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SECOiW IhWZNATlONAL CONGRESS OF MOVEMEIVT DISOmERS

Risk Factors for the Tardive Dyskinesias

Robert E. Burke, MD

Department of Neurology, Columbia University

We define the tardive dyskinesias (TD) as those persistent movement disorders which a re due to treatment with anti-psychotics or other drugs which block do amine receptors. The most widely recognized form of TD is the cksically described oral-buccal-lingual dyskinesia (OBLD). In addition, there is now a consensus that important variant forms exist, including tardive dystonia and tardive akathisia. Other less common, variant forms such as tardive myoclonus and tics probably exist as well. Although TD has been recognized for over 30 years, little is known of its pathogenesis. In the absence of fundamental knowledge about pathogenesis, an understanding of risk factors for TD may help guide therapeutic decisions such that the likelihood of developing this disorder can be minimized. In addition, a knowledge of risk factors may help provide clues to the pathogenesis.

The most reliable information about risk factors for TD comes from epidemiologic studies done in representative patient populations, either on a prospective or a carefully case-controlled retrospective basis. Unfortunately, such studies are few in number, and we are often forced to rely on retrospective analyses done in selected patient groups, with many potential sources of bias. This situation is especially true in relation to the T D variants, where no prospective studies have been done.

Increased a e is an important risk factor for the classic OBLD form of TD. In a review of nine studies, including more than 4,000 patients, Smith and Baldessarini (Arch Gen Psych, 1980) found a striking correlation (r = 0.99) between the prevalence of OBLD and age between the ranges of <40 to 70 ears They also noted strong relationship between increased age [up to 60 years) and the severity of OBLD assessed with the AIMS scale. In addition, they observed a striking inverse relationship (r = -.98) between age and the degree of improvement on follow-up. This latter finding raises the issue of whether the increased prevalence of OBLD among older individuals may in part be due to a longer persistence of the disorder, rather than, or in addition to, an increased incidence.

There is little data available on the relationship between age and the prevalence of tardive dvstonia. Yassa et a1 (Acta Psychiatr Scdnd, 1986) reported a prevalence of 5.9% in the <50 grou and 0.4% in the >50 group. This data is compatible witg the observations of several investi ators that the mean age of onset for tardive dystonia is considera%ly less than that of OBLD. Thus, there appears to be an inverse relationship between age and the occurrence of tardive dystonia, but further prospective study in larger numbers of patients is required. We have also observed an inverse relationship between a e and the severity of tardive dystonia; patients with generalizeftardive dystonia have an earlier age of onset than those with focal dystonia (Kan et al, 1986). However, as for OBLD, we have noted a trenf for younger

atients to be more likely to undergo spontaneous remission following neuroleptic withdrawal.

There has been no study of the relationship between age and either the point prevalence or incidence o f e e gkathisia. In our experience, tardive akathisia tends to be closely associated with OBLD (90% of akathitics had OBLD), and tends to have a later age of onset (58.4 years) (Burke et al, Mov Dis, 1989). However, our patient group is a selected one; in a more representative general psychiatric population, Barnes and Braude (Arch Gen Psych, 1985) noted a mean age of 44 among chronic akathitics. As for OBLD and tardive dystonia, we have noted an inverse relationship between age of onset of akathisia, and the likelihood of being in remission at follow-up.

While many early reports claimed that female a r was more likely to be associated with OBLD, subsequent investigation by

Smith and co-workers (Am J Psych, 1979) clearly showed that fema1e:male prevalence ratios are dependent on the criteria used to diagnose OBLD. It is only when more stringent criteria are used, and therefore more severe cases are selected, that an increased female prevalence is observed. For tardive dystonia, two studies of the revalence in unselected psychiatric populations (Friedman et al, !NNP, 1987, Yassa et al, 1986) have observed more men affected than women. We have noted that men with tardive dystonia also appear to have an earlier age of onset than women. In a group of neurologic referrals with tardive akathisia, we noted a 2:l fema1e:male ratio. However, in unselected psychiatric patients, Barnes and Braude noted about an equal number of men and women with chronic akathisia (1985).

Amon identifiable risk factors for TD, neurole tic reatmen variabfes are those which are most subject to tge 6ysician’f control, and thus they are the most deserving of study to attempt to identify treatment regimens which may lessen the risk of TD. However, little is known. With the exception of the atypical anti- psychotic clozapine, all of the other available anti-psychotics of various classes have been re orted to cause one form of TD or another. There is no availahe prospective, controlled data to indicate that one dru (or class of drugs) is more, or less, likely to induce TD. Data t o m the prospective studies of Kane and colleagues do suggest an important effect of the duration of exposure to neuroleptics on the prevalence and ro nosis of TD (Kane et al, Psychopharm Bulletin, 1984, 19867. t hey clearly showed that, while the incidence of TD remained constant during progressive years of neurole tic exposure, cumulative incidence and prevalence increased. &e relationship between duration of treatment and prevalence is more striking in older patient populations. These investigators have also shown that patients who develop TD have a better prognosis when they have been exposed to drugs for a shorter period of time prior to its onset. Prognosis is also better for those patients who have been maintained on neuroleptics for less time and at lower doses following its onset. Thus, there is a clear rational basis for minimizing exposure to these drugs after TD develops.

Co-administration of other drugs is another important treatment variable. Kane and co-workers have reported that, in their prospective analysis, concomitant administration of lithium appears to diminish the risk of TD. There is no evidence that anticholinergic drugs increase the risk of TD, as roposed in earlier literature. This impression may have been gased on an actual association, noted by Kane and colleagues, between neuroleptic-induced parkinsonism and the occurrence of TD.

Although patients with any Drimarv svchiatric diaenosis are at risk for TD, and non-psychiatric patifnts as well, there is recent evidence that patients with affective illness may be especially vulnerable. Kane and co-workers, in their prospective study of more than 800 sychiatric patients, showed an increased risk even when controlleBfor gender and age. In view of this finding, it is of interest that we noted a particularly high proportion (47%) of patients with a history of depression in our group of 52 patients with tardive akathisia.

In conclusion, while much has been learned about risk factors for the OBLD form of TD since its recognition over 30 years ago, much remains to be learned about these factors for the major variant forms of TD. In particular, there is a need for prospective studies, and case-controlled retrospective and cross-sectional studies.

Supported by NINDS R29 NS26836, PDF and UCP.

Movement Disorders, Vol. 7, Supplement 1 (1992)