A 10-YEAR FOLLOW-UP STUDY OF TARDIVE DYSKINESIA-WITH SPECIAL REFERENCE TO THE INFLUENCE OF NEUROLEPTIC ADMINISTRATION ON THE LONG-TERM PROGNOSIS

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1 Keio Journal of Medicine 34: , 1985 ORIGINAL ARTICLES A 10-YEAR FOLLOW-UP STUDY OF TARDIVE DYSKINESIA-WITH SPECIAL REFERENCE TO THE INFLUENCE OF NEUROLEPTIC ADMINISTRATION ON THE LONG-TERM PROGNOSIS GOHEI YAGI and HITOSHI ITOH Department of Neuropsychiatry, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160, Japan (Received for publication October 14, 1985) ABSTRACT Although it is believed that tardive dyskinesia (TD) is reversible in its early stages, little is known about the long-term effects of the subsequent administration of neuroleptics (NLP). Twenty cases of TD (four men and 16 women, aged 35 to 84, mean 52) who had first been diagnosed between 1968 and 1976, were followed up for an average of 10 years. By 1983, in nine cases (including one patient who died), TD had disappeared; it persisted in six cases (one patient died), and recurred following remission in five (two patients died). After the onset of TD, the administration of NLP was discontinued in eight cases, decreased in six, maintained at the same level in four and increased in two. In most patients whose age at onset was below 60, TD was reversible regardless of the NLP adminis tration pattern. On the other hand, TD persisted in most cases in which the onset age was 60 or more, despite the large numbers in which NLP was discon tinued. Nevertheless, recurrence of TD was occasionally observed among the reversible cases, and, in two of these, the condition became persistent. It is, therefore, speculated that the long-term outcome of TD is determined mainly by the age at onset. However, if the continued administration of NLP is combined with aging, reversible TD observed among young patients may recur or become persistent. Key words: Tardive dyskinesia, Long-term prognosis, Reversible and persistent, Age at onset, Neuroleptic therapy 211

2 212 Gohei Yagi and Hitoshi Itoh INTRODUCTION The pessimistic notion that tardive dyskinesia (TD) is irreversible was contradicted by reports of reversible cases in the late 1970s,1,2,3 and the theory that this condition is usually reversible in its early stages has been gaining in popularity. It was also be lieved that, difficult as it might be to prevent patients on neuroleptics (NLP) from developing TD, it was nevertheless possible to avoid the irreversible outcome of this condition. Early detection and pharmacological management of TD was, therefore, thought very important. However, little evidence has been accumulated either to prove or to refute this optimistic view. The present study examined the relationship between the clinical course of TD with a mean duration of 10 years and the method of NLP administration, in order to clarify how the schedule of NLP treatment affected the outcome of TD. SUBJECTS AND METHODS Of the 28 patients whose TD had been first diagnosed between 1968 and 1976, 20 were traced in September The remaining eight (five men and three women) could not be located after their discharge. The 20 patients consisted of four men and 16 women, their age at onset of TD ranging from 21 to 73 years old (average 43). There were 17 cases of schizophrenia, two of manic depressive psychosis and one of chronic alcohol addiction. Symptoms of TD were assessed by using AIMS4 and the results were then compared with the data of the same cases collected and reported previously (1978).3, The course and present manifestation of TD in each patient was classified as a) the reversible type (disappearance of TD), b) the recurrent type (remission followed by reappearance of at least minimal TD) and c) the persistent type (continuation of at least mild TD). Once TD was recognized, the dose of NLP was reduced or the medication was discontinued insofar as this was not detrimental to the patient's psychiatric condition. Treatment with NLP was classified under four headings: the drug-free type, increased type, decreased type and unchanged type. If the total drug-free period was 25% or more of the whole follow-up period, the NLP administration pattern was categorized as the drug-free type. The average daily NLP dose (including long-acting NLP) was calculated by our methods as an equivalent daily dose of ch!orpromazine expressed as the number of 25 mg chlorpromazine tablets per day. The increased type was defined as treatment where the average daily dose after the onset of TD was at least 25% more than that before it. The decreased type was defined as treatment where the average daily dose after the onset of TD was at least 25% less than that before it. Otherwise the NLP administration pattern was categorized as the unchanged type. The statistical significance was defined as p value of less than 5% by using Fisher's exact probability test.

3 Ten-year Follow-up Study of Tardive Dyskinesia 213 RESULTS The patients' demographic background and details of the deceased cases are tabu lated in Tables 1 and 2. In September 1983, nine patients (45%) had lost TD symptoms, six (30%) continued to manifest them, and five (25%) regained them (with respect to the deceased, their final records were used). These patients were categorized into the reversible, persistent and recurrent groups, respectively (Table 3), and compared on several issues. 1. Sex, age and complications There was no difference between the sex distribution in the reversible and persistent groups (Table 4). While all the patients in the reversible group were less than 60, 83% of those in the persistent group were 60 or more. The age at onset of TD was below 60 for all patients in the reversible group, but 60 or more for the majority of those in the persistent group (Table 5). In the reversible group, the frequency of complications was 22%, 33% and 44% before the onset of TD, after the occurrence of TD and during Background Table 1 of the patients Background Table 2 of the deceased

4 214 Gohei Yagi and Hitoshi Itoh Table 3 Classification of clinical course (N+) number of the deceased. * In respect of the deceased, their final records are used. Table 4 Clinical course and sex Table 5 Clinical course and age of onset

5 Ten-year Follow-up Study of Tardive Dyskinesia 215 the entire observation period, respectively. The corresponding figures for those in the persistent group were 67%, 69% and 83%. No statistically significant difference emerged between the two groups. Each group had one deceased case. 2. Administration of neuroleptics before the onset of TD NLP treatment had been given for less than five years to all the patients in the reversible group, as opposed to more than five years for 50% of the patients in the persistent group. This difference reached a statistical significance (Table 6). The proportion of those who had consumed a total of 10,000 tablets or more was higher in the persistent group (p=0.0440). Since, however, there was no difference in the average daily dose given to the two groups, it was speculated that the difference in the total number of tablets consumed reflected only the difference between the respec tive durations of NLP treatment. Clinical course and total administration Table 6 period of NLP before the onset of TD 3. Administration of neuroleptics after the onset of TD The number of temporary discontinuations of NLP therapy was the same in the reversible and persistent groups. However, the total drug-free period was less than 30% of the duration of treatment for the majority in the latter category (p=0.0470). The daily average NLP dose was the same in both groups. However, the reduction of the dose by 70% or more was more frequent in the persistent group (67%) than in the reversible group (p=0.0110); the proportion of those who had consumed a total of 5,000 tablets or less was higher in the persistent group (p=0.0470). When the drug-tree type of NLP administration was redefined as treatment where the total drug-free period was 25% or more of the total follow-up period and where the NLP dose had been reduced by the rate of 25% or more, patients who had received treatment of drug-free type represented 83% of the persistent group (Table 7).

6 216 Gohei Yagi and Hitoshi Itoh Table 7 Clinical course and NLP administration schedule after the onset of TD DISCUSSION 1. Long-term prognosis of tardive dyskinesia Few investigators have reported the course of TD followed-up for more than one or two years. Ten out of 19 cases (53%) of our two-year follow-up,7 12 out of 21 cases (57%) of Jeste et al's 13-month follow-ups and 18 out of 36 cases (50%) of Seeman's two-year follow-up9 were reversible. The present study has demonstrated that recovery was observed in nearly half of the TD cases with a mean duration of 10 years. It should, however, be noted that 81% of the cases initially recognized as reversible showed relapse later, with 31% of them still manifesting minor abnormal movements. Moreover, two patients (13%) in the recurrent group developed the persistent type of TD. In three out of four cases initially recognized as belonging to the irreversible group, TD became worse in the five years prior to the present examination. Thus, the course of TD over as long a follow-up as 10 years does not seem identical to its course in the intial few years. Factors common to reversible TD are a relatively young age (at onset), mild symp toms and short duration of NLP treatment, raising a question as to whether it differs from classical irreversible TD (which occurs in old age, after a long duration of NLP treatment and which has severe symptoms). While Jeste et al.8 regarded the two types as distinct clinical entities, we, like Gardos,10 consider reversible TD an early or mild type of irreversible TD, since reversible cases tend to relapse and to become persistent. Chouinard11 has reported cases in which initially reversible TD relaped and became persistent. Although the findings for the recurrent group seemed similar to those of the reversible group, there were many items in which the recurrent and persistent groups did not differ significantly. The latter findings suggest that the recurrent group was on the whole closer to the persistent group. The recurrent type of TD will be a focus of TD studies in the future. It is worth noting that among the 20 cases followed up, four (20%) died, and

7 Ten-year Follow-up Study of Tardive Dyskinesia 217 that three of these four patients were less than 50 years old. Mehta et al.12 reported that the life span of patients with TD was shorter than that of a control group and that the mortality rate of TD patients was correlated with the severity of the condition. We found no direct causative relationship between TD and death, but the mortality rate of TD patients under 50 years of age was higher among those whose NLP treatment, after the occurrence of TD, had been either increased or maintained at the same level (p=0.0549). This finding suggests that the long-term administration of large doses of NLP carries a risk factor. 2. Factors related to prognosis 1) Age at onset and drug treatment before onset of TD Reviewing past epidemiological studies on TD, Smith et al.", found a strong nega tive correlation between age (30 to 80 years) and the remission rate of TD, i.e., the remission rate of TD in patients aged less than 60 was three times as high as that in patients 60 or older. Smith et al.13 speculated that the brain's sensitivity to NLP in creases with age. Seeman9 demonstrated that 47% of those aged 40 or less recovered from TD, while only 20% of those aged over 40 recovered. She hypothesized that TD was reversible in its early stage as a result of compensatory mechanisms in the dopaminergic, cholinergic and GABAergic systems, and that these mechanisms became less potent with age. The present finding that the persistent type of TD was overrepre sented among patients in whom the onset occurred at 60 or over strongly supports the notion that aging is an important factor in determining the reversibility as well as the prevalence and severity of TD. It has been considered that long-term treatment with high doses of NLP and poly pharmacy including antiparkinsonian drugs before the onset of TD are risk factors in the occurrence, severity and irreversibility of TD, though no conclusion has been reached as to the causal relationship between TD and the types, doses and durations of NLP, and the presence of combined antiparkinsonian drugs. Jeste et al8 found that long-term (mean 10.8 years) administration of NLP was a factor in the irreversibility of TD. Seeman9 reported a high remission rate of TD among those with NLP treatment lasting 10 years or less. Our study has demonstrated that, while the doses of NLP and combined antiparkinsonian drugs had been the same, the duration of NLP treatment had differed significantly between patients in the reversible and the persistent groups. 2) Drug treatment after the onset of TD Past follow-up studies on TD showed that it was very difficult to discontinue NLP treatment for a long time because this occasionally caused relapse or deterioration of psychotic symptoms. Jeste et at.8 who automatically discontinued NLP therapy in all their TD patients aged 50 or more, found that three months was the limit for a drug free period. Seeman,9 who adjusted the NLP dose to the clinical picture of each TD patient, observed that nearly half of the patients were given no drug-free days. In the

8 218 Gohei Yagi and Hitoshi Itoh present study, the course of NLP treatment reflected the severity of the psychopathology of each case. The drug-free type was overrepresented in those patients who developed TD at the age of 60 or more, because the mental state of the elderly schizophrenics was relatively stable and because the behavioral disturbance and deterioration connected with relapse were less severe. Thus, the course of NLP treatment after the onset of TD among the patients in this study was determined by the age at onset. Some investigations in which the observation period was of short duration have indicated that withdrawal of NLP resulted in an initial deterioration, but later in the amelioration or disappearance of TD symptoms,3,5 and that the continuation of NLP tended to have an adverse effect on the course of TD.14 However, Jeste et al8 found that the patients with the persistent type had had frequent drug discontinuation of two months or more. He explained this paradoxical effect of the drug withdrawal by using the concept of "kindling." Nevertheless, Seeman9 found no significant difference between the recovery rates of the drug-free group (i.e. intermittent therapy group) and the non drug-free group. The present study has shown that the number of drug discontinuations was not significantly correlated with the clinical courses of TD; i.e., that, while patients with an early onset of TD tended to recover despite continued drug therapy, late-onset TD tended to persist despite the discontinued drug therapy. The findings also show that TD tended to worsen with age. CONCLUSION The above findings indicate that the long-term outcome of TD is determined by the patient's age at onset rather than by the course of NLP treatment after the occur rence of TD. Smith et al.13 and Seeman" also regarded the patient's age as an important contributory factor to the irreversibility of TD and expressed optimism as to the prog nosis of TD in the young. Taking into account that there are cases of early-onset rever sible TD that have later become recurrent and persistent, it will be necessary to follow patients up for 10 years or more to examine the effects of aging and the continued use of NLP. There are no data as to the outcome for patients with late-onset persistent TD who had no massive reduction in the NLP dose. Clinicians should avoid the defeatest attitude that once TD is manifested, while early onset TD is reversible, late-onset TD is irreversible regardless of the subsequent NLP treatment. They should try to reduce the NLP dose in TD cases as much as possible. (An outline of this study was presented at the 14th congress of Collegium Internationale Neuropsychopharmacologicum in Florence, 1984)

9 Ten-year Follow-up Study of Tardive Dyskinesia 219 REFERENCES 1. Quitkin, Frederic, Rifkin, A., Gochfeld, L. et al.: Tardive dyskinesia: Are first signs reversible? Am. J. Psvchiat. 134: Wegner, James T. and Kane, J. M.: Follow-up Study on the Reversibility of Tardive Dyskinesia. Am. J. Psychiat. 139: , Yagi, G., Itoh, H., Miura, S. et al.: "Reversible" Tardive Dyskinesia-Its Onset and Long-Term Prognosis. Seishin Igaku 22: , 1978 (in Japanese) 4. Itoh, H.: An international cooperative comparative study on clinical efficacy and safety of antipsychotic drug treatment-annual report of the pharmacopsychiatry research foundation. 8: , 1976 (in Japanese) 5. Yagi, G., Itoh, H., Kamijima, K. et al.: Long-Term Prognosis of Tardive Dyskinesia A Five-Year Follow-Up Study on the Severe and Irreversible Cases-. Jap. J. Clin. Psychiat. 7: , 1978 (in Japanese) 6. Itoh, H.: A survey on pharmacotherapy in chronic schizophrenia. Annual report of the pharmacopsychiatry research foundation. 6: , 1974 (in Japanese) 7. Yagi, G., Ogita, K., Ohtsuka, M. et al.: Persistent Dyskinesia after Long-Term Treatment with Neuroleptics in Japan. Keio J. Med. 25: 27-35, Jeste, Dilip, V., Potkin, S. G., Sinha, S. et al.: Tardive Dyskinesia-Reversible and Per sistent. Arch. Gen. Psychiat. 36: , Seeman, Mary, V.: Tardive Dyskinesia: Two-Year Recovery. Comprehen. Psychiat. 22: , Gardos, George, Cole, J. O. and Tarsy, D.: Withdrawal syndromes associated with anti nsvchotic drugs. Am. 1. Psvchiat. 115: R 11. Chouinard, Guy and Bradwejn, J.: Reversible and Irreversible Tardive Dyskinesia: A Case Report. Am. J. Psychiat. 139: , Mehta, Kinesh, Mallya, A. and Volavka, J.: Mortality of Patients with Tardive Dys kinesia. Am. J. Psychiat. 135: , Smith, James M. and Baldessarini, R. J.: Changes in Prevalence, Severity and Recovery in Tardive Dyskinesia with Age. Arch. Gen. Psychiat. 37: , Gardos, George and Cole, J. 0.. The Prognosis of Tardive Dyskinesia. J. Clin. Psychiat. 44: , 1983