Mechanism of peripheral noradrenergic stimulation by clozapine

Igor Elman, David S. Goldstein, Graeme Eisenhofer, Joan Folio, Anil K. Malhotra, Caleb M. Adler, David Pickar, Alan Breier

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


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 (3H-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 more than three times higher in clozapine-treated patients; whereas NE clearance did not differ among the groups. Production of 3H-dihydroxyphenylglycol (3H-DHPG), a purely intraneuronal metabolite of 3H-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. Copyright (C) 1999 American College of Neuropsychopharmacology.

Original languageEnglish (US)
Pages (from-to)29-34
Number of pages6
Issue number1
StatePublished - Jan 1999
Externally publishedYes


  • Catecholamine
  • Clozapine
  • Fluphenazine
  • Norepinephrine
  • Schizophrenia
  • Spillover

ASJC Scopus subject areas

  • Pharmacology


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