Pathophysiology and drug therapy of tardive dyskinesia: current concepts and future perspectives

Nearly 1% of the world population suffers from schizophrenia, and neuroleptics are the major class of drugs used to treat this disorder. Neuroleptics are associated with wide variety of extrapyramidal side effects, such as akathesia, dystonia, neuroleptic malignant syndrome, Parkinson-ism and tardive dyskinesia. Despite the awareness that neuroleptics could cause extrapyramidal side effects, these drugs remain the most effective means of treating schizophrenia and Tourette's syndrome, as well as for the management of behavioral disorders in developmentally disabled individuals. Tardive dyskinesia is a complex hyperkinetic syndrome consisting of choriform, athetoid or rhythmically abnormal involuntary movements. Estimates of the prevalence rate of tardive dyskinesia in patients receiving neuroleptics range from 0.5-70%, with an average prevalence rate of 24%. Despite much research, the pathogenesis of tardive dyskinesia remains elusive. So far, various neurochemical hypotheses have been proposed for the development of tardive dyskinesia. These include dopaminergic hypersensitivity, disturbed balance between dopamine and cholinergic systems, dysfunctions of striatonigral GABAergic neurons and excitotoxicity. Similarly, different suppressive agents have been tried with limited success. Recently, the role of oxidative stress and structural abnormality in the pathophysiology of tardive dyskinesia has gained much impetus. Induction of free radicals by neuroleptic drugs leading to the oxidative stress and resultant structural abnormality could be the key factor in the pathogenesis of tardive dyskinesia. This hypothesis has been supported by numerous reports that chronic neuroleptic treatment increases free radical production and causes structural damage. More recently, the genetic vulnerability for the predisposition for the development of tardive dyskinesia, i.e., pharmacogenetic aspect of tardive dyskinesia, is also gaining impetus as a research area, and is discussed in detail in this article.