Brain Injury and Mental Retardation: Psychopharmacology and Neuropsychiatry

c. THOMAS GUALTIERI, M.D. Medical Director North Carolina Neuropsychiatry Chapel Hill, North Carolina

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4~ LiPPINCOTT WILLIAMS & WILKINS .. A Wolters Kluwer Company Philadelphia • Baltimore • New York • London Buenos Aires • Hong Kong • Sydney • Tokyo 23 Tardive Dyskinesia and Tardive Akathisia

Serious Side Effects of Neuroleptic Drugs Risk Factors for Tardive Dyskinesia Tardive Dyskinesia Patient-Related Risk Factors Tardive Dyskinesia Variants Treatment-Related Risk Factors Extrapyramidal Reactions Protective Factors Neuroleptic Malignant Syndrome Biological Mechanisms Tardive Akathisia Diagnosis Dysphoria, Anxiety, and Pain Treatment Restless Legs Syndrome The Course of the Disorder Treatment Malignant Tardive Dyskinesia Tardive Akathisia in the Mentally Handicapped Neuroleptic Norrresponders A Behavioral Analog ofTardive Dyskinesia References Is This Really Tardive Akathisia?

SUMMARY related variables predispose to the condition. Patients with neuropsychiatric disorders in general and men­ Do the tardive syndromes deserve a chapter oftheir tally retarded patients in particular appear to be more mvn? Are they not just relics ofthe bad old days when vulnerable to the neurotoxic effects of the old an­ neuroleptics were used indiscriminately in tipsychotic drugs. Malignant TD, conversely, is more homes and institutions for the mentally retarded? The common in patients with affective disorders. epidemic of tardive diskinesia a generation ago was a When one considers the pathophysiology ofTD, the blight on the history of psychopharmacology, but problem of oxidant stress is raised again. The evidence what pertinence does it have today? base may be shallow, but the theory is compelling. For It is appropriate to reflect on historical matters, and that reason, one may be inclined to recommend antiox­ the history oftardive dyskinesia (TD) illuminates two idant supplements to patients who are on long-term an­ points that I have tTied to make on several occasions: tipsychotic drug treatment. Because several other psy­ first, psychotropic drugs are safe and easy to use but chotropics are also capable ofgenerating a free-radical can be dangerous and require careful medical follow­ burden, it is reasonable to propose antioxidants for pa­ up. Second, the long-term effects of psychotropic tients in general who require long-term drug treatment. drugs deserve careful study because toxicity may not Will this issue ever be addressed in controlled studies? be apparent until years have passed. Whether a drug As previously stated, long-term studies of drug toxic­ is prone to long-term side effects is never evident in ity, or the prevention of it, are rarely, if ever, done. the short-term studies needed to win drug approval. This chapter is more than an exercise in historical ~UROLEPTIC DRUGS reflection. The neuroleptics are still prescribed, and even the atypical antipsychotics can occasionally The neuroleptic drugs were so-called by Delay cause tardive syndromes. several clinical (1955) because he believed that their antipsychotic ac­ issues such as the vexing problem oftardive akathisia tion was necessarily correlated with a tendency to pro­ (TDAK), the little-appreciated problem of tardive duce extrapyramidal side effects (EPS). The term is pain, and the possibility of a behavioral analog ofTD now reserved for the old antipsychotic drugs; the new are discussed. This last issue is another opportunity to atypicais are equally effective '>vith a low propensity for consider the neuropsychology of the basal ganglia. EPS. They are much less likely to cause the most seri­ The epidemiology of the tardive syndromes indi­ ous EPS, TD. For this and other reasons, they have won cates that a number of treatment-related and patient- most of the antipsychotic market, and the problem of

395 396 23. TARDIVE DYSKINESIA AND TARDIVE AKATHISJA

TD has receded accordingly, but it is not extinct, by any policy, and research scientists in psychiatry and neu­ means, and in some parts of the world, it continues to ropharmacology. The development of an antipsy­ be a vexing problem. It merits our attention as much chotic drug that did not cause TD became a prime fo­ for its historical importance as for its clinical salience. cus of psychopharmacologic research. My familiarity with the issue stems from a series of It is possible that recognition of TD as a serious, studies done in the late 19708 that demonstrated TD potentially debilitating side effect of neuroleptic and related disorders had achieved alarming dimen­ treatment was responsible for the dramatic decrease sions in children and mentally retarded people. In those in neuroleptic prescription for retarded people that unenlightened days, it was not uncommon to prescribe occurred during the 1980s (10), although other fac­ neuroleptics for children with relatively minor behav­ tors also played a role (e.g., the community move­ ioral problems such as attention deficit'hyperactivity ment, widespread skepticism of the medical model, disorder. As for mentally retarded people, if they were renewed emphasis on behavioral and developmental living in institutions, most of them were taking neu­ programming, new attention to alternative pharmaco­ roleptics, usually at high doses and for long periods of logic treatments). Nevertheless, the problem of TD time. In 1968, the national rate ofneuroleptic prescrip­ was a red flag around which adherents rallied to re­ tion for retarded people was approximately 50% (1) duce the unnecessary prescription of neuroleptic drugs and approximately the same in 1978 (2). It fell to ap­ and to improve programmatic treatments for retarded proximately 30% in 1985 (3). It is now less than 20%. people. It was certainly the specter of TD that led This reflected patterns of psychiatric care in the gen­ general psychiatrists to be more judicious in their use eral population in which neuroleptics were routinely of neuroleptic drugs and child psychiatrists to abjure used for anxiety disorders and affective disorders dur­ their use almost entirely. ing the 1960s and 19708, and then their use declined. TD began to be perceived as a hazard to the public The first descriptions of TD date from the mid­ health. It was widely held that neuroleptics were rel­ 19508 (4,5), and complaints that the side effcct was atively contraindicated in mentally retarded people, potentially dangerous came soon after (6), but little children, patients with brain injury, and the elderly. attention was paid. The problem was that continued Regulations at the state and federal levels reinforced neuroleptic treatment tends to obscure the charactcr­ those clinical beliefs. When neuroleptic prescription istic dyskinetic movements and patients with schizo­ was considered for a patient who was not overtly phrenia are prone to abnormal grimaces and postur­ schizophrenic, the treatment decision was made with ing as part ofthe condition. Institutional psychiatrists great care. Written informed consent and formal TD were oppressed by the job of day-to-day management monitoring systems came to be the standard of care. of many desperate patients. They were much more Drug withdrawal trials or gradual dose reductions impressed by the therapeutic utility of the new drugs, were mandated at appropriate intervals to test for oc­ and justifiably so, than they were by what seemed to cult or covert TD and to detennine whether continued be at the time a .minor side etlect. Looking back, we drug treatment was necessary. It was generally ac­ can afford to shake our heads beeause we have cepted that any patient whose behavioral problems learned from their mistakes. were so severe as to warrant neuroleptic prescription The first report ofTD in mentally retarded people should also have a concomitant behavioral program. on long-term neuroleptie treatment was published in Although this enlightened approach was associated 1975 (7), and there were several subsequent reports with a substantial diminution in the problem ofTD over the next few years (8,9). This was no less than 20 in special populations, even before the new antipsy­ years after the disorder was first described by Euro­ chotics were introduced, it was not without problems of pean psychiatrists, but it was contemporary "ith the its own. The judicious use of antipsychotic drugs was development of serious concern about TD among intcrpreted by some to mean nonuse. The pendulum American psychiatrists. was swinging too far in the other direction. This was It was not until the publieation of the APA Task especially true for the mentally retarded and nursing Force Report in 1979 that medical concern was di­ home elderly, for whom it was difficult for physicians rected to the problem ofTD, even for the mentally ill. to prescribe a neuroleptic for patients who needed it. Five years later, the problem gained widespread pub­ Lawsuits, largely spurious, were filed against physi­ licity, as lawsuits began to multiply, and even the pub­ cians who prescribed conventional neuroleptics, under lic media began to address the issue. TD became a any circumstances, if any side effect ensued at all. major issue for physicians who treated chronic men­ Many patients who might have benefited from a neuro­ tally ill patients, administrators and makers of public leptic were thus deprived of a therapeutic opportunity. 23. TARDIVE DYSKINESIA AND TARDIVE AKATHISIA 397

Since the atypicals have been introduced, attitudes Does that mean that one-third is immune to have relaxed considerably. The new drugs are much neuroleptic toxicity? Perhaps it does. safer, monitoring requirements are less stringent, and In fact, it is hard to be confident in'the numbers regulatory bodies are less critical of their use. Conse­ generated in studies of patients who have not been quently, the use of antipsychotic drugs in the mentally withdrawn from neuroleptic drug treatment because retarded, the elderly, children, and patients with brain maintenance neuroleptic treatment tends to mask the injuries has rebounded. Ironically, the transfer of large presence of the disorder. Therefore, any prevalence numbers of retarded individuals from institutions into estimate will be influenced by the pa­ the community has been associated with a dramatic in­ tient's medication status. A true prevalence rate can crease in antipsychotic prescription. This also reflects only be determined from the study of drug-free pa­ general psychiatric practice, in which the atypicals are tients, and this is not done very often in studies ofpa­ increasingly used for severe anxiety disorders (e.g., tients with disorders. In one survey ofpa­ posttraumatic stress disorder, obsessive-compulsive tients who had no of TD as long as they were disorder) and treatment-refractory affective disorders. taking neuroleptics, new ofTD emerged in no Nevertheless, TD remains a problem, especially in fewer than 34% when the neuroleptics were subse- . mentally retarded people who may well be especially quently withdrawn (12). vulnerable to the side effect. Even atypical antipsy­ The problem is illustrated by the changing preva­ chotic drugs may sometimes cause the disorder. Thus, lence of ID in mentally retarded populations. In a TD remains a continuing problem, even in the face of study by Paulson et a1. (7), the prevalence was 20%, convenient solutions. It is also a prototypical move­ but most patients who were surveyed were still on ment disorder, around which a number of interesting neurolepties. In two other surveys, conducted on the neuropsychiatric problems are concentrated. heels of medication withdrawal, the prevalence was It is appropriate to refer to the tardive syndromes much higher: persistent TD (34% to 45%) and tran­ because TD is only one of a number of related condi­ sient withdrawal dyskinesia (29%) (9,14). tions associated with long-term antipsychotic treat­ Epidemiologic studies of TD and related disor­ ment In addition to TD, there is TDAK, tardive dys­ ders are also complicated by the existence of spon­ tonia, tardive pain, tardive Tourette's syndrome, and a taneous dyskinesias, i.e., choreic, athetoid, and tic­ behavioral analog of TD that has been controversial, like movements that seem to occur quite naturally which will be discussed in this chapter. without medication in the elderly, patients with chronic schizophrenia, and mentally retarded indi­ viduals. There is a 4% rate of mild involuntary SERIOUS SIDE EFFECTS OF movements in healthy elderly volunteers (11), but a NEUROLEPTIC DRUGS much higher rate, approaching 40%, in the elderly with dementia (15). Tardive Dyskinesia One cannot argue that the estimate of TD occur­ Estimates ofTD prevalence published in the psychi­ rence in people with mental retardation is inflated be­ atric literature have varied a great deal, largely as a cause they are given to a wide range of abnormal consequence of idiosyncrasies in measurement and de­ movements, even in the absence of neuroleptic treat­ finition. The average prevalence of TD based on 33 ment. The assessment of dyskinetic movements in studies reported from 1970 to 1979 was 24% (11), but people with severe to profound retardation may be the true rate varies, depending on the clinical popula­ problematic because they are prone to a number of tion: from 12% among outpatients in a of abnormal movements and the patients may not coop­ Veterans Affairs clinic to 13% in an acute psychiatric erate with the examination procedure. Conversely, hospital to 36% in a state hospital to 67% among state Kalachnik et a1. (9) arrived at a true prevalence rate hospital patients older than 65 years The cumu­ for TD by subtracting the basal rate of dyskinesia in lative incidence ofID in patients ""1th psychiatric dis­ drug-free controls. orders is said to be approximately 5% at 1 year, 10% at In a unique prospective study of haloperidol treat­ 2 years, 15% at 3 years, and 19% at 4 years (12). There ment for children with autism, most of whom were is said to be a 40% cumulative rate ofID in adult pa­ mentally retarded, the incidence of TD after 6 to 30 tients with psychiatric disorders after 8 years of expo­ months of follow-up was 25% (16). The dyskinesias sure to neuroleptic drugs (13). With every year oftreat­ that arose were transient, however, as one might ex­ ment, it would appear that the rate ofID increases by pect in young patients treated with low doses of a 5% until it reaches asymptote at approximately 67%. neuroleptic for a relatively short period. Conversely, 398 23. TARDIVE DYSKLVESIA AND TARDIVE AKATHISIA the fact that an early form ofTD arose in onc-fourth acterized by sustained contractions of skeletal muscu­ of treatcd patients within the span of 30 months sug­ lature; it has been found to account for 26% of all TD gests, to me at least, that neuroleptics are relatively cases referred to a movement disorder clinic. TDAK is contraindicated in this group. estimated to comprise 18% of TD cases. Tardive In the face of such extraordinary figures, one is Tourette's syndrome is characterized by motor and compelled to warn patients on long-term neuroleptic phonic tics (5% of cases) (18). Tardive pain syndrome treatment that the development of TD is a likely is a curious phenomenon and is described below. event. Conversely, it is also appropriate to assure pa­ tients that TD can be prevented by judicious use of Extrapyramidal Reactions neuroleptic drugs and by careful and knowledgeable TD is a late extrapyramidal syndrome associated medical supervision. Jt has been suggested that even with neuroleptic treatment, as distinguished from the patients with chronic psychotic disorders can be early EPS. These, of course, are pseudoparkinsonism, maintained on neuroleptic doses that are 10% to 20% acute dystonia, akathisia, akinesia (19), and aphonia of those in common use (17). After all, the highest (20). In fact, the term neuroleptic was coined because rates of TD are found in public institutions for the it was thought that the therapeutic action of antipsy­ mentally ill and mentally handicapped, where drugs chotic drugs was necessarily correlated with their ten­ have been used in lieu of programming and medical dency to produce EPS. (Clozapine, risperidone, olan­ supervision is sometimes less than optimal. If neu­ zapine, quetiapine, and ziprasidone should be called roleptics are used in low-to-moderate doses, even for antipsychotics because they are less prone to produce a sustained period, the level of risk is probably ac­ EPS; they defy the correlation.) ceptable. If the novel antipsychotics are used, in pref­ erence to the conventional neuroleptics, whenever Neuroleptic Malignant Syndrome they are effective, the risk of TD is even lower, and the annual incidence is much lower than 5%. Neuroleptic malignant syndrome (NMS) is a dev­ The issue of TD prevalence, however, obscures a astating, sometimes fatal neuroleptic side effect aris­ more important issue: the need to distinguish between ing early in treatment, especially with high-potency the prcvalence of severe and dcbilitating cases ofTD drugs. The symptoms are muscular ("lead-pipe") and those that are relatively mild and persistent cases rigidity, mental state changes (e.g., delirium), and au­ and those that will only last a few months or a year or tonomic changes (e.g., hyperthermia, hypertension, two. Prevalcnce rates from 25% to 33% should ordi­ tachycardia), accompanied by elevation of the whole narily be cause for alarm. If only a few ofthose cases, blood cell count and serum creatine phosphokinase. however, are severe and persistent and most are mild Ifthe disorder is not recognized promptly and proper or self-limiting, then the problem is manageable. If treatment measures are not instituted immediately, severe cases can be prevented by careful monitoring, the patient may die of renal failure. Treatment is neu­ then physicians will have the right to reassure patients roleptic withdrawal, fluid replacement, and dantro­ and their families. lene or dopamine agonists (e.g., bromocriptine). It is Conversely, if severe and persistent cases comprise said that NMS occurs in 1% to 2% of neuroleptic­ a significant fraction of the population of patients treated patients and that 10% to 20% of cases are fa­ with TD, then draconian measures will be required to tal (21). That estimate is probably too high, but there reduce neuroleptic prescription. Most psychiatrists is no denying that increased familiarity with this ex­ would say that severe cases are only a minority ofpa­ traordinary syndrome leads to increased recognition. tients with TD, and I have never argued with that con­ Although NMS is most likely to occur early in tention. When the issue is put to the test, however, se­ treatment, it may arise at any point, even when the pa­ vere TD variants have been observed in more than tient is on a stable maintenance dose (22). Risk fac­ one-fifth of all diagnosed TD cases (18). tors include a state of psychomotor agitation before neuroleptic treatment, high doses of neuroleptics that are increased rapidly, and intramuscular administra­ Tardive Dyskinesia Variants tion (23). Other risk factors are the use of high-po­ The typical case ofTD is characterized by irregular tency neuroleptics and patient-related variables, such choreoathetoid movements occurring predominantly in as a dehydrated or physically exhausted state or a his­ the buccal-lingual-masticatory musculature and distal tory of neuroleptic toxicity. It is incredible that a side extremities. It is the most common manifestation ofthe effect so severe and presumably so common went un­ syndrome (93% ofTD cases). Tardive dystonia is char­ recognized for so many years (24). 23. TARDIVE DYSKINESIA AND TARDIVE AKATHISIA 399

NMS is a major problem for nursing personnel be­ roleptic dose is lowered, whereas the symptoms ofpa­ cause the keys to successful treatment are early tients with NIA tend to improve. recognition and a high index of suspicion. Any patient TDAK was further described in a series of clinical on neuroleptic treatment with rigidity and mental reports (33-37), and it was operationally defined in a state changes should be reported to the attending systematic stndy by Barnes and Braude (30). The physician immediately as a medical emergency, and prevalence of TDAK was reported to be 18% in pa­ neuroleptics should be withheld until an examination tients referred for evaluation at a TD clinic (18) and can be done and the appropriate laboratory tests can 6% to 14% in mentally retarded patients treated with be done. Dealing with NMS requires special training neuroleptics (38,39), for nurses who care for patients on neuroleptic treat­ TDAK is a relatively common and severe problem, ment and careful monitoring by physicians who are causing distress to the patient and demanding a great familiar with the syndrome. NMS, more than any deal of attention by physicians and direct care person­ movement disorder, should limit the widepread use of nel. Because akathisia is a state of restless, dysphoric neuroleptics. Neuroleptics are not routine treatments hyperactivity, it may also be the occasion of secondary to be administered by primary care physicians with behavioral problems, a "setting event" for the occur­ no special training in psychopharmacology. rence of difficult behaviors such as aggression (40) or The atypical antipsychotic drugs are much less self-injury (41). The emergence ofwhat are refcrred to likely to cause NMS. as target behaviors (e.g., disorganization, agitation, aggression, hyperactivity, self-injurious behavior) in the circumstances of neuroleptic withdrawal might Tardive Akathisia represent the recurrence ofa preneuroleptic psychiatric Akathisia is a Greek word that means "not to sit condition or alternatively the manifestation ofTDAK. still:' (In fact, the Greek word is kathisia, which refers The diaguostic and therapeutic dilemma is daunting. to the act of sitting, and akathisia is a neologism.) The People with akathisia are miserable. They feel as if word describes the subjective state of motor restless­ they were crawling out oftheir skin, and they have to ness and dysphoria that occurs in many clinical condi­ pace constantly just to win a small degree of relief. tions. It was first adopted by Haskovec (25) to refer to They are irritable, unhappy, and emotionally unstable. patients whose problems were hysterical in origin. They are so unhappy and find it so hard to understand Later, Bing (26) described akathisia in patients with what is happening to them that they may.erupt in ex­ postencephalitic parkinsonism. Since then, akathisia plosions of aggressive, destructive, or self-injurious has been considered a disease ofthe basal ganglia (27). behavior. They may be described as hypcractive, dis­ Soon after the introduction of neuroleptic drugs, organized, or psychotic. In other words, they may de­ clinicians noted patients who had symptoms of rest­ velop, as a consequence of long-term neuroleptic lessness and dysphoria (4,28,29). The term neurolep­ treatment, persistent symptoms that are identical to tic-induced akathisia (NIA) joined pseudoparkinson­ the problem behaviors for which neuroleptics were ism and dystonia in the trio of acute extrapyramidal originally prescribed. reactions caused by neuroleptic drugs. The preva­ lence of NIA has been estimated at approximately Dysphoria,Anxiety, and Pain 20%, although the figure may be as high as 45% (30). Early reports of NIA also included descriptions of Several other unpleasant subjective states may also patients whose symptoms arose only after several years occur in association with neuroleptic treatment, occur­ of neuroleptic treatment and co-occurred with symp­ ring as side effects of acute treatment, as tardive syn­ toms ofTD (6,28,31,32). In 1977, Simpson suggested dromes, occurring in association with better known that late-onset NIA was persistent, even after neu­ EPS such as akathisia, or standing alone. One example roleptic withdrawal, and that it was virtually untreat­ is neuroleptic-induced dysphoria (without motor rest­ able. In 1983, Munetz and Comes introduced the term lessness), especially with haloperidol, which can also TDAK: "an akathisia-like syndrome (characterized by) cause anxiety and even overt panic attacks (42). late onset, treatment resistance, and potential irre­ Acutely treated patients may also complain of painful versibility despite discontinuance of neuroleptics." The sensations (43). These are usually described as poorly overt symptoms of TDAK are indistinguishable from localized, intermittent, aching sensations involving all those ofNIA, and the direct examination ofthe patient four limbs symmetrically and sparing the head and yields the same findings. The symptoms of patients ventral torso. Complaints of pain tend to be more fre­ with TDAK, of course, tend to increase when the neu­ quent in patients who also have pseudoparkinsonism or 400 23. TARDIVE DYSKINESIA AND TARDIVE AKATHISIA akathisia (44). Oral and genital pain have been de­ quent success of such drugs in the treatment of scribed as a tardive syndrome, said to be an example of akathisia suggests an effect of chronic neuroleptic pure cognitive akathisia (45). Analogously, patients blockade on noradrenergic neurotransmission. Neu­ with postencephalitic or idiopathic parkinsonism expe­ wleptics are known to increase cerebrospinal fluid rience distressing and ill-defined sensations, com­ and brain levels of norepinephrine; the mechanism monly referred to as primary sensory symptoms (46). may be presynaptic dopamine blockade, a neuroleptic The lesson is that "all the side effects of neuroleptics effect that has been determined to increase norepi­ have already been described between 1920 and 1935 as nephrine release, at least in laboratory animals (56). a sequela of (von Economo) encephalitis" (47). Lorazepam or clonazepam may also be used, with The sensation of pain as an EPS of neuroleptic only occasional success; benzodiazepines may even treatment illuminates the role ofopioid drugs (codeine, be used in conjunction with beta-blockers. There have propoxyphene, nitrous oxide), which seem to be ef­ . been reports of successful treatment with amantadine fective for NIA but not for TDAK. This may have to (57), which I have been unable to confirm, and with do with the presence of opiate receptors on presynap­ buspirone (58), which we have. Gabapentin and tic dopaminergic neurons and on neurons that carry tiagabine are other alternatives. the postsynaptic dopamine receptors (48). The stria­ As in severe cases of TD, the only effective treat­ tum contains high concentrations of both dopamine ment may well be reinstitution of nenroleptics. In the and opioid receptors, and the number of opioid bind­ past, atypical neuroleptics such as molindone or ing sites is reduced after denervation ofdopaminergic thioridazine were recommended, but not any more. neurons (49). They never worked very well, and the pharmacologic treatment of TDAK was for a very long time as un­ Restless Legs Syndrome successful as Paulson et al. (7) suggested in 1975. Since clozapine, however, the clinical picture has Patients with restless syndrome also improve changed dramatically, and since the other atypical an­ whcn they are treated with low doses of opiates (48). tipsychotics were introduced, it has improved even The syndrome was first described by Ekbom who de­ more. Today, one recommends the introduction of an scribed restless movements ofthe legs arising sponta­ atypical antipsychotic in the usual doses and then a neously in some people especially in the elderly and very gradual withdrawal. especially at night (50). The condition is autosomal dominant, but it may also be manifest as a variant of NIAorTDAK. Tardive Akathisia in the Mentally Handicapped The symptoms of restless legs s}'ndrome include Because neuroleptic drugs have been prescribed painful paresthesias of the especially in the quite often for mentally retarded adults (1,2), there calves, occnrring at rest. The patient finds relief only has been a strong movement in recent years to reduce by moving his or her lower extremities. Because the unnecessary or excessive neuroleptic drug use. In problem is most intense at night, the patient experi­ many clinical facilities, however, the reduction of enccs severe insomnia and all the secondary problems neuroleptic prescription has led to the unmasking of that arise from it. The paresthesias are oftcn described neuroleptic side effects such as TD and TDAK (39). as burning or a deep ache. In 1993, I reported the results of a longitudinal study It is interesting that virtually all the treatments rec­ of TDAK and its behavioral concomitants (59). The ommended for NIA and TDAK have also been useful study was undertaken at a residential facility for (on occasion) for cases of restless legs syndrome, the mentally handicapped. Of a population of 356, no most notably, carbamazepine, vitamin E, folate, beta­ fewer than 180 residents had been treated long term bloekers, benzodiazepines, clonidine, and tryptophan with neuroleptic drugs. TDAK was diagnosed in 25 (51). The opiates, then, are hardly unique. None of patients (14% of the population at risk). these treatments, however, is uniformly effective. Re­ Three years after the patients with TDAK were first cently, gabapentin has corne to be one of the most identified, I fmmd that 10 patients (40%) succeeded successful treatments for restless legs syndrome. It in remaining nenroleptic free. Their clinical status may also be useful for NIA and TDAK. was unstable at first, but it gradually improved. Symptoms of akathisia and target behaviors had Treatment abated, and there was no need for continued neu­ Akathisia, acute or tardive, is often treated with roleptic treatment. Fifteen patients (60%) had to re­ beta-blockers (52-54) or clonidine (54,55). The fre­ main on ncuroleptics, despite the TDAK, because of 23. TARDIVE DYSKINESIA AND TARDIVE AKATHISIA 401 severe behavioral problems that could not be con­ oration, and could neuroleptics cause dementia? In trolled by alternative interventions. other words, whether higher cortical functions might One year later, the original 10 patients remained be damaged, much in the same way that motor control stable and neuroleptic free. The other 15 continued on systems were damaged. You can imagine the excite­ neuroleptics, albeit on comparatively lower doses. ment and dismay this question raised. It was a diffi­ With selective concomitant treatment (e.g., beta­ cult point to prove one way or the other. blockers, benzodiazepines) or substitution of novel Cases of supersensitivity psychosis were described antipsychotics, they also stabilized, with no further by Chouinard and Jones (62) (who coined the term), progression ofTOAK (59). Sale and Kristall (63), and Caine et aL (64). These It was encouraging that a substantial number of re­ were neuroleptic-treated patients who developed a tarded people \vith TOAK could be successfully with­ dramatic, rapid-onset psychosis as soon as neurolep­ drawn from neuroleptic drUgs and that their symptoms tics were withdrawn. The psychosis was held to be a gradually abated. It was discouraging that three-fifths consequence of neuroleptic treatment, not simply the of the group could never be withdrawn from the of­ reemergence of a preexisting disorder. The psychi­ fending agents, but at least TOAK was not progressive atric community has not found this contention partic­ as long as their management was judicious. ularly believable (12), although it would be impru­ The problem of TDAK generates difficult clinical dent to dismiss it. situations that seem to be unique to patients who are There is near unanimity, however, on the issue of mentally retarded and patients with brain injury. dementia because virtually every study that has re­ Many are patients who never respond very well to searched the issue has found an association between neuroleptics to begin with but who grow much worse TD and signs of dementia or so-called negative symp­ after they are withdrawn. Their behavior deteriorated toms of schizophrenia. When patients with TD are sharply after the neuroleptic dose is lowered beyond a compared with similar patients who do not have TD, certain point, but they remain difficult and hard to clear evidence of cognitive dysfunction is almost in­ mauage even after the dosc is rcturned to what had variably demonstrated in the TD group (65-74). What earlier been a therapentic level. Their TO symptoms is at issue is how to account for the finding. The usual are accompanied by high levels of hyperactivity and explanation is that patients with preexisting neu­ restlessncss; they are extremely dysphoric when neu­ ropsychological deficits are more vulnerable to the roleptics are withdrawn and seem to be manageable neurotoxic effects of neuroleptic drugs. The alterua­ with any pharmacologic agent. The problem is usu­ tive explanation is that neuroleptics cause cognitive ally TDAK, and the only reasonable solution is to decline in some patients, that neuroleptic treatment switch to an atypical antipsychotic drug and then may cause subcortical dementia (73) or frontal lobe gradually lower the dose. syndrome (66). This idea is supported by a recent positron emission tomography study that demon­ strated long-term neuroleptic effects on brain glucose A Behavioral Analog ofTardive Dyskinesia metabolism in patients with schizophrenia in the di­ For a long time, my colleagues and I were preoc­ rection of decreased metabolism in the frontal lobes cupied with the possibility of a behavioral analog of (hypofrontality) and enhanced metabolism in the cor­ TO (60). It was an important question that seemed to pus striatum (75). Neither alternative is attractive to beg solution. Ifneuroleptics were prescribed for peo­ physicians who treat patients who are retarded, el­ ple who were cognitively impaired and behaviorally derly patients who are demented, or patients with unstable to begin with, how could one know whether head injury Either encephalopathy is a risk factor for cognitive impairment or behavioral instability, the development ofTD or it is a risk inherent to long­ emerging after neuroleptic withdrawal, was in fact the term neuroleptic treatment. result of drug treatment. Because TDAK has been clearly established as one In 1979, Davis and Rosenberg raised the question of the tardive syndromes attributed to neuroleptic of a limbic equivalent ofTD, that is, behavioral toxi­ treatment, the arguments over a behavioral or city as a consequence ofneuroleptic-induced changes tive analog to TD can be considered settled (10). Stahl in mesolimbic dopamine receptors. In the same year, (76), for example, suggested that TDAK is both a investigators reportcd morc intellectual deterioration movement disorder and a mental disorder because it in neuroleptic-treated patients with TD than in non­ has both objective and subjective components. In TD controls (61). Two questions were then posed: other words, TDAK is a movement disorder with a Could neuroleptic treatment lead to behavioral deteri­ psychological dimension. As discussed previously, it 402 23. TARDIVE DYSKINESIA AND TARDIVE AKATHISIA may manifest itself as a purely subjective state with­ slow down neural activities throughout the frontostri­ out the movement disorder. atal circuit (99). Even more compelling, the mosaic Akathisia, like TD, and all the hyperkinetic move­ of deficits caused by lesions of the frontal lobes is re­ ment disorders are manifestation symptoms of basal flected by similar deficits caused by lesions in striatal ganglia disease. Postmortem studies (77,78) and areas to which the frontal cortex projects (102-104). magnetic resonance imaging studies (79,80) have One may surmise, therefore, that affective instabil­ demonstrated basal ganglia lesions in patients with ity and intellectual impairment may be the conse­ TD, especially in the caudate nucleus. Lesions of the quence of neuropathology at the level of the basal basal ganglia may evoke movements that are indistin­ ganglia. Because TD is the result of neurotoxicity in guishable from TO. the basal ganglia, some patients with TD may be ex­ Parkinson's disease (PD), Huntington's chorea (HC), pected to have behavioral and cognitive deficits as and Wilson's disease (WD) are progressive diseases of well. TDAK is one manifestation of that effect. There the basal ganglia that are very similar to TD. Akathisia, are probably others. for example, is a symptom of PD and choreoathetosis is a symptom of HC and Wo. Although persistent Is This Really Tardive Akathiskl? TDAK and TD appear to be static not progressive en­ cephalopathies, their similarity to the major diseases of The emergence of troublesome behaviors, accom­ the basal ganglia goes deeper than the surface mani­ panied by dysphoria and restlessness, when a retarded festations of akathisia and dyskinesia. person is withdrawn from neuroleptic medication, is The issue is especially relevant to the putative cog­ sufficient to suggest the diagnosis of TDAK, espe­ nitive and behavioral analogs of TO. PD, for example, cially when the patient has concomitant signs of is associated with depression and dementia (81-83). drug-induced neurotoxicity (i.e., TD). Conversely, as HC and \VD are associated with affective instability, previously mentioned, the diagnostic problem is psychosis, and dementia (84-88). If behavioral insta­ daunting because the diagnosis is no more than pre­ bility and intellectual impairment are inevitably a part sumptive, and the alternative construction is that the ofPD, HC, and WD, should they not also occur in TD? patient is simply manifesting the reemergence of the Patients with PD, HC, and WD also have neuro­ problem behaviors that led physicians to prescribe pathologic changes in cortical structures, and there­ neuroleptics in the first place. Retarded children who fore it is not possible to attribute all the cognitive and are hyperactive, aggressive, and casily agitated are behavioral elements of those conditions to lesions in likely to be given a strong psychotropic drug. ~When the basal ganglia. Conversely, intellectual impairment that drug is withdrawn, is it any surprise that they are has been noted in patients with PD with lesions in the again hyperactive and dysphoric? subcortical nuclei but not in the cortex (89) and in There is a theoretical answer to that question, as patients with PD after N-methyl-4-phenyl-l,2,3,6­ described in the foregoing section. There is unfortu­ tetrahydropyridine exposure, who had neither cortical nately no direct clinical measure to decide the issue in lesions nor motor impairment (90). In WD, the sever­ the individual case. In practice, one may be told that ity of neuropsychological impairment is correlated a patient with presumcd TDAK was, in fact, 'just like with abnormalities in the basal ganglia but not in the that" before neuroieptics were ever prescribed. In cortex or cerebellum (91). We also know that circum­ contrast, one does see young patients who are re­ scribed lesions in the basal ganglia are sometimes as­ tarded and autistic who are restless, impulsive, irrita­ sociated with significant psychiatric conditions (92, ble, and emotionally unstable. They are like that, 93) or neuropsychological deficits (94-97). never having been treated with ncuroleptic drugs. The basal ganglia may be the "dark basement" of The difference is that for the past 10 or 15 years the brain, but they are not without intelligence of "children like that" have not been treated with neu­ their own. The basal ganglia do participate in, and roleptics in high doses. They havc been treated with may even regulate, some intellectual activities, partic­ serotonergics, or amantadine, or 0.2 agonists, or ularly those involving complex or sequential motor mood stabilizers-drugs that are more specific for activities (81). The corpus striatum subserves a num­ the organic affective disorders, which is what we ber of frontal lobe functions in the juvenile primate usually deal with. Never having been exposed to (98). The frontal lobes are richly connected with ar­ neuroleptics, their outcomes have been much more eas in the neostriatum (99). Neostriatallesions mimic sanguine; when the drugs are withdrawn, they do not the effects of frontal lesions (100,101) and lesions in revert to their original pattern ofhypcractive, disor­ either the frontal lobes or neostriatum disturb and ganized behavior. 23. TARDIVE DYSKINESIA AND TARDIVE AKATHISIA 403

Long-term treatment of retarded people with neu­ particularly well to neuroleptic treatment, but whether roleptics may cause TDAK. Alternatively, long-tenn this is related to high-dose treatment, frequent dose treatment may have another kind of neurotoxic ef­ changes, conjunctive treatment, or some other factor is fectinterfering with learning and preventing devel­ not known. It may be that the neuroleptic nonrespon­ opment in an already compromised brain. The ders are people with affective disorders. reemergence of difficult behaviors after the with­ It appears that patients with affective disorders are drawal of neuroleptics may represent the failure ofthe peculiarly vulnerable to malignant TD (110). This is development of cognitive systems that lend control to very important for the treatment of mentally retarded a primitive, undifferentiated state of irritability and people, among whom affective disordcrs tend to be un­ hyperreactivity. derdiagnosed, and it may explain why the tardive syn­ The atypical antipsychotics are less neurotoxic, dromes have been so troublesome in this population. and the few cognitive studies that have been done to Whether preexisting brain damage may actually date do not indicate impainnent of function. Devel­ predispose to TD or severe and persistent TD is not opmental studies have not been undertaken. We as­ known, although it is an important question for prac­ sume that, like the new antidepressants, the atypical titioners who deal with patients with mental retarda­ antipsychotics are at least neutral with respect to cog­ tion, dementia, or neurobehavioral sequelae of trau­ nitive perfonnance and brain development. That is, of matic brain injury (Ill). Neuroleptics have always course, no more than an assumption. As the drugs are been frequently prescribed for these groups (10). used more often in handicapped children, we will have an opportunity to test its validity. Treatment-Related Risk Factors Several factors related to treatment with neurolep­ RISK FACTORS FOR TARDIVE DYSKINESIA tic drugs have been associated with increased risk of TD, but only one, early development of EPS, has Patient-Related Risk Factors gained wide acceptance on the basis of controlled ex­ Three patient-related risk factors seem to be asso­ periments. ciated with increased risk for TD: age, gender, and af­ Results from the New York Longitudinal Study fective disorder. A fourth, preexisting brain damage suggest that patients who develop TD are more likely may be also be associated, although the data are by no to have EPS early in their treatment (112). The asso­ means definitive. As a general rule, a risk factor that ciation does not appear to bc related to treatment with is linked to a higher likelihood of developing TD will selected neuroleptics with a low proclivity for EPS; also be linked to and to persistence. rather, patients who are prone to early EPS arc at The risk factor most consistently identified with greater risk for TD by virtue of some unique phanna­ the development of TD and severe persistent TD is codynamic tendency (113). age. Elderly patients are more prone to the disorder, If concomitant anticholinergic treatment is associ­ an effect that is probably independent of cumulative ated with TD at all, the effect is probably mediated by neuroleptic dose or the duration of neuroleptic expo­ the occurrence of early EPS. That is, patients who de­ sure (12,105). It is possible that this association is re­ velop early EPS are more likely to receive anticholin­ lated to the age-related decline in dopamine neurons ergics; the fonner confers risk, not the latter. in the striatum, an idea that is strengthened by the One would think that neuroleptic dose has some­ spontaneous occurrence of buccal-lingual dyskine­ thing to do with the development ofTD, but the clin­ sias in elderly patients who have never taken neu­ ical literaturc is equivocal. Cumulative neuroleptic roleptic drugs (70). dose was found to be associated with severe TD in It appears that females are at greater risk than one study of mentally retarded patients (114), but not males to develop TD and severe fonns of the disorder in studies of patients with schizophrenia and other are likelier to occur in females (11). This may speak psychiatric disorders. It is likely that there is no linear to estrogen-related dopamine sensitivity (106). Nico­ association between cumulative dose and TD but that tine can also sensitize the dopamine receptor, and a minimum cumulative dose is necessary to evoke the therefore tobacco addiction must be counted among phenotype in patients who are vulnerable to TD by the risk factors for TD (107). Cannabis may also pre­ virtue of other risk factors. The importance of idio­ dispose to TD and possibly alcohol (108,109). syncrasy cannot be minimized because some patients Clinical lore holds to the ironic contention that TD have been known to develop TD aftcr short-term is more likely to occur in patients who do not respond treatment with very low neuroleptic doses, whereas 404 23. TARDIVE DYSKINESIA AND TARDIVE AKATHISIA

others seem to be free 0 f the disorder even after years production of highly reactive free radicals (117). The of high-dose treatment. theory was supported by the findings that patients Until clozapine, there was never a particular neu­ with TD had higher levels of thiobarbituric acid-re­ roleptic that was more or less likely to cause TD. active substances, an indicator of lipid peroxidation Other serious side effects, such as agranulocytosis (i.e., free-radical damage to body fats) (117,118) and and hepatotoxicity, are more likely with the low-po­ that vitamin E (with or without selenium) prevented tency neuroleptics thioridazine and chlorpromazine, the development of TD in dopamine-hypersensitive and those drugs exhibit more cytotoxicity in tissue rats (119,120). Clinical studies of patients with TD cultures (l15). Among the conventional neuroleptics, have actually demonstrated reduction in AIMS scores however, there is no rank order. when they are treated with vitamin E in doses as high An appreciation of TD risk factors is essential to as 1,600 IU per day (121-124). clinical treatment because it allows the physician to There is no reason why neuroleptic-treated patients recognize cases that require very careful monitoring, should not take concomitant vitamin E, perhaps with more frequent neuroleptic withdrawals or at least some of the other free-mdical scavengers such as se­ dose reductions, and a more aggressive approach to lenium. It seems to be the psychopharmacologic identifYing pharmacologic alternatives. The informed equivalent of one baby aspirin every other day. consent process should address the patient's individ­ ual vulnerability to TD. To reiterate, established risk BIOLOGICAL MECHANISMS factors for neuroleptic-induced TD are advanced age, female gender, smoking, affective disorder, early The prevailing view of the pathophysiology ofTD EPS, and possibly brain damage and cumulative neu­ is that chronic blockade of striatal D2-dopamine re­ roleptic dose. ceptors leads to a state of denervation supersensitiv­ ity and that the abnormal movements are a manifesta­ tion of dopaminc hypersensitivity (125). Support for Protective Factors this idea comes from animal studies in rats, cats, and What may be done to reduce the likelihood ofa tar­ primates in which chronic neuroleptic administration dive syndrome? Reduce the number of patients who is kno\Vn to increase the number and density of stri­ are exposed to neuroleptic drugs, maintain patients on atal dopamine binding sites (126), to elicit behaviors long-term treatment on a minimum effective dose, and such as gnawing or rotation that are mediated by use the novel antipsychotics instead of the conven­ dopamine (127), and to cause choreoathetoid move­ tional neuroleptics. The neuroleptics have joined the ments that are typical of TD (128). The abnormal ranks of "archaic" drugs, which include the sedating movements of TD are topographically identical to anticonvulsants and tricyclic antidepressants. Never­ dyskinesias that characterize other hyperdopaminer­ theless, there are still occasions when the prescription gic states: HC, Tourette's syndrome, and L-dopa-in­ of an archaic drug is necessary, and sometimes, high­ duced dyskinesias (129). dose neuroleptics are necessary for patients with se­ The dopamine supersensitivity hypothesis is not vere aflective disorders, even older female patients sufficient to explain the phenomenon, however. For who drink, toke, and smoke. example, the dyskinesias that arise in animal models In the history ofpsychopharmacology, several pos­ ofTD are early onset and readily reversible. With pro­ sible protectants have been proposed, for example, longed neuroleptic administration, the dopamine re­ lithium and amantadine. None has worked. So it was ceptor hypersensitivity actually disappears (130). In hardly surprising that psychiatrists greeted with human postmortem studies, patients with TD are not skepticism the news that various megavitamin com­ invariably found to have DJ or D2 hypersensitivity binations actually exerted a protective effect. One (131), nor do they show cerebrospinal fluid or neu­ formula, arrived at empirically, contained niacin, roendocrine indices of dopamine sensitivity (130). pyridoxine, ascorbate, and vitamin E (116). The supersensitivity hypothesis may underlie the oc­ The free-radical theory of cytotoxicity that was currence of transient or withdrawal dyskinesias, but current among neurologists who study PD led to a the pathophysiology of persistent unremitting TD is series oftrials ofvitaminE that were for the most part unknown (132). disappointing. At the same time, however, it was If receptor supersensitivity cannot account for suggested that the neuroleptics might be cytotoxic cases of severe and persistent TD, then it is neces­ because by increasing catecholamine turnover and sary to consider alternative hypotheses. The facts metabolism, there should necessarily be increased that the disorder can be irreversible, refractory to 23. TARDIVE DYSKINESIA AND TARDIVE AKATHISIA 405 treatment, and oceasionally associated with eontin­ The first step in diagnosis requires a thorough de­ ued deterioration even after drug withdrawal (133) scription of the patient's abnormal movements, in­ lead inevitably to the idea that neuroleptics may ex­ cluding a topographic analysis of the distribution of ercise, in some patients at least, a cytotoxic effect. dyskinesia and an accurate description of its nature. This may conceivably be a cytotoxic metabolite, The topographic categories are orofacial, buccal-lin­ perhaps a selective product of neuroleptic metabo­ gual-masticatory, truncal (or axial), centrifugal (i.e., lism in patients 'ilUlnerable to severe TO. Alterna­ involving the extremities), and holokinetic (i.e., all tively, TD may be the consequence ofoxidative stress. over). The different types of dyskinesia are choreo­ The neuroleptics are, comparatively speaking, meta­ athetoid, dystonic, myoclonic, ballistic, and tic-like bolically active compounds and strong free-radical movements (so-called tardive Tourette's syndrome). generators. Neuroleptic drugs increase the turnover Topography and dyskinesia interact in relatively and metabolism of dopamine, with the formation of predictable patterns. Choreiform movements are of­ dopamine quinines and hydrogen peroxide. Long­ ten centrifugal, whereas dystonic movements are term exposure to neuroleptics in animals increases more commonly axial in distribution. The area of dis­ manganese and iron, which are free-radical cata­ tribution is significant because severe TD may some­ lysts, in the central nervous system (134). Neurolep­ times have a total body distribution and thus render tic treatment has been found to retard recovery from the patient incapacitated by virtue of holokinetic brain injury in rats (135). movements. Movements that are circumscribed in Neuroleptic blockade of presynaptic dopamine D2 area are not as likely to be incapacitating unless they receptors increases the synaptic release of aspartate are dystonic or involve the oropharyngeal or respira­ and glutamate in the striatum. Persistent activation of tory musculature. These elements are essential for de­ glutaminergic ionotropic receptors causes neuronal termining the severity ofTD and may also aid in the degeneration, an effect that is mediated by increased prediction of outcome. Severe and persistent TD is oxygen free-radical generation and oxidative damage most often associated with mixed types of move­ to the cell membrane, cellular proteins, and DNA. ments with a generalized distribution or with dystonic Markers for enhanced excitatory neurotransmission movements with a more local distribution. have been discovered in the central nervous system of The next step involves the process of differential patients with schizophrenia with TD (136). This rep­ diagnosis. The topography and classification of dys­ resents a cogent rationale for the use of antioxidants, kinesia do not establish diagnosis. Indeed, many other especially vitamin E, for the prevention and possible movement disorders may resemble TD. Stereotypies treatment of TD. As a preventive agent, vitamin E is and manneristic behaviors are common in patients promising, at least on theoretical grounds; as a treat­ with severe mental retardation and autism. These ment measure, especially in advanced cases, it may movements may be suppressed by neuroleptics and not be effective (134). reemerge when the drug is reduced in dose or discon­ Dopamine neurons are remarkably stress sensitive tinued entirely. Such movements are usually more and that is why parkinsonian symptoms are so com­ complex than those seen in TD and are usually stereo­ mon, even with normal Occasional reports of typed in quality. Nevertheless, TD coinciding with postmortem findings in patients with TD have stereotypies may pose a diagnostic problem. demonstrated neuronal degeneration in the substantia The differential diagnosis ofTD includes Tourette's nigra (77) and caudate nucleus atrophy (78,137). syndrome, choreoathetosis attendant on cerebral palsy, Nielson and Lyon (138) observed cell death in the HC, WD, and other disorders of the basal ganglia; corpus striatum of rats given neuroleptics long term. Hallervorden-Spatz syndrome (dystonia); familial dys­ tonia and chorea; ballistic movements related to vascu­ lar disease; and other drug-induced dyskinesias, e.g., DIAGNOSIS those related to phenytoin (139), carbamazepine (140), The diagnosis ofTD requires more than the simple valproate, tricyclic antidepressants, or stimulants. administration of a rating scale like the AIMS or the Dyskinesias may arise ,,.pontaneously in elderly pa­ DISCUS. Those are only screening instruments and tients or patients with dementia. Idiopathic calcifica­ are useful because they ean be reliably administered tion of the basal ganglia is assoeiated with dyskinesia by a nonphysician and because they raise the level of and other neuropsychiatric symptoms (141,142). staff consciousness concerning TD. They are comple­ Other causes of movement disorder include Syden­ ments to the neurologic examination and the process ham's chorea, systemic lupus erythematosus, and some of differential diagnosis, not a substitute for it. encephalitides. Disturbance in thyroid and parathyroid 406 23. TARDIVE DYSKINESIA AND TARDIVE AKATHISJA

function may be associated with dyskinesia (113). The disappointing, and side effects have limited their util­ differential diagnosis of dystonia has been addressed ity (149). most recently by Burke et a1. (143). Tardive dystonia differs clinically from idiopathic The evaluation ofa patient with possible TD may in­ forms of dystonia, yet it may respond to similar treat­ volve a series of steps to exclude alternative causes of ments. In dystonia, physostigmine tends to increase dyskinesia, especially treatable conditions such as WD. the severity of abnormal movements. Anticholinergic A family history is very important. Laboratory diagno­ drugs have been helpful, but their clinical utility is sis may rule out infectious, endocrine, metabolic, and limited by the occurrence of memory impairment, ag­ degenerative disorders. Appropriate studies include a itation, and delirium (150). Dopamine-depleting toxic drug screen, serum electrolytes, sedimentation drugs may be helpful in 10% to 12% of patients with level, ASO titers, thyroid and parathyroid studies, dystonia (150). Dopamine agonists such as L-dopa serum ceruloplasmin, lupus erythematosis (LE) prep, and amantadine may be effective in a similar percent­ and antinuclear antibodies. Appropriate neurodiagnos­ age of patients with dystonia (129). The use of tic studies include computed tomography or magnetic GABAergic drugs has been of limited benefit. resonance imaging, at least in selected cases. Calcifi­ cation of the basal ganglia, iron deposition in the THE COURSE OF THE DISORDER globus pallidus, or degeneration of the caudate and other subcortical structures may provide etiopatho­ It is a mistake to classify TD as irreversible be­ genic evidence that can influence clinical decisions. cause patients with chronic TD may experience re­ The differential diagnosis is important, but a thor­ mission even after several years. It is better to classify ough neurodiagnostic evaluation is not necessary for TD as transient or persistent and specify precisely most cases ofTD. The most important diagnostic ele­ how long the movement disorder has in fact persisted. ment is a history of toxic exposure (to neuroleptics or What proportion of patients has TD that remits af­ other dopamine blockers such as metaclopramide) and ter only a few weeks or a few months, and what pro­ a high index of suspicion on the part of the treating portion persists for years? Although these are impor­ physician. A patient with dyskinesia and a history of tant questions, they cannot be answered based on neuroleptic exposure has TD until proven otherwise. direct research. The persistence ofTD may be masked by continued neuroleptic treatment, and most TD studies in popUlations with psychiatric disorders have TREATMENT been done in patients with schizophrenia who are It is not easy to discuss the treatment ofTD because treated with neuroleptics even after TD is diagnosed. no treatment is reliably effective. The basic treatment is In elderly patients, TD is usually a persistent disor­ to withdraw neuroleptics, keep the patient drug free, der, whereas in studies of children treated with neu­ and wait for the disorder to remit. If antipsychotics roleptics, the remission rate is very high (16,151). Al­ cannot be withdrawn, substitute a novel antipsychotic. though persistent cases are not unknO\\'Il, they are rare There is reason to believe that clozapine may be an (8). There is an age-dependent decrease in dopamine effective treatment for the tardive syndromes. Vita­ neurotransmission that may interact with neuroleptic min E is the third treatment alternative. neurotoxicity to cause severe and persistent forms of Patients with choreiform TD may respond to drugs TD in elderly patients, and this same element could that influence y-aminobutyric acid (GABA) neuro­ conceivably confer a measure of protection to young transmission such as cJonazepam, baclofen, or val­ people (70). Children usually are treated with low proic acid (144). The timing of treatment may be im­ doses of neuroleptics for shorter periods, and they portant because some patients with TD progress to a metabolize drugs more efficiently. The relative per­ severe dystonic form of the disorder that is usually re­ sistence rates for TD in young and elderly patients sistant to pharmacologic treatment (110). Drugs that may be a pharmacodynamic phenomenon or it may deplete presynaptic dopamine such as reserpine or simply be related to prescription habits. tetrabenzamine may be helpful, but they can exacer­ It is possible that even transient TD in early life bate affective illness in vulnerable patients (145,146). may set the stage for neurodegenerative changes in Patient response to acetylcholine agonists is variable. later years, admittedly a speculation but one based on Physostigmine provocation has been advocated as a some established models of the evolution of neu­ screening procedure to identify patients who will re­ ropsychiatric disorders: postencephalitic parkinson­ spond to cholinergic precursors (147,148). Clinically, ism, the late neuropathic sequelae of poliomyelitis, acetylcholine agonist treatment approaches have been late-onset psychosis after traumatic brain injury, and 23. TARDIVE DYSKINESIA AND TARDIVE AKATHISIA 407 the putative kindling psychosis of temporal lobe no change, 18% improved, and 16% grew worse over epilepsy (10). These are all models of early central time. In a 5-year follow-up study by Chouinard et al. nervous system insult followed by late deterioration (155), the annual, remission rate in patients with TD in function. It is possible that some patients who have was 5.5%; this was outweighed by an incidence rate for had transient TD in early life will develop encephalo­ new cases of 8.4%. In contrast, there have been several pathic changes when they are old. reports that TD remits far more often than This is another example of cerebral reserve, a con­ it persists (130,156-159), even ifneurolepti~reatment cept that was introduced in Chapter 6 in the discussion is continued. Exactly how substantial the fraction is of posteoncussion effects. It is said that the dopamine then of those who have persistent TD remains an area system is particularly vulnerable to the effects of in­ of surmise. sult; postencephalitic parkinsonism, post-N-methyl-D­ Well-controlled epidemiologic studies of the course aspartate parkinsonism, and TD are three concrete ex­ ofTD are extremely difficult to do because the recruit­ amples. In the first case, it is youthful exposure to the ment of a large number of subjects will necessarily in­ virus that leads to parkinsonism in middle age. We clude patients on psyehoactive drugs that may influence have no way of knowing whether exposure to neu­ the course ofthe disorder, patients who will drop out for roleptics in childhood may have a similar effect. TD in one reason or another, and patients with degenerative children tends to be transient; they have so many extra central nervous system disorders. As a consequence, re­ neurons, even in the dopamine system, that it is hard to search attention is turning in the direction of case-con­ confirm the possibility of a late effect, but it is possi­ trol It is assumed that at least some patients ble, and with time, we may find out. will have long-term persistent TD and that others will In mentally retarded people, one of our studies re­ remit. The relative proportions are irrelevant; the key to ported TD in 25 of 3 8 individuals who were withdrawn the strategy is accurate assignment to one group or the from neuroleptic treatment, but 13 of 25 had transient other. The next step is to identify clinical elements that TD that remitted within only a few weeks (152). A sub­ are associated with persistence and to replicate the find­ sequent study of a subgroup of that original sample ing. This is the difficult part. First, clinical elements who returned to neuroleptic treatment and who were from the medical history will be hard to discover, espe­ withdrawn from neuroleptics a second time 3 years cially in patients with chronic TD who are institutional­ later demonstrated progressive TD in five patients and ized. Second, subject variance will make a successful TD that had actually decreased in severity in four pa­ replieation difficult. The strategy, however, is impor­ tients; the former had been treated with high doses of tant; if reliable information is attainable, it can be used neuroleptics, the latter group with low doses (l0). Al­ to guide programs for TD prevention. though this was only a small study, it suggests that pa­ A first attempt at this strategy was published by tients with TD may continue on neuroleptics ifthey ab­ Gardos and Casey (110). They found that generalized solutely have to, as long as the doses are kept low. dystonic and athetoid movements characterized a Paulson et al. (7) reexamined a group of mentally more malignant and persistent form ofTD. They also retarded people 4 years after a neuroleptie withdrawal reported that patients with severe and persistent TD trial and found that six (of 15) had persistent TD with displayed a variety of axial and centrifugal move­ no change in severity, five had more severe TD, and ments, with buccal-lingual-masticatory choreoatheto­ four had actually improved. sis early in the clinical course and a gradual evolution If one can surmise anything from these small stud­ to dystonia as the disorder progressed. Males were ies, it is that TD is persistent in some substantial frac­ more commonly affected with severe and persistent tion (one-third or two-thirds) of mentally retarded pa­ TD, and the duration of treatment was relatively short tients who have the disorder, that persistence is to be (less than 1 year). Gardos and Casey concluded that measured in years, but that remission may occur with patients who develop severe and persistent TD have a time and judicious management. How do these con­ unique vulnerability to neuroleptic-induced move­ jectures correspond with the results ofTD research in ment disorders and that this could be defined in terms other patient groups? of the TD risk factors discussed earlier, especially The research data from studies of adults with schiz­ age, eady EPS, and affective disorder. ophrenia are contradictory and hard to interpret. In one study of patients with TD maintained offneuroleptics, Malignant Tardive Dyskinesia no appreciable symptom reduction was noted after 12 months (153). In another, Yassa et al. (154) reported a The severity of TD is defined in terms of persis­ 2-year follow-up: 66% of the patients with TD showed tence, the nature of the dyskinesia, and the degree to 408 23. TARDIVE DYSKINESIA AND TARDIVE AKATHIS'JA which it afflicts the patient's behavior and compro­ 2. Sprague RL, Baxley GB. Drugs used in the manage­ mises the activities ofdaily life. The disagreement over ment of behavior in mental retardation. In: Wortis J, ed. Mental retardation & ,developmental disabilities. relative rates ofpersistence is mirrored in controversies New York: Brunner Mazel, 1978. about relative severity or whether patients with TD are 3, Hill BK, Balow EA, Bruinincks RH. A national study even bothered by their disorder. There is little to be ofprescribed drugs in institutions and community res­ gained from a reiteration ofthese arguments. idential facilities for mental(v retarded people. Min­ The consensus developing among psychopharma­ neapolis: Gniversity of Minnesota, 1983, 4, Steck H. Le syndrome extrapyramidal et dien­ cologists is that TD may sometimes be a malignant dis­ cephalique au cours des traitements au largactil et au order, rapid in onset and extreme in its consequences. serpasil. Ann Med PsychoI1954;112:737-743. It seems that some patients are uniquely vulnerable to 5. Schonecker M. Ein eigentomliches Syndrom in severe and persistent TD, they can develop the disorder oralen Bereich bei Megaphenapplikation. Neruenarzt 1957;28. after only a brief course oflow-dose neuroleptic treat­ 6. Uhrbrand L, Faurbye A. Reversible and irreversible ment, their TD is extraordinarily debilitating, and dys­ dyskinesia after treatment with perphenazine, chlor­ tonia and akathisia are its likeliest manifestations. promazine, reserpine, and electroconvulsive therapy. Patients with so-called malignant TD tend to have Psychopharmacologia 1960; 1 :408-418. affective disorders to begin with (110). They are often 7. Paulson Gw, Rizvi CA, Crane GE. Tardive dyskinesia as a possible sequelae of long-term therapy with phe­ young, and their disorder is persistent and refractory to nothiazines. Clin Pediatr 1975; 14:953-955. treatment. They are rarely if ever anosognosic for the 8. Gualtieri CT, Hawk B. Tardive dyskinesia and other condition. This is a very serious problem (143). drug-induced movement disorders among handi­ There are only estimates of the relative prevalence capped children and youth. J Appl Res Ment Retard 1980;1:55-·69. of severe forms ofTD. The most recent survey, based 9. Kalachnik JE, Harder SR, Kidd-Nielsen P, et aL Per­ on 100 TD cases seen at a movement disorder clinic sistent tardive dyskinesia in randomly assigned that were probably a seriously afflicted group to begin neuroleptic reduction, neuroleptic nonreduction, and with, reported 23 severe manifestations of the disor­ no-neuroleptic history groups: preliminary results. der: persistent bruxism (one case), masseter or lin­ P:,ychopharmacol Bull 1984;20:27-31. 10. Gualtieri CT, Barnhill LJ. Tardive dyskinesia in special gual hypertrophy (three cases), sustained involuntary populations, In: Wolf ME, Mosnaim AD, eds. Tardive tongue protrusion (six cases), incomprehensible dyskinesia, biological mechanisms & clinical speech arising from dysarthria (two cases), spasmodic Washington, DC: American Psychiatric Press, dysphonia (two cases), anterior cervical spondylo­ 137-154. 11, Kane D.1, Smith JM. 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