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Serum concentrations of clozapine, norclozapine, and clozapine-N-oxide were assayed in psychotic patients treated with clozapine alone (N = 17), clozapine with fluoxetine added (N = 6), or clozapine with valproic acid added (N = 11). Subjects were matched for age and other treatments, and concentrations were corrected for daily dose of clozapine (milligrams per kilogram of body weight). With valproic acid, there was a minor increase in total clozapine metabolites, which was even less with dose correction. Fluoxetine increased all clozapine analytes, in some cases to twice the levels in the subjects given only clozapine.

In vivo 19fluorine nuclear magnetic resonance spectroscopy was used to measure the brain concentration of fluoxetine and norfluoxetine in five patients with obsessive-compulsive disorder and three with major depression. The mean brain:plasma ratio of the parent drug plus the metabolite was significantly elevated to 2.6 (SD = 1.0) (95% confidence interval = 1.9-3.3). This accumulation may have implications for understanding both the therapeutic and the toxic effects of fluoxetine.