Psychopharmacology (1982) 78:89- 92 Psychopharmacology �9 Springer-Verlag 1982

Levodopa and Receptor Sensitivity Modification in Tardive Dyskinesia

Daniel E. Casey 1'2, Jes Gerlach 2, and Niels Bj~brndal 2

i Medical Research, Psychiatry, and Neurology Services, Veterans Administration Medical Center, and Departments of Psychiatry and Neurology, School of Medicine, Oregon Health Sciences University, Portland, Oregon, USA

2 Department H, Sct. Hans Hospital, Roskitde, Denmark

Abstract. Tardive dyskinesia (TD), a syndrome of involun- tary hyperkinetic movements, purportedly involves the de- velopment of dopamine (DA) receptor hypersensitivity fol- lowing long-term receptor blockade with neuroleptic drugs. It has been proposed that through a process of receptor hypersensitivity modification, TD can be treated by reversing the receptor hypersensitivity with DA agonists. Thirteen patients with TD were treated for 4 - 8 weeks with levodopa plus benserazide, a peripheral decarboxylase inhibitor (Ma- dopar, Roche, Basel, Switzerland) over a wide dose range cor- responding to 3.0-9.0 g/day levodopa. Drug effects was as- sessed by blind evaluations of randomly sequenced videotapes made before, during, and for 6 weeks following treatment. TD scores moderately increased during levodopa. After the drug was discontinued, TD scores returned to pretreatment base- line levels without further improvement in those patients receiving concurrent neuroleptic medications (N = 9), but in the neuroleptic-free patients TD scores decreased 25 % in three patients and were resolved in one younger patient. Psychological effects of depression or increased psychotic symptoms occurred at higher drug doses. These results do not support the proposal that receptor sensitivity modification with levodopa is an effective therapeutic approach to TD, though selected patient and drug treatment variables, includ- ing other DA agonists, are considerations for further investigation.

Key words: Tardive dyskinesia - Neuroleptic drugs - Dopamine - Receptor hypersensitivity - Levodopa

Tardive dyskinesia (TD) is a potentially irreversible syndrome of involuntary hyperkinetic movements in the oral, facial, limb, and truncal regions which, in predisposed individuals, may develop during or after cessation of prolonged neurolep- tic treatment (Crane 1973; Gerlach 1979; Baldessarini et al. 1980). The pathophysiological basis of this syndrome is hypothesized to primarily involve striatal dopaminergic (DA) receptor hypersensitivity and/or an imbalance between DA- acetylcholinergic influences following long-terrn DA receptor blockade (Klawans 1973; Gerlach 1979; Baldessarini et al. 1980), whereas GABA and other neurotransmitters may play a secondary role in TD (Casey et al. 1981). Data supporting the concept of DA receptor hypersensitivity come from

Offprint requests to." D. Casey, Psychiatry Service, VA Medical Center, Portland, OR 97201, USA

animal models which show augmented behavioral responses to DA agonists and altered biochemical parameters of increased DA receptors following short-term (Klawans and Rubovits 1972; Tarsy and Baldessarini 1974; Christensen et al. 1976; Burt et al. 1977) and long-term (Clow et al. 1979, 1980) DA antagonist treatment in rodents with neuroleptic drugs. Similar findings of behavioral hypersensitivity to DA agonists have also been reported in nonhuman primates (Carlson and Eibergen 1976; Casey et al. 1980; Casey 1981).

The concept of receptor sensitivity modification proposes that the DA antagonist-induced hypersensitivity can be reversed by treatment with DA agonists (Friedhoff 1977). Findings of reduced hypersensitivity with DA agonists fol- lowing short-term neuroleptic treatment in rodents support this proposal (Friedhoff et al. 1977; Ezrin-Waters and Seeman 1978). Preliminary clinical reports of this approach noted that levodopa reduced TD symptoms in three patients during an open trial (Alpert et al. 1976; Alpert and Friedhoff 1980), but additional data from other studies are not available.

Two separate studies with varying doses and duration of treatment with levodopa in TD have been undertaken to evaluate further the effects of receptor sensitivity modifi- cation in the clinical setting. These studies also identified some of the relevant variables associated with the response of TD in psychotic patients treated with DA agonists.

Materials and Methods

Study 1. Seven patients with stable TD participated in this trial. In the preceding 6months, three patients had not received neuroleptic drugs and four patients had been receiv- ing neuroleptic doses which were unchanged. Additional patient characteristics are described in Table 1.

All patients were treated for 4 weeks with levodopa (100 rag) plus benserazide (25 rag), a peripheral decarboxylase inhibitor (Madopar, Roche, Basel, Switzerland). The initial dose was 300 rag/day for 2 weeks, which was then increased for 2 additional weeks to 600 rag/day in the patients not receiving neuroleptics and to 900rag/day in the group receiving neuroleptic drug treatment. These doses correspond to 3.0 and 4.5g/day levodopa without benserazide. The changes in TD were evaluated at 1-week intervals before, during, and for 5 weeks following drug treatment.

Study 2. Six patients with stable TD participated in this study. One patient was drug-free and five patients had been receiving continuous neuroleptic doses for at least 6 months. As in

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Table l . Patient characteristics

Patient no./ Diagnosis Illness TD sex/age (years) (years) (years)

Neuroleptic treatmen t (years)

Treatment during investigation Neuroleptic drugs

Other drugs

Drug rag/day Drug mg/day

Study 1 1/M/45 Manic depressive 15 1 2 2/M/68 Manic depressive 20 1 5 3/M/70 Schizophrenia 52 5 22 4/M/48 �9 Schizophrenia t3 1 13 5/M/58 Schizophrenia 20 2 15

6/M/62 Manic depressive 12 2 8

7/F/72 Schizophrenia 30 3 22

Study 2

1/M/57 - Manic depressive 18 7 17 2/F/70 Schizophrenia 42 5 30

3/M/32 Schizophrenia 7 6 months 5 4/M/25 Schizophrenia 8 2 7 5/F/54 Schizophrenia 22 t 20 6/M/57 Dementia 9 6 8

Lithium 900

Flupenthixol decanoate 37.5 week Penfluridol 20/week Orphenadrine 100 Chlorpromazine 90.0 Pimozide 6.0 Tetrabenazine 37.5 Haloperidol 12.0

Pimozide 3.0 Tetrabenazine 37.5 Levomepromazine 600 Levomepromazine 500 Chlorprothixene 150 Chlorprothixene 150 Chlordiazepoxide 20

study 1, these medications were unchanged throughout the investigation. See Table I for patient data.

Levodopa (200mg) plus benserazide (50 mg; Madopar) was given daily in equally divided doses totalling 4 0 0 - 600 rag/day in the first 2 weeks, and subsequently increased by 400 - 600 mg/day at the end of weeks 2, 4, and 6 of active drug treatment. If side effects developed, the drug was reduced to a lower dose at which side effects were not encountered�9 The final dosage range was 800-1800 mg/day, corresponding to 4 .0-9 .0 g/day of levodopa without benserazide. Changes in dyskinesia scores were evaluated at 2-week intervals before, during, and for 6 weeks after treatment.

Evaluation. TD symptoms were videotaped during a stan- dardized examination that included sitting, standing, walk- ing, distractio n by conversation, and performing voluntary movements of nonaffected muscle groups, such as writing. Recording sessions of approximately 5 min each were con- ducted at the same time of day on the schedules described above for each study. The videotapes were then randomly sequenced and scored blindly by a rater who was experienced in evaluating movement disorders. The rating scale for TD included evaluations of the following eight body regions :jaw; tongue; lips; face; head; trunk; and upper and lower extremities. Scores ranged from 0 - 6 (absent-severe) for each body region assessed (Gerlach 1979).

R e s u l t s

Study 1. TD scores were stable in the pretreatment evaluation phase. During levodopa treatment there was a modest increase in TD scores in both the neuroleptic-treated and neuroleptic-free patients (Table 2).

In the 5-week follow-up period, after levodopa was discontinued, there was a varied response of TD symptoms in the three patients not receiving neuroleptic treatment. The youngest patient (45-years old, with TD for I year) had his symptoms resolve, whereas there was only a modest decrease

in the TD scores of the two older patients (68- and 70-years old). There was no major change in TD scores of the patients concomitantly taking neuroleptic drugs (Table 2).

Psychiatric changes during levodopa were observed in one schizophrenic patient (no. 3) not receiving neuroleptics. He became more active and reported increased auditory halluci- nations�9 These symptoms returned to baseline when the drug w a s discontinued.

Study 2. The one patient not receiving concurrent neuroleptic treatment had his TD symptoms decrease 45 % during drug treatment and maintained this improvement throughout the 6-week follow-up evaluation (Table 2). This patient's symp- toms decreased during the dose range of 1000mg/day, but increased when the dose was raised to 1600mg/day. TD symptoms again improved when the dosage was lowered to 1000mg/day and did not exacerbate when the dose was gradually increased to 1600 mg/day. No additional changes in TD symptoms occurred during the 6-week follow-up period.

There were no significant changes in TD scores in the group of patients taking neuroleptic drugs. TD scores modestly increased at the highest levodopa dose, but returned to baseline levels in the 6-week follow-up period (Table 2).

Psychiatric side effects occurred in four patients�9 The patient (no. 1) not receiving neuroleptics became moderately depressed on 1200mg/day of drug, but then became hy- pomanic on 1600 mg/day. One patient (no. 2) became slightly confused on 800 mg/day. One patient (no. 3) experienced an exacerbation of his psychosis on 1600 mg/day, which resolved when the dose was reduced to 1000mg/day, and another (no. 6) showed increased activation. These treatment-emer- gent symptoms resolved when the drug was discontinued.

D i s c u s s i o n

The results of these investigations lend only limited support to the theory of receptor sensitivity modification with DA

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Table 2. Levodopa in tardive dyskinesia

Patient no. Current Highest Equiv Tardive dyskinesia scores neuro- Madopar dose levodopa dose leptic Before Madopar Highest Madopar After Madopar a Change from

(mg/day) (g/day) dose baseline (~)

Study 1 1 - 600 3.0 5.0 5.5 0.0 - 100 2 - 600 3.0 7.0 8.0 6.0 - 14 3 - 600 3.0 6.5 7.0 5.5 - 18 4 + 900 4.5 3.5 4.0 3.5 0 5 + 900 4.5 8.0 10.0 9.0 + 13 6 + 900 4.5 5.5 7.0 6.0 + 9 7 + 900 4.5 5.0 8.0 7.0 + 40

Study 2 1 - 1600 8.0 10.0 6.0 5.5 - 45 2 + 800 4.0 5.0 5.0 4.5 - 10 3 + 1000 5.0 2.0 2.5 2.5 + 25 4 + 1800 9.0 4.5 4.5 4.0 - 11 5 + 1800 9.0 5.0 6.0 5.0 0 6 + 1800 9.0 5.0 5.5 4.5 - 10

After Madopar (200 mg levodopa + 50 mg benserazide) was discontinued, evaluations were 5 weeks later in study I and 6 weeks later in study 2

agonists in TD (Friedhoff 1977), as the part ial ly beneficial effects of levodopa occurred in the younger patients not concurrently receiving neuroleptic treatment. Elderly patients and those receiving neuroleptic drugs were much less likely to benefit from treatment with levodopa. This finding in youn- ger patients is consistent with the observation that TD tends to improve or resolve in younger age groups (Smith and Baldessarini 1980). The negative correlation between increas- ing age and the improvements in TD may indirectly identify differences between reversible and irreversible TD. Thus, the pr imary role of receptor sensitivity modification with levodopa may be to facilitate the ongoing process of gradual remission in reversible TD.

It is possible that patients receiving concurrent neurolep- tic t reatment did not benefit from levodopa because the existing neuroleptic-induced D A receptor blockade was not overcome by the levodopa doses. However, the increase in TD without subsequent improvement and the presence of psy- chiatric side effects in some patients argue against this explanation.

Both these studies suggest that the dose of levodopa may be a relevant t reatment parameter. In those few patients who did eventually improve, changes in TD were first observed in the levodopa range of 3 - 5 g/day (600-1000 rag/day Madopar) . Higher doses tended to aggravate TD further, but were not followed by improvement and also produced psychological side effects. It will be necessary to determine i ra certain degree of symptom increase with levodopa is a prerequisite for subsequent improvement in TD. Excessively aggravating dyskinesias with high doses of levodopa will make it more difficult to obtain clinical acceptance of this treatment strategy and run the addit ional risk of producing or exacerbating psychosis.

The results of a related investigation with ergot DA agonists do not clarify the role of receptor sensitivity modifi- cation in TD. Neither bromocript ine (10 mg/day) or C F 25 - 397 (60rag/day) altered symptoms (Tamminga and Chase

1980), though the effect of lower or higher doses may influence TD and provide addit ional data. Therefore, the ability to modify TD with DA agonists is complex and depends, at least in part, on the patient variables of age and underlying predisposit ion as well as the possible drug vari- ables of concomitant neuroleptic treatment and optimal dosage range of DA agonists. Our present results suggest that a fruitful line of evaluation may be to evaluate further the effect of levodopa in younger patients with TD who are not taking neuroleptics.

It must also be considered that the limited benefits of receptor sensitivity modification with levodopa may be accounted for by the possibility that D A receptor hyper- sensitivity is an incomplete explanation of TD, as suggested by data from the clinic and animal models. Though it has been proposed that an increased number of D A receptors in the brain is related to TD, a pos tmortem study found that butyrophenone and cis-flupenthixol 'binding were similar in psychotic patients with and without such dyskinesias (Crow et al. 1981). I t has also been shown that not all DA agonists evoke behavioral measures of hypersensitivity. In monkeys, apomorphine and amphetamine produced increased buc- colinguomasticatory movements during and following chronic neuroleptic treatment, but bromocript ine and an- other ergot, CF 2 5 - 3 9 7 , did not (Casey 1981). A separate line of investigation has shown that following repeated treatment with THIP, a G A B A agonist (Krogsgaard-Larsen et al. 1977), the number of DA receptors increased but there were no signs of behavioral hypersensitivity to DA agonist treatment in rodents (Christensen and Hyttel 1982). Thus, there may be a dissociation between dyskinetic phenomena, increased number of DA receptors, and the capacity of different DA agonists to influence behavioral parameters and clinical symptoms. In summary, there is evidence from several areas of study to indicate that an explanation which includes altered DA mechanisms will be necessary, but may not be sufficient for a thorough understanding of TD.

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Acknowledgments. This project was supported by a Veterans Ad- ministration Research Career Development award and The Grass Foundation. Madopar was supplied by Roche (Basel, Switzerland). The typescript was prepared by Marian Karr.

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Received October 1, 1981 ; Final version April 15, 1982