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 (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.
Elman
I
I
Experimental Therapeutics Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA.
Goldstein
D S
DS
Eisenhofer
G
G
Folio
J
J
Malhotra
A K
AK
Adler
C M
CM
Pickar
D
D
Breier
A
A
D000328:Adult; D000704:Analysis of Variance; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002396:Catechols / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology* / Q000627:therapeutic use; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008995:Monoamine Oxidase / Q000378:metabolism; D009638:Norepinephrine / Q000097:blood* / Q000378:metabolism; D012559:Schizophrenia / Q000097:blood / Q000188:drug therapy*; D013997:Time Factors; D014316:Tritium
D014150:Antipsychotic Agents; D002396:Catechols; D014316:Tritium; D004295:Dihydroxyphenylalanine; D008995:Monoamine Oxidase; D003024:Clozapine; C034221:catechol; D009638:Norepinephrine