NEUROLEPTIC MEDICATIONS INHIBIT COMPLEX-I OF THE ELECTRON-TRANSPORT CHAIN

Neuroleptic medications are prescribed to millions of patients, but th eir use is limited by potentially irreversible extrapyrafnidal side ef fects. Haloperidol shows striking structural similarities to the neuro toxin 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine, which produces pa rkinsonism apparently through inhibition of NADH:ubiquinone oxidoreduc tase (complex I) of the mitochondrial electron transport chain. We now report that haloperidol, chlorpromazine, and thiothixine inhibit comp lex I in vitro in rat brain mitochondria. Clozapine, an atypical antip sychotic reported to have little or no extrapyramidal toxicity, also i nhibits complex I, but at a significantly higher concentration. Neurol eptic treated patients have significant depression of platelet complex I activity similar to that seen in idiopathic Parkinson's disease. Co mplex I inhibition may be associated with the extrapyratnidal side eff ects of these drugs.