Tardive dyskinesia: Etiology and epidemiologyAuthor Daniel Tarsy, MD Section Editor Howard I Hurtig, MDDeputy EditorJohn F Dashe, MD, PhDLiterature review current through: Jun 2014. | This topic last updated: May 09, 2013.INTRODUCTION — Tardive dyskinesia (TD) is a hyperkinetic movement disorder that appears with a delayed onset after prolonged use of dopamine receptor blocking agents, mainly the antipsychotic drugs (also called neuroleptics) and the antiemetic drug, metoclopramide [1,2].

TD has numerous clinical manifestations that include chorea, athetosis, dystonia, akathisia, stereotyped behaviors, and rarely tremor. The term "tardive" differentiates these dyskinesias from acute dyskinesia, parkinsonism, and akathisia, which appear very soon after exposure to antipsychotic drugs.

This topic will review the etiology and epidemiology of TD. Other aspects of this condition are discussed separately. (See "Tardive dyskinesia: Clinical features and diagnosis" and "Tardive dyskinesia: Prevention and treatment".)

ETIOLOGY — Tardive dyskinesia (TD) is a unique complication of antipsychotic drugs and metoclopramide; convincing cases have not occurred after the chronic use of antidepressants or anti-anxiety medications [1,2].

Pathophysiology — The prolonged and often irreversible course of TD suggests that structural cellular alterations in the brain are responsible for the disorder. However, pathologic studies in laboratory animals and humans have failed to demonstrate consistent findings following chronic exposure to antipsychotic drugs [3].

The uniform capacity of antipsychotic drugs to block postsynaptic dopamine receptors seems a likely mechanism for the development of both antipsychotic drug-induced extrapyramidal reactions and TD. In animal models, repeated treatment with antipsychotic drugs leads to dopamine receptor supersensitivity [1,4]. In humans, there is evidence for upregulation of striatal dopamine receptors following chronic antipsychotic drug exposure [5], but correlation with clinical evidence of TD is uncertain. In addition, dopamine supersensitivity in animal models is a universal and rapidly appearing pharmacologic phenomenon that lasts for only several weeks. This raises some doubt about its relevance to TD in humans, where it is possible that more lasting structural changes in neurons or receptors may have taken place.

An updated version of the dopamine hypothesis suggests that an imbalance between D1 and D2 receptor-mediated effects in the basal ganglia may be responsible for TD [6,7]. According to this theory, traditional antipsychotic drugs preferentially block D2 receptors, resulting in excessive activity of D1-mediated striatopallidal output, altered firing patterns in medial globus pallidus, and eventual evolution of the clinical features of TD. This model explains the low tendency of the second-generation antipsychotic clozapine to cause TD, since clozapine produces relatively less D2 and relatively more D1 blockade.

The development of TD may also involve changes in other basal ganglia neuronal systems. TD could result from loss of striatal interneurons that exert a feedback influence on nigrostriatal dopamine neurons and also form part of an efferent output pathway from the basal ganglia. Such interneurons may utilize gamma-aminobutyric acid (GABA), acetylcholine, or peptides as their neurotransmitter.

Of these possibilities, the GABA hypothesis has been given the most consideration. Chronic treatment of monkeys with antipsychotic drugs over a period of several years has produced persistent dyskinesia and reduced GABA and glutamic acid decarboxylase levels in several regions of the basal ganglia [8]. An excitotoxic mechanism may account for this selective destruction of a localized population of basal ganglia neurons [9]. According to this hypothesis, chronic blockade of D2 receptors may lead to increased release of glutamate within the striatum, thereby causing excitotoxic destruction of striatopallidal GABA and peptide-containing neurons.

There are two potential mechanisms by which this might occur: First, interference with the inhibitory action of dopamine on corticostriatal terminal D2 receptors could cause excessive release of glutamate in the striatum, leading to degeneration of striatopallidal GABA and peptide neurons; second, blockade of nigrostriatal dopamine activity could, as in Parkinson disease, lead to increased firing of glutamate-mediated subthalamic neurons causing excitotoxic degeneration of globus pallidus neurons. A possible role of free radicals generated by increased neuronal dopamine turnover caused by antipsychotic drugs has also been considered [10]. The major flaw in this hypothetical excitotoxic cascade is the lack of supporting pathologic evidence from animal and human brain tissue.

EPIDEMIOLOGY — Prevalence estimates of TD at a specific time have several limitations when used to establish risks in different patient populations or in those with different treatment exposures. Antipsychotic drugs cause TD but can also mask its manifestations by their hypokinetic effects [11]. The severity of TD often fluctuates with behavioral and

emotional arousal [12], and differences in population age, gender, treatment duration, and type and dose of antipsychotic drugs add complexity to the ascertainment process [13].

Misclassification of spontaneous dyskinesia (ie, dyskinesia occurring independent of antipsychotic drug treatment) may inflate prevalence estimates of TD. Spontaneous orofacial dyskinesia are common in persons older than age 65 even without exposure to antipsychotic drugs; point-prevalence estimates have ranged from 3 to 77 percent [14,15].

The incidence of new cases of TD appearing in a population during a specified period of exposure is a better measure of risk than cross-sectional estimates of prevalence at a particular observation point. However, incidence data are much more difficult to acquire since they require repeated observations over time.

The prevalence and incidence data for TD associated with first-generation (conventional) antipsychotic drugs and second-generation antipsychotic drugs are reviewed in the following sections.

FIRST-GENERATION ANTIPSYCHOTIC DRUGS — When first described in the 1960s, the frequency of TD was widely regarded to be low. This misperception was due to a failure of patients with chronic psychosis to complain of dyskinesia, and to the limited familiarity of movement disorders among psychiatric clinicians [12,16]. By the late 1970s, it became apparent that the prevalence of TD was substantial, ranging from 5 to 45 percent in patients with psychiatric disorders [11,17].

An influential report from 1982 analyzed 56 studies involving nearly 35,000 patients treated with antipsychotic drugs and estimated the overall prevalence of TD to be 20 percent [18,19]. In 19 studies involving 11,000 patients not exposed to antipsychotic drugs, the prevalence of spontaneous dyskinesia was approximately 5 percent, suggesting a best-estimate, corrected rate for antipsychotic drug-associated TD of about 15 percent (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects".).

Incidence of tardive dyskinesia — Most prospective studies of patients treated with conventional antipsychotics suggest the annual incidence of TD is between 3 and 8 percent [19-22].

• Beginning in 1977, the Hillside study enrolled 908 consecutive patients (19 to 40 years old) who were admitted to a single psychiatric hospital in New York [20,21]. These patients were followed for up to 20 years,

and monitored for the presence of dyskinesia. Most subjects had only several months of exposure to antipsychotic drugs at study entry. Psychiatric diagnoses included schizophrenia, affective disorder, schizoaffective disorder, and other conditions. Fifty-one patients (5.6 percent) met diagnostic criteria for TD at initial evaluation or had a prior diagnosis of probable TD. All patients were treated with conventional and predominantly high-potency antipsychotic agents, such as haloperidol or fluphenazine.

• The cumulative incidence of TD after antipsychotic drug exposure of 1, 5, and 10 years was 5, 27 and 43 percent, respectively [23]

• The cumulative incidence of persistent TD lasting for at least three months at 1, 5, and 10 years was 3, 20 and 34 percent, respectively [23]

These rates suggest an overall annual TD incidence of approximately 5 percent [23]. For TD persisting for at least three months, they suggest an annual incidence of approximately 3 percent, and an early spontaneous annual remission rate of approximately 2 percent.

• The Yale study obtained similar results in 362 patients treated with antipsychotic drugs, most of whom had chronic schizophrenia [24,25]. Although previous antipsychotic drug exposure (mean 8 years) was 14 times longer than in the Hillside study, and age was greater (median 41 versus 30 years old), none was considered to have TD at study entry. For TD persisting at least six months, the cumulative five-year incidence was 25 percent, remarkably similar to the incidence of persistent TD in the Hillside study [19].

Incidence in the elderly — Older patients appear to have a higher incidence of TD than younger patients.

• The Hillside group prospectively analyzed 261 patients older than 55 years who were naive to antipsychotic drugs, of whom 63 percent had dementia [26]. After beginning treatment with antipsychotic drugs, they were examined quarterly for 2.2 years, during which time TD developed in 23 percent. TD persisted for at least six months in two-thirds of those who developed TD.

• Another prospective study followed 266 patients (mean age 65 years) with psychiatric disorders but without dyskinesia at study entry who had relatively brief prior exposure to antipsychotic drug treatment [27]. The cumulative incidence of TD at one and three years was 26 and 60 percent.

These data suggest that the annual incidence of TD among older patients, during continuous exposure to a variety of potent antipsychotic drugs, is approximately 10 to 20 percent.

SECOND-GENERATION ANTIPSYCHOTIC DRUGS — The introduction of second-generation antipsychotic drugs, also known as atypical neuroleptics, anticipated a lower risk of acute extrapyramidal reactions and TD because of the weaker affinity of these drugs for blocking the dopamine receptor [13,28-30]. The common term "atypical" emphasizes the relative freedom of second-generation antipsychotic drugs from risks of acute extrapyramidal reactions "typical" of older conventional antipsychotic drugs. (See "Second-generation antipsychotic medications: Pharmacology, administration, and comparative side effects".)

Second-generation antipsychotic drugs approved for general clinical use in the United States include aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone. It is commonly stated that these drugs have lower risks of causing acute dystonia and parkinsonism than the conventional antipsychotic drugs, and produce less cataleptic and other motor-inhibitory effects in laboratory animals. However, evidence from large prospective [31] and retrospective [32] studies comparing first and second generation antipsychotic drugs indicate that any difference between these medication classes in the incidence of acute extrapyramidal side effects may be less than originally thought, or even negligible.

Pharmacologically, second-generation antipsychotic drugs are characterized by relatively low affinity for, or rapid dissociation from, dopamine D2 receptors, thereby limiting antagonistic actions at these receptors [33,34]. In addition, these agents often have potent antagonism at serotonin 5HT2A receptors.

Nevertheless, some second-generation antipsychotic drugs, including aripiprazole, ziprasidone, olanzapine and risperidone, particularly at relatively high doses, have risks of acute extrapyramidal reactions that overlap those of the conventional antipsychotic drugs of moderate or low potency. In addition, all antipsychotic drugs appear to have some risk of akathisia. Antipsychotic drugs have also been associated with rare instances of neuroleptic malignant syndrome.

Risk of tardive dyskinesia among second-generation antipsychotic drugs — Among second-generation antipsychotic drugs, clozapine has an unusually low risk for acute extrapyramidal reactions [35,36]. Reports of TD attributable to clozapine have been rare and unconvincing [23,37].

In the prospective Hillside study, 28 patients with psychosis and an average of six years of previous antipsychotic drug exposure at baseline, but no definite preexisting TD, were treated with clozapine and followed for one year [37]. Two patients (7.1 percent) developed TD that persisted for at least five years. Although neither patient met criteria for definite TD at study entry, both had evidence of some abnormal involuntary movements, raising suspicion that the later dyskinesia was attributable to prior antipsychotic drug use and not to clozapine [3]. In any case, clozapine treatment was associated with a significantly lower cumulative incidence of TD when compared with conventional antipsychotic drug treatment in another group of patients from the same clinic [37].

Among patients never previously exposed to conventional antipsychotic drugs, a review published in 2006 identified 13 reports of TD that developed in patients treated exclusively with second-generation antipsychotic drugs [23], including risperidone, olanzapine, and ziprasidone. Risperidone was the drug used in 10 of these 13 cases.

The same study identified 39 reports of patients with previous exposure to conventional antipsychotic drugs who developed new TD during long-term treatment with second-generation antipsychotic drugs [23]. Risperidone, which has been in clinical use longer than any second-generation antipsychotic drug other than clozapine, was implicated in 22 of these 39 TD cases (56 percent). The remaining drugs associated with TD were olanzapine (n = 6), ziprasidone (n = 5), clozapine (n = 4), and quetiapine (n = 2). Emergence of TD after withdrawal of previous conventional antipsychotic drugs probably account for at least some of these cases.

Compared with risperidone, later introduction into the market and less clinical use may account for the small numbers of TD cases associated with other second-generation antipsychotic drugs such as quetiapine and ziprasidone. However, this reasoning does not explain the rarity of TD cases associated with clozapine, which has been in use for several decades.

Despite severe limitations, these case reports suggest that most second-generation antipsychotic drugs, other than clozapine, carry some risk for TD, and that risperidone and perhaps olanzapine may have a greater risk of TD than other second-generation antipsychotic drugs [23]. Nevertheless, second-generation antipsychotic drugs vary markedly in their neuropharmacologic properties and risks of acute extrapyramidal reactions,

making it unwise to assume that all are equivalent in risks for TD [34,36,38].

Is the rate of tardive dyskinesia declining? — With increased use of second-generation antipsychotic drugs, the prevalence of TD was expected to decline, but data are conflicting.

Several studies published from 1996 to 2002 reported TD prevalence rates of 16 to 43 percent [39-42], suggesting that risk of TD was similar to that found in earlier studies with the use of conventional antipsychotic drugs. However, these studies did not separate patients who received only second-generation antipsychotic drugs from those who received prior or concurrent conventional antipsychotic drug treatment.

In contrast, a systematic review that evaluated four cross-sectional studies published or presented from 2004 through 2007 found that the prevalence of TD was significantly lower in adult patients taking second-generation antipsychotic drugs than in those taking conventional antipsychotics (13 percent [95% CI 11.1-15.2] versus 32.4 percent [95% CI 29.0 to 35.9]) [43]. Furthermore, in 57 patients treated with second-generation antipsychotic drugs who had no prior antipsychotic drug exposure, the prevalence of TD was 5.3 percent.

SECOND- VERSUS FIRST-GENERATION ANTIPSYCHOTIC DRUGS — The risk of TD is probably lower with second-generation than with conventional (first-generation) antipsychotic drugs. However, there is mounting evidence that the incidence of TD associated with second-generation agents is higher than first reported. The following reports illustrate this issue [43,44].

• A systematic review published in 2004 analyzed 11 studies of at least one year duration that examined second-generation antipsychotic drug treatment [44]. The studies included a total of 2769 subjects (average age 45 years); schizophrenia was the diagnosis in 82 percent. The following observations were reported:

• Across all 11 studies, the mean annual incidence of TD associated with second-generation antipsychotic drugs was 2.1 percent.

• In three studies that directly compared treatment using a second-generation antipsychotic drug with a conventional antipsychotic (haloperidol) in young and middle-aged adults (mean age 39 years, range 18 to 65), the mean annual incidence of TD was approximately

five- to six-fold lower with second-generation antipsychotic drugs than with haloperidol (<1 percent versus 5.4 percent).

• A later systematic review from the same investigators identified antipsychotic drug treatment studies of at least one year duration published or presented from 2004 to 2007 [43]. Included were 12 studies with over 28,000 patients (mean age 40 years; dementia was the diagnosis in 92 percent) that reported TD incidence rates. The following observations were noted:

• Across all studies and age groups, the annual incidence rate of TD was significantly lower with second-generation antipsychotic drugs than with conventional antipsychotic drugs (4.0 percent [95% CI 3.6-4.3] versus 5.5 percent [95% CI 5.1-6.1]).

• In six studies directly comparing second-generation antipsychotic drug treatment with conventional antipsychotics, there were 12,924 patients (mean age 51 years, range 25 to 83). The annual incidence rate of TD was again significantly lower with second-generation antipsychotic drugs than with conventional antipsychotic drugs (4.2 percent [95% CI 3.8-4.5] versus 5.5 percent [95% CI 5.0-6.1]).

Thus, the earlier systematic review suggested that second-generation antipsychotic treatment reduced the risk of TD by up to six-fold compared with conventional agents [44], while the later review suggests that the risk reduction is much less [43]. However, these data are not definitive for the following reasons:

• Most findings are based primarily on short-term studies not designed to address TD risk.

• Few of the studies included specific neurologic assessments.• The studies included very few patients not previously exposed to

conventional antipsychotic drugs that may also contribute to TD risk.• In the earlier systematic review, the three studies with a comparator used

haloperidol, a high-potency conventional antipsychotic drug, sometimes given in relatively high doses [44]. The later systematic review covering 2004 to 2007 included several studies that used

moderately dosed, mid-potency conventional antipsychotics [43]. Furthermore, most patients in the earlier systematic review had schizophrenia, while most in the later review had dementia.

• A majority of the included studies in the 2004 to 2007 review used nonstandard definitions of TD [43].

Interpretation of such findings is further complicated by spontaneous remission of TD over time and by suppression of dyskinetic symptoms by antipsychotic drug treatment, even with second-generation agents [25,45-47], possibly resulting in a misleadingly low incidence of TD. However, since several prospective studies excluded patients with dyskinesia at baseline, suppression of TD is unlikely to entirely account for the lower rates of new TD cases observed during treatment with second-generation antipsychotic drugs [44].

Conclusion — While the risk of TD is probably lower with most second-generation antipsychotic drugs than with high-potency conventional antipsychotic drugs, the risk with second-generation agents is not necessarily lower than that associated with low-potency conventional antipsychotic drugs taken at moderate doses [38]. TD still occurs with second-generation agents other than clozapine, possibly most often with risperidone or olanzapine [23].

Further studies of patients never treated with first-generation antipsychotic drugs and exposed to only a single second-generation antipsychotic drug are necessary to establish and quantify any hypothesized decline in the incidence of TD in association with use of particular drugs.

METOCLOPRAMIDE — Metoclopramide is a dopamine receptor antagonist that blocks both D1 and D2 receptors in the central nervous system. When given in higher doses, it also blocks serotonin receptors.

Metoclopramide is used primarily as an antiemetic agent, and/or as a prokinetic agent for the treatment of gastroparesis. It is approved in the US by the FDA for short-term therapy (≤12 weeks) of gastroesophageal reflux, and for treatment of diabetic gastroparesis (≤8 weeks). However, gastroparesis is a chronic condition, and some patients have been exposed to long-term metoclopramide use.

Accumulating evidence, mainly retrospective, suggests that chronic metoclopramide use is a major cause of TD in adults [2,48-51]. However, the precise incidence and prevalence of metoclopramide-induced TD is unclear.

• In a case-control study, patients treated with metoclopramide had a higher risk of developing TD than controls, but the finding did not achieve statistical significance (relative risk [RR] 1.67, 95% CI 0.93-2.97) [2]. Metoclopramide treatment was associated with a significantly increased risk of drug-induced parkinsonism (RR 4.0, 95% CI 1.5-10.5) [2].

• In a study that included 10 patients treated with metoclopramide who developed TD, the average duration of metoclopramide exposure before TD onset was approximately one year [50].

• In some referral centers, metoclopramide has replaced haloperidol as the medication most commonly associated with TD [51].

RISK FACTORS FOR TD — Older age is the most robust risk factor for TD.

• One study found that the incidence of new cases of TD for patients exposed to conventional antipsychotic drugs was three to five times greater in patients above age 50 than in younger patients [20]. In addition, the prevalence of TD was five to six times greater in patients older than age 65 when compared with younger patients.

• In two systematic reviews evaluating second-generation antipsychotic drugs, the incidence of TD was very low in studies involving children, higher in studies involving predominantly middle-aged adults, and highest in studies involving older adults [43,44].

• Rates of spontaneous TD remission decrease with increasing age [18,52].

Other factors that have been tentatively associated with greater prevalence of TD include female sex, brain damage, dementia, major affective disorder, diabetes, longer duration of antipsychotic drug exposure, use of anticholinergic-antiparkinson drugs, and a history of previous acute extrapyramidal reactions to antipsychotic drugs. Most of these associations are based on prevalence rather than incidence studies. Thus, their role as risk factors for TD is not firmly established.

Drug exposure by dose is particularly difficult to evaluate as a potential risk factor. Dosing may be an important risk factor in elderly patients [26], but several retrospective studies have reported little difference in TD prevalence between moderate and high doses of conventional antipsychotic drugs, or between the daily equivalent of 300 and 3000 mg of chlorpromazine [11]. The risk of TD may already be maximal at chlorpromazine-equivalent doses of approximately 300 mg daily, which is in the mid-range of typical antipsychotic doses [38].

In a prospective study, 57 patients with first-episode psychotic disorders and no evidence of TD at baseline were treated with low-dose haloperidol (mean 1.7 mg daily) [53]. At 12 months, dyskinesia developed in seven (12.3 percent). Although there was no control group, the incidence of apparent TD was similar to that in other prospective studies of TD incidence involving treatment with conventional antipsychotic drugs at standard doses.

In a prospective study of 9000 patients with schizophrenia, the presence of extrapyramidal symptoms (dystonia, akathisia, or parkinsonism) at baseline predicted an increased risk for the development of TD over one year of treatment with several different antipsychotics (hazard ratio 2.0, 95% CI 1.6-2.6) [54]. In the prospective Hillside studies, patients with a history of severe, early extrapyramidal reactions to antipsychotic drugs developed TD more frequently than those without early extrapyramidal reactions [20,26]. However, the high rates of acute extrapyramidal reactions may have reflected use of more potent antipsychotic drugs at relatively high doses.

Among older patients, a history of electroconvulsive treatment was a predictor of TD [26]. Female sex and African-American ethnicity were also identified as risk factors for TD [21,24-26].

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• Basics topics (see "Patient information: Tardive dyskinesia (The Basics)")

SUMMARY

• Tardive dyskinesia (TD) is a unique complication of antipsychotic drugs and metoclopramide. (See 'Etiology' above.)

• The ability of antipsychotic drugs to block postsynaptic dopamine receptors is a potential mechanism for the development of TD. An updated version of the dopamine hypothesis suggests that an imbalance between D1 and D2 receptor-mediated effects in the basal ganglia may be responsible for TD. (See 'Pathophysiology' above.)

• In patients treated with conventional (first-generation) antipsychotic drugs, the annual incidence of TD is approximately 3 and 8 percent overall, and approximately 10 to 20 percent in those older than 55 years. (See 'First-generation antipsychotic drugs' above.)

• Among second-generation antipsychotic drugs, also known as atypical neuroleptics, clozapine has a very low risk for TD or acute extrapyramidal reactions. (See 'Second-generation antipsychotic drugs' above.)

• With increased use of second-generation antipsychotic drugs, the prevalence of TD was expected to decline, but data are conflicting. (See 'Is the rate of tardive dyskinesia declining?' above.)

• The risk of TD is probably lower with most second-generation antipsychotic drugs than with high-potency conventional antipsychotic drugs. Nevertheless, it is not certain whether most second-generation antipsychotic drugs have a lower risk in comparison to low-potency conventional antipsychotic drugs taken at moderate doses. (See 'Second- versus first-generation antipsychotic drugs' above.)

• Accumulating evidence, mainly retrospective, suggests that chronic metoclopramide use is a major cause of TD in adults. (See 'Metoclopramide' above.)

• Older age is the most robust risk factor for TD. (See 'Risk factors for TD' above.)

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Tardive dyskinesia: Clinical features and diagnosisAuthor Daniel Tarsy, MD Section Editor Howard I Hurtig, MDDeputy Editor John F Dashe, MD, PhDLiterature review current through: Jun 2014. | This topic last updated: Nov 20, 2013.INTRODUCTION — Tardive dyskinesia (TD) is a hyperkinetic movement disorder that appears with a delayed onset after prolonged use of dopamine receptor blocking agents, mainly the antipsychotic drugs (also called

neuroleptics) and the antiemetic drug, metoclopramide.

TD has numerous clinical manifestations that include chorea, athetosis, dystonia, akathisia, stereotyped behaviors, and rarely tremor. The term "tardive" differentiates these dyskinesia from acute dyskinesia, parkinsonism, and akathisia, which appear very soon after exposure to antipsychotic drugs.

The clinical features and diagnosis of TD will be reviewed here. Other aspects of TD are discussed separately. (See "Tardive dyskinesia: Etiology and epidemiology" and "Tardive dyskinesia: Prevention and treatment".)

CLINICAL FEATURES — Manifestations of tardive dyskinesia (TD) can include a variable mixture of orofacial dyskinesia, athetosis, dystonia, chorea, tics, and facial grimacing. The symptoms involve the mouth, tongue, face, trunk, or extremities. Tardive tremor has been rarely described [1,2].

Oral, facial, and lingual dyskinesia are especially conspicuous in elderly patients. These may include:

• Protruding and twisting movements of the tongue• Pouting, puckering, or smacking movements of the lips• Retraction of the corners of the mouth• Bulging of the cheeks• Chewing movements• Blepharospasm

Tongue movements are insidious in onset and at first may be limited to subtle back and forth or lateral movements. In other patients, tic-like facial movements or increased blink frequency are initial manifestations.

Dyskinesia of the limbs also occur, such as:

• Twisting, spreading, and "piano-playing" finger movements• Tapping foot movements• Dystonic extensor postures of the toes

Limb involvement is often more severe in younger individuals in whom dystonic postures and ballistic movements may occur.

Dyskinesia of the neck and trunk may include the following:

• Retrocollis• Torticollis• Axial dystonia• Shoulder shrugging• Rocking and swaying movements• Rotatory or thrusting hip movements

Respiratory dyskinesia may produce tachypnea, irregular breathing rhythms, and grunting noises that are commonly misinterpreted as primary respiratory problems.

Severe orofacial dyskinesia is highly disfiguring and may greatly interfere with speech, eating, swallowing, or breathing, while truncal dystonia can be extremely distressing and interfere with gait and mobility.

TD is much less common in children than in adults. The manifestations of TD in children have been called "withdrawal emergent symptoms" because they usually occur when antipsychotic drugs are discontinued.

Cognitively intact and psychiatrically stable patients are usually very aware of mild and early manifestations of TD. In contrast, failure to complain of TD symptoms often occurs in patients with little insight who are chronically institutionalized or psychotic.

Subtypes of tardive dyskinesia — A number of TD variants or subtypes have been described based on the type of involuntary movements that predominate in these conditions [3,4].

• Tardive dystonia refers to TD in which more sustained dystonic manifestations such as retrocollis, opisthotonus, shoulder dystonia, hyperextension of the arms or legs, blepharospasm, and jaw dystonia predominate [5]. Tardive dystonia occurs more frequently in patients younger than age 40; it may have a lower spontaneous remission rate than TD.

• Tardive akathisia refers to late-appearing motor restlessness. It differs from acute akathisia by the presence of dyskinesia and absence of subjective motor restlessness [6].

• Tardive tics, tardive myoclonus, tardive stereotypy, tardive tremor, and tardive oral pain syndromes have also been described [3], but these are rare and often difficult to distinguish from other manifestations of TD or from effects of the patient's underlying psychosis. Many of these

additional manifestations were well described in early reports of TD. They typically coexist with the more common manifestations. They illustrate the notion that TD encompasses a variety of motor manifestations without delineating a specific movement disorder [7].

TD has also been classified based upon symptom duration or chronologic appearance and remission. In this scheme, subtypes include transient TD, withdrawal emergent TD, and persistent TD [8].

• Transient TD is limited to a relatively brief period of time during the course of treatment with antipsychotic drugs followed by spontaneous resolution

• Withdrawal emergent TD has been used to describe dyskinesia in pediatric patients that occurs transiently, immediately following the discontinuation of antipsychotic drugs

• Persistent TD refers to long-lasting or permanent TD

Clinical course — The onset of TD is insidious and typically occurs while the patient is receiving an antipsychotic drug. TD may appear as early as one to six months following antipsychotic drug exposure. In the initial literature, it was believed that TD occurred only after two or more years of antipsychotic treatment.

It is common for TD to first appear after a reduction in dose, after switching to a less potent antipsychotic drug, or following discontinuation of an antipsychotic drug. This "unmasking" effect is due to the hypokinetic effects of antipsychotic drugs that frequently cause a delay in the recognition of TD. Withdrawal dyskinesia usually resolves within several weeks of antipsychotic drug discontinuation, but is likely to be a precursor of more persistent forms of TD.

Although once considered a persistent or permanent condition, TD is often reversible [9]. In initial studies, remission rates of persistent TD were only 5 to 40 percent, but early identification of TD in younger outpatient populations is associated with remission in 50 to 90 percent of patients. Remission of TD usually occurs within several months after antipsychotic drug withdrawal, but may occur as late as one to three years [10].

The prognosis of TD in patients who require continued antipsychotic drug treatment is unknown. In most cases, TD either remains unchanged, or is suppressed by the hypokinetic effects of the antipsychotic drug when used

at a higher dose [11,12].

DIAGNOSIS — The diagnosis of TD is based upon the presence of dyskinetic or dystonic involuntary movements, a history of at least one month of antipsychotic drug treatment, and the exclusion of other causes of abnormal movements.

It is important to identify TD as early as possible since, as noted in the preceding section, the potential for remission appears to be related to the duration of symptoms before discontinuation of the antipsychotic drug.

Differential diagnosis — Although the diagnosis of TD is usually straightforward, clinicians should consider other important causes of involuntary movements, such as Wilson disease or Huntington disease, in patients being treated with antipsychotic drugs for a psychiatric disorder. A comprehensive, methodical drug history is an essential part of the diagnostic evaluation. (See "Wilson disease: Diagnostic tests" and "Huntington disease: Clinical features and diagnosis".)

Advanced Huntington disease is readily identified clinically by the positive family history, marked gait abnormality, and dementia. Early-stage Huntington disease can be harder to differentiate from TD because involuntary choreiform movements may be the only manifestation, and may be mild.

TD must be distinguished from the stereotypies and psychotic mannerisms associated with chronic schizophrenia [13], autism, and severe mental retardation. Stereotypies in schizophrenia are usually less rhythmic, more stereotyped, and more complex in appearance than the simpler, repetitive, and often rhythmic involuntary movements associated with TD. Unlike TD, choreoathetosis and dystonia are absent. (See "Schizophrenia: Clinical manifestations, course, assessment, and diagnosis" and "Autism spectrum disorder: Clinical features", section on 'Stereotyped behaviors'.)

TD should also be distinguished from other antipsychotic drug-induced extrapyramidal syndromes that often coexist. (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects", section on 'Side effects' and "Second-generation antipsychotic medications: Pharmacology, administration, and comparative side effects", section on 'Side effects'.)

• Akathisia occurs both early and late in antipsychotic drug treatment and, in the case of tardive akathisia, may persist after cessation of such treatment [6]. Akathisia is a subjective feeling of motor restlessness

accompanied by inability to sit or stand still. Manifestations may include repeated leg crossing, weight shifting, or stepping in place. When akathisic movements of the legs occur late in antipsychotic drug treatment and are associated with dyskinesia elsewhere in the body, they are referred to as tardive akathisia and should be considered a manifestation of TD.

• Acute dyskinesia typically occurs immediately after introduction of an antipsychotic drug, but may resemble TD. Acute dyskinesia can sometimes occur late in treatment after switching to a more potent antipsychotic drug, or can occur episodically during treatment with long-acting injectable fluphenazine esters.

• With rare exception [1,2], tremor is an uncommon manifestation of TD. Tremor is nearly always a reversible sign, usually associated with rigidity and akinesia, due to drug-induced parkinsonism. Rabbit syndrome is a rare perioral tremor that also may occur late in antipsychotic treatment, but, like other tremors, remits with discontinuation of antipsychotic drugs.

• Spontaneous orofacial dyskinesia often occurs in elderly people. The mean prevalence of dyskinesia among patients treated with antipsychotic drugs has been estimated at 20 percent, compared with a mean prevalence of 5 percent in untreated patients [14]. This indicates that a significant background level of spontaneous dyskinesia is present in the general population, especially in the elderly. Spontaneous oral dyskinesia in the elderly is often associated with edentulism and dementia.

• Meige syndrome is an idiopathic cranial dystonia with onset in middle age manifested by blepharospasm and oromandibular dystonia. Meige syndrome, blepharospasm, and oromandibular dystonia are all phenotypically indistinguishable from orofacial TD. Thus, differentiating these conditions from TD depends on an adequate drug history.

• In a young person, tardive dystonia involving axial or cervical muscles should be differentiated from primary torsion dystonia, which has a slowly progressive course and is not related to antipsychotic drug exposure.

• Tourette syndrome is easily identified by a history of fluctuating motor and vocal tics since childhood. (See "Tourette syndrome".)

Other, less common possibilities in the differential diagnosis of TD include the following:

• Facial grimacing and choreoathetosis associated with chronic liver disease• Chorea or dystonia with antiphospholipid antibody syndrome• Chorea due to hyperthyroidism or hypoparathyroidism• Rheumatic or lupus chorea• Acute drug intoxications with levodopa, amphetamines, anticholinergic

drugs, certain calcium channel blockers with dopamine receptor blocking effects (eg, flunarizine and cinnarizine, which are unavailable in the United States), antidepressants, and anticonvulsants

• Basal ganglia calcification and structural disorders of the basal ganglia

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• Basics topics (see "Patient information: Tardive dyskinesia (The Basics)")

SUMMARY

• Manifestations of tardive dyskinesia (TD) can include a variable mixture of orofacial dyskinesia, athetosis, dystonia, chorea, tics, and facial grimacing. The symptoms involve the mouth, tongue, face, trunk, or extremities. Tardive tremor has also been rarely described. (See 'Clinical features' above.)

• A number of TD variants or subtypes have been described based on the type of involuntary movements that predominate in these conditions, including the following:

• Tardive dystonia• Tardive akathisia• Tardive tics• Tardive myoclonus• Tardive stereotypy• Tardive tremor• Tardive oral pain syndromes

(See 'Subtypes of tardive dyskinesia' above.)

• The onset of TD is insidious and typically occurs while the patient is receiving an antipsychotic drug. In addition, it is common for TD to first appear after a reduction in dose, after switching to a less potent antipsychotic drug, or following discontinuation of an antipsychotic drug. (See 'Clinical course' above.)

• Although once considered a persistent or permanent condition, TD is often reversible. (See 'Clinical course' above.)

• The diagnosis of TD is based on the presence of dyskinetic or dystonic involuntary movements, a history of at least one month of antipsychotic drug treatment, and the exclusion of other causes of abnormal movements. (See 'Diagnosis' above.)

• TD should be distinguished from other extrapyramidal syndromes, including:

• Wilson disease• Huntington disease• Akathisia• Acute dyskinesia• Stereotypies associated with chronic schizophrenia, autism, and severe

mental retardation• Spontaneous orofacial dyskinesia• Meige syndrome• Blepharospasm• Oromandibular dystonia

(See 'Differential diagnosis' above.)

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Tardive dyskinesia: Prevention and treatmentAuthor Daniel Tarsy, MD Section Editor Howard I Hurtig, MDDeputy Editor John F Dashe, MD, PhDDisclosures: Daniel Tarsy, MD Nothing to disclose. Howard I Hurtig, MD Nothing to Literature review current through: Jun 2014. | This topic last updated: Oct 03, 2013.INTRODUCTION — Tardive dyskinesia (TD) is a hyperkinetic movement disorder that appears with a delayed onset, usually after prolonged use of dopamine receptor blocking agents, mainly the antipsychotic drugs (also called neuroleptics) and the antiemetic drug metoclopramide.

TD has numerous clinical manifestations that include chorea, athetosis, dystonia, akathisia, stereotyped behaviors, and rarely, tremor. The term "tardive" differentiates these dyskinesia from acute dyskinesia, parkinsonism, and akathisia, which appear very soon after exposure to antipsychotic drugs. TD is a clinical diagnosis, but tests may be performed to exclude other causes of the patient's symptoms.

This topic will review the prevention and management of TD. Other aspects of TD are discussed separately. (See "Tardive dyskinesia: Etiology and epidemiology" and "Tardive dyskinesia: Clinical features and diagnosis".)

PREVENTION — Prevention of tardive dyskinesia (TD) and the early detection and treatment of potentially reversible cases of TD are of paramount importance. The only certain method of TD prevention is to avoid treatment with antipsychotic drugs and metoclopramide.

• The use of antipsychotic drugs, particularly for longer than three months, requires careful evaluation of indications, and risks and should be limited to situations where there is no safer effective therapy.

• Metoclopramide should NOT be used continuously for longer than 12 weeks.

As an iatrogenic disorder, TD has medicolegal implications [1]. Thus, it is important to inform patients of the risk of developing TD before treating with antipsychotic drugs or metoclopramide. Although there is no consensus, some experts also advocate obtaining written informed consent from competent patients or from family members of patients who are unable to consent. Once started on these medications, patients should be monitored

periodically for the development of TD.

Guidelines for antipsychotic drug treatment — The American Psychiatric Association Task Force report on TD lists specific indications for short- and long-term antipsychotic drug treatment [2,3]. This is particularly important since TD is often irreversible despite cessation of the offending drug. (See "Tardive dyskinesia: Clinical features and diagnosis", section on 'Clinical course'.)

The Task Force made the following recommendations:

• Long-term use of antipsychotic drugs in neurosis, depression, anxiety, personality disorder, and chronic pain states should be discouraged.

• Even in schizophrenia or related chronic psychosis, efforts should be made to maintain patients on the lowest effective dose of antipsychotic drugs while reexamining the need for continued treatment at least every six months. After remission of a first acute psychotic episode, the dose of antipsychotic drug should at least be decreased, and probably best discontinued, within 6 to 12 months. Plans to continue treatment beyond six months require discussion with the patient and family regarding the indication for prolonged antipsychotic drug treatment and the risks of TD. (See "Pharmacotherapy for schizophrenia: Side effect management".)

• Particular care is indicated for patients age 50 and older, patients with affective disorder, patients with treatment-resistant schizophrenia and negative symptoms, and possibly women.

• Since acute antipsychotic drug-induced parkinsonism and akathisia are an indicator of the extent of D2 receptor blockade, these adverse effects should be avoided by dose reduction or by use of a less potent agent. Drug-induced parkinsonism may also mask signs of dyskinesia. It is prudent to use the smallest effective dose required to control an individual patient's symptoms.

• Except for prevention of acute dystonic reactions, chronic use of prophylactic anticholinergic drugs should be discouraged since they do not prevent TD and can aggravate the involuntary movements once they emerge.

• Early antipsychotic drug withdrawal results in a better prognosis for recovery. Thus, patients on antipsychotic drugs should be carefully monitored for signs of TD at regular intervals with use of a standard dyskinesia rating scale such as the Abnormal Involuntary Movement Scale (AIMS), which is useful to heighten awareness of mild manifestations of TD [4]. The AIMS is available at

www.cqaimh.org/pdf/tool_aims.pdf.• Where possible, antipsychotic drugs should be tapered and discontinued

as soon as the diagnosis of TD is made, although control of the patient's psychosis may ultimately be the most critical factor in the use of the offending drug.

For patients who are developing signs of TD while receiving first generation (conventional) antipsychotic drugs, but still require treatment for psychosis, it is now considered prudent to switch to second generation (atypical) antipsychotic drugs that may be associated with a lower risk for TD. However, there is no convincing evidence that altering the medication regimen ameliorates the course of TD once symptoms have developed. (See 'Second generation antipsychotic drugs' below.)

Discontinuation of metoclopramide treatment — Metoclopramide is used primarily as an antiemetic agent and/or as a prokinetic agent for the treatment of gastroparesis. It should be stopped immediately if the diagnosis of TD is made, and alternative treatments of the gastrointestinal symptoms should be used. As a preventive measure, metoclopramide should not be used continuously for longer than 12 weeks.

The association of metoclopramide and TD is discussed in detail separately. (See "Tardive dyskinesia: Etiology and epidemiology", section on 'Metoclopramide'.)

PHARMACOLOGIC TREATMENT — Numerous studies have evaluated various pharmacologic treatments of TD, but few therapies have produced more than slight to moderate benefit in clinical practice [5]. Thus, prevention, early detection, and management of potentially reversible cases are the cornerstones of modern treatment.

When clinically appropriate, pharmacologic interventions may be considered for patients who are developing signs of TD. The two main strategies are discontinuation of the offending drug and switching from first to second generation antipsychotic drugs

For patients with a diagnosis of TD, additional pharmacologic interventions include the following:

• Use of benzodiazepines, botulinum toxin injections, tetrabenazine, or anticholinergic drugs to control symptoms of TD

• Paradoxically, resuming treatment with antipsychotic drugs in order to suppress TD (see 'Resumption of antipsychotic drugs' below)

The need for drugs to control symptoms of TD should be carefully assessed, since symptoms are often mild and not sufficiently bothersome to require treatment. In some cases, family members are more disturbed by the involuntary movements than the patient, who may be relatively unaware of their clinical manifestations. However, this is more common among chronic or institutionalized patients than in ambulatory patients, many of whom are in psychiatric remission when TD appears.

Discontinuation of dopamine receptor blocking agent — When feasible, immediate tapering and discontinuation of the offending antipsychotic drug or metoclopramide is recommended if TD becomes apparent [5]. Antipsychotic drug cessation (or dose reduction) must be carefully considered because of the potential for relapse or worsening of psychotic symptoms [6]. The dyskinesia may abate within several weeks of drug cessation, but recurrence is possible if antipsychotic drug treatment is reintroduced.

The effectiveness of discontinuing the offending agent is not proven, since data are limited and no randomized controlled clinical trials have studied complete cessation of antipsychotic drugs for ameliorating TD [7,8]. A systematic review published in 2006 identified two trials that evaluated antipsychotic dose reduction versus dose maintenance in a total of 17 patients with TD [6]. Pooled data showed that dose reduction was associated with a trend toward a clinically significant reduction in TD severity, but the findings just missed statistical significance (relative risk 0.38, 95% CI 0.1-1.0).

New onset dyskinesias may occur during antipsychotic drug withdrawal. Such dyskinesias often clear spontaneously over several weeks and do not require specific treatment. On the other hand, more persistent dyskinesia may recur if antipsychotic drugs are resumed, which should prompt the use of alternative pharmacologic management of the underlying psychosis.

Some patients with bipolar disorder do not require persistent therapy with antipsychotic drugs, as mood-stabilizing medications may adequately control the psychiatric symptoms. However, temporary reintroduction of an antipsychotic drug may be necessary if the patient has an acute exacerbation of psychotic symptoms. When a high-potency antipsychotic is chosen, it should later be replaced by a second generation agent, preferably one with demonstrated low risk for TD.

Second generation antipsychotic drugs — Some reports suggest that the second generation (atypical) antipsychotic drugs clozapine [9-12] and

quetiapine [13-15] have ameliorating effects on TD severity [16,17]. However, these observations may be due to either masking effects of the drugs or, more likely, due to an antipsychotic drug "sparing" effect, in which gradual improvement of TD occurs during treatment with weaker (second generation) rather than more potent (first generation) dopamine blocking agents. Thus, it is unclear if clozapine has definite antidyskinetic effects.

• In a review of eight uncontrolled open studies published in 1991, the response of TD to clozapine was variable and of uncertain significance [9]. However, in several later uncontrolled studies, clozapine produced an apparent therapeutic effect [11,12]. It has been particularly effective in some cases of severe tardive dystonia [9,11], possibly related to its anticholinergic potency.

• Quetiapine appears to have a low or even nonexistent tendency to cause TD [16], and may alleviate TD [13-15]

Although the available data are limited and somewhat conflicting, we suggest changing to a second generation antipsychotic drug in patients who are developing signs of TD if treatment for psychosis remains critical [16]. In contrast to possible benefit in early TD, there is no convincing evidence that altering the medication regimen is effective for ameliorating the course of TD once symptoms have fully developed.

Clozapine is the preferred second generation agent in this setting, but requires frequent blood testing, as discussed in the next section. Clozapine has weak affinity for dopamine receptors whereas most of the other second generation antipsychotic drugs are potent D2 receptor blockers that carry the risk of causing or perpetuating TD. While quetiapine may be capable of exerting clozapine-like therapeutic effects in TD, the evidence supporting its use for ameliorating TD is limited. The risk of TD with second generation antipsychotic drugs is reviewed elsewhere. (See "Tardive dyskinesia: Etiology and epidemiology", section on 'Second-generation antipsychotic drugs'.)

Clozapine dosing — Clozapine titration begins with an initial dose of 25 mg daily. The dose can be increased by 12.5 to 25 mg increments every one to two days, according to the clinical response and as tolerated. The optimal dose for treating TD is uncertain, but maintenance doses of 300 to 600 mg daily are usually required for antipsychotic efficacy.

Systemic side effects of clozapine are frequent and include potentially life-threatening agranulocytosis, reported in 1 to 2 percent of patients during the

first six months of treatment and occurring less frequently thereafter. Other side effects include orthostatic hypotension, weight gain, sedation, dizziness, vertigo, salivation, sweating, dry mouth, tachycardia, syncope, nausea, and constipation. (See "Second-generation antipsychotic medications: Pharmacology, administration, and comparative side effects", section on 'Clozapine'.)

Clozapine treatment requires weekly monitoring of the white blood cell count during the first six months, biweekly monitoring for the next six months, then monitoring every four weeks for the duration of treatment.

Benzodiazepines — Because of evidence for gamma-aminobutyric acid (GABA) depletion in some primate models of TD [18], GABA agonists have been tested in patients with TD with modest success [19]. Benzodiazepines operate through a GABA mechanism, but evidence of benefit in patients with TD is limited and inconclusive [20-22].

A systematic review published in 2006 identified three randomized trials that compared benzodiazepines with placebo or no intervention [20]. The trials included a total of 56 patients with schizophrenia or other chronic mental illnesses who had neuroleptic-induced TD. In two trials with 30 patients, there was no significant difference between benzodiazepine treatment and placebo for clinically important improvement, defined as a ≥50 percent improvement in any validated scale for TD (relative risk 1.08, 95% CI 0.57-2.05). However, in one trial with 24 patients, benzodiazepine treatment resulted in a statistically significant improvement in abnormal movement scores [20].

A fourth double-blind, randomized controlled trial [21] was not included in the meta-analysis [20] because the data were only presented in graphs. In this trial, 19 patients with TD were assigned to clonazepam (2 to 4.5 mg daily) or placebo [21]. At 12 weeks, clonazepam reduced dyskinesia scores by 35 percent compared with placebo. The reduction in dyskinesia scores was greater for patients with predominantly dystonic symptoms than for those with predominantly choreoathetotic manifestations (41 and 26 percent, respectively). Based upon the results of this trial, a guideline from the American Academy of Neurology concluded that clonazepam is probably effective for decreasing tardive dyskinesia symptoms short-term [8]. However, in five patients participating in an open study carried out immediately following the double-blind study, the antidyskinetic effects disappeared after five to eight months [20].

Although evidence of efficacy is limited, we suggest the use of low doses of a benzodiazepine, such as clonazepam, to reduce both dyskinesia and associated anxiety in patients with mild TD. Patients with more severe

manifestations of TD are less likely to show a significant reduction in TD with benzodiazepine treatment.

Clonazepam dosing — Clonazepam is initiated with 0.5 mg daily and titrated by 0.5 mg increments every five days according to response and as tolerated, up to a maximum of 3 to 4 mg/day. Previous benzodiazepine dependency may be a contraindication. Central nervous system depressant effects may be potentiated by barbiturates, hypnotics, anxiolytic, antipsychotic, or antidepressant drugs.

Botulinum toxin injections — Evidence for the effectiveness of botulinum toxin for TD is limited to retrospective case series and case reports [8]. In one multicenter study, botulinum toxin produced marked or moderate improvement in 29 of 34 patients with relatively localized TD manifesting as cervical dystonia or blepharospasm in most cases [23]. In another retrospective study, botulinum toxin treatment was associated with similar improvement in tardive cervical dystonia (n = 7) and idiopathic cervical dystonia (n = 156) [24].

We suggest botulinum toxin injections for patients with localized forms of debilitating tardive dystonia, such as cervical dystonia, retrocollis, or blepharospasm [5]. Adverse effects are excessive weakness of injected or neighboring muscles. Botulinum toxin should generally not be used in patients with myasthenia gravis or other neuromuscular conditions.

Administration — Botulinum toxin type A, onabotulinumtoxinA, is currently available in the United States as Botox. The dose depends on site of injection. The most common forms of TD treated with botulinum toxin are cervical dystonia and blepharospasm (involuntary forced eye closure). Cervical dystonia requires highly individualized dosing, usually in the range of 150 units to start, increasing empirically to a maximum of 300 units according to individual clinical response. Blepharospasm requires a total dose of approximately 25 units injected in multiple sites in the orbicularis oculi muscles.

Botulinum toxin type B, rimabotulinumtoxinB, is available as Myobloc and may be given in unit doses approximately 40 to 50 times higher than botulinum toxin type A, but only in the event of failure to respond first to botulinum toxin type A.

Tetrabenazine — Drugs that deplete dopamine storage in presynaptic vesicles, such as tetrabenazine or reserpine, may be the most effective therapeutic agents for TD, and particularly for tardive dystonia.

Limited data suggest that tetrabenazine is useful for the treatment of TD [8].

The range of findings is illustrated by the following reports:

• In a double-blind study with six patients, tetrabenazine 100 mg daily showed mild to marked improvement in TD that was not greater than the effect of the active control, diazepam [25].

• In a double-blind, crossover trial with 24 patients, tetrabenazine up to 150 mg daily produced marked reduction or disappearance of dyskinesia in 70 percent of patients compared with no change for placebo [26].

• An open-label study in a small group of patients with chronic psychosis found that tetrabenazine was less effective for TD than haloperidol [27]. Several open-label studies have demonstrated improvement in TD with tetrabenazine in doses of up to 200 mg daily [28,29].

Despite limited evidence of effectiveness, we suggest treatment with tetrabenazine (where available) for patients with disturbing and intrusive TD, particularly those with tardive dystonia.

Tetrabenazine dosing — Tetrabenazine is initiated with 12.5 mg daily for one week and increased by 12.5 mg increments every few days, according to clinical response and as tolerated, to a level of 75 to 150 mg daily. Potential adverse effects include parkinsonism, sedation, fatigue, depression, anxiety, akathisia, tremor, insomnia, confusion, nausea, vomiting, hypotension, and dizziness.

Anticholinergic drugs — Trihexyphenidyl or benztropine are usually ineffective or may even exacerbate dyskinesia but are sometimes helpful in tardive dystonia. This is consistent with observations that anticholinergics may be useful in primary dystonia but often exacerbate choreiform disorders.

Retrospective studies have shown improvement in tardive dystonia following trihexyphenidyl (10 to 32 mg daily) in three of eight patients [28] and with trihexyphenidyl (6 to 12 mg daily) in 8 of 21 patients [30].

We suggest trihexyphenidyl for patients with severe and more widespread tardive dystonia that is refractory to other interventions, such as botulinum toxin injection, which is indicated in relatively localized dystonia. We recommend NOT using trihexyphenidyl to treat TD unless accompanied by severe tardive dystonia. Similarly, we suggest tetrabenazine for more generalized tardive dystonia when localized use of botulinum toxin is not practical.

Trihexyphenidyl dosing — Trihexyphenidyl is initiated at 1 mg twice daily and titrated to a total dose of 4 to 6 mg daily as tolerated.

Narrow-angle glaucoma, confusion, and dementia are contraindications to the use of trihexyphenidyl. The possibility of exacerbating underlying psychosis is a particular concern in patients with TD. Trihexyphenidyl should be used with caution in people over 60, and in patients with benign prostatic hypertrophy or obstructive gastrointestinal disorders. Other anticholinergic side effects include dry mouth, blurred vision, constipation, urinary hesitancy or retention, tachycardia, pupil dilatation, and increased intraocular pressure. Patients may develop tolerance to these effects with continued low-dose treatment. Additional side effects of trihexyphenidyl include dizziness, confusion, memory impairment, nausea, vomiting, and anxiety.

Gingko biloba extract — In a randomized controlled trial from China that included 157 patients with schizophrenia and TD, a standardized extract of Ginkgo biloba leaves known as EGb-761 was effective in the treatment of TD [31]. At 12 weeks compared with placebo, treatment with EGb-761 significantly decreased the involuntary movement score.

Resumption of antipsychotic drugs — As a last resort, it may be necessary to resume treatment with a first or second generation antipsychotic drug in order to suppress TD in some patients with permanent and disabling or life-threatening TD that is treatment-resistant, even in the absence of active psychosis.

Data supporting this approach are equivocal, since both short- and long-term studies of conventional antipsychotic drugs have produced mixed results [32]. However, there is some evidence that treatment with second generation antipsychotic drugs may be associated with amelioration of TD. (See 'Second generation antipsychotic drugs' above.)

Fortunately, continued antipsychotic drug exposure does not appear to worsen the severity of TD once it becomes established or chronic [33,34].

Cholinergic agents — Because of the reciprocal relationship between dopamine and acetylcholine in basal ganglia, it had been predicted that cholinergic drugs might ameliorate TD. In available trials, treatment with galantamine, choline, lecithin, deanol, and other cholinergic medications has been ineffective [8,35].

Vitamin E — Vitamin E has been used for the treatment of TD based upon the hypothesis that this antioxidant may reverse a possible toxic effect of free radicals produced during chronic administration of antipsychotic drugs [36].

Clinical trials of vitamin E in relatively small numbers of patients with TD have produced conflicting results [8,37-42]. However, in a systematic review

published in 2001 that included six placebo-controlled trials with 256 patients, vitamin E treatment was not beneficial for a clinically relevant improvement in TD (relative risk 0.95, 95% CI 0.89-1.02) [43]. Vitamin E was given in doses of 600 to 1600 units daily for up to 20 weeks in most of these trials.

Other drug treatments — Amantadine may have some benefit for TD when used as adjunct therapy with antipsychotic drugs [8], as suggested by the results of short-term crossover trial that randomly assigned 16 patients to amantadine (300 mg/d) or placebo; both groups continued their regular antipsychotic drugs [44]. Dyskinesia was significantly reduced in patients taking amantadine.

A large variety of miscellaneous agents have been studied for treatment of TD in case reports and open-label trials without convincing success, including beta blockers, calcium channel blockers, serotonin antagonists, buspirone, vitamin B6, and lithium [7,8,45]. Levetiracetam, an antiepileptic agent with therapeutic effects in levodopa-induced dyskinesia, reduced the severity of TD in two small open-label trials [46,47] and a small randomized trial [48] that was limited by a high dropout rate [8].

Experimental GABA agonists, such as progabide, muscimol, and tetrahydroisoxazolopyridinol (THIP) or gamma-vinyl-GABA, a GABA-transaminase inhibitor that elevates brain GABA levels, have been studied in relatively few clinical trials with mixed results [49], while valproate and baclofen have not shown significant promise.

DEEP BRAIN STIMULATION — The basis for using deep brain stimulation (DBS) of the globus pallidus as a treatment for TD is the established benefit of this procedure for treatment of levodopa-induced dyskinesia and idiopathic dystonia.

One of the larger prospective studies of DBS for TD involved 10 patients with resolved or stabilized psychiatric disease who had severe TD refractory to medical treatment [50]. All were treated with bilateral DBS of the internal part of the globus pallidus. At six months after surgical lead implantation, using double-blind evaluation of stimulation on or off, the Extrapyramidal Symptoms Rating Scale score was significantly lower with stimulation-on compared with stimulation-off (mean decrease, 50 percent; range, 30 to 66 percent).

In case reports and small series, patients with severe forms of TD manifesting primarily as dystonia were successfully treated with DBS of the globus pallidus or subthalamic nucleus [51-56]. These patients displayed various combinations of orofacial, cervical, and truncal dyskinesia and

dystonia that improved dramatically within a relatively short period of time after surgery. One unblinded and uncontrolled study of nine patients with refractory tardive dystonia found that benefit of DBS persisted for longer than one year [56].

For patients who have permanent, disabling TD that is unresponsive to pharmacologic treatment modalities, we suggest DBS in the globus pallidus when it can be performed at centers with expertise in this technique.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

• Basics topics (see "Patient information: Tardive dyskinesia (The Basics)")

SUMMARY AND RECOMMENDATIONS

• The only certain method of TD prevention is to avoid treatment with antipsychotic drugs or metoclopramide. The use of antipsychotic drugs should be limited to situations where there is no alternative effective therapy. Metoclopramide should NOT be used continuously for longer than 12 weeks. (See 'Prevention' above.)

• The need for TD treatment should be carefully assessed, since symptoms are often mild and not sufficiently disturbing to require treatment. (See 'Pharmacologic treatment' above.)

• For patients who develop dyskinesia during treatment with a dopamine receptor blocking agent (ie, antipsychotic drug or metoclopramide), we recommend immediate discontinuation of the offending medication if feasible. However, antipsychotic drug cessation or dose reduction

must be carefully considered because of the potential for relapse or worsening of psychotic symptoms. (See 'Discontinuation of dopamine receptor blocking agent' above.)

• For patients who are developing signs of TD but still require treatment for psychosis, we suggest using a second generation antipsychotic drug rather than a first generation agent (Grade 2C). Clozapine is the preferred second generation agent, but requires frequent blood testing because there is a 1 to 2 percent risk of agranulocytosis. Quetiapine in low doses is an alternative second generation agent. (See 'Second generation antipsychotic drugs' above and 'Clozapine dosing' above.)

• For patients with relatively mild TD and associated anxiety, we suggest the use of low doses of a benzodiazepine (Grade 2C). Our preferred agent is clonazepam. (See 'Benzodiazepines' above and 'Clonazepam dosing' above.)

• For patients with localized forms of severe tardive dystonia, such as cervical dystonia, retrocollis or blepharospasm, we suggest treatment with botulinum toxin injections (Grade 2C). (See 'Botulinum toxin injections' above.)

• For patients who have disturbing and intrusive TD or tardive dystonia not amenable to treatment with botulinum toxin, we suggest treatment with tetrabenazine (Grade 2C). (See 'Tetrabenazine' above and 'Tetrabenazine dosing' above.)

• Anticholinergic drugs are usually ineffective or may even exacerbate dyskinesia but are sometimes helpful in tardive dystonia. For patients with severe debilitating tardive dystonia that is refractory to the interventions above, we suggest treatment with trihexyphenidyl (where available) (Grade 2C). (See 'Anticholinergic drugs' above and 'Trihexyphenidyl dosing' above.)

• For patients with permanent, disabling TD that is treatment-resistant, we suggest TD suppression by resuming treatment with a first or second generation antipsychotic drug (Grade 2C). (See 'Resumption of antipsychotic drugs' above.)

• For patients who have permanent, disabling TD that is unresponsive to pharmacologic treatment modalities, we suggest deep brain stimulation in the globus pallidus when it can be performed at centers with expertise in this technique (Grade 2C). (See 'Deep brain stimulation' above.)

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