effect of cholinergic and anticholinergic agents dyskinesia' · drugs which alter the...

Journial of Neurology, Neurosurgery, alid Psychiatry, 1974, 27, 941-947

Effect of cholinergic and anticholinergic agentson tardive dyskinesia'

H. L. KLAWANS2 AND R. RUBOVITS

Fr-om the Divisioni of Neurology, Michael Reese Medical Center, Chicago, Illinoisanid the Departmentt ofPsychiatry, University of Maryland, Baltimore, Maryland, U.S.A.

SYNOPSIS Tardive dyskinesia, like several other choreiform disorders, is felt to be primarily relatedto dopaminergic activity within the striatum. Physostigmine has been demonstrated to improve theabnormal movements in patients with tardive dyskinesia while scopolamine tends to aggravateabnormal movements and in some cases elicits abnormal movement not previously observed. Thisevidence supports the hypothesis that anticholinergic therapy in patients prone to develop tardivedyskinesia may increase the incidence of this disorder by lowering the threshold for the appearanceof these movements.

Tardive dyskinesia is a well-recognized side-effect of long-term neuroleptic therapy (Crane,1968). The most prominent manifestationis lingual-facial-buccal dyskinesia. Limb andtrunkal chorea may accompany the facial move-ments (Paulson, 1968). The syndrome is mostoften seen in patients ranging in age from 50 to70 years who are most often diagnosed assuffering chronic deteriorating schizophrenia.Tardive dyskinesia occurs late in the course ofneuroleptic therapy, often after a decrease in thedrug dosage or discontinuation of the therapy.The involuntary facial movements often persistfor months to years after the neuroleptic treat-ment is discontinued, and the response to anytype of therapy is poor (Crane, 1968; Delay andDeniker, 1969; Faurbye, 1970).The lingual-facial-buccal masticatory syn-

drome is not unique to tardive dyskinesia. Thesyndrome was first noted as an integral part ofthe hyperkinesia of Huntington's chorea (Hun-tington, 1872). It occurs also as a side-effect ofthe long-term, high dose L-dopa therapy ofParkinson's disease (Cotzias et al., 1967).The pathophysiology and pathogenesis of

lingual-facial-buccal dyskinesias have not yet

This work was supported in part by a grant from the UnitedParkinson Foundation, Chicago, Illinois, U.S.A.2 Address for reprints: Harold L. Klawans, Division of Neurology,Michael Reese Medical Center, Chicago, Illinois 60616, U.S.A.

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been fully elucidated. However, there is evidencewhich suggests that dopamine acting at striataldopaminergic receptor sites may be closelyrelated to the initiation of these choreiformmovements in several clinical settings. Drugswhich alter the availability of dopamine atdopaminergic receptor sites alter choreiformsymptomatology. Huntington's chorea is re-lieved by drugs which decrease the activity ofdopamine at striatal dopamine receptors, whileL-dopa, which markedly increases availabledopamine, exacerbates the symptomatology ofHuntington's chorea (Klawans, 1970, 1973a).

L-dopa-induced dyskinesias are also related tothe activity of dopamine at dopaminergicreceptors in the striatum. It has been suggestedthat the prolonged dopaminergic denervation ofthe striatum characteristic of Parkinson's diseasemay induce cellular changes that produce a typeof dopaminergic denervation hypersensitivitywhich is related to the appearance of L-dopa-in-duced lingual-facial-buccal dyskinesia (Klawanset al., 1970).

Tardive dyskinesia is also thought to be relatedto dopaminergic mechanisms. The neurolepticagents which are felt to be responsible for theproduction of tardive dyskinesia are known toblock the access of dopamine to striatal dopa-minergic receptor sites (van Rossum, 1967) and,as a result, produce the symptoms of Parkinson-

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H. L. Klawans and R. Rubovits

ism (Klawans, 1968). It has been proposed thatthe neuroleptic blockade of dopamine receptorsmay be the equivalent of a 'chemical denerva-tion' of those dopamine-sensitive cells (Klawans,1973b). This chemical denervation may, in a

fashion analogous to the pathological anatomicaldenervation of idiopathic Parkinson's disease,induce alterations in the dopamine-sensitivecells such that, when dopamine access is restoredby the diminution or removal of the chemicalbarrier, an abnormal cellular responsiveness tothe dopamine results in the abnormal clinicalfeatures of lingual-facial-buccal dyskinesia(Rubovits and Klawans, 1972; Klawans, 1973b).Although the pathophysiology of lingual-

facial-buccal dyskinesias seems to be mostclosely related to dopaminergic mechanisms inthe striatum, other neuronal systems, particu-larly cholinergic pathways, also influence striatalfunction. Acetylcholine has been shown toexert an influence on the striatum opposite tothat of dopamine, and a balance of influence ofthe two neurotransmitters on the striatum isthought to be necessary for normal function(Klawans, 1968, 1973a). Since acetylcholine anddopamine have opposite effects on the striatumand a balance is necessary for normal striatalfunction, it is reasonable that manipulation ofthe effect of one system would modify the effectof the other. That manipulation of the choliner-gic system can alter the symptomatology ofdiseases in which the pathophysiology relatesmost directly to dopaminergic mechanisms hasbeen demonstrated in Parkinson's disease andHuntington's chorea.

It is most significant that cholinergic and anti-cholinergic agents have been shown to modifythe hyperkinesias of Huntington's chorea(Klawans and Rubovits, 1972). Physostigminewhich increases the levels of acetylcholine avail-able to act upon the striatum relieves choreiformsymptoms while benztropine, an anticholinergicagent, intensifies choreiform symptomatology. Itappears then that manipulation of the cholinergicsystem significantly influences the symptomatol-ogy of the choreatic movements in a disease(Huntington's chorea) in which the underlyingpathophysiology seems to be more directlyrelated to dopaminergic mechanisms. Tardivedyskinesia is thought to be related to an abnor-mal influence ofdopamine on striatal dopaminer-

TABLE 1DATA ON SUBJECTS STUDIED

Sub- Age Sex Diagnosis Dura- Manifestationject (yr) tion

(yr)

1 4.7 F SCZ 4 LFB2 61 F SCZ 6 LFB3 39 M SCZ 3 LFB+UE+LE4 46 F SCZ 7 LFB+ UE5 58 M SCZ 9 LFB + LE+ trunk6 63 M SCZ 4 LFB1 71 F CBS with para- 6 LFB+UE+LE

noid features8 68 M CBS 3 LFB + UE9 48 F SCZ 4 LFB + trunk10 56 F SCZ 6 LFB11 52 M Chronic anxiety 9 LFB+UE+LE+trunk12 61 F Chronic anxiety 8 LFB+ UE

SCZ: Schizophrenia. CBS: Chronic brain syndrome. LFB: Lingual-facial-buccal dyskinesia. UE: Upper extremity choreatic movement.LE: Lower extremity choreatic movement.

gic receptors. The striatal cells, as a result of pro-longed chemical denervation, may be over orabnormally responsive to dopamine. Thus afunctional imbalance between the cholinergicand dopaminergic systems is established. Thisstudy was undertaken to investigate the influenceof cholinergic and anticholinergic agents inpatients with tardive dyskinesias. It was pre-dicted that, as in Huntington's chorea, choliner-gic agents would tend to restore the functionalbalance of the neurotransmitters and alleviatethe symptoms and that anticholinergic agentswould worsen the abnormal movements.

METHODS

The subjects included in this study were 12 patientsclinically diagnosed as having tardive dyskinesia(Table 1). The patients had been treated with neuro-leptic agents for three to nine years, with an averageof 5-75 years of therapy. Seven subjects were female,five were male, ranging in age from 39 to 71, with anaverage of 55-8 years. The average ages and dura-tions of neuroleptic therapy did not differ betweenthe sexes in our sample. Eight patients had beendiagnosed as chronic schizophrenics, two as having achronic brain syndrome, and two as having chronicanxiety. In all subjects, lingual-facial-buccal dys-kinesias were the most prominent manifestation oftardive dyskinesia; in three cases it was the onlysymptom. The remaining nine cases demonstratedlimb chorea and/or trunkal movement abnormalitiesin addition to the lingual-facial-buccal dyskinesias

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TABLE 2EFFECT OF DRUGS ON DURATION OF TONGUE EXTENSION

Drug Number Duration of tongue extensiontested

Before After(s) (s)

Physostigmine 12 11-4 23-4 P< 0 05(range 4-28) (range 11-30)

Edrophonium 4 13-9 12 1(range 6-20) (range 4-18)

Scopolamine 4 18 4 6-3 P<0 05(range 16-30) (range 3-15)

(Table 1). Eight patients were receiving neurolepticmedication when tested in this study, four (cases 5, 8,11, and 12) were not. At the time they were studiednone of the patients had drug-induced Parkinsonism.Each patient was informed as to the nature of the

two agents to be used, physostigmine and scopol-amine, and the possible side-effects. They were toldthat this study was being carried out to increase ourunderstanding of tardive dyskinesia and that themedications might make the abnormal movementsworse or better or might have no effect. The patientswere never told which medication they were beinggiven, nor what effect the specific medication mighthave on their symptoms.

All medications were given intravenously. Indi-vidual injections consisted of 1 0 mg physostigmineor 10 mg scopolamine; 10 mg methyscopolaminewas given at the same time as physostigmine toblock the peripheral muscarinic effects (Duvoisin,1967; Klawans and Rubovits, 1972). Injections of10 mg edrophonium were also given to four patients.Several parameters were observed during the courseof each drug trial. Each parameter was recorded atleast twice before any single trial. The control levelrepresents an average of these.

UPPER EXTREMITY CHOREA A small pocket flashlightwith a coloured filter over the beam was attached toeach of the patient's hands. The patient was seated ina darkened room and instructed to hold his handsout in front of him and to keep his arms and handsas still as possible. A 20-second time exposurephotograph was then taken. This was repeated aftera 30-second rest period.

DURATION OF TONGUE EXTENSION The patient'sability to keep his tongue protruded was observed byinstructing the patient to keep his mouth open andhis tongue protruded as long as he could. The timebetween extension and retraction of the tongue inside

the inner border of the lower lips was recorded. Thetrial was stopped arbitrarily at 30 seconds. Thisability was measured at least twice per session, eachmeasurement being preceded by a rest period of 30seconds. All numbers represent the average of atleast two trials. The difference between trials wasalways six seconds or less.

DRAWING The ability of each patient to drawArchimedes' screw was periodically observed.

RESULTS

EFFECT OF PHYSOSTIGMINE The length of timethe patient could keep his tongue protruded wasincreased by physostigmine in 10 out of 12patients. As shown in Table 2 the average dura-tion of tongue extension was increased signifi-cantly by physostigmine, from a pretreatmentaverage of 114 seconds (range 4-28 seconds) to23-4 seconds (range 11-30 seconds) after 30minutes. The improvement began within fiveminutes. The maximum effect was seen between

(a) (b)FIG. 1. The effect of physostigmine on drawing. (a)Before and (b) after the administration of 1 mgphysostigmine.

15 and 30 minutes, with a total duration ofeffect between 45 and 60 minutes. Edrophoniumhad no effect on tongue extension (Table 2). Theability to draw Archimedes' screw was tested insix patients (nos 3, 4, 7, 8, 11, 12). This abilitywas improved by physostigmine in four patientsnos 3, 4, 8, 1 1). The effect of physostigmine onthe ability of patient 3 to draw Archimedes'screw is shown in Fig. 1. The figure drawn before

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FIG. 2. The effect ofphysostigmine on limb chorea. (a) Before and (b) after the administrationof I mg physostigmine.

(a) (b)FIG. 3. The effect of scopolamine on drawing. (a)Before and (b) after the administration of 1 mgscopolamine.

the administration of physostigmine showsnumerous interruptions of the smooth circularpattern not seen in those done after the admini-stration of physostigmine. Edrophonium givento four patients including patient 3 had no effecton this performance.

Physostigmine was observed to improve limbchorea in two out of six patients. The effect ofphysostigmine on limb chorea in subject 3 isshown in Fig. 2. Edrophonium had no observ-able effect on limb chorea.

EFFECT OF SCOPOLAMINE The effect of scopol-amine on tongue protrusion was tested only inthe four patients who were able to maintaintongue protrusion relatively well. As shown in

FIG. 4. The effect of scopolamine on limb chorea. (a) Before an1d (b) after the administrationof 1 mg scopolamine.

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Table 2, the average duration oftongue extensionwas 18-4 seconds before the administration of1-0 mg scopolamine. One hour after receivingscopolamine, tongue protrusion was decreased toan average of 6-3 seconds. The effect of scopol-amine on the ability to draw the Archimedes'screw was observed in the six patients not testedfor this ability with physostigmine. These sixpatients were free from upper extremity involve-ment in their disease and were able to performthe test well before the administration of theexperimental medication. The patient's ability todraw the Archimedes' screw deteriorated inthree of the six patients tested under the influenceof 1 0 mg scopolamine. This is illustrated in Fig.3 which shows the effect of scopolamine on theability of subject 2 to draw. The effect of scopol-amine on limb chorea was also observed in thesame six patients by the method described above.Scopolamine produced definite limb chorea inthree out of six patients. An example of theeffect of scopolamine on subject 2 is shown inFig. 4 in which a definite increase in movementis demonstrated. Significantly, two of the threepatients who developed limb chorea and werepreviously free from trunk movements also de-veloped abnormal movements of the trunkduring the period of peak efficacy of scopol-amine. The abnormal movements elicited byscopolamine disappeared within three hours.

DISCUSSION

The results presented above suggest that altera-tions in the degree of central cholinergic activitymay influence the severity of the abnormal move-ments in tardive dyskinesia. Physostigmine is atertiary anticholinesterase that is able to crossthe blood-brain barrier and increase the con-centration of acetylcholine within the brain(Machne and Unna, 1963). Since edrophonium,a quarternary anticholinesterase that is unable tocross the blood-brain barrier, did not improvethe dyskinetic movements, the physostigmine-induced alteration must reflect a central activity.Scopolamine, which worsened the dyskinesias, isa potent, centrally active acetylcholine antagonist(Ahmed and Marshall, 1962). These two agentshave opposite effects on the cholinergic system,and opposite effects on the symptoms of tardivedyskinesia. The most likely site for these agents

to act to influence these symptoms is the neo-striatum. It is well accepted that choreiformmovements are related to some sort of dysfunc-tion of striatal neurones, specifically in theresponse of these neurones to dopamine (Bruyn,1968; Birkmayer, 1969; Klawans, 1970, 1973a,b). The striatum contains the highest concentra-tion of both dopamine (Bertler and Rosengren,1959) and acetylcholine (Feldberg, 1945) foundin the brain. Furthermore, dopamine andacetylcholine frequently have opposite effects onthe neurones of the striatum (Klawans, 1973a).Neuroleptic agents, thought to be responsiblefor the production of tardive dyskinesia, act pri-marily on the striatum to block the dopaminergicreceptors (Van Rossum, 1967). It is hypothesizedthat when the neuroleptic blockade is removedor diminished, the striatal neurones respondabnormally to the restored dopamine, resultingin the symptoms of tardive dyskinesia. The datapresented here demonstrate that the acute ad-ministration of agents which alter the striatalinfluence of the cholinergic system can modifythese dyskinesias.

Based upon studies of dopamine-relatedamphetamine-induced stereotyped behaviour inanimals, it has been suggested that anticholiner-gics may both increase the severity of tardivedyskinesia in patients prone to this type of move-ment disorder and also increase the incidence ofthe disorder by altering the threshold for theappearance of these movements (Rubovits andKlawans, 1972). There is evidence that the inci-dence of tardive dyskinesia is greater in patientsreceiving both neuroleptics and anticholinergicsthan in patients receiving neuroleptics alone(Crane, 1971). This study provides some evidenceto support the hypothesis that anticholinergicmedication may be a predisposing factor inpatients prone to the development of tardivedyskinesia. While all patients in this study hadtardive dyskinesia and anticholinergic medica-tion tended to worsen existing symptomatology,it was also found that in four patients with onlylingual-facial-buccal dyskinesias anticholinergicmedication brought out previously undetectedtrunkal and limb movements. There is at presentno satisfactory explanation as to why lingual-facial-buccal movements are the most prominentmanifestation of tardive dyskinesias. There isalso no satisfactory explanation as to why anti-

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cholinergic agents elicit chorea in those indi-viduals who manifest only lingual-facial-buccaldyskinesias. Anticholinergic medication doesnot cause these movements in normal volunteers(unpublished observations). Several factors maycontribute to both of these phenomena. First,there may be regional variations in sensitivitywithin the caudate nucleus to the neurologicalalterations induced by neuroleptics, such that fora given level of physiological alteration, clinicalmanifestation of the derangement may vary fromsevere-for example, the face-to mild-forexample, in the limbs-in the same patient. It isquite possible that those motor areas related tocontrol of complex, fine movements of the faceand hands may have more sensitive regulatorymechanisms than other areas, and that theseareas may be more sensitive to any neuroleptic-induced alteration in function. This may explainwhy lingual-facial-buccal movements are morefrequently seen than trunkal movements. Alterna-tively, it is possible that the neuroleptics mayalter the physiology of certain caudate areasmore than that of other areas so that there maybe a greater degree of neuroleptic-induced dys-function in the facial area (manifested by lingual-facial-buccal movements) than in the trunk area.It is also possible that the face and hand areas arethose most often clinically affected simply be-cause their representations encompass a majorproportion of the topography of the caudate,hence these caudatal areas would suffer the mostdamage.

In all of these proposed mechanisms there is agradient of dysfunction between clinically mani-fest dysfunction and subclinical dysfunction. It ismost probable that areas of the body whichclinically appear to be symptom-free may berepresented in the caudate nucleus by areaswhich may be significantly altered, needing onlya small additional insult to cross the thresholdbetween subclinical and clinically apparent dys-function. In some cases, the addition of a smallintravenous dose of an anticholinergic agent,which inhibited the cholinergic opposition todopaminergic function, was sufficient 'additionalinsult' to allow previously undetected sympto-matology to emerge. The acute administrationof an anticholinergic agent to a patient with tar-dive dyskinesia may lower the threshold for theappearance of additional symptoms of the dis-

order. This explains why anticholinergic medica-tions may elicit trunkal or limb chorea inpatients with lingual-facial-buccal movementsand not in normal individuals. The concept thatalterations related to limb chorea may bepresent in patients with tardive dyskinesia mani-fested only by lingual-facial-buccal movements isfurther supported by the fact that low dosage oflevodopa has been shown to elicit severe limband trunkal chorea in such patients (Klawansand McKendall, 1971; Klawans, 1973a). Thesesame doses of levodopa do not elicit chorea innormal individuals. This apparent continuum ofdysfunction from subclinical to clinical dyskines-ias may also explain why the chronic administra-tion of anticholinergic agents in conjunction withneuroleptic medications may create a greaterrisk for the development of tardive dyskinesiathan neuroleptic medication alone. Amounts ofdopamine which would be too small to produceclinical symptoms in patients who had not re-ceived anticholinergics may, however, be able todo so in those who had received anticholinergics.It is suggested that the administration of anti-cholinergics to patients undergoing long-termneuroleptic therapy be kept to a minimum.

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Klawans, H. L., Jr, and Rubovits, R. (1972). Centralcholinergic-anticholinergic antagonism in Huntington'schorea. Neurology (Minneap.), 22, 107-116.

Machne, X., and Unna, K. R. W. (1963). Actions at thecentral nervous system. In Heffter's Handbuch der experi-mentellen Pharmakologie. Suppl. 15. Cholinesterases andanticholinesterase agents. pp. 679-700. Springer: Berlin.

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Van Rossum, J. M. (1967). The significance of dopamine-receptor blockade for the action of neuroleptic drugs. InNeuro-Psycho-Pharmacology. Proceedings of the FifthInternational Congress of the Collegiium InternationaleNeuro-Psychopharmacologicum, Washington, 1966, pp.321-329. International Congress Series No. 129. ExcerptaMedica: Amsterdam.

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