Neuroleptic medications inhibit complex I of the electron transport chain

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.