at week 12 by a specific HPLC assay. Psychopa thological state was assessed at baseline and at week 12 by using the Brief Psychiatric Rating Scale, and patients were considered responders if they showed a greater than 20% reduction in total BPRS score compared with basel ine and a final BPRS score of 35 or less. Results: Mean plasma clozapine co ncentrations were higher in responders (n=18) than in non-responders (n=27) (472+/-220 versus 328+/-128.ng/ml, P<0.01), whereas plasma norclozapine le vels did not differ between the two groups (201+/-104 versus 156+/-64 ng/ml , NS). A significant positive correlation between plasma levels and percent decrease in total BPRS score was found for clozapine (r(s)=0.371, P<0.02), but not for norclozapine (r(s)=0.162, NS). A cutoff value at a clozapine c oncentration of about 350 ng/ml differentiated responders from non-responde rs with a sensitivity of 72% and a specificity of 70%. At a cutoff of 400 n g/ml, sensitivity was 67% and specificity 78%. The incidence of side effect s was twice as high at clozapine concentrations above 350 ng/ml compared wi th lower concentrations (38% versus 17%). Conclusions: These results sugges t that plasma clozapine levels are correlated with clinical effects, althou gh there is considerable variability in the response achieved at any given drug concentration. Because many patients respond well at plasma clozapine concentrations in a low range, aiming initially at plasma clozapine concent rations of 350 ng/ml or greater would require in some patients use of unrea listically high dosages and imply an excessive risk of side effects. Increa sing dosage to achieve plasma levels above 350-400 ng/ml may be especially indicated in patients without side effects who failed to exhibit ameliorati on of psychopathology at standard dosages or at lower drug concentrations.