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TreatmentofTardiveDyskinesia

ARTICLEinSCHIZOPHRENIABULLETIN·FEBRUARY1997

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Treatment of Tardive Dyskinesiaby Michael F. Egan, Jose Apud, and Richard Jed Wyatt

AbstractAlthough the new generation of atypical antipsychoticagents could some day eliminate concerns about tar-dive dyskinesia (TD), this disorder remains a signifi-cant clinical problem for both patients and physicians.Fortunately, many, if not most, cases of TD are mild.For patients with mild to moderate TD, therapeuticefforts are primarily directed at minimizing neurolep-tic exposure or, when possible, changing to atypicalagents. Most cases of TD do not seem to progress, sug-gesting that the risk of remaining on typical neurolep-Hcs is probably small. Patients with moderate to severeforms of TD present greater challenges. These patientsfrequently require medication to suppress their dyski-nesias. A variety of suppressive agents have been triedwith limited success. No treatment strategy hasemerged that is clearly superior or even successful inmost patients. Increasing doses of typical neurolepticsmay be useful for short-term suppression; however,the long-term efficacy and risk of this strategy havenot been studied carefully. Data on atypical neurolep-tics are scant. Clozapine's short-term suppressiveeffects seem, at best, weak, but patients may improvewith long-term treatment Medications with relativelyfew side effects that may have suppressive efficacy forsome patients include calcium channel blockers,adrenergic antagonists, and vitamin E. Gamma-amino-butyric acid agonists agents and dopaminedepleters are frequently useful, but have troubling sideeffects of their own. A variety of other medicationshave been employed, but are not well studied. Forpatients with tardive dystonia, anticholinergic agentsor botulinum toxin has been particularly effective.Efforts to understand the neurobiology of TD mayshed light on this persistent clinical conundrum.

Schizophrenia Bulletin, 23(4):583-609,1997.

The introduction of neuroleptics in 1954 for the treatmentof psychotic disorders was a major landmark in medicine.

Although the clinical efficacy of these agents was estab-lished quickly, the subsequent discovery of a sometimespersistent, involuntary movement disorder, tardive dyski-nesia (TD), that was associated with long-term adminis-tration led to more cautious use. The introduction ofclozapine and other putative atypical neuroleptics hasraised hopes that TD will disappear. It is unclear, how-ever, whether the new atypical agents will or will not pro-duce TD. Thus, for the near future at least, clinicians willcontinue to face the conundrum of how to managepatients with TD. In this article, we discuss clinical issuesrelated to TD, including minimizing its risk, whether tocontinue neuroleptics in patients with TD, and what med-ications may be useful for suppressing it.

History-Five years after the introduction of chlorpromazine(Delay and Deniker 1952), Schonecker (1957) describedwhat were probably the first reported cases of TD: After 2to 8 weeks of exposure to chlorpromazine, three elderlywomen developed lip-smacking dyskinetic movements.TD was first described in the American literature in 1960(Kruse 1960). Several years later, Hunter et al. (1964)described dyskinesias in 13 female inpatients with chronicpsychiatric illness, all of whom had been treated with phe-nothiazines. The notion that TD was uncommon persisteduntil studies in the late 1960s began to reveal relativelyhigh prevalence rates. General acceptance of the associa-tion of TD with long-term neuroleptic treatment came inthe early 1970s. The first therapeutic trials for TD fol-lowed shortly thereafter (Kazamatsuri et al. 1972a,19726; Jeste and Wyatt 1982a). In the 1970s, reports ofTD in children and of severe disabling TD in adults

Reprint requests should be sent to Dr. M.F. Egan, NeuropsychiatryBranch, NIMH Neuroscience Or., St. Elizabeths Hospital, 2700 MartinLuther King, Jr. Ave. SE, Washington, DC 20032.

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(Keegan and Rajput 1973; Tarsy et al. 1977; Casey andRabins 1978) began to appear (Tarsy 1983).

Although epidemiological data indicate neurolepticexposure as the most significant etiological factor in thedevelopment of TD, some authors have continued to ques-tion this relationship (Owens et al. 1982; Waddington1986). For example, in a study comparing chronic schizo-phrenia inpatients treated with neuroleptics with a neu-roleptic-naive group, Owens et al. (1982) did not find asignificant difference between prevalence rates of sponta-neous dyskinesia (53.2%) and TD (67%). When the datawere reanalyzed adjusting for a difference in the age ofthe two groups, a slightly higher prevalence in the neu-roleptic-treated patients was found (Owens 1985). Morerecently, Fenton et al. (1994) found that the prevalence ofspontaneous orofacial dyskinesias was 15 percent amongpatients with schizophrenia who had never been on neu-roleptics. This study highlights the difficulty of distin-guishing spontaneous dyskinesias from TD in any givenpatient. Despite the presence of spontaneous dyskinesiasin patients with schizophrenia, epidemiological studies(Kane 1984) strongly suggest that neuroleptics producedyskinesias in patients with a wide variety of psychiatricdiagnoses.

Estimates of the prevalence of TD have ranged from0.5 to 62 percent (Kane 1984; Yassa and Jeste 1992).Several factors may complicate these estimates andexplain differences among studies. These factors includevariability of diagnostic criteria, assessment methods, andthe duration of neuroleptic exposure; differences inpatient age and gender; and the possibility of coexistingmedical and neurological illnesses. Studies reported in the1980s have estimated the average prevalence to be about30 percent (Baldessarini et al. 1980; Casey and Hansen1984; Kane et al. 1985; Chouinard et al. 1988).

Data on incidence provide a more accurate estimateof risk per year of exposure to neuroleptics. These datahave been generated from several rigorous, large-scale,prospective studies. Results indicate that the averageyearly rate of developing TD is about 5 percent per yearfor the first several years. The cumulative 5-year inci-dence rate appears to be 20 to 26 percent (Morgensternand Glazer 1993; Kane 1995). It is unclear whether therisk levels off after 5 years or continues to increase lin-early. Glazer et al. (1993) have suggested that the riskmay indeed be linear for 10 years or longer, with the 10-year risk estimated to be 49 percent and the 25-year riskto be 68 percent.

Epidemiological studies have uncovered a variety ofrisk factors that increase the chances of developing TD(e.g., see Kane 1984; Waddington 1987; Morgenstem andGlazer 1993). Demographic risk factors include increased

age, psychiatric diagnosis (mood disorders have increasedrisk), and gender. However, the findings regarding genderare equivocal. Initial studies suggested that females hadincreased rates of TD, but these findings were confoundedby differences in age or treatment variables betweengroups. More recent, controlled studies find higher ratesonly in women over 65, whereas gender effects are notapparent in younger cohorts. In fact, some studies havefound greater severity in young men than in youngwomen (see Yassa and Jeste 1992 for a review).

The presence of diabetes, organic brain damage, andnegative symptoms (in patients with schizophrenia) alsomay significantly increase risk, perhaps through theireffects on corticostriatal input or on striatal function itself(see below). Studies that focus on patients with organicbrain damage, patients with diabetes, or the elderly sug-gest these factors may increase 1-year incidence rates upto 20 percent or more.

Treatment variables associated with increased riskinclude higher neuroleptic dose, number of medication-free periods, and a history of acute extrapyramidal sideeffects (EPS). The association with increased dose has notbeen found in many studies, but has intuitive appeal(Morgenstern and Glazer 1993; Kane 1995). How med-ication-free periods and acute EPS increase TD incidenceis unclear, but it could theoretically be mediated throughtheir impact on the Dj-mediated striatonigral pathway(e.g., see Egan et al. 1994).

Since the introduction of clozapine into the UnitedStates, it has become apparent that this unusual antipsy-chotic agent is rarely associated with TD, if at all (Kane1995). This observation indicates for the first time that itis possible for a medication to have full antipsychotic effi-cacy while not causing TD. Unfortunately, the use ofclozapine has been limited severely by a variety of otherside effects, such as agranulocytosis. As a consequence,new medications have been designed to mimic cloza-pine's therapeutic profile. Several such putative, atypicalagents have recently been tested in relatively brief clinicaltrials and appear to be promising. These agents, whichinclude risperidone, olanzapine, seroquel (Fleischhackeret al. 1996), sertindole, and ziprasidone, seem to causefewer acute EPS than older "typical" agents. It is unclear,however, whether their long-term use will be associatedwith a lower incidence of TD.

Although one hopes that the new generation of atypi-cal neuroleptics will eliminate TD, this promise has yet tobe fully realized. Many patients continue to develop andsuffer from TD. In addition, for the near future, manypatients will probably continue to depend on typical neu-roleptics. Thus, TD remains a therapeutic conundrum. Thechallenges facing clinicians include how to minimize the

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risk of TD and what to do with patients once they developit.

Prevention and TD

The mainstay of TD prevention has traditionally been tolimit neuroleptic exposure when possible. Unfortunately,the best treatment for many psychiatric disorders is thelong-term administration of neuroleptics. For patientswho require neuroleptics, most experts recommend use ofthe smallest effective dose (American PsychiatricAssociation Task Force 1992). However, the idea that ahigher dose has a significant impact on the incidence orseverity of TD has intuitive appeal, but limited empiricalsupport (American Psychiatric Association Task Force1992; Kane 1995). Most studies have actually failed tofind such a relationship. Those that have are often criti-cized for methodological inadequacies (Kane and Smith1982; Kane et al. 1983, 1986; Kane 1995). A recentlypublished study that has addressed some of the typicalmethodological pitfalls suggested that each increase indose equivalent to 100 mg chlorpromazine is associatedwith a 5 percent increase in the chance of developing TD(Chakos et al. 1996). Conversely, the risk of using verylow doses is that relapse rates are higher (Johnson et al.1983; Kane et al. 1983; Marder et al. 1987). For long-term treatment, intermediate doses (e.g., 400 to 900 mgchlorpromazine equivalents) may be as effective as thehigher doses often used in acute settings (e.g.,Baldessarini and Davis 1980; Van Putten and Marder1986; American Psychiatric Association Task Force1992).

Intermittent treatment or the use of drug holidays hasbeen examined as a way to reduce neuroleptic exposure.Although one study suggested that this strategy may bene-fit some patients (Jolley et al. 1989), it is probably notuseful for most. In fact, well-controlled studies suggestthat intermittent neuroleptic treatment is less effectivethan long-term treatment in preventing psychotic relapse(Carpenter et al. 1990), does not prevent the developmentof TD (Jeste et al. 1979; Newton et al. 1989; Kane andMarder 1993), and may even increase the likelihood ofdeveloping TD (Jeste and Wyatt 19826). One report foundthat depot neuroleptics have a higher tendency to causeTD (Gibson 1978), but this finding requires additionalstudy. Such an association could be due to poor compli-ance and the subsequent intermittent treatment of patientswho are given depot preparations. The long-term use ofneuroleptics is indicated primarily for patients whodemonstrate a clear therapeutic response. Some patientscan be maintained on other agents that are much lesslikely to produce TD. These agents include lithium, anti-

convulsants (e.g., carbamazepine and valproic acid), tri-cyclics, and benzodiazepines.

A second, emerging strategy is to use neurolepticsthat may have a reduced propensity to cause TD.Clozapine, as described earlier, has a minimal risk of pro-ducing TD; however, many other side effects limit its use.Given the risk of agranulocytosis, most experts continueto recommend clozapine as a second-line agent forpatients who are treatment refractory or who developmoderate to severe TD. Of those who develop moderateto severe TD, some will not respond as well to clozapineas they do to other neuroleptics.

Risperidone is the first of the new generation of puta-tive atypical neuroleptics. Clinical and preclinical studiesindicated that it is less likely to produce acute EPS(Klieser et al. 1995). Because lower acute EPS liabilityhas been hypothesized to be associated with a lower riskof producing TD, such results are encouraging (Casey1989). Recent case reports, however, indicate that risperi-done can induce TD (Buzan 1996; Daniel et al. 1996;Woemer et al. 1996). In one case, a schizophrenia patienthad been medication-free for 6 months before risperidonewas started but developed abnormal movements after 1year on risperidone (Woerner et al. 1996). No controlledstudies on the incidence of TD induced by risperidone areavailable, and such long-term data are critical for assess-ing risperidone's risk of inducing TD compared with oldertypical agents.

The development of additional atypical neurolepticsis proceeding rapidly. Olanzapine and sertindole havebeen approved recently by the Food and DrugAdministration and released. Phase II and III studies con-vincingly demonstrated that both medications are veryeffective in treating psychosis and have a low incidence ofEPS (Beasley et al. 1996; Schulz et al. 1996; Tollefson etal. 1996). With such limited use, it is difficult to predictwhether they will assume their touted position as the med-ications of first choice for the treatment of psychosis. Inpreclinical studies, sertindole produced dose-related EPSin Cebus monkeys, but it was also effective in suppressingspontaneous dyskinesias in other monkeys (Casey 1996),suggesting that it might be effective in suppressing TD.Of course, antipsychotics that induce EPS and suppressdyskinesias also have the potential to produce TD.Nevertheless, the introduction of these two new atypicalneuroleptics and indeed of the whole new generation ofagents to come is perhaps the most exciting developmentrelated to TD in decades. Likely their use will becomewidespread.

A third, untested strategy is the prophylactic use ofprotective agents to reduce the incidence of TD. Datausing animal models indicate that antioxidants, such asvitamin E (Klugewicz et al. 1996) and GM1 ganglioside

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(Andreassen and Jorgensen 1994), reduce dyskinesiascores in animals treated with long-term haloperidoldecanoate. Vitamin E has also been shown to attenuate thedevelopment of D2 supersensitivity (Gattaz et al. 1993),likely an important step in the genesis of TD. Clinicalstudies in humans have typically found that vitamin Ereduces the severity of preexisting TD (see below). Theseobservations suggest that prophylactic treatment with vita-min E (1,200 to 2,000 IU/day) could reduce the risk ofdeveloping TD. Although no human studies are availableto support this strategy, long-term use of vitamin E has lit-tle risk. Lithium has also been suggested to reduce theincidence of TD (Cole et al. 1984), although recent dataare conflicting (Kane et al. 1986; Ghadirian et al. 1996),and the routine use of lithium for TD prevention is uncom-mon.

Management of Patients With TDWhen symptoms of TD first appear, a thorough medicalevaluation should be done, including a physical and neu-rological examination, laboratory testing, and a review ofthe differential diagnosis (Hyde et al. 1991). Fortunately,the incidence of organic disorders masquerading as TDseems to be very low (Woerner et al. 1991). The nextissue is whether neuroleptics should be continued. Mostpublished recommendations suggest that drug withdrawalor marked dose reduction, when possible, is indicated; thelikelihood of psychotic relapse, however, is fairly high—amajor risk of this approach. A third issue is whether addi-tional medications are needed to suppress TD. Often, mildto moderate symptoms are either unnoticed or have littleimpact. Those for whom suppressive therapy is neededcan choose from several mildly to moderately successfulmedications.

It is helpful to involve both patients and their familyfrom the outset so that informed decisions can be madeand documented. Patients educated with printed informa-tion sheets (Wyatt 1995) seem to be better informed thanthose educated verbally (Kleinman et al. 1989). Routinemonitoring of TD is essential to track symptomaticchanges and response to medications. The most popularrating procedure is the Abnormal Involuntary MovementScale (AIMS; Guy 1976) examination. Ratings should beperformed every 4 to 6 months on patients with TD andperhaps more often when medication changes are made.Moreover, an examination should also be performed atleast semiannually on patients at risk for developing TD.

Natural Course of TD. Data from several long-termstudies indicate that progression from mild to severe TD, ifit does occur, happens only in a small percentage of cases

(Gardos and Cole 1983; Casey and Gerlach 1986; Gardoset al. 1988, 1994; Gerlach and Casey 1988; Bergen et al.1989). This finding is supported by epidemiological stud-ies indicating that the prevalence of moderately severe TDis roughly 6 to 10 percent of patients with TD or about 4percent of patients treated with neuroleptics (Kane et al.1988; Yassa et al. 1990). The prevalence of very severe TDis probably lower than these figures, but estimates are dif-ficult to obtain (Gardos et al. 1987). By far the most com-mon course for TD is a waxing and waning of mild tomoderate symptoms over many years (Barnes et al. 1983;Robinson and McCreadie 1986; Gardos et al. 1988;Bergen et al. 1992; Kane 1995). Roughly 50 percent ofpatients have recurrent symptoms with neither markedprogression nor extended remission. Although estimatesvary among studies, many suggest that roughly 10 to 30percent will have a reduction in movements or full remis-sion, and another 10 to 30 percent will show some degreeof worsening. These data suggest that, for many patients,continued treatment with neuroleptics after the develop-ment of TD is a reasonable option.

Risk factors have been examined in an attempt toidentify which patients will likely show progression orpersistence of TD with continued treatment. In general,these factors are similar to the risk factors for developingTD (however, see Kane 1995). They include age (Smithand Baldessarini 1980), gender, and exposure to anti-cholinergic agents. Increasing age has been associatedwith fewer spontaneous remissions while on medicationand less improvement after medications are withdrawn.Regarding the effect of gender, the literature is divided.Many suggest that female gender is associated with in-creased risk and persistence, although the opposite has alsobeen found (Bergen et al. 1992; Yassa and Jeste 1992;Yassa and Nair 1992). Other risk factors include durationof exposure to neuroleptics, diagnosis (worse with organicbrain syndromes and affective disorders), duration of TD(Gardos and Cole 1983; Casey and Gerlach 1986; Glazeret al. 1991; Bergen et al. 1992; Yassa and Nair 1992), andfrequent on-off manipulations (Kane 1995). Overall, thesedata suggest that efforts to reduce or discontinue neurolep-tics might be directed toward those at greater risk.

Neuroleptic Withdrawal. Although continued neu-roleptic treatment may be the safest course for manypatients with TD, such as those with a lower risk profile,this continuation must be weighed against the potentialbenefits of withdrawal. Indeed, many experts (AmericanPsychiatric Association Task Force 1992) recommendneuroleptic withdrawal, with the critical caveat that itshould be done only in patients who can tolerate it. In thefirst several weeks after withdrawal, TD often worsens

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(Gardos et al. 1984; Dixon et al. 1993). For example,Gardos et al. (1984) withdrew neuroleptics from 33patients and noted significant increases in dyskinesiaseverity and dysphoria in 33 percent, resulting in theirearly removal from the study. Glazer et al. (1989) with-drew neuroleptics for 3 weeks in 19 patients and noted arelapse of psychosis in 26 percent and TD worsening in53 percent. The magnitude of TD exacerbation in thisstudy is unclear.

After the withdrawal of neuroleptics, TD does seemto improve over the long term despite early exacerbation.In a comprehensive review of 20 studies, Jeste and Wyatt(1979) reported that 36 percent of patients withdrawnfrom neuroleptics showed improvement. Additional stud-ies tend to support their conclusion. Jus and colleagues(1979) found improvement in 49 of 62 patients by slowlytapering neuroleptics over 4 years. Improvement has beenseen up to 5 years after the cessation of treatment(Klawans et al. 1984). In a mostly nonpsychotic patientgroup, Fahn (1985) reported improvement in 13 of 22patients over a 2- to 4-year period. The 22 patients in theFahn (1985) study had concurrent treatment with reser-pine or tetrabenazine. In contrast, Glazer and colleagues(1990) followed 49 patients for an average of 40 weeksafter the discontinuation of neuroleptics. Complete remis-sion was rare (2%), and dyskinesia severity decreased inonly 20 percent. The rate of psychosis relapse for patientswith schizophrenia approached 50 percent (Glazer et al.1984, 1990). One difficulty with drawing conclusionsfrom these studies is that many were unblinded or notwell controlled. Nevertheless, they suggest that neurolep-tic withdrawal is risky but can result in long-term remis-sion of TD in some patients (see also Casey and Gerlach1986).

The degree of improvement during withdrawal maybe related to the same risk factors associated with thedevelopment of TD and with improvement during contin-ued treatment. These factors include age, with patientsover 65 (Smith and Baldessarini 1980) showing littleimprovement; organic brain damage; number of extendedmedication-free periods; and length of neuroleptic treat-ment (Jeste and Wyatt 1979). If drug withdrawal isattempted, very gradual tapering seems less likely toworsen psychosis. A variation of this strategy is an initialincrease in neuroleptic dose to suppress TD, the very grad-ual withdrawal (e.g., 10% per month). This strategy hasworked in several cases of moderate to severe TD withdystonic features (Kleinman, personal communication,May 1996) but has not been studied in controlled trials.

Although withdrawal should be considered, manypatients will not be able to tolerate this approach. Therisks associated with neuroleptic withdrawal include psy-

chotic decompensation (Gilbert et al. 1995) and anincreased likelihood of injury to self or others. Further-more, untreated patients with schizophrenia may have aworse long-term prognosis than patients treated with neu-roleptics (Wyatt 1991). Over the long term, some patientsinitially withdrawn from neuroleptics have actually endedup receiving higher total doses of neuroleptics to copewith symptom exacerbation (Johnson et al. 1983). Manyfactors figure in predicting the success of neurolepticwithdrawal, such as a history of dangerous behavior, cur-rent stressors, the living and working environments, andfamily relationships.

Switching to Atypical Neuroleptics. In lieu of typicalneuroleptics, alternate therapeutic agents can be consid-ered. Most important, one must consider switchingpatients to an atypical neuroleptic. These medicationsoffer the advantage of clear antipsychotic efficacy and thesignificant possibility of reduced TD liability, so it is rea-sonable to conclude that patients with TD will have agreater likelihood of TD remission on atypical neurolep-tics. Unfortunately, this conclusion has not been demon-strated clearly in clinical studies and remains conjectural.As a result, one must clearly delineate the benefits andrisks to patients of the use of atypical neuroleptics. In par-ticular the possible benefits of TD reduction from cloza-pine may not be worth the risk of sedation, seizures, oragranulocytosis for many patients. The fact that somepatients do better on typical agents than they do on cloza-pine or risperidone is also a consideration.

Although a feeling of therapeutic nihilism may creepin regarding patients with TD who require continuedtreatment with typical neuroleptics, one action that couldbenefit them is to ensure adherence (limiting drug-freeperiods) and to vigorously treat substance abuse disorders.Anecdotal reports suggest that patients who abuse suchstimulants as cocaine may develop more severe TD symp-toms.

Who Needs Suppressive Therapy? In our experience,suppressive therapy should be considered if TD poseshealth risks, impairs function, or is otherwise bothersometo the patient, for example, if it creates problems withbreathing, eating, walking, or sleeping. Many patientswith moderate to severe TD are not aware of their symp-toms. Furthermore, a moderate or severe rating on an itemof the AIMS scale does not necessarily mean a patient isfunctionally impaired or disfigured. Suppression in somecases may not be worth the risk. Assessment by an occu-pational or physical therapist can sometimes give insightinto functional impairment and may suggest nondrugstrategies to cope with disabilities.

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Patients with moderate to severe TD are the mostlikely candidates for supressive treatment. Severe TD ismost common in younger men (under age 40) and olderwomen (over 65) and often has a component of dystonia.A variety of functional problems can be produced bysevere TD, depending on the area of the body that isaffected. For example, truncal TD can interfere with walk-ing, sitting, and even sleeping, although TD disappears forthe most part once a patient is able to fall asleep.Orofacial dyskinesia can be particularly disfiguring,sometimes interfering with eating and adequate nutrition,and has been linked to reduced life expectancy(McClelland et al. 1986). Respiratory dyskinesia, oftenoverlooked, can produce a variety of respiratory signs andsymptoms, including irregular respiratory rate, tachypnea,and grunting (Chiu et al. 1991; Nishikawa et al. 1992).Patients with severe TD are at risk for aspiration.

A variety of risk factors for severe TD have beenexamined, such as number of medication-free periods(Yassa et al. 1990; but see Gardos et al. 1987); however, itis difficult to predict who will develop this condition.Anecdotal reports suggest that severe TD comes onquickly, developing over the course of several months,rather than being the result of a relentlessly progressiveprocess that develops over a long period of time with con-tinued neuroleptic exposure. Several authors have notedthat increased blinking or blepharospasm may be a pro-dromal symptom (Gardos et al. 1987; Wojcik et al. 1991).Yet, certainly many patients with increased blinking donot go on to develop severe TD. Treatment of severe TD,as with less pronounced forms, often requires continuedneuroleptic treatment with the serial addition of a varietyof suppressive agents.

Pathophysiology of TD

Several comprehensive reviews (Jeste and Wyatt 1982a,19826; Jeste et al. 1988) have surveyed most of the pub-lished data on the treatment of TD from the 1970s and1980s. In general, the goal of most studies was to demon-strate short-term reduction or suppression of dyskineticsymptoms.

There are no empirically validated guidelines to followwhen choosing a suppressive agent. In general, therapeutictrials have attempted to manipulate one of the followingneurotransmitter systems: dopamine, gamma-amino-butyricacid (GABA), acetylcholine, norepinephrine, and sero-tonin. These systems have received the most attention, inpart due to theories about the pathophysiology of TD.Although an extensive review of this topic is beyond thescope of this article, a brief description of leading ideasmay be instructive.

Dopamine Supersensitivity. The dopamine supersensi-tivity hypothesis of TD was first proposed in 1970 byKlawans et al. Based on the similarity between L-dopa-induced dyskinesias and TD, he suggested that chronicneuroleptic treatment produced supersensitive striataldopamine receptors, similar to denervation-induced super-sensitivity found in peripheral muscles. Since then,dopamine supersensitivity has been an important theoreti-cal construct guiding TD research. Several inconsisten-cies, however, suggest that it cannot explain entirely thepathogenesis of TD. First, supersensitivity occurs within 2to 4 weeks of initiating neuroleptic treatment, whereas TDdevelops after long-term use. Second, in animal studies,most subjects develop supersensitivity, in contrast to onlythe minority of patients who develop TD. Finally, super-sensitivity disappears within weeks after neuroleptics arewithdrawn, whereas TD can persist for months and years.The original version of this idea has been supplanted withthe notion that D2 supersensitivity may be a necessaryfirst step in a path that ultimately leads to the developmentof TD. Interestingly, clozapine does not induce D2 super-sensitivity at standard doses.

A related idea implicates the balance between acetyl-choline and dopamine and is supported, for example, bythe observation that Parkinsonian symptoms are alleviatedby dopamine agonists or cholinergic antagonists. Higherdoses of dopamine agonists can also induce dyskinesias.If dopamine and acetylcholine work in the opposite direc-tion, then cholinergic agonists could alleviate dyskinesias.Although this idea has been heuristically useful, choliner-gic potentiation as a treatment for TD has been largelyunsuccessful.

GABA Depletion. As a result of deficiencies in thedopamine supersensitivity hypothesis, considerable atten-tion has been focused on the GABA system (Mao et al.1977; Gale 1980; Fibiger and Lloyd 1989). Several stud-ies point to decreased GABA turnover or increasedGABA binding sites in one or more areas of the basalganglia in rodents and primates after chronic neuroleptictreatment. This reduction in turnover is most prominent inanimals that have dyskinesias (Gunne et al. 1984).Anderson and colleagues (1989), in a very small humanpostmortem study, found a significant decrease in subtha-lamic glutamic acid decarboxylase activity—the rate-lim-iting enzyme in the metabolic pathway for GABA—inpatients with TD compared with non-TD patients. Otherattempts to assess GABAergic neurotransmission in livingpatients have also suggested that individuals with TDhave particular abnormalities (Thaker et al. 1987, 1988).GABAergic neurons play a central role in the subcorticalregions that generate abnormal movements. Further study

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of this system has led to more detailed notions of whichcomponents may be abnormal.

Neurotoxicity. The idea that long-term neuroleptictreatment may have a toxic effect on the brain has led tomany studies of evidence of neuronal injury. The neuro-toxicity hypothesis is particularly engaging given the per-sistence of TD in some cases and the similarity betweenTD and degenerative diseases of the basal ganglia, such asHuntington's. Unfortunately, most postmortem studies inanimals and patients exposed to long-term neuroleptictreatment have been inconsistent or have suffered frommethodological problems (Christensen et al. 1970;Pakkenberg et al. 1973; Pakkenberg and Fog 1974; Colon1975; Gerlach 1975; Fog et al. 1976; Jellinger 1977;Nielsen and Lyon 1978). Neuroleptics could producemore subtle damage, however, through mechanisms otherthan simple neuronal degeneration. Dopamine is metabo-lized by monoamine oxidase to dihydroxyphenylaceticacid (and then homovanillic acid). A byproduct of thisreaction is hydrogen peroxide, a potent oxidant. It hasbeen hypothesized that hydrogen peroxide could generatea cascade of free radicals that react with proteins, lipids,and other cellular constituents, ultimately leading to sig-nificant neuronal dysfunction. Indeed, several groups havefound evidence suggesting that free radical formation mayoccur both in rodents and humans treated with neurolep-tics (e.g., Pai et al. 1994). Although stronger evidence isclearly required, this hypothesis has led to trials of antiox-idants as a treatment for TD.

Striatal Dysregulation. Studies on the basal gangliaand movement disorders suggest that the final commonpathway for dyskinesias is increased activation of the D,-mediated striatonigral (or "direct") pathway (Albin et al.1989; Crossman 1990; DeLong 1990). These mediumspiny striatal neurons are primarily GABAergic but alsouse several neuropeptides as cotransmitters, includingsubstance P and dynorphin. The direct pathway inhibitsneurons in the substantia nigra, pars reticulata, and itsassociated nucleus, the internal segment of the globus pal-lidus (figure 1). These areas, in turn, project to the thala-mus, which is thought to act as a filter for cortical input.The classical theory is that increased inhibition of theinhibitory GABAergic nigral/pallidal outflow produces anet increase (or loss of inhibition) of thalamocortical pro-jections. The other major outflow tract from the striatum(Albin et al. 1989; Crossman 1990; DeLong 1990), theD2-mediated striatopallidal (or "indirect") loop, may alsoplay a role. The medium spiny neurons of this pathwayare also GABAergic and use the neuropeptide enkephalinas a cotransmitter. Increased activity of this pathway,

SubstantiaNigra

Thalamus

Excitatory corticostriatal projections regulate striatal outflow.Dopamine projections from the substantia nigra, pars compacta,modulate striatal neuronal activity via dopamine D1 and D2 recep-tors. These receptors seem to be segregated into the two majorstriatal outflow tracts: the D2-mediated striatopallidal or "indirect"loop and the D.,-mediated striatonigral or "direct" loop. Theseloops ultimately terminate in the globus pallidus, interna, and thesubstantia nigra, pars reticulata. These two regions modulate thal-amic activity via gamma-amino-birtyric acid (GABA)ergic inhibitoryprojections. ACH = acetylcholine; ENK = enkephalin; SP = sub-stance; DYN = dynorphin.

which results from blockade of the inhibitory D2 recep-tors, may facilitate the expression of D : overactivation(Egan et al. 1994). Indeed, animal studies suggest thathaloperidol increases D] agonist-induced dyskineticmouth movements in rodents.

Although the hypothesis that TD is a result of suchalterations in basal ganglia physiology remains unproved,it suggests that a variety of neurotransmitters and recep-tors could play a role; for example, Dj and D2 receptors,cholecystokinin (CCK), neurotensin, GABA, Af-methyl-D-aspartate receptors, and opiate receptors (mu, kappa, andpossibly delta). Drugs targeting these transmitter systems

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may affect TD symptoms. Unfortunately, animal studiesusing such agents have generally been inconclusive, andhuman studies are limited.

Suppressive Therapies for TD

The competing theories on TD have led to clinical trialsof a wide variety of medications. None has been success-ful in the majority of patients. As a result, one may haveto try several medications in series before finding onewith some utility. In general, selection is guided by a ben-efits-risk analysis, success in prior studies, potential sideeffects of the suppressing agent, and interactions withother medications.

Typical Antipsychotics. Neuroleptics themselves maybe effective to some degree in suppressing TD. A 1979review of 50 studies, totaling 501 patients, found that 67percent showed clinical improvement with neurolepticsuppression, the highest improvement rate of any suppres-sive strategy (Jeste and Wyatt 1979). However, a morerecent review (Jeste et al. 1988) suggested a lower rate ofresponse. Suppressive effects are most pronounced inshort-term studies (Doongaji et al. 1982; Jeste and Wyatt1982a; Perenyi et al. 1985; American PsychiatricAssociation Task Force 1992), although some well-con-trolled studies have found that suppression is often mini-mal (e.g., Lieberman et al. 1988a, 19886). The therapeuticefficacy of long-term (more than 8 weeks) suppression isunclear, in part due to problems with study design. Moststudies have first withdrawn patients from neurolepticsand then compared changes between neuroleptic andplacebo treatment (Roxburgh 1970; Singer and Cheng1971; Kazamatsuri et al. 1912b, 1973; Glazer and Hafez1990). This design may be a better measure of the neu-roleptics' ability to suppress withdrawal dyskinesias thanpersistent TD. Other studies were either unblinded or didnot use appropriate control groups (Roxburgh 1970;Curran 1973; Jus et al. 1979; Smith and Kiloh 1979). Ofthree particularly well-controlled studies, two found sig-nificant long-term suppression (Frangos andChristodoulides 1975; Gerlach and Casey 1983), whilethe third did not (Korsgaard et al. 1984). A fourth studyusing depot neuroleptics showed brief improvement (i.e.,1-2 days) along with increased blood levels immediatelyafter drug injection in 4 of 6 patients (Barnes and Wiles1983). Although these findings are suggestive, the safetyand efficacy of increased neuroleptic dose for long-termsuppression remain questionable.

A primary concern with using higher neurolepticdoses for suppression is the potential that TD couldbecome worse. Nevertheless, in severe cases with life-

threatening complications, increasing the dose many be theonly maneuver that will help. Higher potency neuroleptics,such as haloperidol, may be more effective in suppressingmovements than those of lower potency, such as molin-done. In patients with withdrawal TD, Glazer and col-leagues (1985a) were able to suppress symptoms in 66percent of those using haloperidol versus only 39 percentof those using molindone. If withdrawal dyskinesias aresimilar pharmacologically to persistent dyskinesias, theymay also be suppressed more effectively by high-potencyneuroleptics. Giving medications in divided dosesthroughout the day has also been helpful in masking symp-toms of TD. In a variation of this strategy, we have seenimprovement in several patients after stopping neuroleptictreatment for several weeks, then restarting it at a lowerdose. This strategy has not been studied under controlledconditions, however, and the two patients who improvedhad a marked Parkinsonian tremor in addition to TD.

Atypical Neuroleptics. In addition to their use as drugswith lower TD liability, atypical neuroleptics, particularlyclozapine, have also been tried as suppressive agents.Although early experience with clozapine was generallydisappointing (Gerlach et al. 1974; Gerlach andSimmelsgaard 1978; Caine et al. 1979), more recent stud-ies have been mixed (Lieberman et al. 1991). A descrip-tion of published reports provided in table 1 includes 16clozapine studies—7 case reports, 4 open trials, 1 singleblind, and 4 double-blind, controlled, or crossover studies.All seven case reports, not surprisingly, found improve-ment: two described rapid TD suppression (Carroll et al.1977; Meltzer and Luchins 1984), and four observed dra-matic responses only after months or years (Lamberti andBellnier 1993; Friedman 1994; Trugman et al. 1994;Levkovitch et al. 1995). Four open, uncontrolled trials(Cole et al. 1980; Gerbino et al. 1980; Small et al. 1987;Lieberman et al. 1991) also found beneficial effects withclozapine. The most significant results were observedafter at least 4 weeks of treatment and for patients withsevere TD and tardive dystonia (Carroll et al. 1977;Meltzer and Luchins 1984; Lieberman et al. 1991). Inmost cases, TD symptoms returned to baseline after thediscontinuation of clozapine (Cole et al. 1980; Gerbino etal. 1980; Small et al. 1987; Lieberman et al. 1991), whichsuggests that TD was suppressed.

Of four double-blind, controlled or double-blind,crossover studies, two found significant improvementwith clozapine (Simpson et al. 1978; Tamminga et al.1994). In both positive studies, clozapine was adminis-tered for 22 to 52 weeks. In contrast, the negative studieslasted only 3 to 5 weeks. The study by Tamminga et al.(1994) was particularly lengthy and included a control

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Table 1. Studies of the effect of atypical neuroleptics on tardive dyskinesiaReference

Gerlachetal. (1974)

Caineetal. (1979)

Geriach andSimmelsgaard (1978)

Carroll et al. (1977)

Simpson etal. (1978)

Coleetal. (1980)

Gerbinoetal. (1980)

Meltzer and Luchins(1984)

Small etal. (1987)

Van Putten et al.(1990)

Lieberman et al.(1991)

Lambert and Bellnier(1993)

Friedman (1994)

Tamminga et al.(1994)

Trugmanetal. (1994)

Levkovitch etal. (1995)

Meco etal. (1989)

Kopala and Honer(1994)

Chouinard(1995)

Drug

Clozapine

Clozapine

Clozapine

Clozapine

Clozapine

Clozapine

Clozapine

Clozapine

Clozapine

Clozapine

Clozapine

Clozapine

Clozapine

Clozapine

Clozapine

Clozapine

Risperidone

Risperidone

Risperidone

Design

Double-blind, crossover

Double-blind, placebo-controlled

Crossover

Case report

Single-blind, placebo-controlled, doublecrossover

Open, uncontrolled

Open

Case report

Open, uncontrolled

Case report

Open, uncontrolled

Case report

Case report

Double-blindcontrolled,randomized, non-crossover

Case report

Case report

Crossover,placebo-controlled

Case report

Double-blind,parallel

Duration

3 weeks

3-5 weeks

4 weeks

18 days

22 weeks

Up to 12weeks ormore

4 weeksand 12months

2 weeks

7 weeks

14 weeks

36 months

11 months

> 3 years

12 months

4 years

48 months

4 weeks

4 weeks

8 weeks

Maximum dose

225 mg/day

425 mg/day

62.5 mg/day

1,000 mg/day

523-775mg/day

100-500mg/day

4 weeks: 650mg/day; 12months: downto 50% of initialdose

900 mg/day

340 mg/day

250 mg/day

486 mg/day(averagedaily dose atendpoint)

300 mg/day

350-500mg/day

293.8±171.9mg/day(average dailydose at end-point)

625 mg/day

450-550mg/day

6 mg/day

4 mg/day

6-16 mg/day

Outcome

No significant effect

No significant effect

No significant effect

Significant improvement

Significant improvement

Significant improvement,mainly after > 12 weeks

Significant improvementat both times

Significant improvement

Significant improvementin only 7 of 19 patients

Significant improvement

At least 50% improve-ment in 43% of patients

Significant improvement

Significant improvement

Significant improvement

Significant improvement

Significant improvement

No significant effect

Significant improvement

Significant improvement

group of 32 patients treated with haloperidol during a 12- clozapine, lack of appropriate controls, and inconsistentmonth blind treatment period. Comparison of the different patient followup. Two noteworthy trends are that a longstudies is complicated by the use of different doses of duration of treatment is needed and that dystonic features

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may be more responsive than dyskinetic ones (Liebermanet al. 1991). The mixed results in controlled studies sug-gest that further investigations of clozapine's suppressiveproperties are warranted.

If clozapine is shown to have therapeutic effects inTD, several mechanisms could play a role. An early acuteresponse to clozapine suggests a suppressive effect similarto classical neuroleptics. Longer-term improvement couldbe due to a passive mechanism in which dyskinetic move-ments improve over time in the absence of the offendingagent. A third possibility is that clozapine has an active,not simply suppressive, therapeutic effect on dyskineticmovements.

Little is known about the effect of risperidone on TD.An early, controlled study (see table 1) found no evidenceof suppression (Meco et al. 1989). More recently, a casereport found suppression of severe TD with risperidone(Kopala and Honer 1994), and more convincingly, theCanadian Multicenter Risperidone Study showed an anti-dyskinetic effect in a double-blind, placebo-controlledtrial (Chouinard 1995). Thus, risperidone could be usefulas a suppressive medication, although since it may alsoinduce TD (Buzan 1996; Daniel et al. 1996; Woerner et al.1996), the risk of long-term exacerbation is unknown.

The development of new atypical antipsychotics mayprovide alternatives for the treatment of TD. Olanzapine,sertindole, seroquel, and ziprasidone have been shown tobe efficacious for the treatment of psychosis and to pro-duce fewer EPS than traditional neuroleptics (Seeger et al.1995; Beasley et al. 1996; Borison et al. 1996; Schulz etal. 1996; Tollefson et al. 1996). Like clozapine, thesedrugs are more effective in blocking the 5-hydroxytrypta-mine2 (5-HTj) than the D2 receptor site. In contrast toclozapine, however, all are relatively potent D2 antago-nists. The finding that clozapine is associated with a lowerincidence of TD (Casey 1989) and may suppress TD sug-gests that there are important advantages to using cloza-pinelike medications with selectivity for the 5-HT2 recep-tor. However, it is unclear whether these putative atypicalneuroleptics will be effective in suppressing TD.

Dopamine Depleters. Medications that work primarilyby reducing or depleting presynaptic stores of dopaminehave sometimes been helpful in reducing TD severity.Dopamine depleters act by several different mechanisms.Reserpine and tetrabenazine (not available in the UnitedStates) disrupt the storage of dopamine in presynapticvesicles. Alpha-methyldopa reduces dopamine synthesisby competitive inhibition of dopa decarboxylase and theformation of a false neurotransmitter. Alpha-methyl-para-tyrosine (AMPT) also reduces dopamine (and norepi-nephrine) synthesis via its actions on tyrosine hydroxy-lase, the rate-limiting enzyme in dopamine synthesis.

Studies of dopamine-depleting medications suggestthat they may alleviate symptoms in up to 50 percent ofpatients with TD. For example, using reserpine, Huang etal. (1981) found at least 50 percent improvement in 5 of10 patients, whereas Fahn (1985) showed improvement in8 of 17 patients who were not taking neuroleptics.Nasrallah et al. (1986) found improvement in 5 of 10patients in a 4-week, double-blind study using AMPT;only patients who remained on neuroleptics in addition toAMPT improved. Although not all studies have found thisdegree of success (Lang and Marsden 1982), previousreviews of both uncontrolled case reports and controlledstudies support the 50 percent estimate (Jeste and Wyatt1979; Jeste et al. 1988). For example, a review of fivestudies performed from 1961 to 1977 found that tetra-benazine improved TD in 29 of 42 patients. In the samereview, 17 of 38 patients from another five reportsimproved on reserpine, and 18 of 32 improved on AMPT(Jeste and Wyatt 1979). Although larger, well-controlledstudies are needed to validate these findings, the limitedavailable data support the use of dopamine-depletingmedications for TD suppression. Unfortunately, sideeffects, including hypotension (reserpine, alpha-methyl-dopa), impotence, and depression, as well as Parkin-sonism and akathisia, often limit their use. Depression, arelatively frequent side effect, has been treated success-fully with concurrent antidepressant administration.

Dopamine Agonists. In animal studies, dopamine ago-nists downregulate dopamine receptors and theoreticallycould be useful in TD. A major drawback is that they caninitially exacerbate both TD and psychotic symptoms.Direct (apomorphine and bromocriptine) and indirect(amantadine and levodopa) dopamine agonists have beentried in humans. Some positive case reports or single-blind studies have been published, but most double-blindstudies show little improvement (Jeste et al. 1988; Lieber-man et al. 1989). One exception is a recent report of 35inpatients with severe orofacial TD who showed markedimprovement on L-dopa after 3 months. Symptomsreturned when L-dopa was discontinued and againresponded when treatment was restarted (Ludatscher1989). This study, which suffers from several method-ological shortcomings, needs to be replicated in a double-blind, crossover study but is encouraging nonetheless.

Dopamine autoreceptor agonists—for example, n-N-propyl-3-(3-hydroxyphenyl)piperidine (3-PPP)—decreasethe release of dopamine and present another possiblemechanism to treat TD. 3-PPP has been shown to improveTD in monkeys (Kovacic et al. 1988), but it has not beentried in humans. In low doses, apomorphine is an autore-ceptor agonist, whereas in high doses it is a postsynapticreceptor agonist. Theoretically, low doses should decrease

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dopamine release and improve symptoms of TD, whereashigh doses should do the opposite. Paradoxically, onestudy showed that high doses, up to 6.0 mg, reduced TDmovements (Smith et al. 1977). The usefulness of apo-morphine may be limited by such side effects as nauseaand vomiting at therapeutic doses.

Noradrenergic Antagonists. Although noradrenergicinnervation of basal ganglia structures is sparse and lim-ited primarily to the thalamus, noradrenergic agents havebeen used to treat TD. The beta-adrenergic antagonist,propranolol, has been reported in open studies to partiallysuppress TD in 11 of 15 patients (Jeste and Wyatt 19826).In a double-blind study of four patients, two improvedwith long-term treatment (Schrodt et al. 1982). Un-fortunately, no larger or more recent studies are available,and it is unclear whether or not propranolol's suppressiveeffect is due to increased neuroleptic blood levels. In con-trast, pindolol, another beta blocker, was unsuccessful insuppressing TD in a small placebo-controlled study(Greendyke et al. 1988). Clonidine, an alpha2 agonist,decreases the release of norepinephrine by autoreceptorstimulation and has been reported to have antidyskineticproperties in a majority of patients (Freedman et al. 1982;Nishikawa et al. 1984; Browne et al. 1986). Clonidinemay also have antipsychotic properties (Freedman et al.1982) and has relatively few side effects (hypotension,sedation). Other noradrenergic antagonists with apparentsuppressive effects are disulfiram (Jeste et al. 1986) andfusaric acid, both dopamine beta-hydroxylase inhibitors.Oxypertine depletes norepinephrine and dopamine andmay also improve dyskinesias (Soni et al. 1984).Unfortunately, this line of treatment has not been pursuedin large well-controlled studies. At the present time, nora-drenergic antagonists, particularly clonidine, seem to berelatively safe and somewhat effective as suppressiveagents.

Anticholinergics. As mentioned above, dopamine andacetylcholine seem to have opposite effects on behaviorsmediated by the striatum. One could predict that anti-cholinergics would make TD worse. Although this effecthas been found in some reports (Klawans 1973), othershave found either no change (Wirshing et al. 1989) or evenimprovement in TD with anticholinergics. For example, inan acute challenge study using intravenous administration,Lieberman and colleagues (1988a, 1988f>) showed thatbenztropine tended to decrease movements, whereasphysostigmine worsened them (see also Moore andBowers 1980). This finding suggests that dopamine andacetylcholine are not simply functional antagonists in thebasal ganglia. In general, however, most data indicate that

long-term treatment with anticholinergics either does nothelp or may actually worsen TD (Jeste and Wyatt 1982a,19826; Friis et al. 1983), and their discontinuation may behelpful in up to 60 percent of patients (Jeste et al. 1988;Yassa 1988). An important exception is tardive dystonia,which may markedly improve with moderate to high doses(20 mg/day and higher) of anticholinergics such as tri-hexyphenidyl (Artane) (Burke et al. 1982; Fahn 1983).

Anticholinergics have been also hypothesized to pre-dispose patients to develop TD (Klawans 1976), althoughthis has been disputed (Yassa 1988). The issue may bethat patients exhibiting acute EPS, who are more likely tobe treated with anticholinergics, are more susceptible toTD than patients who do not exhibit acute EPS (Keepersand Casey 1991). Despite such theoretical considerations,for many patients anticholinergics remain useful for acuteEPS.

Cholinergics. Just as anticholinergics theoreticallyshould worsen TD, cholinergic agonists should improveit. Numerous studies conducted primarily in the 1970swith several acetylcholine precursors generally yieldeddisappointing results (Jeste and Wyatt 1979, 1982a).These agents include deanol, choline, and lecithin, a natu-rally occurring precursor of choline. One difficulty withinterpreting these negative findings is the issue of howsuch drugs like deanol actually boost central cholinergicneurotransmission. Physostigmine, a centrally actingcholinesterase inhibitor, has been used to investigate thepharmacology of TD, with mixed results (Lieberman et al.1988a, 19886; Yagi et al. 1989). An encouraging prelimi-nary study using the cholinergic releasing agentmeclofenoxate found improvement in 5 of 11 patients(Izumi et al. 1986). Tacrine (or THA) is a recentlyreleased cholinesterase inhibitor primarily used for thetreatment of Alzheimer's disease. Although this agent isclearly effective in boosting central acetylcholine neuro-transmission, we are not aware of studies of its useinvolving TD. While future experience may alter this sur-prising omission, cholinergic agents do not currently playa significant role in the treatment of TD.

GABA Agonists. A variety of experimental and com-mercially available GABA agonists have been used totreat TD, some with significant success. Jeste and Wyatt'sreview (1982a) described 19 studies totaling 204 patients,with 54 percent having greater than 50 percent improve-ment, making GABA agonists the most effective nonneu-roleptic class of drugs reviewed. In a 1988 review of nineadditional studies, the efficacy of GABA agonists fell toabout 30 percent (Jeste et al. 1988). In contrast, a selec-tive review of the effects of benzodiazepines by Thaker et

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Schizophrenia Bulletin, Vol. 23, No. 4, 1997 M.F. Egan et al.

al. (1990) found that, in 15 reports involving a total of158 patients, 83 percent of patients improved to somedegree. Although side effects, such as sedation, ataxia,and addiction, may limit the use of many GABA agonists,they have an important role, at least as second-line agents,for the suppression of TD.

Experimental GABA agonists have produced mixedresults in clinical studies. For example, 4,5,6,7-tetrahy-droisoxazolo-(5,4-c)pyridine-3-ol, a GABAA agonist(Thaker et al. 1987), and gamma-vinyl-GABA, a GABA-transaminase inhibitor (Stahl et al. 1985), improved TD,but only to a minor degree. Muscimol, another GABAA

agonist, produced a 45 percent reduction in seven patients(Tamminga et al. 1979). Several reports suggested thatprogabide, a mixed GABAA and GABAB agonist, mayhave significant therapeutic effects, but more studies areneeded. Although the efficacy of these experimentalagents supports a role for GABA in the pathophysiologyof TD, they have limited clinical use.

The most-studied commercially available GABAagonists are valproate, diazepam, clonazepam, andbaclofen. A 1979 review described three studies using val-proate that had mixed results (Jeste and Wyatt 1979).Since then, three additional reports were not encouraging.In one, 3 of 6 patients improved (Friis et al. 1983),whereas in a second, none of 10 improved (Nasrallah etal. 1986). In the third, a well-controlled, double-blindstudy, 33 patients treated for 6 weeks with valproate werenot significantly different from 29 patients treated withplacebo (Fisk and York 1987). Diazepam, in contrast, hasbeen more effective. Four studies before 1979 reportedimprovement in 26 of 29 patients on diazepam (Jeste andWyatt 1979). More recently, in a single-blind study,diazepam was again effective in 11 of 20 patients (Singhet al. 1983). One drawback of diazepam is that it can behabit forming or cause sedation, depression, or, less com-monly, impulsiveness and belligerence. Clonazepam is aneffective alternative. Two open studies found markedlydifferent results, with 42 of 42 patients benefiting in one(O'Flannagan 1975) but only 2 of 18 improving in theother (Sedman 1976). In a more recent, well-controlled,double-blind study by Thaker et al. (1990), suppressionwas observed in 26.5 percent of patients with choreo-athetosis and 41.5 percent of patients with dystonia.Tolerance can develop to clonazepam's therapeuticeffects, but it may be overcome by a brief withdrawalperiod (Thaker et al. 1990). In a selective review of eightstudies with baclofen, Glazer et al. (1985&) noted onlytwo that showed significant results. In one study, 75 per-cent of 20 patients improved on 15 to 60 mg per day(Korsgaard 1976), whereas in the second study, TD rat-ings were reduced by 40 percent in 18 patients (Gerlach et

al. 1978). Baclofen seems to act primarily on GABAB

receptors, which may not be as important in TD.In summary, among GABA agonists, benzodiaze-

pines have been the most effective in clinical studies forsuppressing TD. On average, 58 percent of patients inopen studies and 43 percent in double-blind studies haveimproved (Gardos and Cole 1995). Thus, clonazepam anddiazepam are important therapeutic options in treatingTD. Valproate and baclofen are probably less effectiveand cannot be strongly endorsed. Newer agents, such asgabapentin, have not been employed in controlled studies.

Antioxidants. One of the more interesting new treat-ments for TD is vitamin E, an antioxidant and free radicalscavenger. The use of this compound was originally moti-vated by the notion that neuroleptics produce toxic freeradicals that can cause neuronal dysfunction or cell death.In table 2, eleven double-blind, placebo-controlled studieshave examined the effects of vitamin E (Lohr andCaligiuri 1996). Of these, three reported no evidence of atherapeutic effect (Schmidt et al. 1991; Shriqui et al.1992; Lam et al. 1994). These negative studies were eitherbrief (2 weeks), included older patients, or studiedpatients with a relatively long duration of TD. In contrast,the other eight studies found some evidence of reducedTD severity with doses ranging from 1,200 to 1,600 IUfor 4 to 12 weeks. Vitamin E's effects have been mostpronounced in patients with relatively recent onset (e.g.,within 5 years) (Egan et al. 1992; Adler et al. 1993; Lohrand Caligiuri 1996). Overall, improvement in positivestudies has ranged from 18.5 to 43 percent. In addition,several open trials or case reports have also found evi-dence for vitamin E's therapeutic effects in TD or tardivedystonia (Spivak et al. 1992; Peet et al. 1993; Couplandand Nutt 1995). An ongoing large, multicenter studyfunded by the Department of Veterans Affairs may helpclarify issues about therapeutic efficacy and subpopula-tions that respond favorably.

Despite the positive data regarding vitamin E, severalcaveats are indicated. First, a therapeutic effect of vitaminE does not necessarily validate the free-radical hypothesisof TD. Vitamin E may have other neurobiological effects,such as reducing D2 supersensitivity (Gattaz et al. 1993)or altering monoamine metabolism (Jackson-Lewis et al.1991). Furthermore, several other drugs with antioxidantproperties (e.g., selegiline and coenzyme Q) have notbeen effective in TD. Finally, in most cases, the effects ofvitamin E are fairly minor. Thus, although vitamin Ecould be a reasonable addition to the therapeutic arma-mentarium, its beneficial effects seem to be limited. Casereports have suggested an association between vitamin Eand thrombophlebitis in the elderly (Roberts 1981), but

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Table 2. Studies of the effect of vitamin E on tardive dyskinesia (TD)

Reference

Lohretal. (1988)

Elkashef et al. (1990)

Schmidt et al. (1991)

Eganetal. (1992)

Junker etal. (1992)

Shriqui etal. (1992)

Adleretal. (1993)

Aktaretal. (1993)

Dabirietal. (1994)

Lam etal. (1994)

Lohr and Caligiuri(1996)

Maximum dose

1,200 IU

1,200 IU(4 weeks)

1,200 mg(2 weeks)

1,600 IU(6 weeks)

1,200 mg

1,200 IU(6 weeks)

1,600 IU(8-12 weeks)

1,200 mg(4 weeks)

1,200 IU(12 weeks)

1,200 IU(4 weeks)

1,600 IU(2 months)

Design

Double-blind,crossover

Double-blind,crossover

Double-blind,crossover

Double-blind,crossover

Double-blind,crossover

Double-blind,crossover

Double-blind,parallel

DouWe-blind,parallel

Double-blind,parallel

Double-blind,crossover

Double-blind,parallel

DurationofTD

2.6 ± 1.9 year

3.8 ± 2.8 years

10 patients > 1 yr;9 patients < 1 yr

5.9 ± 4.8 years

Not significant

"Longduration"

9 patients > 5years; 4 patients< 5 years

6.5 years

14 weeks

Notavailable

11 months

Number ofpatients

15

8

19

18

16

27

28

32

11

12

35

Outcome

43% improvement

27% improvement

No overall effect

No overall effect; 9patients with TD s 5years showed 18.5%improvement

Significant improvementin patients over age 40

No effect

32% improvement onvitamin E; patients withTD < 5 years did better(52% vs. 27%)

Greater improvement inpatients on vitamin E(20%)

36% improvement

No difference; olderpatients (mean age 61.8years); long duration ofillness (> 20 years)

24% improvement

this or other serious side effects have not been found inwell-controlled studies. Generally, vitamin E is safe, pro-ducing few side effects. Rarely, patients report abdominalpain, headaches, muscle cramps, nausea, or fatigue.Vitamin E may elevate triglycerides and cholesterol anddecrease thyroid indices, although it has not been reportedto cause hypothyroidism. These abnormalities and symp-toms all disappear after its discontinuation. Vitamin Emay also interact with coumadin to prolong bleedingtime. Additional research is needed to establish the thera-peutic efficacy of vitamin E.

Calcium Channel Blockers. Observations that calciumchannel blockers may help alleviate TD symptoms comeinitially from case reports in the late 1980s (Barrow andChilds 1986; Ross et al. 1987; Buck and Harvey 1988;Falk et al. 1988) (see table 3). Unfortunately, despite the

plethora of anecdotes, only three double-blind, placebo-controlled or double-blind, crossover studies have beenpublished. Suppressive efficacy is most convincing fornifedipine. Two open, one single-blind, and one double-blind study all found significant improvement withnifedipine. Data on verapamil are more limited; three casereports (Barrow and Childs 1986; Buck and Harvey 1988;Abad and Ovsiew 1993) and one single-blind, placebo-controlled study of nine patients (Reiter et al. 1989) foundthat verapamil suppressed moderate to severe TD. Casereports suggested that diltiazem may also have at least atemporary suppressive effect (Ross et al. 1987; Falk et al.1988). Similarly, an acute, single-dose, double-blind chal-lenge study concluded that diltiazem suppressed TD (Leyset al. 1988). In contrast, in a 3-week double-blind cross-over study, diltiazem was no different from placebo(Loonen et al. 1992).

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Schizophrenia Bulletin, Vol. 23, No. 4, 1997 M.F. Egan et al.

Table 3. Studies of the effect of calcium channel blockers on tardive dysklnesiaReference

Kushnir and Ratner(1989)

Duncan et al. (1990)Stedman et al. (1991)Suddathetal. (1991)

Barrow and Childs(1986)

Buck and Harvey (1988)

Reiteretal. (1989)

Abad and Ovsiew (1993)

Rossetal. (1987)

Falketal. (1988)

Leysetal. (1988)

Adleretal. (1988)

Loonen etal. (1992)

Drug

Nifedipine

Nifedipine

Nifedipine

Nifedipine

Verapamil

Verapamil

Verapamil

Verapamil

Diltiazem

Diltiazem

Diltiazem

Diltiazem

Diltiazem

Design

Open

Single-blind

Open

Double-blind, crossover

Case report

Case report

Single-blind

Case report

Case report

Case report

Single-dose,double-blind,placebo-controlled

Single-blind

Randomized,double-blind,crossover

Duration 1

1-8months

7-14 days

6 weeks

8 weeks

Unspecified

6 months

2-5 days

1 week and> 1 month

Few hoursto 3 weeks

25 weeks

180minutes

2-12 days

3 weeks

Maximum dose

20-80mg/day

60 mg/day

60 mg/day

90 mg/day

320 mg/day

320 mg/day

160-320mg/day

1 week: 240mg/day; >1month: 360mg/day

120-240mg/day

240 mg/day

60 mg

240 mg/day

240 mg/day

Outcome

Significant improvement

Significant improvement

Significant improvement

Significant improvement

Significant improvement

Significant improvement

Significant improvement

Significant improvement

Significant improvement

Temporary improvement

Temporary improvementup to 90 minutes

No significant effect

No significant effect

Although the paucity of controlled, double-blind stud-ies of calcium channel blockers limits conclusions abouttheir efficacy, several trends emerge from prior reports.First, of the three, nifedipine may be the most effective(Kushnir and Ratner 1989; Duncan et al. 1990; Stedman etal. 1991). Second, regardless of the calcium channelblocker used, there seems to be a dose-related response(Adler et al. 1988; Kushnir and Ratner 1989; Reiter et al.1989; Stedman et al. 1991). Third, older rather thanyounger patients may respond better to nifedipine (Buckand Harvey 1988; Kushnir and Ratner 1989).

Several mechanisms could be involved in the actionof calcium channel blockers. It may be due to trivial phar-macokinetic effects, as nifedipine has been shown toincrease plasma neuroleptic activity (Stedman et al.1991). Alternatively, these drugs may exert therapeuticeffects by their actions on dopamine neurotransmission.In animals, calcium channel antagonists have beenreported to block postsynaptic D2 receptors and inhibitpresynaptic dopaminergic activity (Mena et al. 1995).Single photon emission computed tomography studiesshow that calcium channel blockers reduce [123]iodobenza-

mide (a D2 ligand) binding to D2 receptors in the striatum,suggesting a weak antidopaminergic effect (Brucke et al.1995). Finally, calcium channel blockers exert severalindirect effects (Sabria et al. 1995), such as reducing nora-drenergic activity, that could be related to the apparentdecrease in TD severity. Well-controlled clinical studiesand more data on the neurochemical effects are needed,but the data to date suggest that these agents may be worthconsidering for patients requiring TD suppression.

Serotonin. Preclinical studies have shown that sero-tonin modulates striatal dopamine release and could theo-retically influence dyskinetic movements (Seibyl et al.1989). There is increasing evidence that serotonergicagents may affect TD in humans, although their efficacyas suppressive agents is not clear. For example, buspirone,a serotonin 5-HT1A partial agonist, has been observed tosuppress TD (Neppe 1989) and levodopa-induced dyski-nesias (Kleedorfer et al. 1991). Subsequent reports, how-ever, raise doubts about the utility of buspirone as a robustsuppressive agent. Of two open trials, one found that TDimproved in eight patients (Moss et al. 1993), while in the

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second, if anything, buspirone worsened TD in sevenpatients (Brody et al. 1990). In a third open trial of 19patients treated for 6 weeks, a nonsignificant 25 percentreduction in TD severity was observed; haloperidol levels,however, were significantly increased by 26 percent (Goffet al. 1991). Paradoxically, buspirone has also beenreported to induce akathisia (Newton et al. 1986), dystonia(Boylan 1990), and oral dyskinesia (Strauss 1988).Buspirone's disparate effects could be attributed to neuro-transmitter systems other than serotonin; it is weakly anti-dopaminergic with mixed D2 agonist/antagonist properties,and it reverses neuroleptic-induced D2 supersensitivity inrats (McMillan 1985). It is also a sigma receptor antago-nist. Based on these few reports, routine use of buspironefor TD suppression cannot be recommended. In patientswho have failed other modalities, however, it could beconsidered.

Serotonin re-uptake inhibitors (SRIs) are a secondclass of serotonergic medications that sometimes seem toaffect hyperkinetic disorders. Preclinical studies showthat SRIs reduce dopamine synthesis in a variety of brainareas, including the striatum (Baldessarini and Marsh1990). In monkeys, SRIs inhibit amphetamine-inducedrepetitive movements and worsen neuroleptic-inducedParkinsonism (Korsgaard et al. 1984). Furthermore, inhumans, SRIs have been noted to exacerbate Parkinsoniansymptoms (Bouchard et al. 1989). Theoretically, onemight expect SRIs to improve symptoms of TD.Surprisingly, these medications seem to induce "oralhyperkinesias" in monkeys (Korsgaard et al. 1984),although it is difficult to know the relationship betweenthese movements and TD. Case reports have suggestedthat SRIs might rarely produce TD in humans as well(Budman and Bruun 1991; Stein 1991; Arya and Szabadi1993). Finally, unpublished observations by Egan andDaniel in 1991 of a double-blind, placebo-controlled trialof fluvoxamine in patients with TD have not been impres-sive. These limited observations, although supporting arole for serotonin in movement disorders, do not indicatea prominent role for SRIs as suppressive medications.

If SRIs fail to improve TD, one might try the oppo-site strategy by using a serotonin antagonist. Two suchstudies have noted some improvement with cyprohepta-dine (Goldman 1976; Kurata et al. 1977); a third found noeffect (Gardos and Cole 1978). In general, interventionsusing the serotonin system have not been rewarding (butsee earlier discussion of clozapine).

Botulinum Toxin. Advances in treating other move-ment disorders are often put to use to treat TD. This strat-egy has been particularly successful with the recent intro-duction of botulinum toxin to treat tardive dystonia.

Botulinum toxin (type A) blocks acetylcholine release atthe neuromuscular junction, producing a chemical dener-vation. The resulting focal muscle paralysis persists for upto 3 or 4 months (Hughes 1994). Botulinum toxin injec-tions have been used to treat blepharospasm, laryngealdystonia, hemifacial spasm, and torticollis. Patientsresponsive to botulinum injections may also do well witha newly described surgical procedure involving selectiveperipheral denervation of the involved musculature(Braun and Richter 1994).

Miscellaneous Therapeutic Agents. A variety of otherdrugs and neurotransmitter systems have been implicatedin the physiology of dyskinetic movements and could the-oretically play a role in the suppression of TD. However,many potential therapeutic agents are described only incase reports, small series, animal studies, or unblinded tri-als, making conclusions problematic. One particularlyinteresting approach has been to use ceruletide, a CCKanalog. CCK is a neuropeptide coexpressed in dopami-nergic neurons and seems to function as a neuromodularin the striatum. It purportedly exhibits neurolepticlikeeffects on dopamine receptors, metabolism, and behavior.Ceruletide itself seems to inhibit some of the behavioraleffects of amphetamine, reduces striatal dopamine metab-olism (Matsumoto et al. 1984), and blocks dyskineticmouth movements in an animal model of TD (Stoessl etal. 1989). Ceruletide has been found to be beneficial inone study of seven patients (Nishikawa et al. 1988) thatincluded several patients with severe TD. In a much larger(n = 77) well-controlled, parallel study, long-lasting mod-erate to marked improvement was seen in 42.5 percent ofpatients receiving the active drug compared with 9.1 per-cent improvement in the placebo group (Kojima et al.1992). Although seemingly promising, one difficulty withinterpreting these data is that ceruletide is a peptide that,administered peripherally, may not get into the brain inappreciable amounts (Passaro et al. 1982). On the otherhand, peripherally administered ceruletide has beenshown to have central effects on dopamine neuronal activ-ity (Skirboll et al. 1981) and on metabolism in rats(Matsumoto et al. 1984).

Lithium is frequently mentioned in conjunction withTD, although limited data on its effects are available.Lithium seems to prevent dopamine supersensitivity inrats when used with neuroleptics (Klawans et al. 1977). Inhumans, epidemiological data suggest that when lithiumis added to neuroleptic treatment, the incidence of TD isreduced (Kane 1995). In contrast, lithium has not beensuccessful as a suppressive agent (Gardos and Cole 1995).

Anecdotes of successful treatments with a panoply ofother, often unusual, interventions abound. A very low

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dose of prednisolone, for example, surprisingly produceda complete remission in two patients with severe TD(Benecke et al. 1988). Estrogen replacement producedmarginal improvement in postmenopausal women (Glazeret al. 1985c). The use of dentures and the correction ofother dental problems have been observed to markedlyreduce oral TD. Canes, braces, or biofeedback may offerlimited benefit in severe cases. Electroconvulsive therapy(ECT) has had variable effects, with a few patients report-edly showing dramatic improvement (Hay et al. 1990).

Other Experimental Approaches: Striatonigral Inhibi-tion. Theoretically, attempts to reduce the Dj -mediatedstriatonigral pathway should reduce hyperkinetic move-ments by increasing GABAergic projections from the sub-stantia nigra to the thalamus. This increase, in turn, woulddecrease thalamocortical activity and ultimately motoractivity (see figure 1). What is not clear, however, is howto reduce striatonigral activity. One strategy from animalbehavioral work is to use Dj antagonists. Several investi-gators have looked at the role of Da antagonists in move-ment disorders and dyskinesia (e.g., see Boyce et al.1990). Although no D] antagonist is currently availablefor clinical use in the United States and controlled studiesare few, at least one trial of a mixed Dl and D2 antagonistelicited no better results than a more pure D2 antagonist insuppressing TD (Lublin et al. 1991). Furthermore, despitepreclinical data from rats and primate studies (e.g., Boyceet al. 1990; Nutt 1990) suggesting a role for Dj receptorsin L-dopa-induced dyskinesias, at least one study inhumans did not support this notion (Braun et al. 1987).

A second approach is to reduce neurotransmission ofthe colocalized neuropeptides, in this case dynorphin andsubstance P. In humans, several case reports suggest thatintravenous naloxone, a relatively nonspecific opioid recep-tor antagonist, reduces L-dopa-induced dyskinesias (Sandykand Snider 1986) and TD (Blum et al. 1984; see alsoLindenmayer et al. 1987). In contrast, naltrexone failed toimprove L-dopa-induced dyskinesias in Parkinsonianpatients (Rascol et al. 1994). Such case reports are sugges-tive, but more data are needed before the clinical utility orfeasibility of striatonigral inhibition is clear.

Summary

Despite the promise of a new generation of neurolepticswith reduced EPS, TD remains a vexing clinical issue.Prevention is still an important approach; clinicians mustconsider whether other treatments are more effective thanneuroleptics. This is particularly true for high-risk groups,such as the elderly and patients with brain damage or dia-betes. Switching to an atypical agent is becoming a com-

mon first step, although the efficacy of this approach isunclear (figure 1). If typical agents are needed, the doseshould be tapered to the lowest possible effective level.Adding vitamin E to typical agents may also be worth-while. For many patients, however, neuroleptics areunavoidable for the treatment of chronic psychosis.

Fortunately, the incidence of severe TD is relativelylow. When TD does cause distress or disfigurement oraffects health or function adversely, suppressive agentsmay be needed. Preliminary data suggest that atypicalneuroleptics may be useful in such cases, although moredata are needed. At present, many consider them to be afirst-line treatment for suppression. Clozapine is oftenconsidered a second-line agent due to the complicationsassociated with its use. As a third step, suppression can betried using drugs that are fairly safe and have at leastsome moderate record of success, including vitamin E,calcium channel blockers, and adrenergic antagonists suchas clonidine. Medications that have more side effects orrisks but are probably more effective in the short terminclude benzodiazepines and dopamine-depleting agents.These fourth-line agents are sometimes used first bymovement disorder specialists when a rapid response isneeded. A fifth approach is to increase the dose of typicalneuroleptics in an attempt to achieve temporary suppres-sion, followed by a gradual reduction. This strategy doesnot always produce suppression and runs the theoreticalrisk of producing long-term worsening. More experimen-tal agents can be tried when other attempts fail: agentssuch as cholinergic agonists (e.g., tacrine), dopamine ago-nists (e.g., amantadine), buspirone, GABA agonists (e.g.,gabapentin), an SRI, cyproheptadine, opioid antagonists,estrogen, steroids, or even ECT. When dystonia is aprominent feature, specific therapeutic agents includeanticholinergics and, if sufficiently localized, botulinumtoxin injections.

The use of suppressive agents is typically a highlyindividualized process: one approach is outlined in table4. However, this approach should be considered only aproposal based on our experience. It has not been evalu-ated prospectively, and other experts may have differingstrategies. Furthermore, it may not be the best approach inall circumstances. Many patients will have special needsindicating that third- or fourth-line agents should be triedfirst. Often, a trial of several drugs is needed before aneffective one is found. In our experience, success cansometimes be achieved by patiently trying several agents,one after another. This approach requires not only famil-iarity with the many strategies already described, but alsoa strong working alliance with the patient.

TD will remain a major public health issue in psychi-atry at least for the near future. With better understanding

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Table 4. Possible treatment approach to tardive dyskinesia (TD)

A. For mild to moderate TD that does not require suppression1. Reevaluate need for antipsychotics; use other classes of medications when possible.2. If an antipsychotic is required, switch to a putative atypical antipsychotic (olanzapine, risperidone, seroquel, sertin-

dole).3. If typical antipsychotics must be used, taper to lowest possible levels and follow for improvement in TD.4. Add vitamin E to neuroleptic if TD persists. If no improvement in 3 months, discontinue vitamin E.5. If symptoms progress, consider clozapine.

B. For suppression of moderate to severe TD1. Switch to a putative atypical agent; begin with olanzapine. Increase dose until TD is suppressed or maximum dose is

reached. Gradually taper to lowest effective dose that suppresses psychosis and TD. Consider other putative atypicalagents (risperidone, seroquel, sertindole) if no response is seen to the first.

2. Switch to clozapine.

If steps 1 and 2 fail, try adding the following medications, one at a time, to whatever antipsychotic (typical or atypical) isbeing used. For careful evaluation of response, antipsychotic dose should remain stable. If no response is seen after anadequate trial, one suppressive agent should be discontinued before trying the next.

3. Add vitamin E to antipsychotic.4. Add calcium channel blocker (e.g., nifedipine) to antipsychotic.5. Add noradrenergic antagonist (e.g., clonidine) to antipsychotic.6. Add benzodiazepine (e.g., clonazepam) to antipsychotic.12

7. Add dopamine depleter (e.g., reserpine) to antispychotic.1

8. Increase dose of typical antipsychotic until TD is suppressed, then very gradually taper dose.3

9. Try other possible suppressive agents3: cholinergic agonists (e.g., tacrine), dopamine agonists (e.g., amantadine),buspirone, GABA agonist (e.g., gabapentin), an SRI, cyproheptadine, opioid antagonists, estrogen, steroids, ECT.

C. For suppression of tardive dystonia1. Add anticholinergics (increase gradually to "high" doses).2. Add vitamin E.3. Add clonazepam.4. Go to steps 1, 2, 4, 7, and 8 in part B.5. Consider botulinum injections.

Note.—QABA . gamma-amtno-bytyric add; SRI = sertonln re-uptake Inhibitor, ECT = etectroconvulsive therapy.

'May be tried first particularly if rapid relief Is needed.2Be cautious when adding to clozapine due to case reports of respiratory depression.'These therapies should be considered experimental. Although the other therapies have some support for their efficacy In well-controlled studies, In generalthese have less support Clear benefit and risk data may not be available.

of the mechanisms of action of atypical neuroleptics andthe physiology of the basal ganglia, continued improve-ments can be anticipated. As the new millennium dawns,perhaps these advances will leave TD as a footnote in thehistory of medicine.

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The Authors

Michael F. Egan, M.D., is Acting Branch Chief, ClinicalResearch Services Branch, and Medical Director and Act-ing Chief Executive Officer; Jose Apud, M.D., Ph.D., isSenior Staff Fellow, Neuropsychiatry Branch; andRichard Jed Wyatt, M.D., is Chief, NeuropsychiatryBranch, Intramural Research Program, National Instituteof Mental Health Neurosciences Research Center, St.Elizabeths Hospital, Washington, DC.

Announcement

The 16th Annual Therapeutic Activities & PsychosocialRehabilitation Conference entitled "Setting New Goals:The Recreation and Rehabilitation Revolution" will beheld in Philadelphia, Pennsylvania, March 23-24, 1998.The conference, sponsored by the Allegheny University ofthe Health Sciences, focuses on the development of activ-ity and psychosocial rehabilitation skills for client popula-tions. The presentations will include program developmentand experiential workshops.

For further information, please contact:

TAL Conference, BHEAllegheny University Health Sciences3200 Henry AvenuePhiladelphia, PA 19129Telephone: 215-842-4340

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