CLINICAL COURSE AND CELLULAR PATHOLOGY OF TARDIVE DYSKINESIA

Tardive dyskinesia (TD) is an iatrogenic human hyperkinetic movement disorder associated with chronic antipsychotic drug treatment. The cause of the syndrome, namely, chronic dopamine-receptor blockade, is specifically known and is straightforward to model. Thus, disease pathophysiol-ogy has been approached with surrogate preparations. Tra-ditionally, factors mediating TD have been sought in striatal dopaminergic transmission. However, several incompatibil-ities have developed between the characteristics of the dopa-minergic model and the presentation of the disorder (10). -aminobutyric acid (GABA)–ergic transmission within the basal ganglia has also been targeted as the putative patho-physiologic agent in TD. Here, although biochemical char-acteristics between the model and the disease have appeared compatible, therapeutic implications have not been fully met, possibly because of inadequate pharmacologic tools (10). Research has suggested that both these transmitter altera-tions, dopaminergic and GABAergic, may reflect an action of antipsychotic drugs on neuronal activity within the basal ganglia thalamocortical motor circuit. Clinically, antipsy-chotic drug action overall tends to normalize mental status in psychosis and produces symptom remission in diverse psychotic illnesses, including schizophrenia, bipolar disease, and dementia (8); parkinsonism characteristically occurs with traditional antipsychotics as a major side effect (42). On a cellular basis, gradual alterations produced by these drugs over time, within selected subcortical brain regions and at selected synapses of this circuit, likely result in TD. The mechanism of all these clinical actions is thought to begin with dopamine-receptor blockade, but thereafter it is critically mediated by altered neuronal activity (includin