Pathophysiological mechanisms underlying tardive dyskinesia

Abstract

Movement abnormalities in neuroleptic-treated, psychiatric patients are classified as (a) initial syndromes, including dystonia, parkinsonism, and hyperkinetic abnormalities such as initial dyskinesia (ID) and akathisia, all of which are related to the neuroleptic dose and can be considered as overdose phenomena; (b) tardive syndromes, mainly the classic tardive dyskinesia (TD) syndrome, more seldom tardive akathisia and tardive dystonia, which may all develop or aggravate after withdrawal of neuroleptic treatment; and (c) age-related, spontaneous dyskinesia, akathisia, and dystonia, and schizophrenia-related, hyperkinetic, often stereotyped, movements and restlessness. ID and TD can occur simultaneously, and may depend, at least partially, on identical mechanisms. The pathophysiology of TD is still not clear, and the traditional dopamine (DA) hypersensitivity model seems inadequate. Animal experiments suggest that blockade of some DA receptors in the brain (e.g., in ventromedian striatum) may counteract hyperkinesia and produce parkinsonism, while a concomitant blockade of other similar receptors in other brain regions (e.g., in anterodorsal striatum) may aggravate movements. This offers an explanation for the concomitant occurrence of parkinsonism and hyperkinetic movement abnormalities (ID and akathisia) relatively early in a neuroleptic treatment, and may also contribute to the understanding of the pathophysiology of TD. It is concluded that pathophysiologically TD is a heterogeneous syndrome depending on a subtle balance between several neurotransmitters in the brain, including DA receptor blockade and hypersensitivity of DA and GABA receptors.