It is interesting to note that the three classes of psychotropic drugs that were introduced into psychiatry within the span of a few years around 1950 have had greater impact in the treatment of the major psychiatric disorders than have any other forms of treatment in this century. These include the antipsychotic drugs or neuroleptics, the tricyclic antidepressants, and lithium. Of the three groups, neuroleptics are easily the most widely prescribed agents worldwide. They are being used – and sometimes overused and misused – to treat not only schizophrenia and other psychoses but also a host of additional behavioral disorders. Although neuroleptics continue to be indispensable in the management of a majority of schizophrenic patients, as well as some other psychotic individuals, they have not proved to be an unmixed blessing. In terms of frequency, persistence, and overall impact on the quality of wellbeing for patients and caregivers, movement disorders are the most serious adverse side effects of neuroleptics.

The importance of iatrogenic movement disorders in psychiatry can be deduced from the fact that the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), recently published by the American Psychiatric Association, includes a separate category of “medication-induced movement disorders.” This newly delineated group of conditions primarily includes neuroleptic-induced movement disorders such as parkinsonism, dystonia, akathisia, and, especially, tardive dyskinesia. The American Psychiatric Association had previously appointed two task forces on tardive dyskinesia, and those groups published reports in 1980 and 1992.

As discussed elsewhere in this book, several neurotransmitter systems have been implicated in the development of tardive dyskinesia. The most consistently cited abnormality is a disturbance in the dopaminergic–cholinergic balance at the nigrostriatal level (Klawans, 1973; Berger & Dunner, 1985). According to that hypothesis, dopaminergic overactivity can lead to an imbalance between dopamine and acetylcholine in the nigrostriatum and consequently can lead to the development of tardive dyskinesia (Klawans, 1973).

Since the early descriptions of tardive dyskinesia, anticholinergic drugs have been reported to be ineffective for treatment of this condition (Jeste & Wyatt, 1982). Indeed, that lack of efficacy has been considered an important diagnostic aspect of the condition (Jeste & Wyatt, 1982). In the ensuing years, two claims relating to increasing use of antiparkinsonian medications vis-à-vis tardive dyskinesia have been made:

• Antiparkinsonian medications increase the risk for development of tardive dyskinesia (Klawans, 1973).

• Antiparkinsonian medications may aggravate existing tardive dyskinesia (Chouinard, DeMontigny, & Annable, 1979).

To test those claims, we have reviewed the pertinent literature, seeking to discern the importance of prescribing antiparkinsonian medications for patients with tardive dyskinesia and the effects of such drugs on tardive dyskinesia. This review does not deal with animal models.

Do Anticholinergic Drugs Increase the Risk for Tardive Dyskinesia?

Klawans, Goetz, and Perlik (1980) recommended avoidance of anticholinergic drugs, because those medications potentiate anew the development of tardive dyskinesia.

Until recently, it was believed that the basal ganglia had a small role in behavior limited to the control of motor behavior. Research during the past decade, however, suggests that the basal ganglia are involved in a wide range of behaviors, including not only skeletomotor and oculomotor activities but also limbic, affective, and cognitive functions. These changes in our understanding of the organization and function of the basal ganglia have followed important advances deriving from anatomic, pharmacologic, and physiologic studies.

Structures of the Basal Ganglia

The basal ganglia include the caudate, putamen, and ventral striatum, as well as the globus pallidus, subthalamic nucleus, and substantia nigra. Together, the caudate, putamen, and ventral striatum form the neostriatum; they also constitute the input stage of the basal ganglia. The globus pallidus, which is divided into internal (GPi) and external (GPe) segments, lies medial to the putamen. The substantia nigra has two components: the pars compacta (SNc) and the pars reticulata (SNr). The SNr and the GPi are cytologically similar and often are considered as a single structure. Both the SNr and GPi are recognized as major sources of the basal-ganglia output (Nauta, 1979).

Input to the Basal Ganglia

The neostriatum is the largest and most important receptive region of the basal ganglia. Inputs to the neostriatum originate mainly in the cortex, thalamus, and SNc, with less prominent inputs arising in the globus pallidus, subthalamic nucleus (STN), dorsal raphe, and pedunculopontine tegmental nucleus.