Mechanism of peripheral noradrenergic stimulation by clozapine

Elevated plasma norepinephrine (NE) levels is a relatively consistent clinical effect of clozapine. Plasma NE levels reflect an interplay of release, reuptake, metabolism, and excretion. To explore the mechanism of clozapine-induced plasma NE elevation, we measured arterial plasma levels of NE and other catechols during intravenous infusion of tritium-labeled NE (H-3-NE) in schizophrenic patients treated with clozapine, fluphenazine, or placebo. Clozapine treated patients had markedly higher levels of NE than did the patients treated with fluphenazine or placebo. NE spillover averaged move than three times higher in clozapine-treated patients; whereas NE clearance did not differ among the groups. Production of H-3-dihydroxyphenylglycol (H-3-DHPG), a purely intraneuronal metabolite of H-3-NE in clozapine-treated patients was normal, indicating that clozapine did not affect neuronal uptake of NE. Because plasma levels of DHPG and dihydroxyphenylacetic acid (DOPAC), deaminated metabolites of catecholamines, in clozapine-treated patients were normal, clozapine also did not seem to inhibit intraneuronal monoamine oxidase (MAO). High plasma NE levels in clozapine-treated patients, therefore, resulted from increased NE spillover rather than decreased reuptake, metabolism, or clearance. [Neuropsychopharmacology 20:29-34, 1999] Published by Elsevier Science Inc.