The purpose of the present study was to assess the relationship between plasma monoamine levels and changes in psychopathology in a sample of children and adolescents with schizophrenia (DSM-III-R criteria) during conventional neuroleptic therapy and during short-term treatment with clozapine. After failing on conventional neuroleptics in open-labeled clinical trials lasting a mean of 1.6 years, 15 inpatients (aged 11-20 years) received clozapine. Weekly ratings of psychopathological symptoms using standard rating scales were performed in parallel to blood samplings for measurements of biogenic amines and serum levels of clozapine. These measures were obtained for 6 weeks during conventional neuroleptic treatment and for 6 weeks during the open-label clozapine trial. Serum levels of serotonin and plasma norepinephrine levels were significantly higher during treatment with clozapine than during pretreatment with typical neuroleptics. A comparison of plasma epinephrine levels in responders (n = 7) and non-responders (n = 8) to clozapine revealed that response to clozapine can be predicted by epinephrine levels prior to initiation of treatment with clozapine (responders ranging from 32.2-90.3 pg/ml; non-responders ranging from 92.5-473.5 pg/ml). Additionally, subjects who responded to clozapine showed increased mean plasma concentrations of methoxyhydroxyphenylglycol (MHPG) and epinephrine during treatment with this drug in comparison to the levels measured during pretreatment with typical neuroleptic medication. In conclusion, our results demonstrate that plasma epinephrine levels prior to initiation of clozapine therapy predict response to this atypical neuroleptic.