Recent research supports the idea that tardive dyskinesia is an etiologically heterogeneous disorder, with multiple neurochemical abnormalities contributing to its pathophysiology. A neurotransmitter imbalance has been the most frequently suggested pathophysiological mechanism, referring mainly to dopaminergic hyperactivity, GABAergic deficiency, or serotonergic imbalance (Ebadi & Hama, 1988).

The dopamine-supersensitivity hypothesis has been shown to be inadequate as a unitary explanation (Fibiger & Lloyd, 1984; Stoessl, Dourish, & Iversen, 1989). Some current proposals suggest that dopamine-receptor supersensitization resulting from chronic blockade by neuroleptics may be the first step in the pathogenesis of tardive dyskinesia, followed by necessary processes (not yet identified) in other neurochemical systems (Cassady et al., 1992).

Involvement of the GABA system in the development of persistent dyskinesia accounts for some of the evidence unexplained by the hypothesis of dopamine-receptor supersensitivity (Scheel-Krüger, 1986; Thaker et al., 1989b). Recent studies have supported the idea of GABA neuronal hypofunction in the substantia nigra pars reticulata (Monteleone et al., 1988; Thaker et al., 1989b).

There is also evidence for a serotonergic abnormality in patients with tardive dyskinesia. Much of our information suggests an inhibitory role for serotonin (5-HT) on nigrostriatal dopaminergic functioning (Sandyk, 1989). It seems that, in contrast to classic neuroleptics, clozapine does not induce tardive dyskinesia, the reason being that it is a potent 5-HT2 antagonist, the role of which is to release tonic inhibition of dopaminergic transmission and prevent depolarization inactivation at the presynaptic dopaminergic neuron, as well as to prevent denervation supersensitivity at the postsynaptic dopaminergic neuron (Coward, 1992).