Neuroleptic medications inhibit complex I of the electron transport chain

Ann Neurol. 1993 May;33(5):512-7. doi: 10.1002/ana.410330516.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Animals
  • Antipsychotic Agents / pharmacology*
  • Antipsychotic Agents / therapeutic use
  • Blood Platelets / drug effects
  • Blood Platelets / metabolism*
  • Brain / enzymology*
  • Chlorpromazine / pharmacology
  • Clozapine / pharmacology
  • Dose-Response Relationship, Drug
  • Electron Transport / drug effects
  • Electron Transport Complex III / metabolism
  • Female
  • Haloperidol / pharmacology
  • Humans
  • Kinetics
  • Male
  • Mitochondria / drug effects
  • Mitochondria / enzymology*
  • Mitochondria / metabolism
  • NAD(P)H Dehydrogenase (Quinone) / antagonists & inhibitors*
  • Rats
  • Thiothixene / pharmacology


  • Antipsychotic Agents
  • Thiothixene
  • NAD(P)H Dehydrogenase (Quinone)
  • Electron Transport Complex III
  • Clozapine
  • Haloperidol
  • Chlorpromazine