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... 1. Neuroleptic use ranges from 19 peof institutional and community-baserate was about 50 percent (2).

2. Most patients lack a clear psychiatric,in institutions, less than 3 percent16).

3. Many patients are treated with relaiations involving polypharmacy (15,

TARDIVE DYSIGNESIA IN CHILDRENAnecdotal reports of neuroleptic-induced movement disorders haveappeared in the literature for quite some time (5, 6). Systematicinvestigations concerned with the epidemiology and course of TDin children are a more recent phenomena, however (7). The reasonsfor this delayed interest are myriad, derived perhaps from the notionthat children were relatively safe from irreversible neuroleptic effects(8); that small neuroleptic doses posed few risks; or that in severepsychiatric disease, no alternative treatments were available or con­sidered. The present application of TD as a public health problemhas helped to revise this attitude. '

Clinical investigations of TD follow a predictable trend. Earlystudies focused on case descriptions, and then came studies of in­cidence and prevalence. Subsequent epidemiologic work focuses onprevention and reducing morbidity. Prevention studies try to defineat-risk populations; try to solidify diagnostic processes and the jus­tification for neuroleptic treatment; emphasize trial drug withdrawalsand low-dose treatment techniques; and try to find alternatives toneuroleptic treatment. The development of sophisticated "at risk"strategies and of alternative treatment approaches has been compli­cated in child psychiatry by relative weakness of neuropsychiatricresearch in the field. Relative unawareness of advances in biologicaland psychopharmacological treatments by child psychiatrists <l?dp~­diatricians has probably compounded the problem of TD m thispopulation.

Part of the difficulty, however, lies in the complexity ofTD. At­tempts to map the pathophysiology ofTD have yielded ambiguousresults. Neuroleptic-induced dopaminergic supersensitivityis too simplea model and fails to explain the existence of persistent dyskinesia.Other ambiguous factors include the varying effects of cholinergicdrugs, the occasional favorable responses to dopamine agonists (9),and inconsistent results from attempts to manipulate the gamma­arninobutyric (GABA) receptor (10).

In addition, the variability of dyskinetic movements in responseto manipulation of neuroleptics confounds the issue. Breakthroughdyskinesias seem different from withdrawal dyskinesias, mainly interms of persistence and perhaps severity (5, 7,11). In children, theunanswered question is'why there is a preponderance of withdrawalor transient dyskinesias relative to the incidence of persistent dyski-

nesias. The simplest explanation is thatdren is rarely sufficient to induce a pthat is only a hypothetical explanationaction between age and neuroleptic tcsuch an interaction would also explainspectrum, elderly people appear to be r:persistent TD.The description of childhood TD 1

The repertoire of movements was inittrifugal in distribution, involving predcand choreiform-like movements (12).perience, this topographical distributiorthe pattern of adult TD (5, 7).

Various neurochemical studies of chtimate a high incidence of dopaminergintroduction of neuroleptics may not 0]potential, long-term maturational chan]levels in prepubertal children may alsoon dopamine neurotransmission and re

One additional question remains unaterm effects of disruption of neurotraturing organism? Does the fact that TD .actually, mean that they have really esc;The question is whether early neurolelatent weakness in dopamine systems suwill appear in later years. Precedents exislobe epilepsy, postpoliomyelitis deterickinson's disease, and late-onset psychos

TD in the Mentally RetardedAlthough neuroleptics are commonly pIdisabled patients, they are usually misajpopulations have revealed similar findu

one of "therapeutic nihilism"-emphasizing rehabilitation, deem­phasizing pharmacology. CHI patients represent a third group forwhom neuroleptics are "relatively contraindicated" (4).

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4. Many treatment programs are carried on for extended periods oftime without careful monitoring (3, 5, 17, 18).

off the drug, even if it has not bplace, with dramatic increasesemergence of new "rebound" S'bility requires special strategiesmental structure, behavioral msumption of the offending neur

COURSEOFTARDIVE DY~RETARDEDADULTS

A more critical concern, once ta:is the course of tardive dyskineneuroleptic treatment.

Does the resumption of neuthat the disorder will grow wo:variable or idiosyncratic? The Iimost tardive dyskinesia researchat a single point in time. Furthepart of a patient evaluation for tof maintenance neuroleptic tresessment of severity of dyskinesistudy of tardive dyskinesia of VIyet gathered data sufficient to aIn one study of TD patients rnaciable symptom reduction was ncconcluded that the disorder is jThis is at variance with clinical eimprovement in symptoms of Tafter the disorder is originally dDanish sample, not yet publish:even in patients who continuepersonal communication, 1984Yassa, Nair, and Schwartz (21showed no change, while equalor worsened (16 percent). Howecompromise this fmding. Paulsoinstitutionalized retarded childredrawal trial and found no changemore severe dyskinesias, and fi,tients' medication status in theduring the follow-up period wa

One aspect of our researchdyskinetic movements during ain 12mentally retarded individu:

These practices have created a large pool of patients who are athigh risk for TD. On the basis of available data, rates for TD mayexceed 34 percent of patients on chronic neuroleptic treatments (3,5). This figure falls within the ranges associated with neuroleptictreatment in nonhandicapped psychiatric populations (19). It is notclear whether severe or persistent dyskinesias are more common inthe developmentally disabled.

Several risk factors may be involved in the development ofTD inthe developmentally disabled. At this point, total cumulative doseappears to correlate most clearly with the emergency of TD (3, 7,10). The prescribing patterns noted earlier may surely heighten thisfactor. A higher incidence of encephalopathy associated with severedevelopmental disorders may also influence vulnerability (3, 20).

The retarded population displays an increased rate of behavioralabnormalities such as hyperactivity, aggression, self-injurious behav­ior, and stereotypies, as well as high rate of institutionalization. Itis likely that rates of neuroleptic treatment are high, especially bypoorly trained physicians who do not appreciate the availability ofalternative treatments. In many of these clinical situations, neuro­leptics have been considered front-line treatment (17).

As the level of intellectual function and communication skills di­minishes' the reliability of psychiatric diagnoses tends to follow suit(21). Low IQ may also affect a physician's assessment of emergingextrapyramidal symptoms, in particular, akathisia. A patient's poorverbal skills combined with an unusual akathisia may prompt theunwitting physician to increase the neuroleptic dose. Such a phar­macologic tail-chase will only increase the patient's eventual risk ofdeveloping TD by guaranteeing continued neuroleptic use at in­creasing doses, while potential warning signs ofTD are suppressed.More troublesome is the relative lack of reported breakthrough dys­kinesias on maintenance neuroleptics (3). These emergent symptoms(particularly vermicular tongue movements and choreiform handmovements) alert clinicians to the presence ofTD. Such harbingersymptoms may signal the need to reduce or to discontinue neuro­leptics and presumably reduce the risk for more severe persistentdyskinesia. Lacking this signal, clinicians must episodically reducethe dose of neuroleptics. Even with this approach, dyskinetic move­ments may emerge only after a lag of between 1 to 4 weeks (3, 7).The mentally retarded patient may have some difficulty toleratingthis lag. Many patients will show significant behavior deterioration

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Note. AIMS-Abnormal Invodrawal. b. = secondwit

'Chlorpromazine equivalent.

M

F

11,18

31

16

M5

6

9

Group 3: Medication discon4 M 4

1,13

3,20

M

F

3,47F

12

10

8

Group 2: Medication decrea1 M 3,95

6M

4,17F

56M

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11

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Group 1: Medication increas2 F 5,80

Cumulativbefore :study'Sex

Group,subject

Table 1. Occurrence of INeuroleptic DnIndividuals

followed as closely as theRaters were assigned randcwere not aware of any subAfter a variable baseline, suin a double-blind fashion. J

Tardive Dyskmes

withdrawal 3 years previously (7). It was hypothesized that the se­verity of dyskinetic movements in the second withdrawal wouldincrease following continued treatment and would be associated witheach subject's increment in lifetime cumulative dose of neurolepticdrug.

Subjects were eight male and four female profoundly retarded,long-term residents of a state mental retardation facility who hadparticipated in a previous study (7). The 12 residents were on theaverage 30.7 years old (range = 22-41 years), had mean IQs of 11(range = 10-23) and mean Vine1and Social Quotients oflO.2 (range= 4-25). All subjects had a continuous, lengthy neuroleptic historyprior to the original study and did not have other conditions (forexample, cerebral palsy) which might produce abnormal involuntarymovements. At the start of the original and the present studies re­spectively, 12 of 12 and 8 of 12 subjects were receiving neurolepticmedication. Each resident's cumulative neuroleptic history before thefirst study and average daily dose in a comparable period before eachstudy is presented in Table 1. The medications were prescribed foraberrant behaviors such as aggression, self-injury, property destruc­tion, or noncompliance. Each subject lived in a 24-hour residentialtreatment unit with 15 to 25 similarly functioning individuals andreceived several hours of adaptive skill training each day. Prior tothe second withdrawal, four subjects were receiving thioridazine,three haloperidol, one thiothixene, and four not any psychoactivemedication at all. All subjects were healthy and on no intercurrentmedication.

Three psychologists rated location and severity of dyskinetic move­ments using the Abnormal Involuntary Movement Scale (AIMS)(29). Raters were trained in a fashion similar to a previous study,using videotapes, "live" observation of individuals with dyskineticmovements, and discussion of practice ratings to clarify disagree­ments. Practice ratings continued until all three observers indepen­dently and simultaneously agreed on the specific location of eachsubject's dyskinetic movements with no difference greater than oneunit of severity (none, minimal, mild, moderate, severe). Reliabilitywas also checked with a rater (the first author) who had conductedexaminations in the original study (7). The four raters agreed onlocation and severity of 93 percent of items with a difference of 1or less and the remaining 7 percent of items showed a difference of2. The three psychologists showed agreement in this observationsimilar to that initially established.

During each weekly examination, the rater and the subject werealone in a quiet room. The AIMS examination procedure (29) was

TARDIVE DYSKINESIA142

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movements that were less sany dyskinetic movementstrial.

One may draw the followdyskinetic 'movements mayneuroleptic status. This wareturned to a neuroleptic a5 and 6 who displayed dyslnot returned to a neuroleptstudy. These results repliesneuroleptic-induced dyskir»verity of dyskinetic movemdirection as the increase ordent of prior cumulative eXIprestudy 1 cumulative doseneuroleptics between srudi,increase in the severity of d2 received lower doses of na decrease in severity of rnecessarily contradict the irpredictor for occurrence ofsuggest that severity of dystime may be related more trather than to a lifetime e)represent indirect support 0

ofTD (10).It is not possible to draw

12 patients. Further, data fbe generalized to patients cTD, its severity, and perhap:in the former group (7). .withdrawal method is unicdemands careful attention.tarded patients, and continumay make it worse. On tI­treatment is necessary, the aaggravation ofTD.

lVHY NEUROLEPTIC U~IN CLOSEDHEAD INJU

Each year, there are more tJUnited States. Ninety perce]10 percent survived 10 v=

ication from 1 to 15 weeks. Subjects 10 and 11 were not withdrawnfrom medication because of staff concerns about aberrant behavior.The criteria for diagnosing TD were those recommended by Gual­

tieri et al (30). Three additional casesofTD were noted in the secondwithdrawal (Subjects 3, 6, and 11) in addition to the six cases reportedin the original trial (Subjects 1,2,5, 7,8, and 12). Five subjects (2,3, 6, 7, and 11) displayed more severe dyskinetic movements afterthe second withdrawal. These subjects, except for Subject 6, receivedneuroleptics at a mean daily oral dose greater than a similar periodprior to the first withdrawal (see Table 1). Subject 6 was not returnedto a neuroleptic after the first withdrawal but showed a small increasein dyskinetic movements. Four subjects (1, 5, 8, and 12) displayedless severe movements during the second withdrawal; these individ­uals received lower doses of neuroleptic medication between studies.Three subjects (4,9, and 10) did not display dyskinetic movementsin either withdrawal trial.These withdrawal data were categorized into three groups based

on neuroleptic status between studies: medication increased (Group1), decreased (Group 2), and discontinued (Group 3). Mean totalAIMS data were analyzed using a 3 X 2 analysis of coveriance (GroupX Trial) with cumulative lifetime neuroleptic dose prior to the firstwithdrawal as the covariate. This analysis, which was statisticallycontrolled for cumulative dose, was not significant for main groupeffects but yielded the following for the interaction terms: F(2, 8)= 3.81, P < .07. A post-hoc Newman-Keuls analysis revealed sig­nificant differences for the following comparisons: Group 2, Trial 1versus Group 1, Trial 1 (p < .01); Group 2, Trial 1 versus Group1, Trial 2 (p < .05); Group 2, Trial 1 versus Group 3, Trial 1 (p< .05); Group 2, Trial 1 versus Group 3, Trial 2 (p < .01); andGroup 2, Trial 1 versus Group 2, Trial 2 (p < .05). Salient aspectsof the Newman-Keuls comparisons are as follows: 1) Group 2, theindividuals with the highest cumulative neuroleptic history, had sig­nificantly more severe dyskinetic movements than Groups 1 or 3during the first trial. 2) Group 2 showed a significant decrease inseverity of movements between withdrawal trials. 3) Differences be­tween groups during the second withdrawal trial were nonsignificant.And 4) Group 1 was the only group that showed an increase between~rials in severity of dyskinesia with a trend toward statistical signif­icance,

The results of this second withdrawal trial indicated that 9 of 12individuals met the tardive dyskinesia movement criteria, 3 morethan in the first trial. Within-subject comparisons revealed that fivesubjects displayed more severe movements, four subjects displayed

Tardive DyskinesTARDIVE DYSKINESIA144

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treatment. The more intellijtaper the neuroleptic afterfor a couple of weeks. Neuwithdrawn abruptly. Abrupcipitate seizures (34); abrufor prompt relapse with seition by 25 percent decrenproblems.

Agitation, explosiveness, (psychosis in CHI patientsmediate post-recovery pericCHI. In such instances, neumay not always be effectiveneuroleptics, in succession,0treatment is going to be sicommon sense to withdrawa baseline, and try some orbusually sufficient to establi:High-dose treatment is rarwarn against long-term treaiwith neuroleptics, the parteTourette's syndrome rna'

dose neuroleptics are cecamay actually enhance cognitional tasks (7), probably a

Low-potency neurolepticpromazine (Thorazine) ten.ticular is a strongly antichothe neuroleptic chlorpromadoses below those requireddrugs probably should be avneuroleptics are less sedatiris required. Representativeslixin), trifluoperazine (Stekperidol commonly causes (roleptics are more likely to I

the neuroleptic malignant sNeuroleptics can lower t

phenazine are two neurolepthioridazine are among the I

(34, 36).Do neuroleptics compro

tients ? Yes, if one extrapola

suffer injuries that leave severe residual symptoms or deficits. Sincethe majority of CHI victims are young (peak: incidence is betweenag~ 18 and 24), the cumulative number of such patients will continueto nse, year by ye~r, for a long time to come. (Figures are from theNational Head Injury Foundation.)

Even mild head injuries may result in significant symptoms: theso-called "post-concussive syndrome." Many mild head injuries arenever r~ported. ~?st physicians fail to relate psychological problemsto a mild head illJUry; the tendency, then, is to underestimate theextent o~the problem. The actual number of CHI patients is probablymuch higher than we have ever believed.

Br~ injury will necessarily lead to a wide range of symptoms anddeficits. J:s a general rule, the severity of the injury will determinethe seventy of outcome. Some of the problems of CHI patients areattribut~ble to the specific focus of damage. More commonly, how­ever, residual prob~ems a:e the consequence of diffuse cortical damageor of damage to axial brain structures that modulate cortical function.Since anterior, frontal, and temporal lobe structures are most fre­quently damaged in CHI, many of the sequelae are referable to thesestructu~es. It is believ~d that the shear forces that damage axial or~ubcortical structures ill CHI are probably responsible for problemsill ?le~ory, att~nti?n, emotio~al re~ation, and arousal (32, 33).It IS. this combination of specific COrticaldamage and diffuse sub­COrticaldamage that renders the CHI patient a unique specimen.Advocates insist that the clinical needs of CHI patients are different

from those of other patients, and in this contention they are probablycorre~t. CHI pa~ents are not ~e s~rokepatients, or developmentallyh~dicapped p~nents, or psychiatric panents; they are different, anduruque. ~hysicians and therapists who were originally trained withother .panent groups soon discover that major adjustments in ther­ape~~c approach are necessary when the sequelae of CHI are at issue.So It IS,too, when pharmacological approaches are brought to bear.

Th~ fo~owing is ~ typical neuroleptic scenario for CHI patients:A panent IStr.eat~dWIthmtramuscular and then with oral haloperidol,to control. agitano~ and assaultiveness during emergence from coma.The drug IS ~ost madvertently c.ontinued for months after dischargefrom the hospital. Then the panent appears for evaluation at a re­habilitation facility, anergic, depressed, and apathetic, with fine andgross motor coordination problems and deficits in attention mem­?1"f' and ~mo~onal control. The neuroleptic is withdrawn, an'd thereISImmediate rmprovement in all of these areas.. ~his_is a typical ex~rle of short-term benefit for an appropriateindication-s-acute agitation-s-turning into inappropriate long-term

TARDIVE DYSKINESIA Tardive Dyskines146

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between neuroleptics andfunction of one sort or ancthe patients who are treatecan one draw inferences bneuroleptic-treated patientsmost commonly prescribedcourse, and when the patielives in degrading circumstschological deterioration? Ereceptor proliferation in hursystem, the natural questioiquence of the drugs or of theThere is no clearer demonsthan this; if one cannot cuIdefinitive answer will alwajThere are several alterna

deal with the question. Corinteresting lesson in the sci

Alternative 1 is to ignore tto test, and any result willresearch priorities.This is not a bad idea. A

neuroleptic effect should ncwith respect to neurolepticthe face of TD or the neun

However, there is a protportunity to surmount a ~difficult. We lose an oppothe dynamics of neural systetoday, but they may haveantipsychotics that do not 1

and the need to measure .upon us.Alternative 2 is to assume

centers. After all, why shoiproof on those who maintpsychological effects. Thisevery clinical survey that haTD patients, compared toof dementia (41). It is th­issue-whether one presurror that dementia predisposdevelop TD, or that some

human studies. ~f neuroleptic-~du~ed anhedonia (37), dysphoria~38),.and cogruuve and motor rmpaument (39).Yes, indeed, if oneISgwded. by the prevailing belief that deficits in dopaminergic neu­rotr~s~ssIOn are ce~tral to the pathophysiology of CHI. One isthus mcl!-lled to consider neuroleptics relatively contraindicated inCHI pa~Ients, ex~ept.for th~se subjects with neuroleptic-responsivepSyCh?SI~,hallucinosis, .mama, Tourette's syndrome, assaultiveness,or agrtanon. The key IS to determine whether the symptoms arein.d~ed"neuroleptic responsive," that is, that the drugs exert dramaticclinical effects when no other treatment will work as well, that theirefficacy is established at a "minimal effective dose'" and that theircontinued clinical utility is a~sessedat reasonable int~rvals, say, every6 months, by gradually tapenng the dose. There is nothing "rational"about l?ng-t~rm large-dose neuroleptic treatment for CHI patients.The Issue _Isnot o~y even the negative cognitive or motor effects

of ~eurolep?cs, or.their tenden~ to "blunt" the personality of treatedpatlents. It ISonly insmall part influenced by their serious side effects:dysphoria, pseudo-parkinsonism, dystonia, tardive dyskinesia hy­~e~ermia, and ~~ "ne~oleptic malignant syndrome," phot~sen­S~tlVIty,cholestatic Jaundice, hypotension. It is in its largest dimen­sions defm~d by their limited utility in the long-term managementof CHI pauents, an~ the superior effects to be won by more carefullyselected psychotropic treatments. Neuroleptics may be the best ando~y drug treatment .for sc~p~renia, but they are usually a poorthird to carbamazepme and lithium for patients whose symptomsare a consequence of "organic" brain disorder.

Preexisting brain damage is sometimes listed as a risk factor fortardive dyskines~a. The c~ical evidence is equivocal on this point,~JUtthe rese~ch ISsu~gestlve (40). Long-term neuroleptic treatmentm CHI pauents requIres careful monitoring for TD.

A Behavioral Analog of TDThe 9u~sti?n of a.behavi~ral "analog" of TD is a good example ofthe limitations of inferential research. The idea is that chronic neu­roleptic. treatment .may also afflict "higher" areas of brain and thatdementia, psychosis, and/or emotional instability may be the con­s~guence of suprastriatal neuroleptic effects. Terms like "supersen­sitiviry psychosis" and "tardive dysmen~a" have been coined to cap­ture the phenome~~n? an.d there are ~nnal models of postsynapticrec~pto~ supersensitrvity m the mesolimbic dopamine system. Thenotion ISnot supported by any direct evidence' it is only a surmisebased on indirect evidence. 'The fundamental problem is how to demonstrate a connection

Tardive DyskinesTARDIVE DYSKINESIA148

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1. American Psychiatric Asskinesia: Washington, DC

2. Gualtieri CT: Pharmacotmatic brain injury. Brain

3. Gualtieri CT, Schroeder,mentally retarded individi

4. Gualtieri CT: Mental retders: A Task Force Rep.Washington, DC, Ameri.

5. Gualtieri CT, Barnhill J, I'Imovement disorders in c510,1980

6. Polizos P, Engelhardt D:children treated with psy'Research and Treatment.et al. Jamaica, NY, Spect

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REFERENCES

in making work for new tacquire some fundamentalwe are left with the imperthat are less explicit and mto study the epidemiologyuntangling the neuropsych

a reason to suppose that one interpretation is preferred?It is our opinion that the first interpretation is not tenable and

that the truth of the matter probably rests with the second or thethird. The reasoning behind this opinion is as follows: Patients with"organic" brain disease have not been shown to be at greater riskfor TD than patients with "functional" disorders. The prevalence ofTD in retarded people is probably no higher than in schizophrenicpatients (1, 3). Incontrast, patients with affective disorders may beat greater risk to develop TD than any other clinical group (42, 43).The high prevalence of persistent TD in elderly populations sug­

gests an interaction between antipsychotic drug neurotoxicity andsome pharmacodynamic elements intrinsic in the aging process (8).Persistent TD is probably the consequence of irreversible striatal

damage. But the corpus striatum is responsible for more than motorcontrol; it is a complex organ that influences awide range of complexhuman behaviors (44, 45). No disease that affiicts striatal tissue isknown to have only motor consequences; Parkinson's disease andHuntington's diesease are only two examples.This approach sidesteps the issue of mesocortical and mesolimbic

damage and emphasizes the psychological importance of straital dam­age. It is an interesting approach because it generates a testablehypothesis: that TD patients, compared to non-TD patients, willhave specific neuropsychological impairment in tests known to besensitive to striatal lesions, delayed response, for example (46). Aresearch strategy like this will only be effective, however, if it is linkedto a prospective study design. If the hypothesis were tested in adesign that identified patients in a point-prevalence survey, therewould be no way of distinguishing between drug-induced striataleffects of predrug deficits in striatal function that predisposed patientsto the development ofTD.

It is likely that the best way to approach the question of whetherdopamine receptor proliferation in human brains is the consequenceof the drug or the primary disease will be to look for specific psy­chological or behavioral changes in primates treated with long-termneuroleptics. Here the research is simplified considerably by thepossibility of comparing neuroleptic-treated animals to untreatedcontrols. If a specific behavioral syndrome were to be demonstratedin primates with TD, then the model of that syndrome could beinvestigated in humans with and without TD. The strategy is stillindirect, but less so than strategies relying exclusively on humanpopulations.The lesson of science is that as simple questions are addressed,

more complicated questions arise. Scientists only succeed, it seems,

Tardive Dyskine.TARDIVE DYSKI!\'ESIA150

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TARDIVE DYSKINESIA Tardive D)152

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William

Tard2and'.

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