title: Neuroleptic medications inhibit complex I of the electron transport chain.
abstract: Neuroleptic medications are prescribed to millions of patients, but their use is limited by potentially irreversible extrapyramidal side effects. Haloperidol shows striking structural similarities to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which produces parkinsonism apparently through inhibition of NADH:ubiquinone oxidoreductase (complex I) of the mitochondrial electron transport chain. We now report that haloperidol, chlorpromazine, and thiothixene inhibit complex I in vitro in rat brain mitochondria. Clozapine, an atypical antipsychotic reported to have little or no extrapyramidal toxicity, also inhibits complex I, but at a significantly higher concentration. Neuroleptic treated patients have significant depression of platelet complex I activity similar to that seen in idiopathic Parkinson's disease. Complex I inhibition may be associated with the extrapyramidal side effects of these drugs.
authors.affiliation: Department of Neurology, University of Colorado School of Medicine, Denver.
authors.forename: C
authors.initials: C
authors.lastname: Burkhardt
authors.forename: J P
authors.initials: JP
authors.lastname: Kelly
authors.forename: Y H
authors.initials: YH
authors.lastname: Lim
authors.forename: C M
authors.initials: CM
authors.lastname: Filley
authors.forename: W D
authors.initials: WD
authors.lastname: Parker
mesh_terms: D000328:Adult; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000201:enzymology*; D002746:Chlorpromazine / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport / Q000187:drug effects; D014450:Electron Transport Complex III / Q000378:metabolism; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors*; D051381:Rats; D013888:Thiothixene / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D013888:Thiothixene; D016660:NAD(P)H Dehydrogenase (Quinone); D014450:Electron Transport Complex III; D003024:Clozapine; D006220:Haloperidol; D002746:Chlorpromazine