orofacial dyskinesia

Refer to: Kobayashi RM: Orofacial dyskinesia-Clinical features,mechanisms and drug therapy (Medical Progress). WestJ Med 125:277-288, Oct 1976 Medical

PROGRESS

Orofacial DyskinesiaClinical Features, Mechanisms and Drug Therapy

RONALD M. KOBAYASHI, MD, San Diego

Orofacial or tardive dyskinesias are involuntary repetitive movements of themouth and face. In most cases, they occur in older psychotic patients who are

in institutions and in whom long-term treatment with antipsychotic drugs of thephenothiazine and butyrophenone groups is being carried out. These dyski-nesias are frequent in occurrence and characteristically are irreversible.Several biochemical mechanisms have been proposed as causes, includinghypersensitivity or partially deneverated brain dopamine receptors and lowaffinity of the offending drugs for brain muscarinic cholinergic receptors.Clinical therapy has been attempted primarily with drugs that antagonizedopamine receptors or deplete brain dopamine. The benefits of drug treatmenthave been variable and lack of consistent improvement has been discourag-ing. Early recognition of dyskinesia should be attempted, and the dose reducedor the drug omitted at the first sign.

DRUG THERAPY of certain disorders, especiallytreatment of schizophrenia with phenothiazinesand parkinsonism with L-dopa, has been associ-ated with the emergence of certain abnormal in-voluntary movements termed dyskinesias.1-4 Theseare involuntary, repetitive and stereotyped move-ments, involving the head, face and oral struc-tures. In their typical presentation, tardive ororofacial dyskinesias consist of tongue protrusionwith licking of the lips, sucking and smackingmovements with the lips, chewing movements,

From the Department of Neurosciences, University of California,San Diego, School of Medicine, and Veterans AdministrationHospital, San Diego.

Dr. Kobayashi is supported by a Clinical Investigatorshipawarded by the Veterans Administration.

Reprint requests to Ronald M. Kobayashi, MD, Neurology Serv-ice, Veterans Administration Hospital, 3350 La Jolla VillageDrive, San Diego, CA 92161.

grunting and similar sounds, puffing of the cheeks,forehead furrowing and eye opening and closing.In many cases, the limbs and trunk are also in-volved. When drug-induced, these manifestationsmay appear at any point during the drug treat-ment, including while the drug is being given,after termination of treatment or upon reinstitu-tion of treatment. In many cases, the dyskinesiaspersist for months or years and there is poor re-sponse to drug manipulation or they are irre-versible. The significance of orofacial dyskinesiasis underscored by the fact that these now appearto be the major side effect limiting the use of theantipsychotic drugs, which are currently the mostfrequent cause of dyskinesia. Similar movementswere reported to occur following epidemic en-

THE WESTERN JOURNAL OF MEDICINE 277

OROFACIAL DYSKINESIA

cephalitis in the first part of the 20 century5 andas being among the clinical features of certainbasal ganglia disorders such as Huntington'schorea,6 Sydenham's chorea7 and Wilson's dis-ease.8

This review will focus on clinical characteristics,basic mechanisms and therapeutic approaches.Drug-induced dyskinesias will be stressed becausedrugs are at present the most frequent cause ofdyskinesias. The major responsible drugs are thephenothiazines and butyrophenones,9 which arethe two main classes of antipsychotic or neuro-leptic agents (defined as drugs that cause psycho-motor slowing and emotional quieting). Since theavailable literature on orofacial dyskinesias hasgrown enormously in recent years, the emphasiswill be on concepts and therapeutic approachesrather than comprehensive citation of all thereports.

Clinical Features

A variety of terms have been applied to theseinvoluntary dyskinetic movements, includingtardive dyskinesia, orobuccolingual dyskinesia,facial dyskinesia, extrapyramidal insufficiencysyndrome, drug-induced dyskinesia, cephalic dys-kinesia and dyskinetic syndrome. Tardive dyski-nesia, the first of these terms, was applied at firstto abnormal orofacial movements that appear onlyfollowing a long course of treatment or even afterthe discontinuation of therapy with the implicateddrug, and hence the designation that the dyski-nesia is "tardive."2 However, because in somecases the dyskinesia occurs even in the earlyphases of the administration of the offendingdrug or the history of drug exposure is uncertain,it may be more appropriate to use the broaderterm of orofacial dyskinesia, since this denotesboth the topography of involvement as well as thetype of abnormal movement. Most cases of dyski-nesia are drug-induced; however, in some casesthere is no history of drug exposure. Of this lattergroup, in some patients there is a history of braindamage, electroconvulsive therapy (ECT) or pre-vious surgical operation involving the brain, whilerelatively few of the cases are idiopathic. Inmany cases, the orofacial dyskinesia is accompa-nied by cervical or truncal dyskinesias (includinginvolvement of respiratory function) and limbdyskinesias, including choreoathetosis, ballismus,myoclonus, dystonia, and restless legs (akathisia).However, the orofacial component is often the

most disturbing to the patient and to the familyfor several reasons. Besides the obvious cosmeticdisfigurement, orofacial involvement may signifi-cantly impair the important functions of eating,speaking and in some cases breathing.10 Thesemovements appear to be a common expression ofa diverse group of disorders and occur in patientsin whom dyskinesia is part of a more generalizeddisorder or in whom it is the major if not solitarymanifestation. Thus it may be most appropriateto view orofacial dyskinesia as part of a symptomcomplex rather than as a specific expression ofparticular diseases.

The clinical history of this disorder, includingincidence, predisposing factors, spontaneous re-missions and responsiveness to drugs is not fullyknown and is disputed at best. The reported fre-quency of occurrence has ranged from as little as0.5 percent of patients being treated with pheno-thiazines to as high as 41 percent."' There was anoverall 17.6 percent incidence in a review of 22reported series involving 22,399 patients treatedwith neuroleptics."1 Several factors that may ac-count for this discrepancy include variable defi-nition of the syndrome and differentiation fromother extrapyramidal syndromes, differing patientpopulations (especially regarding drug usage)and different techniques of assessing clinicalstatus. A recent estimate suggests that drug-in-duced dyskinesias occur in 3 to 6 percent ofpsychiatric patients and in approximately 20 per-cent of elderly patients who are long-term orfrequent residents of institutions.'2

Orofacial dyskinesias should be clearly dif-ferentiated from other abnormal movements,especially those arising after exposure to neuro-leptic drugs. Other extrapyramidal syndromes areacute dystonic reaction, drug-induced parkin-sonism and akathisia.2"2 Acute dystonic reactionstypically occur in younger rather than in olderpatients and in males more than in females. Sincethey appear within a day or two of initial druguse, they reflect individual sensitivity to the drugused and respond promptly to parenteral adminis-tration of antihistamines or antiparkinsonianagents. Drug-induced parkinsonism is character-ized primarily by rigidity, tremor and bradykinesiarather than by hyperkinesia, and is reversed bydiscontinuing administration of the drug or reduc-ing the dose. Akathisia or the "restless legs" syn-drome is characterized by an uncontrollable stateof constant motion consisting of relentless pac-ing (tasikinesia) or repetitive movements espe-

278 OCTOBER 1976 * 125 * 4


cially of the legs, such as foot tapping or alternateadduction and abduction. This condition usuallyresponds to a reduction of drug dosage or additionof a sedative. The relative incidence of the dif-ferent extrapyramidal complications has been re-ported as parkinsonian in 38 to 48 percent, oro-facial dyskinesia in 41 percent and akathisia in22 percent of the patients receiving long-termtherapy with trifluoperazine.13 Of a series of 3,775phenothiazine-treated patients, akathisia wasnoted in 21 percent, parkinsonism in 15 percentand dyskinesia in 2.3 percent.'4 However, thislast category combined cases of acute dystonicreaction with those of orofacial dyskinesia. De-spite this grouping, these results serve to suggesta low occurrence rate for these two side effects.

It has been suggested that underlying braindamage predisposes to orofacial dyskinesia.'5Furthermore, most neuroleptic-induced dyski-nesias occur in chronic schizophrenics receivinglong-term pharmacotherapy, many of whom havebeen treated in the past with leukotomies or elec-troconvulsive therapy. Dementia has been asso-ciated with drug-induced dyskinesias and has beensuggested to support the role of underlying braindamage. In one series, all 13 women with pheno-thiazine-induced dyskinesia were demented.'6 Of29 cases related to phenothiazine and reserpinetreatment, 12 (or 41.3 percent) were either de-mented or had a history of organic brain dam-age.'7 By contrast, the occurrence of dementiawas not statistically increased in 213 patients withwith dyskinesia.'8 In this last series, the overallincidence of dementia in 45.5 percent of the totalof 683 patients studied appears high, especiallysince patients from the "subnormal ward" wereexcluded. No relationship between dementia anddyskinesia was observed in a nursing home popu-lation in which dementia occurred in 36 percentof those with dyskinesia and in 33 percent ofthose without dyskinesia.'9 No relationship wasshown between dyskinesia and a variety of brainlesions, including head trauma, central nervoussystem infections, vascular disease, underlyingmedical diseases or treatment with ECT or insulinshock.20 Therefore, it seems that brain damage isnot a prerequisite to drug-induced dyskinesias.The fact that most cases of dyskinesia have

been reported in patients with chronic psychosisor dementia indicates that these are the patientswho receive long-term therapy with neurolepticdrugs. There is no evidence indicating that chronicpsychosis is a prerequisite or plays a specific role

in the dyskinesias. This is supported by the re-ports of dyskinesia occurring in nonpsychotic pa-tients treated with neuroleptics for personalitydisorders, psychoneurosis, gastrointestinal symp-toms and chronic pain.2'20-23

Other forms of psychiatric treatment that alterbrain function have been studied for possiblecausal association. A two-fold increase in the inci-dence of drug-induced dyskinesias was reportedin 127 patients who had received electroconvul-sive therapy compared with that in 86 patientswho had not.2 By contrast, no definite relation-ship between orofacial dyskinesia and electrocon-vulsive therapy could be shown to exist in 214cases when compared with 468 other cases inwhich electroconvulsive therapy was not used.'8

Prefrontal leukotomy in 105 patients was notreported to predispose to dyskinesias.2"8 Insulincoma treatment in 55 patients was associated withan incidence of drug dyskinesia lower than thatin patients who did not receive such treatment.'8

Assessment of the role of brain damage in theproduction of dyskinesias may also be approachedby neuropathologic examination. In the largestseries, brains of 28 patients with dyskinesia werecompared with those in 28 controls matched fordiagnosis (15 with schizophrenia, 8 with seniledementia and 4 with other forms of psychoses).24Of the dyskinetic group, degeneration of sub-stantia nigra cells was seen in 27, compared withonly 7 in the control series. Gliosis of the mid-brain and brainstem was found in 25 of the dys-kinetic group but in only 4 of the control group.In a report of two cases, gliosis of the caudate nu-cleus together with nerve cell satellitosis andneuronophagia was noted.25 In contrast to thepronounced differences reported in these twoseries, no specific lesions were found in the brainsof three dyskinetic patients.26 These neuropatho-logical studies suggest that there is a higher inci-dence of neuropathologic change in the striatalnigral pathway, and this may predispose to neuro-leptic-induced dyskinesias, but the evidence is notconclusive.

Brain damage appears to predispose to L-dopa-induced dyskinesias-L-dopa being the majordrug besides neuroleptics associated with orofacialdyskinesia. Dopa-induced dyskinesias have beenobserved only in parkinsonian patients and neverin control patients given L-dopa.2728 However,control patients have not been exposed to pro-longed high dose treatment and may not be di-rectly comparable to parkinsonian patients.



Age appears to be an important factor, with ahigher incidence reported in older patients. In oneseries of 910 cases, the incidence of drug-induceddyskinesias in those under 50 years of age was3.8 percent of males and 13 percent of females,while in those over 50 years of age, the incidencerose to 20 percent of men and 35 percent ofwomen.18 Similar results were reported for a seriesof 398 patients, in which less than 5 percent ofthose under 44 years but 33 percent of those olderthan 65 years were found to have dyskinesia."1Women are affected more often than men by

neuroleptic induced dyskinesias, with reportedratios of 2 to 1 up to 5 to 1.13,16,18 Other re-ports suggest an equal incidence between thesexes."129'30 It has been suggested that the ap-parently higher incidence in women actually re-flects the increased number of older women re-ceiving neuroleptics in institutions." Of interestis the higher incidence of more severe casesamong women as shown when mild or doubtfulcases are eliminated." These results are sum-marized in Table 1.

Administration of drugs for increasing periodsappears to increase the risk of dyskinesias. In aseries of 109 cases, the incidence was 2.7 percentafter less than six months of treatment, 5.5 per-cent after six months to a year of treatment, 29percent for one to three years of treatment and31 percent for more than three years of treat-ment.2 These results suggest that with continuedtherapy the risk of dyskinesias developing doesnot increase appreciably after the first year oftherapy. Similar results have been reported morerecently in a series of 85 neuroleptic-treated pa-tients, all over 65 years of age, who were studiedin three groups." Of 28 patients treated for sixmonths, in only two, or 7.1 percent did dyski-nesias develop. Of those treated for more than

five years, the incidence rose to 29 percent. Nodyskinesias developed in nontreated patients.

In addition to appearing during continuedtherapy, dyskinesia may develop for the first timeafter therapy with the associated drug is stopped.Dyskinesia appearing for the first time was ob-served in 30 percent of 53 patients with chronicschizophrenia in whom long-term neuroleptictherapy was suddenly stopped in a double-blindstudy."1 Furthermore, in all of the patients withdyskinesia during therapy there was an intensifica-tion when therapy was discontinued.31 A recentreview indicates that in 5 to 40 percent of asymp-tomatic patients dyskinesias develop upon discon-tinuation of chronic antipsychotic treatment."In an attempt to reduce the risk of tardive dys-kinesia and to increase recognition in latent cases,it has been recommended that in cases of patientswith chronic psychoses administration of anti-psychotic medication should be periodicallystopped (considered a "drug holiday").12

Increased incidence of dyskinesias with longertreatment periods has also been documented forL-dopa-induced dyskinesia; these include oro-facial as well as cases with limb and truncal in-volvement. After one month of dopa therapy, theincidence was 17 percent and this increased pro-gressively with each month of treatment up to 73percent at 12 months.10 Increased doses appear toincrease the incidence of dyskinesia, which oc-curred in 9 percent of patients receiving 2 gramsper day and rose to 44 percent of patients receiv-ing 71/2 grams per day.'2

Orofacial dyskinesias have been reported tooccur with the use of virtually all the antipsychoticdrugs, including the phenothiazines and butyro-phenones. In one series, the maximum incidencewas 25 percent of those receiving chlorpromazine,with an incidence of 13 percent of these receiving

TABLE 1.-Incidence of Dyskinesia According to SexMales Females

Number Percent Number Percentwith Total with with Total with

Source Dyskinesia Number Dyskinesia Dyskinesia Number Dyskinesia

Hunter (1964)16 ..... 0....Degwitz (1967)20 ........ 33

* ......... ............ 14Brandon (1971)'18 ....... 65

* .. 17Kennedy (1971)13.17*..8

Fan (9723°...................4Fann (1972)30 ........... 49Crane (1973)1"............ 27

*Mild and doubtful cases eliminated.

280 OCTOBER 1976 * 125 * 4

2006196194264263232144210

05.32.3153.9

53253411

1397651487322182423

250672672484484313157138

5149.6

301571584214


haloperidol and thioridizine, and 19 percent ofthose receiving perphenazine and prochlorpera-zine.' Of 63 patients on trifluoperazine for an

average of 9.4 years, definite orofacial dyskinesiadeveloped in 41 percent.'3 Treatment in highdosage may increase the incidence of dyskinesia,as suggested by the findings in a study of 175 pa-tients treated with trifluoperazine. At high doses(80 mg per day) for five months, orofacial dyski-nesia developed in 26 percent of treated patients,while low dose treatment (16 mg per day) was

associated with only a 4 percent incidence.29These results take into account an incidence of17 percent of dyskinesias in placebo treated pa-

tients. Similar results, with dyskinesia appearing in25 percent, were noted when chlorpromazine was

administered.33 Determining the incidence of dys-kinesias following use of a specific drug is virtuallyimpossible because most patients have receivedmultiple drugs by the time the abnormal move-

ment is recognized. When it occurs following thechangeover from one antipsychotic drug to an-

other, orofacial dyskinesia is more likely relatedto the discontinued drug than to the new drugwhich the patient was actually receiving when thedyskinesia was first recognized.

Irreversibility is a widely accepted character-istic of neuroleptic induced dyskinesias. Morecomplete knowledge of the true incidence of re-

missions after drug termination or upon reductionof dose would be of great value both in under-standing the basic pathophysiology as well as inmanagement. Another pertinent question iswhether duration of the dyskinesia is a factor indetermining reversibility. If this is in fact shownto be the case, then early detection and appro-priate management become critical, and suggestthe need for periodic termination of neuroleptic

treatment.12 When remissions occur followingdiscontinuation of the drug, they generally occur

within a period of weeks to several months. How-ever, six to seven months were required in one

case.'7 It has been argued that irreversible oraldyskinesias following administration of pheno-thiazines were rare when cases with brain damagewere excluded and the duration of follow-up ex-

ceeded six months.34 However, brain damage iscommonly found in patients with dyskinesia,even in reports which do not consider it as pre-

disposing to dyskinesia.18" 9 There are relativelyfew studies providing sufficient detailed data toanalyze the incidence of remissions, and some ofthese studies are summarized in Table 2. Of the354 drug-induced cases followed for more thansix months, in 293 or 82 percent dyskinesias con-

tinued to occur and in only 17 percent overall werethere remissions. High remission rates of 41 per-

cent'7 and 38 percent35 have been reported, butfollow-up duration was mentioned in only one ofthese series.'7 The apparent irreversibility may

reflect the bias of studies made up predominantlyof patients who have been in institutions for longperiods and have been receiving long-term highdose treatment. Evaluation of an outpatient popu-

lation who are presumably less incapacitated bypsychosis, are younger, have a lower incidenceof brain damage and are in a situation in whichearlier recognition of dyskinesias might be pos-

sible might show different characteristics, espe-

cially with regard to incidence and reversibility.It is likely that cases of dyskinesias that have re-

mitted on drug termination have gone unrecog-

nized or unreported. At the present level ofknowledge, most cases of orofacial dyskinesiasshould be considered as irreversible, even whendrug use has been terminated.

TABLE 2.-Remission of Dyskinesia After Drug TerminationDyskinesias Persistent

Follow-up PeriodDyskinesias Remitted

Total Less Than More ThanSource Number Number Percent Six Months Six Months

Uhrbrand (1960)17 . . . 17 7 41 2 8Hunter (1964)16 .. 13 0 0 0 13Degwitz (1969)31 273 52/52* 19/19* 0 169tEdwards (1970)15 19 1* 5 0 18tCrane (1971)36 27 1§ 3 0 26§Hershon (1972) 37 ... 23 0 0 23 0Klawans (1974) 23 ... 7¶ 0 0 0 7

*Severity was reduced but dyskinesia was persistent.tlncludes 43 cases in whom severity was increased.$Includes five cases which worsened without administration of phenothiazines.§Net result is shown; actual results include three who improved and two in whom orofacial dyskinesia

developed when phenothiazines were not given.fNonpsychotic phenothiazine induced cases.



A possible role of dental malocclusion hasbeen considered in several papers. In one report,the dyskinesia of five patients with nonpheno-thiazine-related orofacial dyskinesia respondedfavorably to prosthetic dental therapy to correctthe malocclusions.38 A tendency to relapse whendentures were removed for long periods was com-mented upon and the authors suggested disrup-tion of dental proprioception as a factor in thegenesis of orofacial dyskinesia.38 The dental statuswas examined in 368 cases of drug-induced oro-facial dyskinesia.'8 Of 207 edentulous patients,dyskinesias developed in 46 percent. By contrast,of 161 patients who either wore dentures or hadat least four of their own teeth, dyskinesias de-veloped in only 21 percent. The authors concludedthat patients with facial dyskinesias have difficultyin retaining dentures in their mouths, and thatthe edentulous state was a manifestation of oraldyskinesia rather than a significant cause in thisdisorder.18 In several other series, the state ofdentition was evaluated and not considered to bea significant factor.'3" 5

Spontaneous orofacial dyskinesias-that is, dys-kinesias occurring in the absence of drug exposureand diseases known to be associated with dyski-nesias-are considered to be rare, with a reportedincidence of 1 to 2 percent.'9 20'39'40 However,several series report that in as many as 10 percent2 and 20 percent'8 of patients dyskinesias de-velop spontaneously. Most spontaneous dyskinesiacases occurred in patients residing in nursinghomes or mental hospitals, and most of the pa-tients were of advanced age.2 As in the drug-induced variety, the spontaneous cases occur moreoften in women and in those with organic braindisease. Of 285 nonphenothiazine treated mentalhospital patients, spontaneous dyskinesia wasnoted in 29 percent of the women and in 12 per-cent of the men.'8 Even when the cases of sixwomen with a history of electroconvulsive therapyare eliminated, the incidence remains high at 24percent. Clinical dementia was observed in halfof the 20 men and in three quarters of the 36women in this series; this was significantly higherthan in drug-induced dyskinesia in women.'8 Inanother series, in more than a third of 40 patientswith spontaneous dyskinesias there were diagnosesindicative of organic brain disease.2 The mostcommon underlying diagnosis, as in drug-induceddyskinesia, was either schizophrenia or affectivepsychosis.2 Spontaneous orofacial dyskinesiapresents -a clinical picture indistinguishable from

the drug-induced form.3' The natural history, in-cluding spontaneous remissions, is largely un-known and no extensive series has been reportedconcerning this aspect. Two cases described indetail were refractory to multiple drug trials,39while a favorable response was obtained in mostof 15 patients treated with tetrabenazine, pimo-zide or both.4'

Basic MechanismsA biochemical explanation for orofacial dys-

kinesias has been advanced, based on several linesof evidence. The first is that neuroleptic drugsappear to act in part by blockade of central do-pamine receptors.42 This blockade has been postu-lated to then result in a state of "chemical dener-vation" of dopamine receptors in the striatum.43Some of these altered receptors are regarded asthen developing "denervation hypersensitivity."Those neurons whose dopamine receptors havebecome hypersensitive may then respond abnor-mally to any dopamine to which they are exposed.However, direct proof of this hypothesis is stilllacking. Besides receptor blockade, neurolepticsincrease synthesis and block the reuptake of do-pamine, thereby presenting sensitized receptorswith additional amounts of dopamine. Theseeffects would be expected to aggravate a state ofreceptor hypersensitivity.A pharmacologic model of two types of dopa-

mine receptors has been formulated.43 One typeof receptor is inhibited by dopamine and is asso-ciated with larger striatal neurons. This type isresponsible for the rigidity of Huntington's choreaor drug-induced parkinsonism. The other type ofreceptor is facilitated by dopamine and is asso-ciated with smaller striatal neurons. This type isresponsible for the chorea of Huntington's choreaand for orofacial dyskinesia. Furthermore, thislatter type is blocked by doses of haloperidol andphenothiazines that do not affect the dopamineinhibited receptors. This model would be con-sistent with the observation that neuroleptic-in-duced dyskinesias may appear for the first timeafter reduction of the drug dose, and this is ex-plained as reduced blockade of dopamine facili-tated receptors.43

Recently, it has become possible to character-ize dopamine receptors using dopamine and halo-peridol labeled radioactively with tritium.44 Find-ings in these studies indicate the presence of twotypes of dopamine receptors: one which is anagonist and binds dopamine and the other which

282 OCTOBER 1976 * 125 * 4


is an antagonist and exhibits greater affinity forhaloperidol. Affinity for the antagonistic bindingsite was shown by phenothiazines in a rank ordersimilar to their antipsychotic potency. In thesestudies, fluphenazine and haloperidol had 8 timesthe potency of chlorpromazine, 52 times thepotency of promazine and 200 times the potencyof promethazine. Application of these techniquesto laboratory models of dyskinesia and to humancases may in the future permit more precise char-acterization of dopamine receptors and eithersupport or invalidate the dopamine receptor hy-pothesis.

Certain other phenothiazine drugs are morepotent dopamine receptor antagonists than othersand this property has been linked to similarity ofthe molecular conformation to that of dopamine.45According to this hypothesis, substitutions on thebasic phenothiazine nucleus will determine do-pamine receptor blockade activity. Figure 1 indi-cates that basic phenothiazine nucleus with pos-sible points of substitution indicated as Rl andR2. Halogen substitution at Rl such as in chlor-promazine, fluphenazine or trifluoperazine andsubstitution at R2 with a piperazine side chainsuch as fluphenazine or trifluoperazine is asso-ciated with high degrees of dopamine receptorblockade and with antipsychotic potency.45

Dopaminergic activity altered by neurolepticsmay result in dyskinesia upon exposure to an-other drug. A guinea pig model for dyskinesiashowed that stereotyped oral behavior analogousto human orofacial dyskinesia results when chlor-promazine pretreatment for several weeks is fol-lowed by omission of drug for one week and thenby administration of amphetamine in low doses.46In mice, the period of dopaminergic supersensi-tivity in this paradigm appeared to be brief (ob-served at two but not nine days) and striataladenyl cyclase activity was not altered.47 In mon-keys regularly treated with methadone (which isknown to block dopamine receptors) and thenmaintained drug-free for at least two months,conspicuous oral dyskinesias developed in re-

sponse to low doses of methamphetamine.48 Theauthors suggested that the oral dyskinesias re-sulted from amphetamine-induced stimulation ofstriatal dopamine receptors made supersensitiveby long-term methadone administration. Further-more, they suggest that human patients main-tained on methadone might exhibit hypersensi-tivity to amphetamine.

Another fundamental aspect of orofacial dys-

kinesia is that cholinergic and dopaminergicactivity are in a state of balance. Certain observedeffects suggest that cholingeric hypofunction, be-sides dopamine receptor hypersensitivity, is partlyresponsible for dyskinesias. Anticholinergic agents,given to reduce parkinsonism, have been reportedto increase the incidence of drug-induced dyski-nesias3'43 and may increase the severity and lowerthe threshold for appearance.43 Administration ofscopolamine, an anticholinergic agent, worsenedvoluntary tongue activity, limb chorea and draw-ing ability in patients with tardive dyskinesias.49The opposite effects were observed after the ad-ministration of physostigmine, a centrally activecholinergic agent.49 Similar effects of physostig-mine and scopolamine were reported on the oro-facial movements of patients with tardive dyski-nesia.50 Reversible orofacial dyskinesias appearedfor the first time in six patients treated with anti-cholinergic agents.5' Because of these deleteriouseffects on orofacial dyskinesias, it has been recom-mended that anticholinergic therapy be avoidedas a routine addition to the use of neuroleptics.43

Reports of a relationship between extrapyram-idal side effects and binding to the cholinergicmuscarinic receptor in the brain is additional evi-dence of cholinergic involvement in orofacial dys-kinesia.52'53 According to this hypothesis, a highincidence of extrapyramidal side effects, includ-ing dyskinesia, result from low affinity of a neuro-leptic drug for muscarinic receptor binding sites.Conversely, a low incidence of extrapyramidalside effects results from high affinity of a drug formuscarinic binding sites. Furthermore, this modelprovides a system whereby drugs may be screenedfor extrapyramidal side effects.52 Therefore, it istheoretically possible to develop the "ideal" neu-roleptic drug which combines potent antischizo-phrenic activity based on high dopamine receptorblockade and minimal extrapyramidal side effectsrelated to high affinity for muscarinic receptors.

Clinical TherapyAttempts to treat tardive dyskinesia have been

disappointing and largely unsuccessful. At times,initial optimism following a preliminary report ofsuccess with a particular drug has been replacedby skepticism when subsequent reports indicatetherapeutic failure. In this section, the variouspharmacotherapeutic approaches to the treatmentof tardive dyskinesias will be reviewed, primarilyas to the effects on dopamine at central nervoussystem synapses.



Dopamine-depleting drugs

Reduction of dopamine should be beneficial, ifreceptor hypersensitivity to dopamine is a validmodel. Reserpine, which depletes catecholaminesfrom intraneuronal storage sites, has been evalu-ated in several series. Of 16 patients who received1 mg per day of reserpine along with a neurolep-tic, three had improved after one month andtwo more improved after more prolonged ther-apy.54 Of another 16 patients treated with reser-pine alone after the neuroleptic was discontinued,seven had improved after one month.54 Neitherwithdrawal of the antipsychotic medication norreserpine-induced rigidity was considered respon-sible for the improvement. Higher doses of re-serpine (from 3 to 5 mg per day) were successfulin five patients when lower doses were not effec-tive.55'50 Once the dyskinesia was controlled, thedoses of reserpine were gradually reduced with-out recurrence of the dyskinesia.56

Tetrabenazine, like reserpine, prevents cate-cholamine storage, but is more rapid in onset andoffset and has less hypotensive effect. Beneficialeffects on the orofacial dyskinesia of three schizo-phrenic patients was observed within several dayswith administration of 75 mg per day of tetra-benazine, but 150 to 300 mg per day were re-quired in a demented patient.57 Rapid benefitwithin 24 hours was reported in a dyskinetic pa-tient who received 200 mg of tetrabenazine.58 Inanother patient, in whom there were acute dys-tonia, limb dyskinesia and akathisia after a singleinjection of fluphenazine, there was prompt re-sponse to administration of 150 mg of tetrabena-zine.58 Of six patients treated with 50 to 100 mgof tetrabenazine daily for one week, dyskinesiawas abolished temporarily in three patients, butrecurred shortly after administration of tetrabena-zine was stopped.59 At dosages up to 150 mg perday of tetrabenazine for six weeks, in 58 percentof 24 dyskinetic patients there was an improve-ment of 50 percent or more; the abnormal move-ments were totally suppressed in'eight of thesepatients.60 However, dyskinesia returned follow-ing the discontinuation of treatment with tetra-benazine.00 Similar results were obtained whenthe treatment period was extended to 18 weeks,with alleviation of dyskinesia in two of six pa-tients.6' No further suppression of dyskinesia wasachieved despite the longer treatment period orhigher doses of up to 200 mg per day.6'

Remarkable benefit has been reported with the

use of tetrabenazine or pimozide (a dopaminereceptor blocking agent), or both, in the treat-ment of 15 patients with spontaneous orofacialdyskinesia.41 At a dose of 40 to 150 mg per dayof tetrabenazine (median dose 75 mg) for 3 to36 months, dyskinesia disappeared in four andimproved in five other patients treated with thisdrug alone. When 2 to 3 mg per day of pimozidewas combined with tetrabenazine, dyskinesia dis-appeared in all eight patients treated with thecombination. Of particular interest is the rarity ofrecurrence when both drugs were administeredtogether.

Lithium carbonate is widely used for the treat-ment of acute mania, and is regarded to act byreduction of dopamine at central synapses: Oneexplanation for this effect was enhancement ofmonoamine oxidation, as suggested by reducedo-methylated and increased deaminated metabo-lites.62 In a single patient in one early report63and in all six patients in another report, therewas benefit from therapeutic doses of lithium.64Further studies appear warranted by these favor-able reports.

Alpha methyl dopa has been reported to bene-fit some patients with tardive dyskinesia. Therewas improvement in two of three patients aftertreatment with 750 mg per day for one month.54By contrast, administration of 500 to 1,000 mgper day for six weeks failed to achieve benefit inany of nine patients with tardive dyskinesia.65This drug has two principal effects, namely inhibi-tion of the enzyme dopa decarboxylase resultingin decreased dopamine formation and as a falseneurotransmitter that has' less "dopaminergiceffect" than endogenous dopamine.66 This dualaction suggests this to be a potentially usefulagent, but present data are not encouraging.

Alpha-methyl para tyrosine reduces dopamineconcentrations by inhibition of the catecholaminesynthesizing enzyme tyrosine hydroxylase. Treat-ment of eight dyskinetic patients with 3 gramsper day for three days notably benefited six pa-tients, with less definite reduction in one addi-tional patient.50

Dopamine-augmenting drugs

Monoamine oxidase inhibitors increase theamount of dopamine available to synapses and ifanything would be expected to worsen dyskinesia.Surprisingly, isocarboxazide, a monoamine oxi-dase inhibitor, when combined with chlorproma-

284 OCTOBER 1976 * 125 * 4


zine was effective in seven of eight patients withoral dyskinesia treated with this combination.67

Amantadine has clinical efficacy in the treat-ment of parkinsonism, and has some dopaminergicaction, although preclinical studies have failed toclarify its specific effects.68 Treatment of tardivedyskinesia with amantadine has been unreward-ing as indicated by reports of failure in a com-bined total of 44 patients.69-72 Earlier reports ofbenefit have been criticized as incorrect diag-nosis73 or retracted by the authors after conduct-ing more extensive double blind studies.74

Dopamine-blocking drugsIt would appear logical to use drugs that block

dopamine receptors to treat a condition that ismodeled on hypersensitivity of these receptors.Available and potent receptor blockers includethe phenothiazines and butyrophenones, whichare also the major dyskinesia-producing agents.As a consequence, a paradoxical situation is en-countered in which an antipsychotic drug mightb2 used to control manifestations caused by thatsame or related drug. It has been observed clinic-ally that increasing the dosage of the same neuro-leptic drug the patient already had been receivingmay improve orofacial dyskinesia.75'76 Caution hasbeen suggested in this approach, since a viciouscycle may be initiated of increasingly higher dosesbeing required for dyskinesia suppression.76

Of the phenothiazines, thiopropazate in par-ticular has been reported to benefit dyskineticpatients.77-82 Pronounced reduction or completedisappearance of dyskinesia was reported in four

PHENOTHIAZINES

71 RIR2

RI R2Al

CHLORPROMAZINE(THORAZINE)

FLUPHENAZINE(PROLIXIN) CF3

TRIFLUOPERAZINE(STELAZINE) CF3

PERPHENAZINE(TRILAFON)

THIORIDAZINE(MELLARIL)

iLKYLAMINO

CH2-CH2-CH2-N(CH3)

PIPERAZINE

CI

PIPERIDINE

SCH3

CH2-CH2-CH2-Nx J-CH2-CH2-OH

CH2-CH2-CH2-N N-CH3\_

CH2-CH2-CH2-N N-CH2-CH2-OH

CH2-CH2..()

\CH3

Figure1.-Structures of phenothiazines and substituents.

of nine patients treated with 40 to 80 mg per dayfor four weeks.8' It has been suggested thatperphenazine is the active compound resultingfrom metabolism of thiopropazate, and perphena-zine in a daily dose of 24 mg was effective in 14dyskinetic patients.8' Both perphenazine andthiopropazate contain the piperazine side chain(see Figure 1) and have potent dopamine andcholinergic receptor blocking action.44 45'52'53 Ithas been suggested that the most potent dyski-nesia-producing phenothiazines are also the mostefficacious in suppressing dyskinesias.82 Recentstudies support a biochemical basis for this corre-1ation.44,45,52,53

Haloperidol, a butyrophenone agent, is one ofthe most potent dopamine receptor antagonists44and is similar to the phenothiazines in that it hasboth dyskinesia producing83 and dyskinesia alle-viating action.82 In six of 16 patients, orofacialdyskinesias were completely relieved by 8 to 16mg per day of haloperidol given for four weeks.82In most of the patients in whom there was re-sponse to therapy with haloperidol, there hadbeen favorable response to tetrabenazine admin-istration in an earlier trial.82 However, whenhaloperidol was given for 18 weeks, the initialalleviation of dyskinesias in five of seven patientswas progressively lost, despite a doubling ofdose.6' Consequently, the clinical benefit fromhaloperidol may be of limited duration. As withphenothiazines, a cycle of increasing dosage maybe necessary.

Pimozide, a diphenylbutylpiperidine, has rela-tively specific blocking activity against dopaminereceptors.84 In a double-blind study of 20 dys-kinetic patients, pimozide produced significantbenefit during a six-week trial.84 The major sideeffect was the development of parkinsonism,which is consonant with the view that dyskinesiaand parkinsonism represent opposite ends of aspectrum of excessive or insufficient dopaminergicactivity.84 In four patients with nondrug (spon-taneous) oral dyskinesia, therapy with 2 to 3 mgper day of pimozide eliminated the dyskinesia.4'When pimozide and tetrabenazine were com-bined, dyskinesia was totally suppressed in alleight patients receiving the combination. Further-more, recurrence was rare when the two drugswere used in combination.

Cholinergic drugsA balance of cholinergic and dopaminergic

function is considered necessary for normal motor



activity.49 Cholinergic hypofunction has beenconsidered dyskinesia-inducing and administra-tion of anticholinergic drugs may actually increasethe incidence of orofacial dyskinesia.343 It hasbeen recommended that therapy with antiparkin-sonian agents with anticholinergic action, such astrihexyphenidyl and benztropine, be avoided as aroutine addition to treatment with antipsychoticdrugs.43

Use of cholinomimetic agents, by contrast, mayhave beneficial effect in dyskinesias. Physostig-mine is an anticholinesterase that crosses theblood brain barrier and increases the concentra-tion of brain acetylcholine.85 Intravenous injec-tion of 1 mg of physostigmine lessened tonguemovements in ten of 12 dyskinetic patients, andimproved drawing ability in four of six patientstested.49 However, these favorable results have notbeen found by others. After 1 mg of intravenouslygiven physostigmine, only a slight reduction ofdyskinesia was noted in four patients and nobenefit in four others.50 In another report of sevenpatients, no benefit or an increase in the dyskine-sia was observed after the intravenous injectionof 1 mg of physostigmine.86

Deanol, which is the dimethylaminoethanol saltof para acetamidobenzoic acid, is regarded as acholine precursor, and augments the cholinergicsystem.87 Two brief reports indicated clear bene-fit in two patients receiving 600 mg per day88 andin another receiving 1,600 mg per day.89 How-ever, subsequent reports indicate therapeuticfailure despite doses of 1,600 mg per day in twopatients90 and in another series, despite treatmentwith 1,200 to 1,600 mg per day in 11 patients.91These results indicate a need for continued clini-cal trials to determine the role of deanol in themanagement of tardive dyskinesia.

In a patient with dyskinesia refractory todeanol (maximum of 2 grams per day for threeweeks), there was response to 16 grams per dayof choline chloride, after lower doses had beenineffective during the first week of treatment.92When administration of choline was stopped,dyskinesia returned.

Additional therapeutic agents

Pyridoxine (vitamin B6) neutralizes the effectsof L-dopa administration in patients with parkin-sonism93 including the side effect of dopa-induceddystonia.94 Based on these observations, ten pa-tients with neuroleptic-induced dyskinesia were

treated with 300 mg of pyridoxine per day for10 to 14 days, but with no benefit.95Therapy with papaverine, a smooth-muscle re-

laxant used clinically as a cerebral vasodilator,improved orofacial dyskinesias in three patientswhen they were given 300 to 600 mg per day.96

Imbalance between serotonin and dopamine inthe basal ganglia has been considered as con-tributing to orofacial dyskinesias.97 In an attemptto increase brain serotonin, 6 grams per day ofthe serotonin precursor L-tryptophan was admin-istered to four dyskinetic patients in a double-blind study.97 This treatment temporarily sup-pressed dyskinesia in all the patients, but atendency to relapse in a few days was observed.97This unsustained benefit was ascribed to temporarycompensation of catecholamine predominance byenhancement of serotonin. Another serotonin pre-cursor, 5 hydroxytryptophan, failed to benefit theone dyskinetic patient in whom it was tried.98

Clonazepam, an anticonvulsant of the benzo-diazepine group, was reported to improve the dys-kinesia in 42 patients treated with one to three mgper day.99 This brief report offers the prospect ofeffective therapy for tardive dyskinesia, if theseresults are corroborated by other workers.

Therapeutic Approach and SummaryPresent data on tardive dyskinesia suggest it is

a symptom complex and not a single diseaseentity. Additional knowledge regarding the sig-nificance of such factors as duration of dyski-nesia, the effect of continued administration ofneuroleptics after recognition of dyskinesia andthe optimal dose as well as duration of varioustherapeutic approaches may indicate these to besalient variables. It may be most appropriate toconsider several biochemical mechanisms at thesame time, with particular focus on the balanceof cholinergic and dopaminergic activity.When the results summarized in this review are

considered, an appropriate approach might be totherapeutically challenge dyskinetic patients withdifferent categories of rapidly acting agents.50"10'This approach should include cholingeric agents(such as physostigmine), anticholinergic agents(such as benztropine), dopamine-depleting agents(such as tetrabenazine) and dopamine-blockingagents (such as pimozide and haloperidol). Theresponses to such a series of drugs may then pro-vide a more rational basis to pursue specific thera-peutic courses subsequently.As discussed, administration of antipsychotic

286 OCTOBER 1976 * 125 * 4


medication should periodically be stopped andstudies made for the presence of dyskinesia aswell as to determine the need for continued treat-ment.12'100 When dyskinesia is initially recognized,administration of the antipsychotic drug shouldb_ discontinued, or at least reduced to the mini-mum therapeutic level. Recent preclinical andclinical studies indicate that clozapine, a diben-zodiazepine, has potent antipsychotic activity andthe lowest incidence of extrapyramidal sideeffects.52 5302 This drug may be especially suitedfor the patient in whom neuroleptics are requiredbut in whom orofacial dyskinesia is present. Earlyrecognition and, ultimately, prevention may bethe only effective means of reducing the incidenceof this disorder.

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