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Conferences and Reviews Tardive Dyskinesia DANIEL E. CASEY, MD, Portland
Tardive dyskinesia is a potentially irreversible syndrome of involuntary hyperkinetic movements that occur in predisposed persons receiving extended neuroleptic (antipsychotic) drug therapy. It is usually characterized by choreoathetoid dyskinesias in the orofacial, limb, and truncal regions, but subtypes of this syndrome may include tardive dystonia and tardive akathisia. Although the mechanisms underlying the pathogenesis and pathophysiology of this disorder are unproven, altered dopaminergic functions will likely play a role in any explanation of it. Tardive dyskinesia develops in 20% of neuroleptic-treated patients, but high-risk groups such as the elderly have substantially higher rates. Risk factors include age, female sex, affective disorders, and probably those without psychotic diagnoses, including patients receiving drugs with antidopaminergic activity for nausea or gastrointestinal dysfunction for extended periods. Total drug exposure is positively correlated with tardive dyskinesia risk. Management strategies include a careful evaluation of both the psychiatric and neurologic states, a broad differential diagnosis, and adjustment of neuroleptic agents to the lowest effective dose that controls psychosis and minimizes motor side effects. No drug therapy is uniformly safe and effective for treating this disorder. A favorable long-term outcome of improvement or resolution correlates with younger age, early detection, lower drug exposure, and duration of follow-up. (Casey DE: Tardive dyskinesia. West J Med 1990 Nov; 153:535-541)
Tardive dyskinesia (TD) is a drug-induced syndrome of involuntary hyperkinetic abnormal movements that occur in predisposed persons during or after the cessation of long-term neuroleptic (antipsychotic) drug therapy. Although these agents are highly efficacious in controlling psychotic symptoms, concern regarding the possible irreversibility of TD has led to a reconsideration of the appropriate indications for neuroleptic drug use. The clinical challenge is to optimize the many benefits attainable with these agents and to minimize their risks. Tardive dyskinesia has stimulated much research into the desirable and undesirable mechanisms of action of these agents and has also fostered the pursuit of new neuroleptic drugs that both control psychosis and have no neurologic motor side effects. Tardive dyskinesia was first described in 1957 in German by Schonecker,I and a second report appeared in 1959 in French.2 The first English-language publication came from a group in Denmark in 1960.3 During the next several years, other reports confirmed these original observations and variously labeled the syndrome as "bucco-linguomasticatory syndrome," "terminal extrapyramidal insufficiency syndrome," and "tardive dyskinesia." The last phrase was coined in 1964 and remains in use today.4 During the 1960s, there was a lively debate about whether TD existed as a separate entity; was a group of symptoms to be included in the already-recognized, early-onset, and fully reversible extrapyramidal syndrome of acute dystonia, drug-induced parkinsonism, or akathisia; or was associated with the underlying psychotic illness and unrelated to drug therapy. During the 1970s TD was recognized as a specific syndrome, and efforts primarily focused on characterizing the epidemiology and risk factors associated with it. In the 1980s, drugs for the treatment of TD were pursued and indications for the proper use of neuroleptic agents to prevent TD were developed.
Clinical Description Tardive dyskinesia is characterized by repetitive, involuntary, purposeless movements. The typical signs include chewing; tongue protrusion; vermicular tongue activity; lip smacking, puckering, and pursing; or paroxysms of rapid eye blinking. Choreoathetoid movements in the limbs and trunk can also occur. Dyskinesias in the fingers may look as if the patient is playing an invisible guitar or piano. Very rarely TD produces aerophagia, irregular respiratory rates, and grunting noises. Recent attention has focused on atypical or nonclassical forms of TD. Tardive dystonia is a syndrome of sustained abnormal postures or positions such as torticollis, blepharospasm, grimacing, and truncal torsion.5 Tardive akathisia is a syndrome of persisting subjective or objective signs of restlessness.6 Both these atypical disorders may occur alone, with typical signs of TD, or with the other acute extrapyramidal syndromes. It is unclear if these typical and atypical presentations of TD have distinctly different pathophysiologic mechanisms or if they are better explained by a single underlying pathophysiology that is phenomenologically expressed in varied symptom clusters. Tardive dyskinesia can also occur in children. In some, there may be few orofacial dyskinesias and a predominance of limb and truncal symptoms; in others, TD is more similar to that typically found in adults.' 8
Terminology Several descriptive and temporal aspects of the disorder apply to both clinical care and research. Covert TD refers to existing tardive dyskinesia that is unmasked when neuroleptic drug treatment is reduced or discontinued. Withdrawal TD appears under similar treatment conditions but disappears spontaneously in one to three months. Irreversible TD has been arbitrarily defined as that persisting be-
From the Psychiatry Service (Psychiatric Research and Psychopharmacology), Veterans Administration Medical Center, and the Departments of Psychiatry and Neurology, Oregon Health Sciences University, Portland. Dr Casey is a Collaborative Scientist at the Oregon Regional Primate Research Center, Beaverton. Reprint requests to Daniel E. Casey, MD, Psychiatry Service (1 16A), VA Medical Center, Portland, OR 97207.
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ABBREVIATIONS USED IN TEXT GABA = -y-aminobutyric acid TD = tardive dyskinesia
yond 6 to 12 months. Such categorizing, however, unnecessarily conceptualizes the course of TD into too narrow a time frame and does not account for symptom resolution noted in many patients observed for several years. Recent terminology has therefore emphasized the concept of persisting versus resolving TD.9 Although no specific pathophysiologic mechanism for each time course and outcome has been verified, the most plausible explanation is that these symptoms occur along a continuum ranging from reversible to irreversible. Research criteria have also been established for characterizing TD.'0 These are at least three months of cumulative neuroleptic drug treatment, at least mild movements in two or more body areas or moderate dyskinesias in one, persistence of symptoms for three months or longer, and the absence of other conditions that produce involuntary hyperkinetic dyskinesias. The most commonly used rating tool for TD is the abnormal involuntary movement scale.1I Although helpful in characterizing abnormal movements, rating scales are primarily used for descriptive purposes. They are not diagnostic instruments. Diagnoses require a complete analysis of epidemiologic, etiologic, and temporal aspects of any symptom constellation in conjunction with a thorough examination.
Differential Diagnosis Abnormal involuntary movements have many causes and may occur spontaneously in idiopathic syndromes, arise from other drug treatments, may be associated with hereditary diseases, or may be part of systemic illnesses. Idiopathic Syndromes Long before the introduction of neuroleptic drugs, spontaneous hyperkinetic dyskinesias of "grimacing" and "irregular movements of tongue and lips" were described in psychotic patients, most notably when the current-day concepts of schizophrenia and manic-depressive illness were established by Kraepelin at the turn of this century and by Bleuler.' 2-14 Stereotypies (purposeless, meaningless actions) and mannerisms (peculiar ways of carrying out normal actions) of psychosis are part of a differential diagnosis of tardive dyskinesia. Syndromes now classified as focal dystonias were previously identified as "spontaneous orofacial dyskinesia," "senile dyskinesia," and "blepharospasmoromandibular dystonia."''5 These dyskinesias (dystonias) occur increasingly with aging. It has also been noted that patients with underlying neuromedical conditions have higher rates of "spontaneous" involuntary dyskinesias when compared with healthy age-matched controls.'6 Tourette's syndrome is defined by involuntary tics and vocalizations. It begins in childhood and continues with a waxing and waning course throughout a patient's lifetime. Simple persisting tics in an isolated muscle group must also be differentiated from TD. Dental problems can also cause oral dyskinesias that look like this disorder.'7 Neuroleptic Drug-induced Acute Extrapyramidal Syndrome Neuroleptic drugs also produce an acute extrapyramidal syndrome that develops with the initiation of treatment and may continue throughout the course of drug therapy.
The syndrome gradually resolves over a few days to weeks when neuroleptic therapy is discontinued. Because the acute extrapyramidal syndrome and tardive dyskinesia can coexist,I'I 8 both disorders must be considered in the differential diagnosis. Acute dystonia is a syndrome of episodically sustained abnormal postures such as oculogyric crisis, torticollis, trismus, laryngopharyngeal spasm, and torsion of the limbs and trunk. It occurs most often during the first four days of drug therapy. Neuroleptic-induced parkinsonism of tremor, rigidity, or bradykinesia usually develops after several days or weeks of drug therapy. It is symptomatically identical to idiopathic parkinsonism. Akathisia is a syndrome of subjective feelings or objective signs of restlessness that may have motor manifestations of walking in place, continuous motions of the trunk, or an inability to sit still. The rabbit syndrome is an uncommon form of druginduced parkinsonism characterized by rapid rhythmic tremors in the lips and perioral area.'9 Paradoxic TD is a syndrome that is rarely reported but probably occurs more often. It is symptomatically similar to typical TD but is pharmacologically like acute extrapyramidal syndromes because it often reverses with antiextrapyramidal syndrome drug therapy.'720 2' Paradoxic tardive dyskinesia emphasizes the important point that different pathophysiologic mechanisms may be expressed clinically by a limited number of common pathways to produce similar symptoms, such as these hyperkinetic dyskinesias. All acute extrapyramidal symptoms respond to antiextrapyramidal syndrome drugs, but tardive dyskinesia remains unchanged or worsens with their use. Some drugs commonly prescribed for extrapyramidal syndromes include the anticholinergic agents benztropine mesylate (Cogentin), biperiden (Akineton), procyclidine hydrochloride (Kemadrin), and trihexyphenidyl hydrochloride (Artane); the antihistaminic-anticholinergic diphenhydramine hydrochloride (Benadryl); and the prodopaminergic drug amantadine hydrochloride (Symmetrel). Other Drug-induced Dyskinesias Many other drugs can produce hyperkinetic movement disorders that must also be differentiated from TD.'7 Dopamine agonists such as bromocriptine mesylate and the dopamine precursor levodopa can produce hyperkinetic dyskinesias. The abuse of amphetamines and other stimulants can cause chorea and stereotyped behavior during both drug intoxication and withdrawal. Anticholinergic and antihistaminic agents have rarely been associated with orofacial dyskinesias. Several anticonvulsant agents can produce dyskinesias resembling TD when these drugs are taken either at or above therapeutic levels. Oral contraceptives and the chloroquine-based antimalarial agents can also cause chorea and other dyskinetic symptoms. Rarely, the use of benzodiazepines has been correlated with orofacial dyskinesias. Both lithium carbonate use and that of tricyclic antidepressants have been associated with aggravating existing TD. These agents can also produce rapid, fine, irregular tremors that may be superimposed on tardive dyskinesia. This brief list is not intended to exhaustively review all drug-related involuntary hyperkinetic dyskinesias. Rather, it identifies some of the more commonly prescribed drugs that need to be differentiated as causes of
dyskinesias. Hereditary and Systemic Illnesses Hereditary neurologic diseases may provide a difficult differential diagnosis for tardive dyskinesia if patients have
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also received previous neuroleptic drug treatment. Huntington's disease is characterized by choreoathetosis and dementia that may be preceded or accompanied by symptoms of psychosis. The family history, the progressive nature of the symptoms, and the development of dementia aid in the differential diagnosis. Wilson's disease (hepatolenticular degeneration), a disorder of copper metabolism, is also usually distinguishable by clinical signs, laboratory tests, and perhaps family history. As these patients are often treated with neuroleptic drugs, the eventual development of dyskinesias makes distinguishing between TD and hereditary neurologic disease difficult. Though rare, Hallervorden-Spatz disease of iron metabolism usually has its onset during childhood and is characterized by bradykinesia and dystonia. The dystonic symptoms of Hallervorden-Spatz disease make it necessary to distinguish this disorder from neuroleptic drug-induced tardive dystonia in children. Hyperkinetic movement disorders are also part of the overall constellation of symptoms occurring in many illnesses or disturbances in normal physiologic mechanisms. Endocrinopathies of hyperthyroidism, hypoparathyroidism, or hyperglycemia are infrequently associated with choreoathetosis. Chorea in pregnancy, known as chorea gravidarum, may possibly share some pathophysiologic mechanisms in common with oral contraceptive-induced chorea. Dyskinesias associated with the immune syndromes of lupus erythematosus, Schonlein-Henoch purpura, and Sydenham's chorea-as well as encephalitis or other inflammatory diseases of the central nervous system-must likewise be distinguished from TD."7 Epidemiology The prevalence (number of existing cases) of tardive dyskinesia varies widely, ranging from 0.5% to more than 70%.9,14.22 23 This broad range reflects the relative contributions of many different variables, including special populations at risk, past and current drug treatment, strictness of criteria for diagnosis, and the publication year. Realistic rates of TD prevalence average from 15% to 20%. They may, however, exceed 50% in high-risk populations such as elderly persons with long-standing psychosis, several decades of neuroleptic treatment, and confounding neuromedical conditions such as dementia. To account accurately for those patients with spontaneous dyskinesias who would have eventually presented with abnormal involuntary dyskinesias even if no neuroleptic drug treatment had ever been prescribed, we must reduce the approximate TD prevalence rate of 20% by the 1% to 5% prevalence rate for naturally occurring spontaneous dyskinesias, as described earlier. Schizophrenia develops in about 1% (2.5 million) of the population (250 million), and most are treated with neuroleptic agents. Tardive dyskinesia develops in 14% (350,000) of these patients. Add to this the substantial number of demented and behaviorally disturbed persons receiving neuroleptic drugs, and the actual prevalence of the syndrome is evident. The incidence (new cases per year) of TD is about 3 % to 5%.24-27 Because prevalence studies reflect the number of patients at a single cross-sectional point in time, these numbers do not account for the addition of new cases and the subtraction of those that have resolved. Although longterm outcome data are just now becoming available, it seems that the relatively stable prevalence rate of 15% to
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20% reflects a considerable turnover in affected cases because about as many cases resolve as new ones develop.27 Risk Factors Age and Sex The prevalence of tardive dyskinesia steadily increases with age. It occurs in 5% to 10% of patients younger than 40 and rises to a range of 50% to 70% in patients older than 65.9 28 Most but not all studies show that TD occurs more often in women at an approximate ratio of 1.7 to 1.9,22 23 Psychiatric Diagnosis The vulnerability to tardive dyskinesia may be greatly influenced by psychiatric diagnosis. It is not known why more severe TD develops in patients with affective disorders, particularly depression, and it does so after relatively brief exposures to low doses of neuroleptic drugs.29.30 This implies that patients with schizophrenia may be relatively less vulnerable to TD.31 Persons without psychotic diagnoses who receive extended treatment with neuroleptic agents are also at substantial risk for TD development. Included are those patients receiving long-term treatment with antiemetic drugs such as prochlorperazine (Compazine) and others or with the widely used compound metoclopramide hydrochloride (Reglan). Although metoclopramide hydrochloride is marketed for gastrointestinal disorders and nausea, its mechanism of action-like that of antiemetics and all neuroleptics agents-is through dopamine-receptor blockade. Metoclopramide has antipsychotic effects at higher doses and can produce all the acute extrapyramidal symptoms and TD from the doses commonly prescribed for gastrointestinal disorders.32 While there is relatively little risk of inducing TD with a short-term course (about four weeks or less) of antiemetics or metoclopramide, this risk increases steadily with extended treatment. It is essential to periodically reassess the need for these drugs when their use is long term to ensure that the risk-benefit ratio remains favorable.
Neuroleptic Dose and Duration of Treatment The relationship between TD and drug treatment variables is complex. A large, long-term, prospective study of tardive dyskinesia shows a significant positive correlation between its onset and both total treatment duration and total drug dose.24 No studies have yet teased apart the complex interaction between concomitantly increasing age and total duration of treatment. Prospective studies correlating blood levels of neuroleptic agents with tardive dyskinesia have not yet been done. In cross-sectional evaluations, blood levels of these drugs were higher in patients with TD than in those without the disorder in one study, but this was not confirmed in a subsequent
investigation.33'34
Neuroleptic Drug Type While it has been occasionally claimed that one drug or particular characteristics of certain drugs (for example, a specific chemical class, high versus low doses, receptor-site specificity) are associated with a greater or lesser risk of tardive dyskinesia, the widely conflicting findings across studies do not sufficiently resolve this issue. The proposal that long-acting neuroleptic agents are associated with a greater risk of TD is also highly questionable because of difficulties in interpreting the pharmacologic consequences of treatment with injectable depot drugs that may have
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different rates and amounts of drug absorption compared with oral agents. At present, an objective evaluation of the data must conclude that the commercially available neuroleptic drugs appear more similar than different (with the probable exception of clozapine) and that it is impossible to implicate one drug or drug class as more or less liable to produce TD. Clozapine (Clozaril), whose mechanism of action is unknown, is the best example of an atypical neuroleptic agent. Although it has weak dopamine-receptor antagonist properties, it has more potent antagonistic activity at several other neurotransmitter sites-serotonergic, cholinergic, histaminic, a-adrenergic. Clozapine produces exceptionally low rates of acute extrapyramidal syndromes, and there are no well-documented cases of TD from extended clozapine use.35 The effect of clozapine on tardive dyskinesia is highly variable. In some patients the drug suppresses the syndrome while in others it has no effect.35 Because experience with clozapine is still limited, it is too early to draw firm conclusions about the liability of clozapine to produce TD. The risk of agranulocytosis (1% to 2%) and the limited indication for use in treatment-resistant schizophrenia make clozapine a second line of drug therapy reserved for special situations. Drug-free Periods Time off neuroleptic agents ("drug holiday") has the advantage of reducing drug exposure, unmasking covert dyskinesias, and evaluating if the drug therapy is still required. On the other hand, such time off exposes patients to the risk of a psychotic relapse. The most appropriate strategy is to gradually decrease the dose to the lowest effective level. Some patients show signs of impending psychotic relapse before the drug can be discontinued. In these patients, continuing the drug dose at the previous effective level is recommended. For other persons neuroleptic agents can gradually be reduced to much lower levels and possibly even discontinued. In this case, patients should remain off neuroleptic therapy as long as possible. It is still unclear whether periodic drug holidays are associated with higher rates of irreversible TD, as has been suggested.36
Anticholinergic Drugs and the Extrapyramidal Syndrome The etiologic role of anticholinergic drugs in tardive dyskinesia is disputed. Data exist both for and against a correlation with TD risk.22 23 In contrast to the controversial etiologic role, it is consistently shown that anticholinergic agents may temporarily aggravate existing TD, but the symptoms return to baseline when these drugs are discontinued.20-22'37 The acute extrapyramidal syndromes have been hypothesized as a risk factor for TD.38 In a prospective study of tardive dyskinesia, parkinsonian side effects significantly correlated with the early (defined as less than a year of drug treatment) onset of TD but were not associated with TD of a later onset.39 Why such a risk factor would be evident in the first year of treatment and not thereafter is unclear. Clarifying the relationship between TD and acute extrapyramidal symptoms is very difficult because these symptoms are multidetermined. Patient (age, sex, psychiatric diagnosis), drug (dose, type, duration) factors, and the presence or absence of agents that prevent extrapyramidal symptoms may alter the vulnerability to this disorder.40 41 Because anticholinergic drugs are used to treat extrapyramidal symptoms, the retrospective associations between tardive dyskinesia and anticholinergic agents may actually represent
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indirect measures of the correlation between acute extrapyramidal symptoms and late TD risk.
Organic Brain Factors Organic brain disease was identified as a risk factor in the early TD studies, but subsequent reviews questioned these associations.2223 Computed tomographic studies have also produced conflicting findings.42'43 Several methodologic problems-such as lack of age-matched controls, confounding effects of masked symptoms from concurrent neuroleptic drug treatment, and lack of standardized measurement techniques-all may have contributed to these inconsistent results. Despite the lack of consensus about the associations between brain disease and tardive dyskinesia, there is face, validity to the rationale that preexisting deficits enhance the vulnerability to other dysfunctions in the same system. Management Strategies Prevention of tardive dyskinesia is the best strategy because there is no uniformly safe and effective treatment of this syndrome. Although some researchers have strongly admonished against using neuroleptic drugs in any patient with TD, this is not practical as it leads to the unacceptable consequences of denying highly beneficial treatment to psychotic patients. The central question is how to provide appropriate neuroleptic drug treatment and at the same time minimize treatment risks (Figure 1).44 The same strategy is used to manage patients with and those without TD. Physicians should have a high index of suspicion and keep a vigilant watch for the early beginning or worsening of TD symptoms. If they develop, a thorough differential diagnosis and treatment strategies should be considered. As in all other branches of medicine, informed consent is
Figure 1.-An algorithm has been developed for managing tardive dyskinesia (TD) (adapted and reprinted by permission of the publisher from Casey and Gerlach,4 Figure 2, page 184).
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an important aspect of neuroleptic drug use and TD. The risks and benefits of treatment, alternative treatments, and no treatment should be discussed with patients and, if possible, a concerned family member or friend and should be documented. This best occurs when patients can understand the information and should be done whether or not TD is present. It is useful to periodically review this information with patients during long-term care. Informed consent is more of a process that occurs over time than it is a ritualized signing of a form as a one-time event. The American Psychiatric Association Task Force on Late Neurological Effects of Antipsychotic Drugs advocates using neuroleptic agents in the lowest effective dose for only those patients who benefit from therapy.22 Neuroleptic drugs are primarily indicated for acute and chronic schizophrenia and other uncommon neurologic disorders such as Tourette's syndrome and Huntington's disease. Secondary indications include acute mania or psychotic depression. Extended use may be justified with unstable manicdepressive illness where patients have failed to benefit from lithium or carbamazepine. Neuroleptic agents are not indicated for neurosis, personality disorders, insomnia, or other nonpsychotic conditions. It is important to adjust periodically to the lowest effective level the doses of neuroleptic drugs and those preventing extrapyramidal symptoms. Some patients can eventually discontinue these agents, but others must maintain therapy to prevent an exacerbation of psychosis. Regularly reevaluating medication requirements and benefits, discussing them with patients and their families, and documenting such efforts should be established principles of practice. Tardive dyskinesia either persists or gradually remits. The mental state may remain stable or deteriorate with an exacerbation of psychosis. When such a relapse occurs, it is necessary to reassess the risks and benefits of treatment with neuroleptic agents as was done when it was started and then reevaluated at each medication adjustment.
Long-term Outcome The possibility of a reversible course of tardive dyskinesia, even in patients continuing on neuroleptic agents, has been noted since the earliest reports.'-3 This favorable outcome is not well known, though, because it has been overshadowed by the reports that TD may not resolve. Improvement across studies varies from 0% to 92%.9,26.45 This wide range is due to the multiple factors of patient variables (for example, age), treatment variables (drug dose and cumulative exposure), and temporal aspects (early diagnosis, duration of treatment, and duration of TD follow-up). Age is consistently correlated with improvement in tardive dyskinesia: Younger patients are more likely to improve.9 26.21 Nevertheless, this does not exclude older patients from having improvement or resolution, as this favorable course can occur in any age group. Data are insufficient to clarify whether gender or psychiatric diagnosis correlates with TD outcome. Early diagnosis is often but not always associated with a good prognosis, perhaps because most TD outcome studies are initiated after symptoms are identified, and it is impossible to know when symptoms first developed as longstanding covert TD may have been masked by neuroleptic therapy. One large prospective study shows that a favorable outcome correlates with less drug treatment," although another study and a review of the subject noted that a uniformly good outcome is not predictable.47
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The few studies specifically addressing TD outcome when neuroleptic therapy is continued also show that symptoms may stabilize, lessen, or resolve over many years. Only a few patients have increased TD during continued treatment with neuroleptic agents.926 Overall, the longer the follow-up period, the better the outcome. The most important caveat, however, is that most outcome studies in patients remaining on neuroleptic therapy have evaluated the effects of these drugs only at low to moderate doses (for example, chlorpromazine equivalents of 600 mg or less per day). The effect of extended treatment in TD patients at doses above this level is unknown. The recommendation for the lowest effective dose (which includes discontinuing neuroleptic agents if possible) may be questioned if some data suggest that TD does not worsen with continued drug therapy. Still, there are several reasons for this "less is better" strategy. First, if a lower dose does as well as a higher one, the lower dose is desirable because it is less likely to produce acute and longterm side effects. Second, this will lead to better compliance, as dose-related side effects are often the reason why patients discontinue taking medicines. Third and most important, some evidence suggests that patients not receiving neuroleptic drugs have better outcomes than those continuing to take these drugs.46 This implies that these agents retard, but do not necessarily prohibit, the course of spontaneous remission. Thus, managing psychosis and tardive dyskinesia rests on a basic tenet of medicine: Use the lowest effective dose of drugs only in patients who benefit from them. An intriguing but unexplainable question is how neuroleptic agents can cause TD, which then gradually abates or resolves even with continued treatment with the class of drugs that caused the initial symptoms. This raises the possibility that neuroleptic agents play only a partial role in the pathophysiology of TD, perhaps by converting a covert vulnerability to overt dyskinetic symptoms. It also challenges the commonly held view that the central nervous system cannot compensate for long-standing dysfunction. Treatment Treating tardive dyskinesia is a clinical challenge. Unfortunately, no drugs are uniformly safe and effective over extended treatment periods. The long list of the many drugs used to study TD attests to their general lack of therapeutic benefits. Depending on one's perspective, there are many treatments for TD or there are none.9,37 Several assessments are frequently necessary to accurately account for the masking and unmasking effects of drug treatment. Without the opportunity to follow symptoms over time, it is possible to develop misleading impressions about the course of tardive dyskinesia. For example, the disorder may appear to emerge or worsen when the drug dosage is decreased because symptoms are unmasked. This unmasking could also occur when anticholinergic agents are added. Similarly, TD symptoms may appear to lessen or resolve when the neuroleptic drug dose is increased or when anticholinergic agents are decreased because symptoms are masked.
Dopamine Reducing dopaminergic function is the most effective way of suppressing (masking) tardive dyskinesia. Yet this strategy, when used solely to suppress TD, is justified only in those rare cases when TD is severe, debilitating, or lifethreatening. Functional reduction of dopamine can be
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achieved with presynaptic depletion (reserpine) or by false transmission (methyldopa [Aldomet]) but yields only variably beneficial effects.22,37 Although reserpine has rarely if ever been associated with causing TD, it and other drugs that decrease catecholamine function should be used cautiously because of the theoretic possibility that this approach, like the use of neuroleptic agents, reproduces the same biochemical pathophysiology as dopamine-receptor blockade. In addition, these drugs have their own undesirable and potentially troublesome side effects. The theoretically attractive approach of resetting dopaminergic hypersensitivity back to normal sensitivity with dopamine agonists (bromocriptine mesylate [Parlodel]) or dopamine precursors (levodopa) has not been consistently successful. As with so many other treatment trials of TD, the initial positive results have not been replicated in subsequent investigations.922'37
Acetylcholine Anticholinergic agents usually aggravate existing tardive dyskinesia or unmask covert TD. Rarely, they seem to be beneficial in TD-like hyperkinetic dyskinesias but are probably treating the uncommon syndrome of paradoxic TD (see Differential Diagnosis). Another theoretically attractive approach to treating TD was to augment the cholinergic system with the cholinesterase inhibitor physostigmine or through dietary cholinergic-precursor loading. Trials with physostigmine have been inconsistent, and the lack of a widely available oral form makes its use impractical. Dietary approaches with choline or lecithin (PhosChol) were again initially encouraging but subsequently disappointing.9'22'37 Other Drugs Compounds aimed at enhancing y-aminobutyric acid (GABA) activity, either through direct agonism or by inhibiting the catalytic enzyme GABA-transaminase, all have produced inconsistent results. Preparations such as baclofen (Lioresal) and sodium valproate (Depakene)-with mechanisms of action that may or may not be related to GABA function-have not been consistently effective and are not recommended for routine use. Benzodiazepines often temporarily reduce TD but rarely may aggravate it. The nonspecific sedative effects of these drugs may be their main benefit. Although diazepam may provide symptomatic relief of TD, it is not routinely recommended because of the potential problems with dependence during extended use. Other drugs that have been generally ineffective include the serotonergic agent, tryptophan, and cyproheptadine hydrochloride (Periactin); the noradrenergic agents such as lithium carbonate (Lithane, Eskalith); the ,B-adrenergic receptor antagonist propranolol hydrochloride (Inderal); and the a-adrenergic agonist clonidine hydrochloride (Catapres). Studies that have more theoretic implication than practical application and that have also failed to yield convincingly positive results include the neuropeptides metenkephalin, destyrosine-y-endorphin, vasopressin, and approaches through the opiate system with morphine and naloxone hydrochloride (Narcan). In addition, trials with estrogen, pyridoxine, fusaric acid, manganese chloride, phenytoin (Dilantin), ergoloid mesylates (Hydergine), papaverine hydrochloride, and several others have produced no or only sporadic benefits.9 22'37 While the results of these many varied trials are generally not encouraging, it may be worthwhile considering one of these therapeutic ap-
proaches if TD symptoms are severe and there are no indications for the appropriate use of neuroleptic agents. Much has been learned about tardive dyskinesia in recent years, but much more needs to be unraveled. It is thus appropriate to retain an open view on all aspects of this syndrome. Developing new drugs that treat psychosis and do not bring on tardive dyskinesia or extrapyramidal symptoms is a priority of researchers. Achieving this goal will be a major breakthrough both in patient care and knowledge about the mechanisms underlying psychosis. REFERENCES
1. Schonecker M: Ein eigentumliches syndrom im oralen bereich bei megaphen-applikation. Nervenarzt 1957; 28:35-36 2. Sigwald J, Bouttier D, Raymondeaud C: Quatre cas de dyskinesie faciobucco-linguo-masticatrice a 1'evolution prolong6e secondaire a un traitment par les neuroleptiques. Rev Neurol (Paris) 1959; 10:751-755 3. Uhrbrand L, Faurbye A: Reversible and irreversible dyskinesia after treatment with perphenazine, chlorpromazine, reserpine, and electroconvulsive therapy. Psychopharmacologia 1960; 1:408-418 4. Faurbye A, Rasch PJ, Bender Peterson P, et al: Neurological symptoms in the pharmacotherapy of psychoses. Acta Psychiatr Scand 1964; 40:10-26 5. Burke RE, Fahn S, Jankovic J, et al: Tardive dystonia: Late-onset and persistent dystonia caused by antipsychotic drugs. Neurology (NY) 1982; 32: 1335-1346 6. Barnes TRE, Braude W: Akathisia variants and tardive dyskinesia. Arch Gen Psychiatry 1985; 42:874-878 7. Campbell M, Grega DM, Green WH: Neuroleptic-induced dyskinesias in children. Clin Neuropharmacol 1983; 6:207-222 8. Gualtieri CT, Quade D, Hicks RE, et al: Tardive dyskinesia and other clinical consequences of neuroleptic treatment in children and adults. Am J Psychiatry 1984; 141:20-23 9. Casey DE: Tardive dyskinesia, In Meltzer H (Ed): Psychopharmacology: The Third Generation of Progress. New York, Raven, 1987, pp 1411-1419 10. Schooler NR, Kane JM: Research diagnoses for tardive dyskinesia. Arch Gen Psychiatry 1982; 39:486-487 11. Guy W: ECDEU Assessment Manual for Psychopharmacology, revised 1976. Washington, DC, Government Printing Office, 1976, pp 534-537 12. Kraepelin E: Clinical Psychiatry. New York, Macmillan, 1907 13. Bleuler E: Dementia Praecox or the Group of Schizophrenias. New York, International Universities Press, 1950 14. Casey DE: Spontaneous and tardive dyskinesia: Clinical and laboratory studies. J Clin Psychiatry 1985; 46:42-47 15. Jankovic J, Ford J: Blepharospasm and orofacial-cervical dystonia: Clinical and pharmacologic findings in 100 patients. Ann Neurol 1983; 13:402-411 16. Leiberman J, Kane J, Woerner M, et al: Prevalence of tardive dyskinesia in elderly samples. Psychopharmacol Bull 1984; 20:22-26 17. Casey DE: The differential diagnosis of tardive dyskinesia. Acta Psychiatr Scand 1981; 63(Suppl 291):71-87 18. Richardson MA, Craig TJ: The coexistence of parkinsonism-like symptoms and tardive dyskinesia. Am J Psychiatry 1982; 139:341-343 19. Villeneuve A: The rabbit syndrome: A peculiar extrapyramidal reaction. Can Psychiatr Assoc J 1972; 17:69-72 20. Gerlach J, Reisby N, Randrup A: Dopaminergic hypersensitivity and cholinergic hypofunction in the pathophysiology of tardive dyskinesia. Psychopharmacologia 1974; 34:21-35 21. Casey DE, Denney D: Pharmacological characterization of tardive dyskinesia. Psychopharmacology (Berlin) 1977; 54:1-8 22. Baldessarini RJ, Cole JO, Davis JM, et al: Tardive Dyskinesia: A Task Force Report. Washington, DC, American Psychiatric Press, 1980 23. Kane JM, Smith JM: Tardive dyskinesia: Prevalence and risk factors, 1959 to 1979. Arch Gen Psychiatry 1982; 39:473-481 24. Kane JM, Woerner M, Weinhold P, et al: Incidence of tardive dyskinesia: Five-year data from a prospective study. Psychopharmacol Bull 1982; 20:387-389 25. Barnes TRE, Kidger T, Gore SM: Tardive dyskinesia: A 3-year follow-up study. Psychol Med 1983; 13:71-81 26. Casey DE, Gerlach J: Tardive dyskinesia: What is the long-term outcome? In Casey DE, Gardos G (Eds): Tardive Dyskinesia and Neuroleptics: From Dogma to Reason. Washington, DC, American Psychiatric Press, 1986, pp 75-97 27. Casey DE, Gardos G, Gerlach J: The Long-Term Outcome of Tardive Dyskinesia (Abstr). Proc American Psychiatric Association 1989, p 41D 28. Smith JM, Baldessarini RJ: Changes in prevalence, severity and recovery in tardive dyskinesia with age. Arch Gen Psychiatry 1980; 37:1368-1373 29. Casey DE: Tardive dyskinesia and affective disorders, In Gardos G, Casey DE (Eds): Tardive Dyskinesia and Affective Disorders. Washington, DC, American Psychiatric Press, 1984, pp 1-20 30. Kane JM, Woerner M, Weinhold P, et al: Incidence and severity of tardive dyskinesia in affective illness, In Gardos G, Casey DE (Eds): Tardive Dyskinesia and Affective Disorders. Washington, DC, American Psychiatric Press, 1984, pp 22-28 31. Casey DE: Affective disorders and tardive dyskinesia. Encephale 1988; 14:22 1-226 32. Casey DE: Metoclopramide side effects. Ann Intern Med 1983; 98:673674
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33. Jeste DV, DeLisi LE, Zalcman S, et al: A biochemical study of tardive dyskinesia in young male patients. Psychiatry Res 1981; 4:327-334 34. Fairbairn AF, Rowell FJ, Hui SM, et al: Serum concentration of depot neuroleptics in tardive dyskinesia. Br J Psychiatry 1983; 142:579-583 35. Casey DE: Clozapine: Neuroleptic-induced EPS and tardive dyskinesia. Psychopharmacology (Berlin) 1989; 99:S47-S53 36. Jeste DV, Potkin SG, Sinha S, et al: Tardive dyskinesia-Reversible and irreversible. Arch Gen Psychiatry 1979; 36:585-590 37. Jeste DV, Wyatt RJ: Therapeutic strategies against tardive dyskinesia. Arch Gen Psychiatry 1982; 39:803-816 38. Crane GE, Smeets RA: Tardive dyskinesia and drug therapy in geriatric patients. Arch Gen Psychiatry 1974; 30:341-343 39. Kane JM, Woerner M, Weinhold P, et al: Incidence of tardive dyskinesia: Five-year data from a prospective study. Psychopharmacol Bull 1984; 20(1): 40. Keepers GA, Clappison VJ, Casey DE: Initial anticholinergic prophylaxis for neuroleptic-induced extrapyramidal syndromes. Arch Gen Psychiatry 1983; 40:1113-1117
41. Casey DE, Keepers GA: Neuroleptic side effects: Acute extrapyramidal syndromes and tardive dyskinesia, In Casey DE, Christensen AV (Eds): Psychopharmacology: Current Trends. Berlin, Springer-Verlag, 1988, pp 74-93 42. Famuyiwa 00, Rasch PJ, Peterson PB, et al: Tardive dyskinesia and dementia. Br J Psychiatry 1979; 135:500-504 43. Hoffman WF, Labs SM, Casey DE: Neuroleptic-induced parkinsonism in older schizophrenics. Biol Psychiatry 1987; 22:427-439 44. Casey DE, Gerlach J: Tardive dyskinesia: Management and new treatment, chap 12, In Spencer HC, Garfinkel PE, Rakoff VM (Eds): Guidelines for the Use of Psychotropic Drugs: A Clinical Handbook. Jamaica, NY, Spectrum, 1984 45. Casey DE: Tardive dyskinesia: Reversible and irreversible, In Casey DE, Chase T, Christensen AV, et al (Eds): Dyskinesia: Research and Treatment. Berlin, Springer-Verlag, 1985, pp 88-97 46. Kane JM, Woerner M, Sarantakos S, et al: Do low-dose neuroleptics prevent or ameliorate tardive dyskinesia? In Casey DE, Gardos G (Eds): Tardive Dyskinesia and Neuroleptics: From Dogma to Reason. Washington, DC, American Psychiatric Press, 1986, pp 99-108 47. Gardos G, Cole J, Haskell D, et al: The natural history of tardive dyskinesia. J Clin Psychiatry 1988; 8:31S-37S
WALKING THE QUILT (The NAMES PROJECT, AIDS Quilt)
incomprehensible size does not cauterize; this room throbs with unreprieved tales of harbors and streets, palettes and boots related to an emptiness that names itself -
this purple slash riots like laughter along the careful names I carefully read unknowing yet kin-known through and throughgilt could not mean more
this is a beachwalking among the dead full of wise driftwood and sudden wind, memory without decay, sunset sans romance, the accompaniment of one's need to know -
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musical notes plummet down the sewn edge where this devotee of blues forever meets a benefactor of rainbows, such smiles one would grope blind alleys to find
tissue boxes bespeak the common round; these silent, gentle faces freely give like abolished forests creating their last air before the saw's undebatable limitation -
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sometimes something scarlet beaks forward panels of mesmeric sorrow; I founder as in a valley whose mountains have wept their entire faces all down across
helpers dressed in reality patiently groundskeep the long rows shockingly cruciform, attention's punctuation marking the ways every one of us came together here -
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teddybears and glitter, denim and books, the told lives irreducibly braved, these panels I walk my sisterhood along, distance and memory joined with unimpeachable love PAT EVERITT
Orinda, California
Conferences and Reviews Tardive Dyskinesia DANIEL E. CASEY, MD, Portland
Tardive dyskinesia is a potentially irreversible syndrome of involuntary hyperkinetic movements that occur in predisposed persons receiving extended neuroleptic (antipsychotic) drug therapy. It is usually characterized by choreoathetoid dyskinesias in the orofacial, limb, and truncal regions, but subtypes of this syndrome may include tardive dystonia and tardive akathisia. Although the mechanisms underlying the pathogenesis and pathophysiology of this disorder are unproven, altered dopaminergic functions will likely play a role in any explanation of it. Tardive dyskinesia develops in 20% of neuroleptic-treated patients, but high-risk groups such as the elderly have substantially higher rates. Risk factors include age, female sex, affective disorders, and probably those without psychotic diagnoses, including patients receiving drugs with antidopaminergic activity for nausea or gastrointestinal dysfunction for extended periods. Total drug exposure is positively correlated with tardive dyskinesia risk. Management strategies include a careful evaluation of both the psychiatric and neurologic states, a broad differential diagnosis, and adjustment of neuroleptic agents to the lowest effective dose that controls psychosis and minimizes motor side effects. No drug therapy is uniformly safe and effective for treating this disorder. A favorable long-term outcome of improvement or resolution correlates with younger age, early detection, lower drug exposure, and duration of follow-up. (Casey DE: Tardive dyskinesia. West J Med 1990 Nov; 153:535-541)
Tardive dyskinesia (TD) is a drug-induced syndrome of involuntary hyperkinetic abnormal movements that occur in predisposed persons during or after the cessation of long-term neuroleptic (antipsychotic) drug therapy. Although these agents are highly efficacious in controlling psychotic symptoms, concern regarding the possible irreversibility of TD has led to a reconsideration of the appropriate indications for neuroleptic drug use. The clinical challenge is to optimize the many benefits attainable with these agents and to minimize their risks. Tardive dyskinesia has stimulated much research into the desirable and undesirable mechanisms of action of these agents and has also fostered the pursuit of new neuroleptic drugs that both control psychosis and have no neurologic motor side effects. Tardive dyskinesia was first described in 1957 in German by Schonecker,I and a second report appeared in 1959 in French.2 The first English-language publication came from a group in Denmark in 1960.3 During the next several years, other reports confirmed these original observations and variously labeled the syndrome as "bucco-linguomasticatory syndrome," "terminal extrapyramidal insufficiency syndrome," and "tardive dyskinesia." The last phrase was coined in 1964 and remains in use today.4 During the 1960s, there was a lively debate about whether TD existed as a separate entity; was a group of symptoms to be included in the already-recognized, early-onset, and fully reversible extrapyramidal syndrome of acute dystonia, drug-induced parkinsonism, or akathisia; or was associated with the underlying psychotic illness and unrelated to drug therapy. During the 1970s TD was recognized as a specific syndrome, and efforts primarily focused on characterizing the epidemiology and risk factors associated with it. In the 1980s, drugs for the treatment of TD were pursued and indications for the proper use of neuroleptic agents to prevent TD were developed.
Clinical Description Tardive dyskinesia is characterized by repetitive, involuntary, purposeless movements. The typical signs include chewing; tongue protrusion; vermicular tongue activity; lip smacking, puckering, and pursing; or paroxysms of rapid eye blinking. Choreoathetoid movements in the limbs and trunk can also occur. Dyskinesias in the fingers may look as if the patient is playing an invisible guitar or piano. Very rarely TD produces aerophagia, irregular respiratory rates, and grunting noises. Recent attention has focused on atypical or nonclassical forms of TD. Tardive dystonia is a syndrome of sustained abnormal postures or positions such as torticollis, blepharospasm, grimacing, and truncal torsion.5 Tardive akathisia is a syndrome of persisting subjective or objective signs of restlessness.6 Both these atypical disorders may occur alone, with typical signs of TD, or with the other acute extrapyramidal syndromes. It is unclear if these typical and atypical presentations of TD have distinctly different pathophysiologic mechanisms or if they are better explained by a single underlying pathophysiology that is phenomenologically expressed in varied symptom clusters. Tardive dyskinesia can also occur in children. In some, there may be few orofacial dyskinesias and a predominance of limb and truncal symptoms; in others, TD is more similar to that typically found in adults.' 8
Terminology Several descriptive and temporal aspects of the disorder apply to both clinical care and research. Covert TD refers to existing tardive dyskinesia that is unmasked when neuroleptic drug treatment is reduced or discontinued. Withdrawal TD appears under similar treatment conditions but disappears spontaneously in one to three months. Irreversible TD has been arbitrarily defined as that persisting be-
From the Psychiatry Service (Psychiatric Research and Psychopharmacology), Veterans Administration Medical Center, and the Departments of Psychiatry and Neurology, Oregon Health Sciences University, Portland. Dr Casey is a Collaborative Scientist at the Oregon Regional Primate Research Center, Beaverton. Reprint requests to Daniel E. Casey, MD, Psychiatry Service (1 16A), VA Medical Center, Portland, OR 97207.
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ABBREVIATIONS USED IN TEXT GABA = -y-aminobutyric acid TD = tardive dyskinesia
yond 6 to 12 months. Such categorizing, however, unnecessarily conceptualizes the course of TD into too narrow a time frame and does not account for symptom resolution noted in many patients observed for several years. Recent terminology has therefore emphasized the concept of persisting versus resolving TD.9 Although no specific pathophysiologic mechanism for each time course and outcome has been verified, the most plausible explanation is that these symptoms occur along a continuum ranging from reversible to irreversible. Research criteria have also been established for characterizing TD.'0 These are at least three months of cumulative neuroleptic drug treatment, at least mild movements in two or more body areas or moderate dyskinesias in one, persistence of symptoms for three months or longer, and the absence of other conditions that produce involuntary hyperkinetic dyskinesias. The most commonly used rating tool for TD is the abnormal involuntary movement scale.1I Although helpful in characterizing abnormal movements, rating scales are primarily used for descriptive purposes. They are not diagnostic instruments. Diagnoses require a complete analysis of epidemiologic, etiologic, and temporal aspects of any symptom constellation in conjunction with a thorough examination.
Differential Diagnosis Abnormal involuntary movements have many causes and may occur spontaneously in idiopathic syndromes, arise from other drug treatments, may be associated with hereditary diseases, or may be part of systemic illnesses. Idiopathic Syndromes Long before the introduction of neuroleptic drugs, spontaneous hyperkinetic dyskinesias of "grimacing" and "irregular movements of tongue and lips" were described in psychotic patients, most notably when the current-day concepts of schizophrenia and manic-depressive illness were established by Kraepelin at the turn of this century and by Bleuler.' 2-14 Stereotypies (purposeless, meaningless actions) and mannerisms (peculiar ways of carrying out normal actions) of psychosis are part of a differential diagnosis of tardive dyskinesia. Syndromes now classified as focal dystonias were previously identified as "spontaneous orofacial dyskinesia," "senile dyskinesia," and "blepharospasmoromandibular dystonia."''5 These dyskinesias (dystonias) occur increasingly with aging. It has also been noted that patients with underlying neuromedical conditions have higher rates of "spontaneous" involuntary dyskinesias when compared with healthy age-matched controls.'6 Tourette's syndrome is defined by involuntary tics and vocalizations. It begins in childhood and continues with a waxing and waning course throughout a patient's lifetime. Simple persisting tics in an isolated muscle group must also be differentiated from TD. Dental problems can also cause oral dyskinesias that look like this disorder.'7 Neuroleptic Drug-induced Acute Extrapyramidal Syndrome Neuroleptic drugs also produce an acute extrapyramidal syndrome that develops with the initiation of treatment and may continue throughout the course of drug therapy.
The syndrome gradually resolves over a few days to weeks when neuroleptic therapy is discontinued. Because the acute extrapyramidal syndrome and tardive dyskinesia can coexist,I'I 8 both disorders must be considered in the differential diagnosis. Acute dystonia is a syndrome of episodically sustained abnormal postures such as oculogyric crisis, torticollis, trismus, laryngopharyngeal spasm, and torsion of the limbs and trunk. It occurs most often during the first four days of drug therapy. Neuroleptic-induced parkinsonism of tremor, rigidity, or bradykinesia usually develops after several days or weeks of drug therapy. It is symptomatically identical to idiopathic parkinsonism. Akathisia is a syndrome of subjective feelings or objective signs of restlessness that may have motor manifestations of walking in place, continuous motions of the trunk, or an inability to sit still. The rabbit syndrome is an uncommon form of druginduced parkinsonism characterized by rapid rhythmic tremors in the lips and perioral area.'9 Paradoxic TD is a syndrome that is rarely reported but probably occurs more often. It is symptomatically similar to typical TD but is pharmacologically like acute extrapyramidal syndromes because it often reverses with antiextrapyramidal syndrome drug therapy.'720 2' Paradoxic tardive dyskinesia emphasizes the important point that different pathophysiologic mechanisms may be expressed clinically by a limited number of common pathways to produce similar symptoms, such as these hyperkinetic dyskinesias. All acute extrapyramidal symptoms respond to antiextrapyramidal syndrome drugs, but tardive dyskinesia remains unchanged or worsens with their use. Some drugs commonly prescribed for extrapyramidal syndromes include the anticholinergic agents benztropine mesylate (Cogentin), biperiden (Akineton), procyclidine hydrochloride (Kemadrin), and trihexyphenidyl hydrochloride (Artane); the antihistaminic-anticholinergic diphenhydramine hydrochloride (Benadryl); and the prodopaminergic drug amantadine hydrochloride (Symmetrel). Other Drug-induced Dyskinesias Many other drugs can produce hyperkinetic movement disorders that must also be differentiated from TD.'7 Dopamine agonists such as bromocriptine mesylate and the dopamine precursor levodopa can produce hyperkinetic dyskinesias. The abuse of amphetamines and other stimulants can cause chorea and stereotyped behavior during both drug intoxication and withdrawal. Anticholinergic and antihistaminic agents have rarely been associated with orofacial dyskinesias. Several anticonvulsant agents can produce dyskinesias resembling TD when these drugs are taken either at or above therapeutic levels. Oral contraceptives and the chloroquine-based antimalarial agents can also cause chorea and other dyskinetic symptoms. Rarely, the use of benzodiazepines has been correlated with orofacial dyskinesias. Both lithium carbonate use and that of tricyclic antidepressants have been associated with aggravating existing TD. These agents can also produce rapid, fine, irregular tremors that may be superimposed on tardive dyskinesia. This brief list is not intended to exhaustively review all drug-related involuntary hyperkinetic dyskinesias. Rather, it identifies some of the more commonly prescribed drugs that need to be differentiated as causes of
dyskinesias. Hereditary and Systemic Illnesses Hereditary neurologic diseases may provide a difficult differential diagnosis for tardive dyskinesia if patients have
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also received previous neuroleptic drug treatment. Huntington's disease is characterized by choreoathetosis and dementia that may be preceded or accompanied by symptoms of psychosis. The family history, the progressive nature of the symptoms, and the development of dementia aid in the differential diagnosis. Wilson's disease (hepatolenticular degeneration), a disorder of copper metabolism, is also usually distinguishable by clinical signs, laboratory tests, and perhaps family history. As these patients are often treated with neuroleptic drugs, the eventual development of dyskinesias makes distinguishing between TD and hereditary neurologic disease difficult. Though rare, Hallervorden-Spatz disease of iron metabolism usually has its onset during childhood and is characterized by bradykinesia and dystonia. The dystonic symptoms of Hallervorden-Spatz disease make it necessary to distinguish this disorder from neuroleptic drug-induced tardive dystonia in children. Hyperkinetic movement disorders are also part of the overall constellation of symptoms occurring in many illnesses or disturbances in normal physiologic mechanisms. Endocrinopathies of hyperthyroidism, hypoparathyroidism, or hyperglycemia are infrequently associated with choreoathetosis. Chorea in pregnancy, known as chorea gravidarum, may possibly share some pathophysiologic mechanisms in common with oral contraceptive-induced chorea. Dyskinesias associated with the immune syndromes of lupus erythematosus, Schonlein-Henoch purpura, and Sydenham's chorea-as well as encephalitis or other inflammatory diseases of the central nervous system-must likewise be distinguished from TD."7 Epidemiology The prevalence (number of existing cases) of tardive dyskinesia varies widely, ranging from 0.5% to more than 70%.9,14.22 23 This broad range reflects the relative contributions of many different variables, including special populations at risk, past and current drug treatment, strictness of criteria for diagnosis, and the publication year. Realistic rates of TD prevalence average from 15% to 20%. They may, however, exceed 50% in high-risk populations such as elderly persons with long-standing psychosis, several decades of neuroleptic treatment, and confounding neuromedical conditions such as dementia. To account accurately for those patients with spontaneous dyskinesias who would have eventually presented with abnormal involuntary dyskinesias even if no neuroleptic drug treatment had ever been prescribed, we must reduce the approximate TD prevalence rate of 20% by the 1% to 5% prevalence rate for naturally occurring spontaneous dyskinesias, as described earlier. Schizophrenia develops in about 1% (2.5 million) of the population (250 million), and most are treated with neuroleptic agents. Tardive dyskinesia develops in 14% (350,000) of these patients. Add to this the substantial number of demented and behaviorally disturbed persons receiving neuroleptic drugs, and the actual prevalence of the syndrome is evident. The incidence (new cases per year) of TD is about 3 % to 5%.24-27 Because prevalence studies reflect the number of patients at a single cross-sectional point in time, these numbers do not account for the addition of new cases and the subtraction of those that have resolved. Although longterm outcome data are just now becoming available, it seems that the relatively stable prevalence rate of 15% to
5
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20% reflects a considerable turnover in affected cases because about as many cases resolve as new ones develop.27 Risk Factors Age and Sex The prevalence of tardive dyskinesia steadily increases with age. It occurs in 5% to 10% of patients younger than 40 and rises to a range of 50% to 70% in patients older than 65.9 28 Most but not all studies show that TD occurs more often in women at an approximate ratio of 1.7 to 1.9,22 23 Psychiatric Diagnosis The vulnerability to tardive dyskinesia may be greatly influenced by psychiatric diagnosis. It is not known why more severe TD develops in patients with affective disorders, particularly depression, and it does so after relatively brief exposures to low doses of neuroleptic drugs.29.30 This implies that patients with schizophrenia may be relatively less vulnerable to TD.31 Persons without psychotic diagnoses who receive extended treatment with neuroleptic agents are also at substantial risk for TD development. Included are those patients receiving long-term treatment with antiemetic drugs such as prochlorperazine (Compazine) and others or with the widely used compound metoclopramide hydrochloride (Reglan). Although metoclopramide hydrochloride is marketed for gastrointestinal disorders and nausea, its mechanism of action-like that of antiemetics and all neuroleptics agents-is through dopamine-receptor blockade. Metoclopramide has antipsychotic effects at higher doses and can produce all the acute extrapyramidal symptoms and TD from the doses commonly prescribed for gastrointestinal disorders.32 While there is relatively little risk of inducing TD with a short-term course (about four weeks or less) of antiemetics or metoclopramide, this risk increases steadily with extended treatment. It is essential to periodically reassess the need for these drugs when their use is long term to ensure that the risk-benefit ratio remains favorable.
Neuroleptic Dose and Duration of Treatment The relationship between TD and drug treatment variables is complex. A large, long-term, prospective study of tardive dyskinesia shows a significant positive correlation between its onset and both total treatment duration and total drug dose.24 No studies have yet teased apart the complex interaction between concomitantly increasing age and total duration of treatment. Prospective studies correlating blood levels of neuroleptic agents with tardive dyskinesia have not yet been done. In cross-sectional evaluations, blood levels of these drugs were higher in patients with TD than in those without the disorder in one study, but this was not confirmed in a subsequent
investigation.33'34
Neuroleptic Drug Type While it has been occasionally claimed that one drug or particular characteristics of certain drugs (for example, a specific chemical class, high versus low doses, receptor-site specificity) are associated with a greater or lesser risk of tardive dyskinesia, the widely conflicting findings across studies do not sufficiently resolve this issue. The proposal that long-acting neuroleptic agents are associated with a greater risk of TD is also highly questionable because of difficulties in interpreting the pharmacologic consequences of treatment with injectable depot drugs that may have
538
different rates and amounts of drug absorption compared with oral agents. At present, an objective evaluation of the data must conclude that the commercially available neuroleptic drugs appear more similar than different (with the probable exception of clozapine) and that it is impossible to implicate one drug or drug class as more or less liable to produce TD. Clozapine (Clozaril), whose mechanism of action is unknown, is the best example of an atypical neuroleptic agent. Although it has weak dopamine-receptor antagonist properties, it has more potent antagonistic activity at several other neurotransmitter sites-serotonergic, cholinergic, histaminic, a-adrenergic. Clozapine produces exceptionally low rates of acute extrapyramidal syndromes, and there are no well-documented cases of TD from extended clozapine use.35 The effect of clozapine on tardive dyskinesia is highly variable. In some patients the drug suppresses the syndrome while in others it has no effect.35 Because experience with clozapine is still limited, it is too early to draw firm conclusions about the liability of clozapine to produce TD. The risk of agranulocytosis (1% to 2%) and the limited indication for use in treatment-resistant schizophrenia make clozapine a second line of drug therapy reserved for special situations. Drug-free Periods Time off neuroleptic agents ("drug holiday") has the advantage of reducing drug exposure, unmasking covert dyskinesias, and evaluating if the drug therapy is still required. On the other hand, such time off exposes patients to the risk of a psychotic relapse. The most appropriate strategy is to gradually decrease the dose to the lowest effective level. Some patients show signs of impending psychotic relapse before the drug can be discontinued. In these patients, continuing the drug dose at the previous effective level is recommended. For other persons neuroleptic agents can gradually be reduced to much lower levels and possibly even discontinued. In this case, patients should remain off neuroleptic therapy as long as possible. It is still unclear whether periodic drug holidays are associated with higher rates of irreversible TD, as has been suggested.36
Anticholinergic Drugs and the Extrapyramidal Syndrome The etiologic role of anticholinergic drugs in tardive dyskinesia is disputed. Data exist both for and against a correlation with TD risk.22 23 In contrast to the controversial etiologic role, it is consistently shown that anticholinergic agents may temporarily aggravate existing TD, but the symptoms return to baseline when these drugs are discontinued.20-22'37 The acute extrapyramidal syndromes have been hypothesized as a risk factor for TD.38 In a prospective study of tardive dyskinesia, parkinsonian side effects significantly correlated with the early (defined as less than a year of drug treatment) onset of TD but were not associated with TD of a later onset.39 Why such a risk factor would be evident in the first year of treatment and not thereafter is unclear. Clarifying the relationship between TD and acute extrapyramidal symptoms is very difficult because these symptoms are multidetermined. Patient (age, sex, psychiatric diagnosis), drug (dose, type, duration) factors, and the presence or absence of agents that prevent extrapyramidal symptoms may alter the vulnerability to this disorder.40 41 Because anticholinergic drugs are used to treat extrapyramidal symptoms, the retrospective associations between tardive dyskinesia and anticholinergic agents may actually represent
TARDIVE DYSKINESIA
indirect measures of the correlation between acute extrapyramidal symptoms and late TD risk.
Organic Brain Factors Organic brain disease was identified as a risk factor in the early TD studies, but subsequent reviews questioned these associations.2223 Computed tomographic studies have also produced conflicting findings.42'43 Several methodologic problems-such as lack of age-matched controls, confounding effects of masked symptoms from concurrent neuroleptic drug treatment, and lack of standardized measurement techniques-all may have contributed to these inconsistent results. Despite the lack of consensus about the associations between brain disease and tardive dyskinesia, there is face, validity to the rationale that preexisting deficits enhance the vulnerability to other dysfunctions in the same system. Management Strategies Prevention of tardive dyskinesia is the best strategy because there is no uniformly safe and effective treatment of this syndrome. Although some researchers have strongly admonished against using neuroleptic drugs in any patient with TD, this is not practical as it leads to the unacceptable consequences of denying highly beneficial treatment to psychotic patients. The central question is how to provide appropriate neuroleptic drug treatment and at the same time minimize treatment risks (Figure 1).44 The same strategy is used to manage patients with and those without TD. Physicians should have a high index of suspicion and keep a vigilant watch for the early beginning or worsening of TD symptoms. If they develop, a thorough differential diagnosis and treatment strategies should be considered. As in all other branches of medicine, informed consent is
Figure 1.-An algorithm has been developed for managing tardive dyskinesia (TD) (adapted and reprinted by permission of the publisher from Casey and Gerlach,4 Figure 2, page 184).
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an important aspect of neuroleptic drug use and TD. The risks and benefits of treatment, alternative treatments, and no treatment should be discussed with patients and, if possible, a concerned family member or friend and should be documented. This best occurs when patients can understand the information and should be done whether or not TD is present. It is useful to periodically review this information with patients during long-term care. Informed consent is more of a process that occurs over time than it is a ritualized signing of a form as a one-time event. The American Psychiatric Association Task Force on Late Neurological Effects of Antipsychotic Drugs advocates using neuroleptic agents in the lowest effective dose for only those patients who benefit from therapy.22 Neuroleptic drugs are primarily indicated for acute and chronic schizophrenia and other uncommon neurologic disorders such as Tourette's syndrome and Huntington's disease. Secondary indications include acute mania or psychotic depression. Extended use may be justified with unstable manicdepressive illness where patients have failed to benefit from lithium or carbamazepine. Neuroleptic agents are not indicated for neurosis, personality disorders, insomnia, or other nonpsychotic conditions. It is important to adjust periodically to the lowest effective level the doses of neuroleptic drugs and those preventing extrapyramidal symptoms. Some patients can eventually discontinue these agents, but others must maintain therapy to prevent an exacerbation of psychosis. Regularly reevaluating medication requirements and benefits, discussing them with patients and their families, and documenting such efforts should be established principles of practice. Tardive dyskinesia either persists or gradually remits. The mental state may remain stable or deteriorate with an exacerbation of psychosis. When such a relapse occurs, it is necessary to reassess the risks and benefits of treatment with neuroleptic agents as was done when it was started and then reevaluated at each medication adjustment.
Long-term Outcome The possibility of a reversible course of tardive dyskinesia, even in patients continuing on neuroleptic agents, has been noted since the earliest reports.'-3 This favorable outcome is not well known, though, because it has been overshadowed by the reports that TD may not resolve. Improvement across studies varies from 0% to 92%.9,26.45 This wide range is due to the multiple factors of patient variables (for example, age), treatment variables (drug dose and cumulative exposure), and temporal aspects (early diagnosis, duration of treatment, and duration of TD follow-up). Age is consistently correlated with improvement in tardive dyskinesia: Younger patients are more likely to improve.9 26.21 Nevertheless, this does not exclude older patients from having improvement or resolution, as this favorable course can occur in any age group. Data are insufficient to clarify whether gender or psychiatric diagnosis correlates with TD outcome. Early diagnosis is often but not always associated with a good prognosis, perhaps because most TD outcome studies are initiated after symptoms are identified, and it is impossible to know when symptoms first developed as longstanding covert TD may have been masked by neuroleptic therapy. One large prospective study shows that a favorable outcome correlates with less drug treatment," although another study and a review of the subject noted that a uniformly good outcome is not predictable.47
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The few studies specifically addressing TD outcome when neuroleptic therapy is continued also show that symptoms may stabilize, lessen, or resolve over many years. Only a few patients have increased TD during continued treatment with neuroleptic agents.926 Overall, the longer the follow-up period, the better the outcome. The most important caveat, however, is that most outcome studies in patients remaining on neuroleptic therapy have evaluated the effects of these drugs only at low to moderate doses (for example, chlorpromazine equivalents of 600 mg or less per day). The effect of extended treatment in TD patients at doses above this level is unknown. The recommendation for the lowest effective dose (which includes discontinuing neuroleptic agents if possible) may be questioned if some data suggest that TD does not worsen with continued drug therapy. Still, there are several reasons for this "less is better" strategy. First, if a lower dose does as well as a higher one, the lower dose is desirable because it is less likely to produce acute and longterm side effects. Second, this will lead to better compliance, as dose-related side effects are often the reason why patients discontinue taking medicines. Third and most important, some evidence suggests that patients not receiving neuroleptic drugs have better outcomes than those continuing to take these drugs.46 This implies that these agents retard, but do not necessarily prohibit, the course of spontaneous remission. Thus, managing psychosis and tardive dyskinesia rests on a basic tenet of medicine: Use the lowest effective dose of drugs only in patients who benefit from them. An intriguing but unexplainable question is how neuroleptic agents can cause TD, which then gradually abates or resolves even with continued treatment with the class of drugs that caused the initial symptoms. This raises the possibility that neuroleptic agents play only a partial role in the pathophysiology of TD, perhaps by converting a covert vulnerability to overt dyskinetic symptoms. It also challenges the commonly held view that the central nervous system cannot compensate for long-standing dysfunction. Treatment Treating tardive dyskinesia is a clinical challenge. Unfortunately, no drugs are uniformly safe and effective over extended treatment periods. The long list of the many drugs used to study TD attests to their general lack of therapeutic benefits. Depending on one's perspective, there are many treatments for TD or there are none.9,37 Several assessments are frequently necessary to accurately account for the masking and unmasking effects of drug treatment. Without the opportunity to follow symptoms over time, it is possible to develop misleading impressions about the course of tardive dyskinesia. For example, the disorder may appear to emerge or worsen when the drug dosage is decreased because symptoms are unmasked. This unmasking could also occur when anticholinergic agents are added. Similarly, TD symptoms may appear to lessen or resolve when the neuroleptic drug dose is increased or when anticholinergic agents are decreased because symptoms are masked.
Dopamine Reducing dopaminergic function is the most effective way of suppressing (masking) tardive dyskinesia. Yet this strategy, when used solely to suppress TD, is justified only in those rare cases when TD is severe, debilitating, or lifethreatening. Functional reduction of dopamine can be
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achieved with presynaptic depletion (reserpine) or by false transmission (methyldopa [Aldomet]) but yields only variably beneficial effects.22,37 Although reserpine has rarely if ever been associated with causing TD, it and other drugs that decrease catecholamine function should be used cautiously because of the theoretic possibility that this approach, like the use of neuroleptic agents, reproduces the same biochemical pathophysiology as dopamine-receptor blockade. In addition, these drugs have their own undesirable and potentially troublesome side effects. The theoretically attractive approach of resetting dopaminergic hypersensitivity back to normal sensitivity with dopamine agonists (bromocriptine mesylate [Parlodel]) or dopamine precursors (levodopa) has not been consistently successful. As with so many other treatment trials of TD, the initial positive results have not been replicated in subsequent investigations.922'37
Acetylcholine Anticholinergic agents usually aggravate existing tardive dyskinesia or unmask covert TD. Rarely, they seem to be beneficial in TD-like hyperkinetic dyskinesias but are probably treating the uncommon syndrome of paradoxic TD (see Differential Diagnosis). Another theoretically attractive approach to treating TD was to augment the cholinergic system with the cholinesterase inhibitor physostigmine or through dietary cholinergic-precursor loading. Trials with physostigmine have been inconsistent, and the lack of a widely available oral form makes its use impractical. Dietary approaches with choline or lecithin (PhosChol) were again initially encouraging but subsequently disappointing.9'22'37 Other Drugs Compounds aimed at enhancing y-aminobutyric acid (GABA) activity, either through direct agonism or by inhibiting the catalytic enzyme GABA-transaminase, all have produced inconsistent results. Preparations such as baclofen (Lioresal) and sodium valproate (Depakene)-with mechanisms of action that may or may not be related to GABA function-have not been consistently effective and are not recommended for routine use. Benzodiazepines often temporarily reduce TD but rarely may aggravate it. The nonspecific sedative effects of these drugs may be their main benefit. Although diazepam may provide symptomatic relief of TD, it is not routinely recommended because of the potential problems with dependence during extended use. Other drugs that have been generally ineffective include the serotonergic agent, tryptophan, and cyproheptadine hydrochloride (Periactin); the noradrenergic agents such as lithium carbonate (Lithane, Eskalith); the ,B-adrenergic receptor antagonist propranolol hydrochloride (Inderal); and the a-adrenergic agonist clonidine hydrochloride (Catapres). Studies that have more theoretic implication than practical application and that have also failed to yield convincingly positive results include the neuropeptides metenkephalin, destyrosine-y-endorphin, vasopressin, and approaches through the opiate system with morphine and naloxone hydrochloride (Narcan). In addition, trials with estrogen, pyridoxine, fusaric acid, manganese chloride, phenytoin (Dilantin), ergoloid mesylates (Hydergine), papaverine hydrochloride, and several others have produced no or only sporadic benefits.9 22'37 While the results of these many varied trials are generally not encouraging, it may be worthwhile considering one of these therapeutic ap-
proaches if TD symptoms are severe and there are no indications for the appropriate use of neuroleptic agents. Much has been learned about tardive dyskinesia in recent years, but much more needs to be unraveled. It is thus appropriate to retain an open view on all aspects of this syndrome. Developing new drugs that treat psychosis and do not bring on tardive dyskinesia or extrapyramidal symptoms is a priority of researchers. Achieving this goal will be a major breakthrough both in patient care and knowledge about the mechanisms underlying psychosis. REFERENCES
1. Schonecker M: Ein eigentumliches syndrom im oralen bereich bei megaphen-applikation. Nervenarzt 1957; 28:35-36 2. Sigwald J, Bouttier D, Raymondeaud C: Quatre cas de dyskinesie faciobucco-linguo-masticatrice a 1'evolution prolong6e secondaire a un traitment par les neuroleptiques. Rev Neurol (Paris) 1959; 10:751-755 3. Uhrbrand L, Faurbye A: Reversible and irreversible dyskinesia after treatment with perphenazine, chlorpromazine, reserpine, and electroconvulsive therapy. Psychopharmacologia 1960; 1:408-418 4. Faurbye A, Rasch PJ, Bender Peterson P, et al: Neurological symptoms in the pharmacotherapy of psychoses. Acta Psychiatr Scand 1964; 40:10-26 5. Burke RE, Fahn S, Jankovic J, et al: Tardive dystonia: Late-onset and persistent dystonia caused by antipsychotic drugs. Neurology (NY) 1982; 32: 1335-1346 6. Barnes TRE, Braude W: Akathisia variants and tardive dyskinesia. Arch Gen Psychiatry 1985; 42:874-878 7. Campbell M, Grega DM, Green WH: Neuroleptic-induced dyskinesias in children. Clin Neuropharmacol 1983; 6:207-222 8. Gualtieri CT, Quade D, Hicks RE, et al: Tardive dyskinesia and other clinical consequences of neuroleptic treatment in children and adults. Am J Psychiatry 1984; 141:20-23 9. Casey DE: Tardive dyskinesia, In Meltzer H (Ed): Psychopharmacology: The Third Generation of Progress. New York, Raven, 1987, pp 1411-1419 10. Schooler NR, Kane JM: Research diagnoses for tardive dyskinesia. Arch Gen Psychiatry 1982; 39:486-487 11. Guy W: ECDEU Assessment Manual for Psychopharmacology, revised 1976. Washington, DC, Government Printing Office, 1976, pp 534-537 12. Kraepelin E: Clinical Psychiatry. New York, Macmillan, 1907 13. Bleuler E: Dementia Praecox or the Group of Schizophrenias. New York, International Universities Press, 1950 14. Casey DE: Spontaneous and tardive dyskinesia: Clinical and laboratory studies. J Clin Psychiatry 1985; 46:42-47 15. Jankovic J, Ford J: Blepharospasm and orofacial-cervical dystonia: Clinical and pharmacologic findings in 100 patients. Ann Neurol 1983; 13:402-411 16. Leiberman J, Kane J, Woerner M, et al: Prevalence of tardive dyskinesia in elderly samples. Psychopharmacol Bull 1984; 20:22-26 17. Casey DE: The differential diagnosis of tardive dyskinesia. Acta Psychiatr Scand 1981; 63(Suppl 291):71-87 18. Richardson MA, Craig TJ: The coexistence of parkinsonism-like symptoms and tardive dyskinesia. Am J Psychiatry 1982; 139:341-343 19. Villeneuve A: The rabbit syndrome: A peculiar extrapyramidal reaction. Can Psychiatr Assoc J 1972; 17:69-72 20. Gerlach J, Reisby N, Randrup A: Dopaminergic hypersensitivity and cholinergic hypofunction in the pathophysiology of tardive dyskinesia. Psychopharmacologia 1974; 34:21-35 21. Casey DE, Denney D: Pharmacological characterization of tardive dyskinesia. Psychopharmacology (Berlin) 1977; 54:1-8 22. Baldessarini RJ, Cole JO, Davis JM, et al: Tardive Dyskinesia: A Task Force Report. Washington, DC, American Psychiatric Press, 1980 23. Kane JM, Smith JM: Tardive dyskinesia: Prevalence and risk factors, 1959 to 1979. Arch Gen Psychiatry 1982; 39:473-481 24. Kane JM, Woerner M, Weinhold P, et al: Incidence of tardive dyskinesia: Five-year data from a prospective study. Psychopharmacol Bull 1982; 20:387-389 25. Barnes TRE, Kidger T, Gore SM: Tardive dyskinesia: A 3-year follow-up study. Psychol Med 1983; 13:71-81 26. Casey DE, Gerlach J: Tardive dyskinesia: What is the long-term outcome? In Casey DE, Gardos G (Eds): Tardive Dyskinesia and Neuroleptics: From Dogma to Reason. Washington, DC, American Psychiatric Press, 1986, pp 75-97 27. Casey DE, Gardos G, Gerlach J: The Long-Term Outcome of Tardive Dyskinesia (Abstr). Proc American Psychiatric Association 1989, p 41D 28. Smith JM, Baldessarini RJ: Changes in prevalence, severity and recovery in tardive dyskinesia with age. Arch Gen Psychiatry 1980; 37:1368-1373 29. Casey DE: Tardive dyskinesia and affective disorders, In Gardos G, Casey DE (Eds): Tardive Dyskinesia and Affective Disorders. Washington, DC, American Psychiatric Press, 1984, pp 1-20 30. Kane JM, Woerner M, Weinhold P, et al: Incidence and severity of tardive dyskinesia in affective illness, In Gardos G, Casey DE (Eds): Tardive Dyskinesia and Affective Disorders. Washington, DC, American Psychiatric Press, 1984, pp 22-28 31. Casey DE: Affective disorders and tardive dyskinesia. Encephale 1988; 14:22 1-226 32. Casey DE: Metoclopramide side effects. Ann Intern Med 1983; 98:673674
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33. Jeste DV, DeLisi LE, Zalcman S, et al: A biochemical study of tardive dyskinesia in young male patients. Psychiatry Res 1981; 4:327-334 34. Fairbairn AF, Rowell FJ, Hui SM, et al: Serum concentration of depot neuroleptics in tardive dyskinesia. Br J Psychiatry 1983; 142:579-583 35. Casey DE: Clozapine: Neuroleptic-induced EPS and tardive dyskinesia. Psychopharmacology (Berlin) 1989; 99:S47-S53 36. Jeste DV, Potkin SG, Sinha S, et al: Tardive dyskinesia-Reversible and irreversible. Arch Gen Psychiatry 1979; 36:585-590 37. Jeste DV, Wyatt RJ: Therapeutic strategies against tardive dyskinesia. Arch Gen Psychiatry 1982; 39:803-816 38. Crane GE, Smeets RA: Tardive dyskinesia and drug therapy in geriatric patients. Arch Gen Psychiatry 1974; 30:341-343 39. Kane JM, Woerner M, Weinhold P, et al: Incidence of tardive dyskinesia: Five-year data from a prospective study. Psychopharmacol Bull 1984; 20(1): 40. Keepers GA, Clappison VJ, Casey DE: Initial anticholinergic prophylaxis for neuroleptic-induced extrapyramidal syndromes. Arch Gen Psychiatry 1983; 40:1113-1117
41. Casey DE, Keepers GA: Neuroleptic side effects: Acute extrapyramidal syndromes and tardive dyskinesia, In Casey DE, Christensen AV (Eds): Psychopharmacology: Current Trends. Berlin, Springer-Verlag, 1988, pp 74-93 42. Famuyiwa 00, Rasch PJ, Peterson PB, et al: Tardive dyskinesia and dementia. Br J Psychiatry 1979; 135:500-504 43. Hoffman WF, Labs SM, Casey DE: Neuroleptic-induced parkinsonism in older schizophrenics. Biol Psychiatry 1987; 22:427-439 44. Casey DE, Gerlach J: Tardive dyskinesia: Management and new treatment, chap 12, In Spencer HC, Garfinkel PE, Rakoff VM (Eds): Guidelines for the Use of Psychotropic Drugs: A Clinical Handbook. Jamaica, NY, Spectrum, 1984 45. Casey DE: Tardive dyskinesia: Reversible and irreversible, In Casey DE, Chase T, Christensen AV, et al (Eds): Dyskinesia: Research and Treatment. Berlin, Springer-Verlag, 1985, pp 88-97 46. Kane JM, Woerner M, Sarantakos S, et al: Do low-dose neuroleptics prevent or ameliorate tardive dyskinesia? In Casey DE, Gardos G (Eds): Tardive Dyskinesia and Neuroleptics: From Dogma to Reason. Washington, DC, American Psychiatric Press, 1986, pp 99-108 47. Gardos G, Cole J, Haskell D, et al: The natural history of tardive dyskinesia. J Clin Psychiatry 1988; 8:31S-37S
WALKING THE QUILT (The NAMES PROJECT, AIDS Quilt)
incomprehensible size does not cauterize; this room throbs with unreprieved tales of harbors and streets, palettes and boots related to an emptiness that names itself -
this purple slash riots like laughter along the careful names I carefully read unknowing yet kin-known through and throughgilt could not mean more
this is a beachwalking among the dead full of wise driftwood and sudden wind, memory without decay, sunset sans romance, the accompaniment of one's need to know -
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musical notes plummet down the sewn edge where this devotee of blues forever meets a benefactor of rainbows, such smiles one would grope blind alleys to find
tissue boxes bespeak the common round; these silent, gentle faces freely give like abolished forests creating their last air before the saw's undebatable limitation -
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sometimes something scarlet beaks forward panels of mesmeric sorrow; I founder as in a valley whose mountains have wept their entire faces all down across
helpers dressed in reality patiently groundskeep the long rows shockingly cruciform, attention's punctuation marking the ways every one of us came together here -
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teddybears and glitter, denim and books, the told lives irreducibly braved, these panels I walk my sisterhood along, distance and memory joined with unimpeachable love PAT EVERITT
Orinda, California
