126

CLINICAL COURSE AND CELLULARPATHOLOGY OF TARDIVE

DYSKINESIA

CAROL A. TAMMINGAMARGARET G. WOERNER

Tardive dyskinesia (TD) is an iatrogenic human hyperkineticmovement disorder associated with chronic antipsychoticdrug treatment. The cause of the syndrome, namely,chronic dopamine-receptor blockade, is specifically knownand is straightforward to model. Thus, disease pathophysiol-ogy has been approached with surrogate preparations. Tra-ditionally, factors mediating TD have been sought in striataldopaminergic transmission. However, several incompatibil-ities have developed between the characteristics of the dopa-minergic model and the presentation of the disorder (10).�-aminobutyric acid (GABA)–ergic transmission within thebasal ganglia has also been targeted as the putative patho-physiologic agent in TD. Here, although biochemical char-acteristics between the model and the disease have appearedcompatible, therapeutic implications have not been fullymet, possibly because of inadequate pharmacologic tools(10).

Research has suggested that both these transmitter altera-tions, dopaminergic and GABAergic, may reflect an actionof antipsychotic drugs on neuronal activity within the basalganglia thalamocortical motor circuit. Clinically, antipsy-chotic drug action overall tends to normalize mental statusin psychosis and produces symptom remission in diversepsychotic illnesses, including schizophrenia, bipolar disease,and dementia (8); parkinsonism characteristically occurswith traditional antipsychotics as a major side effect (42).On a cellular basis, gradual alterations produced by thesedrugs over time, within selected subcortical brain regionsand at selected synapses of this circuit, likely result in TD.The mechanism of all these clinical actions is thought tobegin with dopamine-receptor blockade, but thereafter it iscritically mediated by altered neuronal activity (including

Carol A. Tamminga: Maryland Psychiatric Research Center, Universityof Maryland School of Medicine, Baltimore, Maryland.

Margaret G. Woerner: Department of Psychiatry Research, Hillside Hos-pital, Long Island Jewish Health System, Glen Oaks, New York.

GABAergic) in gray matter regions in the segregated, paral-lel frontal-subcortical modulatory motor circuits (35).

CLINICAL FEATURES AND COURSE OFTARDIVE DYSKINESIA

The presentation of TD is typical of a dyskinesia, with oro-facial, axial, and extremity hyperkinetic movements. Themovements worsen with stress and concomitant physicalactivity and diminish or disappear during sleep. TD onset isdefining, in that all dyskinesias with their first onset within 6months of ongoing antipsychotic treatment are diagnosedas TD (50). Consequently, it is expected that the diagnosiswill be confounded by other categories of dyskinesia, includ-ing dyskinesias of schizophrenia and of the elderly. TD isdistinguished from parkinsonism, the other major categoryof antipsychotic-induced movements, by being hyperki-netic, with delayed onset and delayed resolution after medi-cation discontinuation, and by its contrasting pharma-cology.

Movements in TD are typically suppressed by antipsy-chotic drugs, and they are suppressed or even show remis-sion with potent GABA agonists; dopamine agonists exacer-bate the movements, as can anticholinergic drugs (11).Although TD has a characteristic pharmacology, none ofthe drugs that suppress movements in probe studies arepotent enough to be used as a treatment (36). Treatmentapproaches for TD are discussed later.

Although TD risk is inevitable with the traditional anti-psychotics, the risk appears to have dropped significantlywith the second-generation antipsychotic drugs, includingclozapine, olanzapine, and risperidone, with which reducedrisk has been demonstrated (38,63,66), and with quetia-pine, with which reduced risk is probable. Therefore, eventhough TD may be diminishing as a significant clinical riskwith modern antipsychotic treatment, its study has enabled

Neuropsychopharmacology: The Fifth Generation of Progress1832

TABLE 126.1. CUMULATIVE INCIDENCE OF TARDIVE DYSKINESIA

Tardive Dyskinesia Persistent TardiveNeuroleptic Cumulative Incidence, Dyskinesia, (85% CI) Tardive DyskinesiaExposure (y) (95% CI) Cumulative Incidence Hazard Ratea

1 .05 (.04–.07) .03 (.02–.04) —5 .27 (.23–.31) .20 (.17–.23) 6.1%10 .43 (.38–.47) .34 (.30–.39) 4.7%15 .52 (.46–.57) .42 (.36–.47) 3.3%20 .56 (.50–.63) .49 (.41–.57) 2.1%

aHazard Rate is the rate of tardive dyskinesia occurrence per year among those remaining at risk.The number represents the average yearly hazard rate over the 5-year block of time.

identification of cellular and circuit determinants of dyski-nesias in mammalian brain.

The clinical course of TD varies by psychiatric diagnosis,age, sex, and concomitant medical or neurologic illness.Data from a prospective study of 971 young adult psychiat-ric patients followed for up to 20 years indicated a increasingcumulative incidence rate of TD over the 20-year interval(Table 126.1). The cumulative incidence of persistent TDwas lower but increased proportionally (40). These data areconsistent with a declining rate of TD over time, illustratedby the declining hazard rate (Table 126.1). A similar patterndevelops in the hazard rates over 20 years for persistent TD.A decline in hazard rate over time was also reported byMorganstern and Glazer (46), although their data show asharper decline after the first 5 years.

Rates of TD are significantly affected by the age andother characteristics of the several samples studied. An in-creased vulnerability to TD associated with increasing ageis the most consistently reported finding in TD research.A prospective study of 261 geriatric patients with a meanage of 77 years revealed cumulative rates of 25%, 34%, and53% after, 1, 2, and 3 years of antipsychotic drug treatment(74). Similar findings were reported by Jeste et al. (37) andby Yassa et al. (75). In the younger adult sample (40), thehazard rate for TD was lowest for patients in their twentiesand thirties at study entry, increased for those in their for-ties, and sharply increased for those aged 50 to 60 years.

Other variables associated with a significantly increasedTD risk in the prospective study (Table 126.1) included thepresence of extrapyramidal symptoms during antipsychotictreatment, diagnosis of unipolar depression, the number ofpeaks in dosage of antipsychotic drug (more than 1,000 mgin chlorpromazine equivalents), and intermittent antipsy-chotic treatment. Treatment with lithium is associated witha lower risk of TD development.

In this prospective study of 971 psychiatric patients(Table 126.1), the initial episode of TD was persistent forat least 3 months for half of the cases. Of these persistentcases, 68% remitted within the next 2 years. For the halfwhose initial episode was transient, there was a high risk(32%) of developing a persistent episode within 1 year of

additional antipsychotic exposure. Regardless of the dura-tion of the initial TD episode, if it remitted, there was a highlikelihood (61%) of developing a second episode within 1year.

Preliminary data suggest that prognosis for TD remissionis better for patients who are treated for shorter times withinthe follow-up period after TD diagnosis and for thosetreated with lower doses of antipsychotic during follow-up(41). These facts about TD encourage future study in ani-mals and humans on TD mechanisms and treatment andfacilitate the research by providing a firm baseline and aclear description of course.

FUNCTIONAL HUMAN NEUROANATOMY OFANTIPSYCHOTIC DRUG ACTION

The human central nervous system (CNS) has been thefocus of studies to determine the mechanism of antipsy-chotic drug action with both acute and chronic antipsy-chotic drug administration. These antipsychotic data arerelevant to TD mechanisms insofar as the localization ofthe neural pathways subserving antipsychotic drug actioncan suggest the regions that likely contain the neurochemi-cal disorder underlying TD. The firm association betweenstriatal dopamine-receptor blockade and antipsychotic drugaction was established early and has been consistently con-firmed in subsequent study (4,7,53). It has been suggestedthat antipsychotic drugs deliver their full antipsychotic ac-tion by blocking the D2 dopamine receptors in limbic cor-tex (25,54). Alternatively, as argued here, antidopaminergicdrugs could deliver their antipsychotic action by alteringactivity in neuronal populations within the long-loop feed-back neurons in the basal ganglia thalamocortical pathways,at least in part, thereby modulating neocortical activity indi-rectly. The mechanisms responsible for TD may well occurat sites within these modulatory pathways.

Early investigators observed an elevation of neuronal ac-tivity in the human caudate and putamen with antipsy-chotic drug treatment using functional in vivo imaging (33,69). To refine the localization of the signal, our laboratory

Chapter 126: Tardive Dyskinesia 1833

FIGURE 126.1. The regions ofcolor indicate quantitatively theareas of regional cerebral bloodflow (rCBF) activation (ON-30 dayOFF) or inhibition (30 day OFF-ON)with subchronic haloperidol treat-ment (0.3 mg/kg/day). In the toptwo figures, at �04 and 00 mmfrom the anterior commisure/poste-rior commissure line (ACPC) plane,the basal ganglia show significantrCBF activation with haloperidol. Inthe bottom two figures, at �04 and�04 mm from the ACPC plane, boththe anterior cingulate cortex andthe middle frontal cortex show sig-nificant diminished rCBF with halo-peridol. See color version of figure.

conducted a within-subject crossover study comparing halo-peridol (0.3 mg/kg/day for 4 weeks) to placebo (0 mg/kg/day for 4 weeks), with a positron emission tomography scanusing [18F]fluorodeoxyglucose carried out at the end of eachtreatment period (35). Regional cerebral metabolic rates ofglucose, calculated using the usual analytic techniques, wereused for pixel-by-pixel regional comparisons. Haloperidolsignificantly activated neuronal activity in the basal ganglia(caudate and putamen) and thalamus, whereas the frontalcortex (especially the middle and inferior regions) and theanterior cingulate cortex demonstrated a reduction in re-gional cerebral metabolic rates of glucose with haloperidol(Fig. 126.1). Activational differences between the on-drugand off-drug conditions were surprisingly restricted to theseareas, despite the systemic manner of drug delivery andsteady-state kinetic conditions at testing. The striatalchanges had been previously reported (6,68). Subsequentevaluation of haloperidol action using regional cerebralblood flow analysis pharmacodynamically verified these re-gional actions.

The regions identified in the foregoing experiment,whose activity is perturbed by haloperidol, are the same

ones already known to be connected within the basal gangliathalamocortical pathway (15) and involved in modulationof motor and cognitive function (2). In an animal prepara-tion, Abercrombie and DeBoer demonstrated the principlethat a pharmacologic perturbation delivered to a restrictedregion in the basal ganglia (e.g., striatum) can exert distantneurochemical and functional effects (1). The model ofantipsychotic drug action we propose suggests that a pri-mary effect of dopamine-receptor blockade occurs in thecaudate and putamen with antipsychotic drug treatment,and the transmission of this primary action through thebasal ganglia thalamocortical pathway to limbic and neocor-tex mediates antipsychotic and motor aspect of the drugactions in humans. The full mechanism of antidopami-nergic actions therefore could include altered GABAergictransmission in the globus pallidus (GP), which alters activ-ity in the basal ganglia output nuclei; these changes thenmodify GABAergic transmission from substantia nigra parsreticulata (SNR) to the thalamus, inhibit thalamic nuclei,and reduce the overall excitatory glutamatergic signal to thecortex. These observations suggest the hypothesis that thesame basal ganglia thalamocortical circuits that mediate

Neuropsychopharmacology: The Fifth Generation of Progress1834

basal ganglia modulatory influence on prefrontal cortex mayalso mediate the therapeutic effect of antidopaminergic anti-psychotic compounds in schizophrenia. We have reasonedthat a drug-induced regional change, occurring over timewithin this basal ganglia–thalamocortical pathway, associ-ated with a regional increase in the thalamocortical signalcould be associated with TD.

ROLE OF THE BASAL GANGLIATHALAMOCORTICAL PATHWAY INMEDIATING AND TRANSMITTING THEANTIDOPAMINERGIC ACTION INSTRIATUM TO CORTEX

Basal ganglia and thalamic structures modulate functionsof the frontal cortex through parallel segregated circuits, aprocess that has been most fully studied for motor function.This topic is directly addressed in Chapter 122. For theCNS motor system, specific areas of primary motor cortex,primary sensory cortex, and supplementary motor cortexproject topographically to the putamen. These projectionsare thought to remain segregated but parallel throughoutthe full course of the circuit, but they are subject to basalganglia and thalamic influences within each region. Investi-gators have proposed a family of these frontal circuits whosepathways originate in specific frontal cortex areas, coursethrough the basal ganglia and thalamus, and return to thesame areas of cortex, to modulate regional frontal corticalfunction (3). For the motor system, these subcortical struc-tures appear to contribute to the planning and executionof body movements; for other frontal systems, these samesubcortical structures may contribute to maintenance andswitching of behaviors and aspects of cognition (2,26).

The thalamus exerts an excitatory effect on frontal cortexpyramidal cell activity, partially delivered within each fron-tal region by the paired parallel segregated circuit. The basalganglia output nuclei with their high rates of spontaneousdischarge keep their own target nuclei of the thalamus undertonic GABAergic inhibition. These inhibitory output nucleistimuli are, in turn, regulated by two parallel but opposingpathways from the caudate and putamen, one excitatoryand the other inhibitory. The primary cortical signal to basalganglia is mediated by an excitatory glutamatergic pathway.It would be rational to suspect some role of these parallelsegregated motor circuits in antipsychotic drug–induceddyskinesias, as well, especially because the primary actionof antipsychotic drugs is D2 dopamine-family–receptorblockade in striatum.

ANIMAL MODELS OF TARDIVEDYSKINESIA

The cause of TD in antipsychotic drug–treated patientsis, by definition, long-term drug treatment. Thus, putative

models of the condition have been developed in nonhumanprimates and in small animals using long-term administra-tion of antipsychotics and applied to the study of TDmech-anisms. The structural and functional brain characteristicsof nonhuman primates are reasonably similar to those ofhuman primates; hence, primate preparations may makemore valid TDmodels (9). Yet, it is the reality of nonhumanprimate models that many treatment years are required fordyskinesia development (2 to 6 years), and monkey care isinvolved and expensive. Alternatively, putative rat modelshave also been proposed; rat oral dyskinesias develop fasterwith chronic treatment (6 to 12 months), yet they retainmany phenomenologic and pharmacologic characteristics ofhuman TD (61,70). These models often provide a morerealistic experimental platform, even if not more valid, thanthe nonhuman primate for developing hypotheses abouthuman TD.

Animal models of all human diseases have been soughtfor pursuing pathophysiologic hypotheses and for identify-ing new therapeutics. Investigators have suggested the char-acteristics of good animal models for an expressed humanillness as similarities in (a) origin, (b) phenomenology, (c)biochemical characteristics, and (d) pharmacology (45,73).Similarities of these features provide greater validation ofthe model. Across all the TD models, both primate androdent, origin and phenomenology approximate character-istics of human TD. Biochemical determinants are un-known for the TD models as well as for the disease itself.However, extensive similarities exist in pharmacologic re-sponse between the human illness (TD) and the modelpreparations. Because rodent models are more practical topursue, their pharmacology has been more broadly de-scribed than the primate model. It would be obvious tosuggest that the use of both rat and monkey models wouldbe ideal, as the efficiency and specificity of the questionsdictate.

Nonhuman Primate Models

Antipsychotic treatment in the nonhuman primate has beenstudied to define the mechanism of acute drug-induced par-kinsonism and of chronic drug-induced TD (22,31).Gunne et al. (28,31) showed not only the partial penetrationof the syndrome in the nonhuman primate, but also differ-ences in glutamic acid decarboxylase synthesis, the rate-lim-iting synthetic enzyme for GABA, and GABA levels in GPand SNR between drug-treated monkeys with and withoutthe dyskinesia. Based on these data, Gunne et al. proposedthat the mechanism of TD involved a reduction in GABAer-gic transmission in these regions of the basal ganglia, GP,and SNR. This idea correlated with the known clinical phar-macology of TD, namely, that GABA agonist treatment canimprove drug-induced dyskinesias (65).

Chapter 126: Tardive Dyskinesia 1835

Rodent Models

Results from many laboratories suggested that rats treatedchronically with traditional antipsychotics (e.g., fluphen-azine, haloperidol) exhibit seemingly involuntary, irregular,and purposeless oral chewing movements (CMs) over time,often called vacuous chewing movements (13,16,18,23,27,30,56,61). The phenomenology of CMs resembles TD, in thatmovements have a gradual onset (61), partial penetrance(34), and a delayed offset, and they are sensitive to stress(49). However, the movements in rats remain limited tothe oral region and rarely extend to other body parts. Thepharmacology of CMs resembles that of TD: CMs are sup-pressed by antipsychotics, but not by anticholinergics (52);they are reduced by GABAmimetics (20), and they are at-tenuated with benzodiazepines. Rat CMs are associated withmolecular and cellular changes in CNS histology, includingan increase in perforated synapses in striatum and an alter-ation in relative synaptic number in striatum (47). Adminis-tration of the antipsychotic on an irregular schedule canadvance the onset and severity of the rat CMs (24). Thesimilarities across phenomenology and pharmacology areclose enough between human TD and rat CMs for investi-gators to pursue the biochemical basis of CMs as a clue topathophysiology in TD. Moreover, the pharmacology ofthe two are similar enough for the use of this model as ascreen for new antipsychotic drugs to rule out TD potential.

Early pharmacologic studies in the rodent preparationreported that although all traditional antipsychotics are as-sociated with CMs (70,71), clozapine is not (19,27). Subse-quently, the other ‘‘new’’ antipsychotics have been testedand have generated results consistent with clinical data,demonstrating low TD potential for the second-generationantipsychotics (29,39). Neither olanzapine nor sertindoleproduce the CM syndrome at drug doses that producehuman therapeutic plasma levels in the animals (21); risperi-done at low doses is not associated with CMs, whereas highdoses produce haloperidol-like CMs (Gao, unpublished ob-servations). Data using quetiapine or ziprasidone in thisanimal model have not been reported.

NEUROCHEMICAL CHANGES WITHIN THEBASAL GANGLIA THALAMOCORTICALPATHWAYS IN A RODENT MODEL OFTARDIVE DYSKINESIA

We designed and carried out a series of studies in a putativerodent model of TD based on the broadly accepted, func-tional architecture of the basal ganglia and thalamus alreadydescribed. These studies were based not only on the exis-tence of these theoretic models, but also on early experimen-tal data in nonhuman primates with chronic antipsychotictreatment implicating GABAergic transmission in TD (30,31). The drug- and time-induced changes in GABAergic

transmission in nonhuman primate basal ganglia directlyaffected the output nuclei, and from there, the thalamic andfrontal regions associated with the segregated motor circuit.

With chronic (6 months) haloperidol treatment, somebut not all laboratory rats acquired hyperkinetic oral CMsover time (61,63). In comparison, the newer antipsychotics,including clozapine, olanzapine, sertindole, and low-doserisperidone, failed to induce the rat ‘‘syndrome’’ of CMs(21,39). Can these preparations contribute to knowledgeof TD pathophysiology? Can they contribute unique infor-mation to the mechanism of antipsychotic drug action?Comparison of several different animal treatment groupshas been useful in addressing these questions: (a) haloperi-dol-treated rats, with versus without rat CMs and (b) halo-peridol-treated rats versus newer antipsychotic drug–treatedrats.

Chronic haloperidol induces similar D2-receptor up-reg-ulation in striatum in the CM compared with the non-CMrat (Fig. 126.2), a finding discouraging consideration of thisfeature as a correlate of the CMs. Antipsychotic drugs blockthe inhibitory D2 receptor and disinhibit the medium spinyneuronal projections to the GP. In these studies, striataldisinhibition is reflected in the glutamic acid decarboxylasemRNA increases in GP, especially in the CM rats (Table126.2). At the same time, activity in the direct striatonigralpathway appears also to be altered possibly by the haloperi-dol-induced increase in dopamine release in striatum andits action there on the unblocked D1 receptor (12). In theSNR, a primary basal ganglia output nuclei in the rat, ab-

FIGURE 126.2. Specific binding of 3H-spiperone to D2-family do-pamine receptors in the nucleus accumbens of control and chroni-cally haloperidol-treated rats. D2 binding data were similar in thecaudate and putamen. Significant dopamine-receptor up-regula-tion was apparent in the haloperidol-treated rats with chewingmovements (CMs) and in those without CMs; there was no appar-ent difference between CM and non-CM rats in the magnitudeof increase. *p � .05.

Neuropsychopharmacology: The Fifth Generation of Progress1836

TABLE 126.2.

Haloperidol Haloperidol Olanzapine, Sertindole,+ VCMs – VCMs no VCMs no VCMs

Striatum ↑D2R, ↑GAD ↑D2R, ↑GAD S1 ↑D2R No ∆ D2RNo ∆ GAD ↑GAD

Globus pallidus ↓GAD, No ∆ GAD, No ∆ GAD No ∆ GAD,↓GABAAR No ∆ GABAAR No ∆ GABAAR ↓GABAAR

Substantia nigra ↑GABAAR Tr ↑GABAAR∆ Nl, GABAAR Nl, GABAAR1

pars reticulata ↓D1R No ∆ D1R No ∆ D1R No ∆ D1RMD thalamus ↑GABAAR No ∆ GABAAR No ∆ GABAAR No ∆ GABAAR

GABAAR/ No correlation No correlation No correlationVCMcorrelation

Right thalamus ↑GAD mRNA ↑GAD mRNA ↑GAD mRNA ↑GAD mRNA

arrow, significant change; D1R, D1 family dopamine receptor; D2R, D2 family dopamine receptor;GABAAR, GABAA receptor; GAD, glutamic acid decarboxylase mRNA; Tr, trend; VCMS, vacuous chewingmovements.

normalities also occur. Here the CM rats show reducednigral D1-receptor numbers, whereas the non-CM treatedrats show no change in D1-receptor density (Fig. 126.3).Moreover, this CM-associated receptor change in SNR isblocked (along with the CMs) by concomitant chronictreatment with the GABA agonist progabide (Fig. 126.3),a finding strengthening the association between altered SNRD1 receptors and CMs (45). The reduction in D1-receptornumber in SNR could be associated with an antipsychotic-induced increase in the dendritic release of dopamine (Fig.126.4). D1 receptors in SNR mediate the release of GABA.Hence, an increase in dopamine release within SNR couldmediate the release of GABA at striatonigral terminals andsubsequently could inhibit activity in the GABA-mediated

FIGURE 126.3. Specific binding of 3H-SCH23390 to D1-family do-pamine receptors in the substantia nigra pars reticulata (SNR). D1binding was down-regulated by chronic haloperidol (HAL) treat-ment only in the rats that displayed the vacuous chewing move-ments (CMs). This reduction was blocked by the GABA agonistprogabide (P), as were the CMs themselves. Progabide alone hadno effect on the D1 binding. *p � .05.

efferent pathway to thalamus. A reduction in GABA-me-diated transmission from SNR to the target nucleus in thethalamus could produce a compensatory up-regulation ofthalamic GABAA receptors, hence marking altered SNR ac-tivity. In the haloperidol-treated animals, a significant eleva-tion of GABAA receptor occurred, and a significant correla-tion developed between the elevated receptor number andCMs in the mediodorsal thalamus (Fig. 126.5). This posi-tive correlation implicates a nigral D1 defect along withan overinhibition of the nigrothalamic efferent GABAergicpathway as an important mediator of CMs in rat (56). Theidea that a reduction in the activity of the basal gangliaoutput nuclei disinhibits the thalamus and is associated withdrug-induced rat hyperkinetic oral CMs is consistent withthe already established functional models of these interac-tions (2).

Two second-generation antipsychotics tested in the sameanimal chronic treatment paradigm differed from haloperi-dol in their actions. Both olanzapine and sertindole, eachat two doses, were compared with haloperidol after 6months of treatment (56). Neither olanzapine nor sertin-dole substantially up-regulated striatal D2 binding in therat, even though we know from human studies that D2blockade of some strength and duration occurs with eachof these drugs (21). Because of the relatively high receptoraffinities of these drugs at the D2 receptor, the data suggestthat any regional reduction in blockade may occur only atsome of the D2 receptors, and the resultant antidopami-nergic action is weaker or of a reduced duration than withhaloperidol. Nonetheless, olanzapine shows mild, haloperi-dol-like actions in striatum, and sertindole shows mild,haloperidol-like actions in GP and STN. Still, in SNR, nei-ther new compound is associated with D1-receptor down-regulation or GABAA up-regulation (Table 126.2), nor areGABAA receptors altered in mediodorsal thalamus by eithernew drug in contrast to the haloperidol effect. It is possible

Chapter 126: Tardive Dyskinesia 1837

FIGURE 126.4. Hypothetical model for themechanism of chronic haloperidol-inducedchewing movements (CMs) in rat. The datacollected can be parsimoniously explainedby postulating an increase in dendritic do-pamine release associated with the devel-opment of dyskinetic movements in the CMrats. An increase in dopamine could stimu-late the release of GABA presynapticallyfrom the striatonigral GABAergic neuronsand thereby increase the overall GABAergicinhibition on the GABA-containing nigralefferent fibers, including those to the thal-amus. This alteration would serve to de-crease the level of GABAergic inhibition oncritical nuclei of the thalamus. This inter-pretation of the data, even though parsi-monious, is speculative.

FIGURE 126.5. Correlation of GABAA receptor density withchewing movements (CMs) in mediodorsal thalamus in ratstreated chronically with haloperidol. The significant positive cor-relation between these two factors suggests their relationship.This correlation supports the hypothesis that CMs are associatedwith diminished GABAergic transmission from the SNR to signifi-cant thalamic nuclei, evidenced by the up-regulation in GABAA-receptor density associated with the putatively reduced GABAer-gic nigral signal with CMs. However, no other thalamic nucleishow this type of correlation, even the ventral nuclei traditionallyassociated with motor control in thalamus.

that the mechanism whereby these two effective antipsy-chotics (each antidopaminergic) fail to induce CMs is differ-ent in striatum, but both result in a common sparing of acritical change in SNR. It may be that the common seroto-nergic influence exerted within the basal ganglia nuclei byboth these compounds spares SNR changes.

WORKING HYPOTHESIS OF THE CM-TDMECHANISM

The data summarized here are consistent with many reportsin the literature and confirm the central role of the basalganglia output nuclei and thalamus in mediating hyperki-netic movements in chronic antipsychotic-treated animals.It would be our current notion that traditional antipsychoticdrugs alter the dynamic balance of neurotransmitter activitywithin the indirect and direct striatonigral pathway. Thischange, perhaps associated with sustained increase in nigraldendritic dopamine release, results in rodent hyperkineticoral movements through the feedback of this informationto motor regions of neocortex through thalamus. This anti-psychotic-induced alteration acutely would merely inhibitactivity within the indirect pathway and would be associatedwith parkinsonism. As treatment progresses and CMs begin,the indirect pathway inhibition could be progressively coun-terbalanced by direct pathway overactivity in the vulnerableanimals. We postulate that the changes in SNR in D1-receptor (decrease) and GABAA-receptor (increase) num-bers reflect CM-related pathophysiology. These availabledata so far derive from animal model studies and providea putative framework for TD pathophysiology. Work nowmust proceed with the human illness itself, by testing theseand other ideas in in vivo brain imaging studies and post-mortem tissue analysis.

Neuropsychopharmacology: The Fifth Generation of Progress1838

These findings illustrate not only the basal ganglia mech-anisms of one type of dyskinesia, but also one outcome ofCNS plasticity in response to chronic dopamine-receptorblockade. The difference between those animals who arevulnerable to develop CMs and those who are not remainsobscure, as is the vulnerability to TD with antipsychotictreatment in humans.

TREATMENT APPROACHES

There is still no definitive treatment for TD. Nonetheless,therapeutic strategies are often used for patients with TDsymptoms. Prevention, reversal, and suppression or (clinicalmanagement) all need to be considered (57) . Preventionand reversal used to be only theoretic possibilities, but thisis no longer the case. The newer generation of antipsychoticdrugs, with their low TD incidence, has introduced thesevarious new options.

Prevention

Patients who require antipsychotic treatment for extendedtimes today have the opportunity of treatment with one ofthe newer antipsychotic drugs and thus are at reduced riskof developing TD, probably at considerably reduced risk.Clozapine (48), olanzapine (50), risperidone (58), and que-tiapine (67) all have been reported to have reduced associa-tion with TD. Data are not yet available for new antipsy-chotic treatment of neuroleptic-naive persons, in whom theexpectation may be for an even lower association with thesyndrome. However, these data will be generated in time.

Whether treatment with very low-dose traditional anti-psychotic drugs will result in the same low incidence of TDis a possibility, but it is nowhere nearly as probable as withthe use of the newer drugs. Very low-dose traditional drugtreatment, such as haloperidol, 2 to 3mg/day, is being testedin several centers for efficacy in psychosis and for side effects.However, low-dose haloperidol at 4 mg/day has the sameincidence of acute parkinsonism and akathisia as a haloperi-dol dose of 16 mg/day (76), a finding suggesting that low-dose haloperidol still has considerable potency in modifyingmotor function. Nonetheless, the economic advantage oftraditional antipsychotic treatments, when necessity de-mands it, deserves thorough testing.

The cellular basis for the advantage of the newer antipsy-chotics with respect to TD risk is being examined and hasbeen inferred from what is known of their pharmacology.Clozapine has a complex pharmacology, and consequentlyits TD advantage can be theoretically associated with severaltransmitter mechanisms (14). The possibilities include a D1antagonist action, a serotonin2A antagonist action, an anti-muscarinic action, particularly at the M1 receptor, and eventhe antihistaminic action that can spare drug-induced TD.Parsimoniously, because this TD advantage appears to be

a property of several or all of the newer antipsychotics, onecould propose a common mechanism for the TD sparing.Speculations would then center most strongly on the roleof the serotonin2A-receptor blockade in striatum to attenu-ate the tardive motor effects of the dopamine-receptorblockade. This could bemediated by a blockade of serotoninaction on striatal neurons, and a resultant modulation ofdopamine-receptor blockade. Alternatively, the newer drugsmay modulate dopamine blockade regionally to attenuatethe cellular changes produced by the drugs. The results ofthe chronic treatment experiments in rat would favor thislatter explanation. Additional possibilities exist, includinga thalamic or cortical action of the drug at the serotonin2A receptor.

Reversal

Clinical data with traditional antipsychotic treatment sug-gests that dyskinesia reversal occurs in persons with TDduring ongoing treatment (Table 126.1), however, still con-ferring future risk. Data suggest that this reversal may hap-pen faster with newer drug treatment than with the contin-ued use of traditional drugs. TD reversal occurs frequently,although not inevitably, with cessation of antipsychotictreatment (43). This reversal appears to be more likely inthe young rather than in the older patient, presumably be-cause of greater tissue or system plasticity. The reversal oc-curs over the course of months to years, not in the rangeof weeks, so the phenomenon is challenging to document.Based on the simplistic formulation that relieving the brainof the inducing agent will allow the drug-induced tissuechanges to reverse, then drugs such as clozapine or othernewer antipsychotics, which have clinical efficacy with re-duced dopamine-receptor occupancy, may reverse existentTD. Clozapine has been tested in a double-blind protocolcomparing dyskinesia scores between two treatment popula-tions during ongoing drug treatment (haloperidol versusclozapine) over the course of 12 months (63). Dyskinesiain the clozapine-treated group tended to be reduced afterclozapine compared with haloperidol treatment (p � .057).Of some significance is that the rebound dyskinesia withdrug withdrawal after a year of haloperidol treatment wassignificant, whereas after a year of clozapine treatment, thepreviously sensitive group failed to show any dyskinesia re-bound after drug withdrawal, a finding suggesting the lackof system sensitivity (perhaps dopamine-receptor sensitiv-ity) with clozapine. Olanzapine is currently being tested inpersons with TD for its ability to relieve dyskinesia symp-toms over 12 months compared with haloperidol.

Suppression

The feature that most consistently characterizes the resultsof suppression trials in TD is the variability within patients

Chapter 126: Tardive Dyskinesia 1839

and among clinical centers conducting trials. No drugs havebeen reliably demonstrated to suppress TD across all patientgroups and ages, although some drug classes show morepromise and consistency in this regard than other ap-proaches (32).

Benzodiazepines most reliably reduce the dyskinesias ofTD, even at doses that do not produce sedation (64). Clo-nazepine has been widely used and seems to be one of themore effective benzodiazepines (51,64,72). Even when ef-fective, clonazepam shows tolerance over time and requirescontinual dose increases to sustain efficacy. Thus, treatmentmust be occasionally withdrawn to ‘‘resensitize’’ the systemto its effects for treatment to sustain action. The mechanismof therapeutic action has always been thought related to theGABA-enhancing drug action. Because the biology of TDhas suggested regional GABA reductions, a GABA agonistis rational as a therapeutic choice.

Based on a continuation of this reasoning, other GA-BAmimetics have been tested in TD (60). It has been chal-lenging to find a therapeutic window for a GABA agonistin TD, in which the GABA agonist action is potent enoughto be antidyskinetic but the side effects are not limiting.Valproic acid has not been shown to be an effective thera-peutic agent in TD, presumably because of its low potency(44). More potent GABAmimetic, such as �-vinyl-GABAand tetrahydroisoxazolopyridinol, have shown antidyski-netic efficacy, but in some cases with limiting side effects(62,65). The studies that have shown efficacy of GABAmi-metics in TD have used younger patients (i.e., less than 50years old). Studies in older volunteers have not demon-strated efficacy with GABAmimetics (12). Although thequestion of age effect on TD reversal has not been directlytested, it is generally believed that symptoms are more likelyto be suppressed with a GABAergic drug in the young pa-tient than in the older one.

Other drug treatment strategies include vitamin E (17,48,59), melatonin (55), noradrenergic-receptor antagonistssuch as propranolol or clonazepan, amantadine (5), and cal-cium channel blockers, especially nifedipine (58). Whereaseach of these approaches provides clinical interest, none hasdeveloped into a therapeutic approach.

Treatments for TD will always be needed, even thoughthe incidence of new cases may fall significantly with time.Treatments will always be more effective in younger thanin older patients. Opportunities for drug development arelikely to be found in the GABAergic or the glutamatergicneurotransmitter systems.

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