Ever since the syndrome of tardive dyskinesia was introduced into the literature more than 30 years ago, older age has been the only consistent risk factor confirmed by most authors (Smith & Baldessarini, 1980). However, several other factors, detailed elsewhere in this volume, have now been implicated.

Gender has been suggested to be an important factor in the development of tardive dyskinesia, and whereas some authors have concluded that women have a higher prevalence of tardive dyskinesia than do men, others have found no gender difference (Jeste & Wyatt, 1981). Elsewhere, we have reviewed, in detail, the studies that discussed and compared the prevalences of tardive dyskinesia for the two genders (Yassa & Jeste, 1992). Only articles published in English or French (or in other languages, if a detailed summary was provided in English or French) were reviewed. We found 93 English or French prevalence studies published prior to the end of 1989. To be included in our review, a study had to meet the following criteria:

• report on 50 patients or more. The study by Crane and Smeets (1974), a study of 39 patients, was therefore excluded.

• include both genders in its sample. We excluded three women-only studies (Uhrbrand & Faurbye, 1960; Pryce & Edwards, 1966; Edwards, 1970) and two studies of men only (Dynes, 1970; Goldberg et al., 1982).

• include the numbers of men and women affected by tardive dyskinesia. Eleven studies were excluded (Paulson, 1968; Yagi et al., 1976; Bell & Smith, 1978; Alexopoulos, 1979; Gardos et…

Although tardive dyskinesia is defined as a movement disorder that develops after 3 months of drug treatment (Jeste & Wyatt, 1982), the fact that some patients develop this side effect earlier means that they may have a greater predisposition to the condition. Various authors have speculated as to the different mechanisms for this vulnerability; in this chapter we shall look at genetic factors and smoking.

Genetic Factors

Recently, hereditary susceptibility to tardive dyskinesia has been the subject of much discussion. Brandon, McClelland, and Protheroe (1971), for example, have suggested that blue-eyed men are more prone to develop tardive dyskinesia than brown-eyed men, although Gardos, Sokol, and Coel (1976) could not confirm that finding, nor could it be confirmed in women. In a study of six pairs of twin patients (four monozygotic and two dizygotic) treated with high-dosage neuroleptics, Jacob Brody found that the specific type of neurological side effect was not determined genetically, inasmuch as the identical twins showed distinctly different reaction patterns (Jeste & Wyatt, 1982). Moreover, Jeste, Phelps, and Wyatt (1982), in a study of 50-year-old female schizophrenic quadruplets on neuroleptic treatment, found that only one of the four had definite tardive dyskinesia. Weinhold, Wegner, and Kane (1981), however, reported the presence of tardive dyskinesia in two schizophrenic brothers treated with neuroleptics. Yassa and Ananth (1981) found that of eight pairs of family members, two were concordant for tardive dyskinesia, and six for the absence of tardive dyskinesia.

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.

In February 1952, Laborit, Huguenard, and Alluaume published an article concerning the anesthetic properties of a new medication, chlorpromazine, mentioning therein the induction of a “psychic disinterest.” That same year, Delay, Deniker, and Harl (1952a,b), Delay et al. (1952c), and Hamon, Paraire, and Velluz (1952) first reported the effects of chlorpromazine in patients with various psychiatric conditions. A few months later, the effectiveness of the first neuroleptic was considered to have been demonstrated.

Initial Descriptions

The first description of an extrapyramidal syndrome during the course of neuroleptic treatment dates back to the 1953 Swiss symposium on chlorpromazine. The next year, Labhardt (1954) and Staehelin (1954) reported certain extrapyramidal complications caused by neuroleptics. It was Steck (1954, 1956), however, who vividly described such symptoms in a convincing manner. (Not until 1961 did Lambert and Broussolle note that it was not surprising that the Swiss authors had reported good results from their use of neuroleptics, given the high dosages used, which of course entailed a greater likelihood of developing extrapyramidal side effects.) Steck (1954) stated that “since the summer of 1953, we were impressed by the appearance of a well-developed parkinsonian syndrome in a chronic, cyclically agitated patient who also manifested schizophrenic symptomatology. This patient presented the well-known picture of post-encephalitic parkinsonism with psychomotor rigidity, tremors, facial seborrhea, marked salivation and akathisia.” Steck (1954) also reported the presence of extrapyramidal symptoms in 78 of 232 (34%) women and 33 of 77 (43%) men treated with neuroleptics.