Extrapyramidal disorders: a possible underlying mechanism

In vivo and in vitro studies have been presented to suggest an interrelationship between drugs used in the management of, or known for their induction of extrapyramidal disorder and certain dehydrogenase enzymes involved in this metabolic pathway of the biogenic amines. This relationship is discussed to advance a tentative hypothesis explaining a possible underlying mechanism and to provide an explanation for the implication of alcohol consumption in worsening of extrapyramidal symptoms during certain pharmacotherapy. The major neutral metabolites of the biogenic amines acted as substrate to or induced rat liver alcohol dehydrogenase (L-ADH) and drugs used in the management of tardive dyskinesia similarly induced L-ADH. This induction of L-ADH could enhance the metabolic biotransformation of the neutral metabolites of the monoamines. Conversely, drugs known to evoke extrapyramidal dyskinesias inhibited rat liver aldehyde dehydrogenase (L-ALDH). This inhibition of ALDH may give rise to toxic condensation products between biogenic amine aldehydes and their precursors which may be implicated in certain dyskinesias. It is proposed that one of the mechanisms underlying the biogenic amine involvement in the pathogenesis of certain extrapyramidal diseases may include a critical balance between their reductive and oxidative routes of metabolism.