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Tardive dyskinesia: Etiology, risk factors, clinical features, and diagnosis

Tardive dyskinesia: Etiology, risk factors, clinical features, and diagnosis
Authors:
Andres Deik, MD, MSEd
Daniel Tarsy, MD
Section Editors:
Howard I Hurtig, MD
Stephen Marder, MD
Deputy Editor:
April F Eichler, MD, MPH
Literature review current through: Dec 2022. | This topic last updated: May 26, 2022.

INTRODUCTION — Tardive dyskinesia (TD) is a medication-induced hyperkinetic movement disorder associated with the use of dopamine receptor-blocking agents, including antipsychotic drugs and two antiemetic agents, metoclopramide and prochlorperazine. TD encompasses a wide range of abnormal, involuntary movements that often persist after discontinuation of the causative medication. TD can be irreversible and lifelong. The condition can be disfiguring and disabling, with major negative impacts on psychologic health and quality of life.

TD is a clinical diagnosis that requires vigilance and screening of all patients taking dopamine-blocking agents, and exclusion of other conditions associated with abnormal movements. TD is important to recognize, since early discontinuation of the offending drug may offer the best chance of recovery.

The clinical features and diagnosis of TD will be reviewed here. Treatment and prevention of TD and other drug-induced movement disorders are reviewed separately. (See "Tardive dyskinesia: Prevention, treatment, and prognosis" and "Medical management of motor fluctuations and dyskinesia in Parkinson disease" and "Drug-induced parkinsonism".)

DEFINITIONS — TD is a medication-induced hyperkinetic movement disorder caused by exposure to dopamine receptor-blocking agents, most often antipsychotic drugs, that persists for at least a month after discontinuation of the offending agent [1]. Dyskinesia encompasses a variety of involuntary movements and postures, including chorea, athetosis, stereotyped behaviors, dystonia, akathisia, tics, respiratory dyskinesias, and very rarely tremor.

The term "tardive," or late, differentiates TD from other medication-induced extrapyramidal symptoms (EPS) that usually appear either acutely or very soon after exposure to dopamine receptor-blocking agents and that resolve after the drug is discontinued. Whereas parkinsonism may arise while using a dopamine-blocking agent (in what is known as drug-induced parkinsonism), it should never be thought of as a tardive phenomenon. (See 'Other drug-induced movement disorders' below.)

Withdrawal-emergent TD has been used to describe dyskinesia in children that occurs transiently (eg, <1 month) immediately following the discontinuation of an antipsychotic drug. (See 'Children' below.)

Withdrawal dyskinesia is a form of TD in adults that occurs immediately after discontinuing or reducing the dose of a dopamine receptor-blocking agent; the related term "masked TD" refers to tardive movements that resolve when a dopamine receptor-blocking agent is resumed or its dose is increased [2]. (See 'Clinical course' below.)

CAUSATIVE AGENTS — All dopamine receptor-blocking agents have the potential to cause TD. First- or second-generation antipsychotic drugs and metoclopramide are most commonly implicated.

Whether any non-dopamine-blocking agents are associated with a risk of TD remains controversial. Although antidepressants have very rarely been reported to cause TD [3], close examination of published case reports and small retrospective case series indicates that the reported prevalence has been lower than the accepted prevalence of spontaneous dyskinesia in older adults, and moreover, that in most cases affected patients had either previously or concurrently been treated with an antipsychotic drug [4-6].

Antipsychotic drugs — Antipsychotic drugs, including both first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs), are responsible for most TD cases.

FGAs – The estimated annual incidence of TD with continuous exposure to an FGA is 5 to 6 percent overall [7,8] and 10 to 25 percent among older adults [9,10]. With long-term continuous exposure, the 5- and 10-year cumulative risk of TD is approximately 25 and 50 percent, respectively. The risk appears to be similar across different FGAs when used at comparable dose equivalents. (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects".)

SGAs – The estimated annual risk of TD with continuous exposure to an SGA is approximately 4 percent overall [11] and 5 to 7 percent among older adults [12-14]. Unlike FGAs, the risk is not uniform across all SGAs. Although direct comparative data are limited, the risk appears to be highest for paliperidone and risperidone; intermediate for aripiprazole, lurasidone, olanzapine, and ziprasidone; lower for iloperidone; and low or absent for pimavanserin, quetiapine, and clozapine [15]. Brexpiprazole, an antipsychotic with partial dopamine type 2 (D2) and 5HT1A receptor agonist activity, demonstrated a low incidence of extrapyramidal symptoms in short-term clinical trials [16], but cases of TD have been reported subsequently [17]. (See "Second-generation antipsychotic medications: Pharmacology, administration, and side effects".)

While SGAs are associated with a lower incidence of TD than FGAs, the difference between these two classes is not as great as initially thought [18]. In six studies directly comparing SGAs with FGAs in a total of 12,924 patients (mean age 51 years, range 25 to 83), the annual incidence rate of TD was approximately 25 percent lower with SGAs than FGAs (4.2 percent [95% CI 3.8-4.5] versus 5.5 percent [95% CI 5.0-6.1]) [11]. Earlier studies had suggested a nearly sixfold lower risk with SGAs [14].

Similarly, the overall prevalence of TD has not fallen as much as had initially been expected [19,20]. A meta-analysis of 41 cross-sectional studies published between the years 2000 and 2015 that examined rating scale-based TD rates during treatment with FGAs and/or SGAs found a global TD prevalence of 25.3 percent [19]. Prevalence rates were higher for current FGA treatment compared with current SGA treatment (30 versus 20.7 percent), and the difference remained significant after controlling for moderators including age and duration of illness.

In the four studies within this meta-analysis that were restricted to patients with schizophrenia receiving an SGA without previous FGA exposure, the prevalence of TD was only 7.2 percent. Of note, these estimates reflect TD of any severity as diagnosed by systematic screening with standardized rating scales, mostly using a cutoff of at least mild symptoms in two body parts [19].

Several important limitations of the available data remain. For SGAs, annual incidence estimates have primarily been derived from randomized controlled trials, many of which were relatively short term, and which tend to include a healthier, lower-risk population than what is seen in clinical practice. In addition, many studies of TD risk associated with SGAs have been confounded by prior FGA exposure, which could lead to an overestimation of risk. Additional risk factors for TD are reviewed below. (See 'Risk factors' below.)

Metoclopramide — Metoclopramide is a benzamide antiemetic with D2 receptor-blocking action. It has been associated with a spectrum of involuntary movements, including acute dystonic reactions, drug-induced parkinsonism, and TD, that derive from its mechanism as a centrally acting dopamine receptor antagonist.

Chronic oral metoclopramide, used as a promotility agent or antiemetic, is a major cause of TD in adults [21-25]. Since 2009, metoclopramide labeling has included a boxed warning from the US Food and Drug Administration (FDA) on the risk of TD with long-term or high-dose use. The FDA warning advises against use for longer than 12 weeks to mitigate the risk of TD. As of 2006, before the FDA warning went into effect, metoclopramide had exceeded haloperidol in some referral populations in the United States as the most common cause of TD [23,25].

Although the link between metoclopramide and TD is well established, the absolute risk for TD due to metoclopramide has not been defined prospectively [21,22]. Incidence and prevalence estimates are hindered by the difficulty in establishing an accurate denominator of chronic metoclopramide exposure and lack of standard reporting of TD. Two European prescription database studies in the 1980s estimated the prevalence to be 1 in 2000 to 2800 treatment years, but these studies did not provide information concerning how many patients were on chronic therapy, and also likely detected only more severe cases of TD [26,27]. A study published in 2019 estimated the risk of TD to be much lower, suggesting it may be in the range of 0.1 percent per 1000 patient-years [28]. Adoption of alternative management strategies for gastroparesis may reduce the prevalence of metoclopramide-induced TD even further [29].

In case series, the average duration of metoclopramide exposure before TD onset has ranged from 14 to 31 months, with a mean daily dose of approximately 30 mg [30]. Beyond treatment duration and total cumulative dose, risk factors are similar to those identified in patients exposed to antipsychotic drugs, including older age, female sex, comorbid psychiatric conditions, and diabetes. (See 'Risk factors' below.)

TD due to metoclopramide appears to be rare in children, despite acute extrapyramidal symptoms (EPS) being among its most common side effects [31]. Case reports in children describe persistent symptoms for up to 15 months after drug discontinuation [32,33].

Other antiemetics — Other dopamine receptor-blocking agents used as antiemetics (eg, prochlorperazine, chlorpromazine) also have the potential to cause TD with chronic use. Domperidone, which is available outside of the United States, appears to be an exception.

The absolute risks and prevalence of TD due to prochlorperazine and chlorpromazine are even less well defined than those of metoclopramide, possibly because currently they are not used chronically nearly as often as metoclopramide [34].

Antipsychotic drugs such as haloperidol and olanzapine are sometimes used for control of refractory nausea due to chemotherapy or in palliative care settings. Although these drugs have the potential to cause TD, this complication has not been reported in this setting because therapy is usually intermittent and time limited.

Others — Several other medications have very rarely been implicated in TD [35,36]. The two most common examples are the tetracyclic antidepressant amoxapine, which is a dopamine receptor-blocking agent, and aripiprazole, which is a partial agonist at dopamine and 5HT1A receptors and a postsynaptic 5HT2A antagonist.

In many case reports, amoxapine was administered concurrently or after exposure to an antipsychotic drug. In other cases, the medication may have served to exacerbate dyskinesia in a patient with latent TD due to prior antipsychotic drug exposure. Aripiprazole is widely used in patients with treatment-resistant depression and has become an increasingly common cause of TD.

Selective serotonin and serotonin-norepinephrine reuptake inhibitors may cause akathisia, which sometimes closely resembles TD [37]. Anticholinergic drugs (eg, trihexyphenidyl and benztropine) or antidepressants with anticholinergic properties may unmask or activate TD by virtue of their anticholinergic effects but do not directly cause TD. Antihistamines (eg, hydroxyzine) have very rarely been reported to cause acute dyskinesia but do not cause TD.

RISK FACTORS — Older age and duration of exposure to dopamine receptor-blocking agents, particularly first-generation antipsychotics (FGAs), are the most important risk factors for TD. For FGAs, the incidence of TD approaches 50 percent by 10 years of continuous exposure. (See 'Causative agents' above.)

Older adults are particularly susceptible to TD [38]. Rates of TD associated with FGAs are three to five times higher in older adults (over age 55 years) compared with younger adults, despite older adults typically receiving lower doses of antipsychotic drugs for shorter periods of time [9,12,13,39]. Risk is also increased in older adults exposed to second-generation antipsychotics (SGAs) compared with younger adults, although the magnitude of this difference may be smaller (eg, 1.5 to 2 times higher) [10].

Patients who develop extrapyramidal symptoms (EPS; dystonia, akathisia, or parkinsonism) as a side effect of early antipsychotic drug therapy appear to be at increased risk for TD. In a prospective study of over 7000 patients with schizophrenia treated with antipsychotic drugs who did not have TD at baseline, EPS at baseline were associated with increased risk of TD over three years of follow-up (hazard ratio [HR] 1.71, 95% CI 1.27-2.30) [15].

Higher doses of antipsychotics are believed to be associated with increased risk of TD. However, drug dose is difficult to evaluate, and studies have not consistently found a correlation independent of drug type and treatment duration. Although less common, TD is well known to occur even at low doses of FGAs [40].

Additional risk factors for TD include female sex (most consistent in older adults), schizophrenia and other psychotic disorders, preexisting mood disorder, intellectual disability, dementia, alcohol or substance misuse, a history of electroconvulsive therapy, and comorbid diabetes (table 1) [18,41].

Children are believed to be at lower risk for TD than adults. Use of antipsychotic drugs in this population has become more common, however, and estimates may evolve over time. In cross-sectional studies, the prevalence of TD in children and adolescents taking FGAs, SGAs, or a combination of both ranges from 6 to 9 percent [42,43]. In a multicenter observational study of antipsychotic-naïve or quasi-naïve children treated with antipsychotic drugs, the incidence of TD at one year of follow-up was 5.7 percent [44]. Factors associated with increased risk included younger age, history of psychotic symptoms, and longer exposure time.

PATHOPHYSIOLOGY — The pathophysiology of TD is not fully understood, and several hypotheses exist. The most commonly proposed mechanisms suggest that dopamine receptor hypersensitivity and/or an imbalance between dopamine type 1 (D1) and type 2 (D2) receptor-mediated effects in the basal ganglia are primarily responsible for TD [45,46].

According to the dopamine hypothesis, first-generation antipsychotics (FGAs) 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 lower tendency of the second-generation antipsychotics (SGAs), especially clozapine, to cause TD, since clozapine produces relatively less D2 and relatively more D1 blockade.

In animal models, repeated treatment with antipsychotic drugs leads to dopamine receptor supersensitivity [47,48]. In humans, there is evidence for upregulation of striatal dopamine receptors following chronic antipsychotic drug exposure [49], but correlation of this finding with clinical evidence of TD has not been established. In addition, dopamine supersensitivity in animal models is a universal and rapidly appearing pharmacologic phenomenon that lasts for only several weeks, raising some doubt about its relevance to TD in humans, where it is possible that more lasting structural changes in neurons or dopamine receptors may have taken place.

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 for several years has produced persistent dyskinesia and reduced GABA and glutamic acid decarboxylase levels in several regions of the basal ganglia [50]. An excitotoxic mechanism may possibly account for this selective destruction of a localized population of basal ganglia neurons [51]. 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. A possible role of free radicals generated by increased neuronal dopamine turnover caused by antipsychotic drugs has also been considered [52].

The prolonged and often irreversible course of TD suggests that structural cellular alterations in the brain are responsible for this disorder. Whereas pathologic studies in animals and humans have failed to demonstrate consistent findings following chronic exposure to antipsychotic drugs [53], neuroimaging studies suggest there may be differences in gray matter volume (GMV) in schizophrenic patients with TD [54]. Changes in neuronal circuitry may also play a role [55].

CLINICAL SPECTRUM — Manifestations of TD can include a variable mixture of orofacial dyskinesia, athetosis, dystonia, chorea, and tics. The symptoms most commonly involve the mouth and tongue, but the arms, legs, trunk, and respiratory muscles can also be affected.

Oro-bucco-lingual and facial dyskinesia — Oral, facial, and lingual dyskinesia are the most common manifestations of TD (movie 1). They are observed in nearly three-quarters of patients, either alone or in combination with other dyskinetic movements [56]. They are especially conspicuous in older adults. Types of perioral movements 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. Tardive orolingual movements may worsen with the use of anticholinergic drugs, which should be avoided [57].

Severe orofacial dyskinesia is highly disfiguring and can greatly interfere with speech, eating, swallowing, or breathing [58]. Dysarthria due to the orolingual movements is common. Some patients develop temporomandibular pain and problems with dentition related to ongoing jaw and mouth movements.

Limb, trunk, and respiratory involvement — Dyskinesia of the limbs also occurs, such as:

Twisting, spreading, and "piano-playing" finger movements (movie 2)

Tapping foot movements

Dystonic extensor postures of the toes

Dyskinesia of the neck and trunk may include the following:

Shoulder shrugging

Retrocollis, torticollis, or blepharospasm (see 'Dystonia' below)

Rocking and swaying movements

Rotatory or thrusting hip movements

Respiratory dyskinesia can manifest as tachypnea, irregular breathing rhythms, and grunting noises that are commonly misinterpreted as primary respiratory problems [59]. Rarely, these movements can be life threatening.

Limb involvement is often more severe in younger patients in whom dystonic postures and ballistic movements may occur. Truncal dystonia and lower-extremity dyskinesia can interfere with gait, posture, and mobility. Postural instability can lead to problems with balance and increased risk of falls.

Dystonia — Tardive dystonia refers to TD in which dystonic manifestations predominate. Dystonia is sustained or repetitive muscle contractions that result in twisting and repetitive movements or abnormal fixed postures. Types of dystonia that occur as a manifestation of TD include retrocollis (which may be sustained or jerky), torticollis, opisthotonus, shoulder dystonia, hyperextension of the arms or legs, blepharospasm, and jaw dystonia [60].

Tardive dystonia occurs more frequently in patients younger than age 40; it may have a lower spontaneous remission rate than TD.

Akathisia — Tardive akathisia refers to late-appearing motor restlessness. Manifestations may include repeated leg-crossing, weight-shifting, or stepping in place. Tardive akathisia differs from acute akathisia by the presence of dyskinesia and absence of subjective motor restlessness [61]. Tardive akathisia can be focal or generalized, and is often refractory to treatment [38].

Tics, tremor, and other rare manifestations — Tardive tics, tardive myoclonus, tardive stereotypy, tardive tremor, and tardive oral pain syndromes have also been described [62], but these are 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 [63].

Children — The manifestations of TD in children have been called "withdrawal-emergent symptoms" because they usually first appear as a withdrawal phenomenon when antipsychotic drugs are discontinued. Patients with this often self-limited condition often exhibit choreiform movements below the neck reminiscent of Sydenham chorea [38].

CLINICAL COURSE — The onset of TD is insidious and is sometimes difficult to recognize because the movements can be subtle and fluctuating. TD may appear as early as one to six months following initiation of a dopamine receptor-blocking agent, and the risk rises with cumulative exposure.

As with other movement disorders, the movements of TD worsen with emotional stress, diminish with sedation, and remit during sleep.

Cognitively intact and psychiatrically stable patients are usually very aware and self-conscious of mild and early manifestations of TD. By contrast, those with intellectual disability, dementia, or severe psychosis may lack awareness of TD symptoms. In case series, one-half to two-thirds of patients with TD have been unaware of their involuntary movements [64]. Although patients may not be aware of mild involuntary movements, they are often obvious to others and can be stigmatizing.

It is very common for TD to first appear after a reduction in antipsychotic drug dose, after switching to a less potent antipsychotic drug, or following discontinuation of an offending drug. This "unmasking" effect is most likely due to the hypokinetic effects of the antipsychotic drug having caused a delay in the appearance of TD. The term "masked tardive dyskinesia" refers to tardive movements that resolve when a dopamine receptor-blocking agent is resumed or its dose is increased [2]. Withdrawal dyskinesia usually resolves within several weeks of drug discontinuation, but is likely to be a precursor of more persistent forms of TD.

SCREENING — All patients receiving long-term antipsychotic drugs or metoclopramide should be regularly screened for the development of TD. It is important to remember that subtle oro-bucco-lingual movements can be missed by the practice of mandatory face masking, which has become widespread since the coronavirus disease 2019 (COVID-19) pandemic [65]. (See "Tardive dyskinesia: Prevention, treatment, and prognosis", section on 'Prevention'.)

Screening for TD consists of direct observation. While the patient is sitting, the clinician observes whether there are abnormal movements in the face, mouth, jaw, or extremities. The tongue should be observed with the mouth held open. While standing or walking, the patient is observed for abnormal movements of the trunk or limbs. Clinicians may choose to use the Abnormal Involuntary Movement Scale (AIMS) for documenting results of the examination (form 1). The AIMS includes both a standardized examination and a system for rating abnormal movements.

EVALUATION — TD should be suspected as a cause of involuntary movements in patients with ongoing or previous exposure to dopamine receptor-blocking agents. (See 'Causative agents' above.)

A complete medication history is imperative. This often requires coordination and verification with family members, caretakers, other care providers and review of pharmacy records. It is helpful to inquire about exposure to specific agents by name when taking a medication history, rather than only asking patients whether they have ever been exposed to antipsychotic drugs or other dopamine blockers.

While TD most commonly emerges three to six months or longer after initiation of a dopamine receptor-blocking agent, symptoms occasionally may occur after as little as one month of treatment. Older adults are most vulnerable. When drug exposure is relatively short, TD must be distinguished from acute extrapyramidal side effects. When multiple drugs may be implicated, a stepwise approach to discontinuation may be required. (See 'Other drug-induced movement disorders' below.)

A neurologic examination should be performed, with specific attention to cognition, muscle tone, coordination, and gait. In general, the presence of neurologic signs other than dyskinesia or dystonia (eg, focal weakness, ataxia, prominent dementia) suggest an alternative or underlying neurologic disorder. (See 'Primary movement disorders' below.)

Patients with a typical history of oro-bucco-lingual dyskinesia that emerges after more than three to six months of continuous exposure to an antipsychotic drug or metoclopramide require little additional evaluation. The next step is to determine whether the offending drug can be safely tapered and ultimately discontinued. (See "Tardive dyskinesia: Prevention, treatment, and prognosis", section on 'Initial management'.)

Patients with atypical clinical features, additional neurologic findings, or a remote or atypical drug exposure history (eg, relatively brief duration of antipsychotic drug therapy, exposure to a medication that rarely causes TD) may require additional evaluation and follow-up to exclude alternative etiologies. Useful laboratory studies in selected patients may include liver function tests and ceruloplasmin for Wilson disease, thyroid function tests, serum calcium, complete blood count, and antiphospholipid antibodies. (See 'Primary movement disorders' below and 'Systemic causes of hyperkinetic movements' below.)

Brain MRI is not part of the routine evaluation of suspected TD but should be pursued if the history or examination raise suspicion for a structural cause of hyperkinetic movements (eg, unilateral movements that are maximal at onset; associated headache and lethargy; focal findings on neurologic examination). Certain MRI abnormalities may suggest an underlying neurodegenerative disorder, such as bilateral caudate atrophy in Huntington disease or neuroacanthocytosis. (See 'Primary movement disorders' below.)

DIAGNOSIS — TD is a clinical diagnosis based upon the presence of typical dyskinetic or dystonic involuntary movements, a history of at least one month of ongoing or previous dopamine receptor-blocking agent exposure, and the exclusion of other causes of abnormal movements. There is no confirmatory test or biomarker for TD [38].

If dyskinesia appears six months or more after discontinuation of a dopamine receptor-blocking agent, TD may not be the cause of dyskinesia. Although exceptions are certainly possible, it is generally accepted that TD develops either while exposed to a dopamine receptor-blocking agent, within four weeks of withdrawal from an oral medication, or within eight weeks of withdrawal from a depot formulation [36].

It is important to identify TD as early as possible after onset, since the potential for remission correlates with the duration of symptoms before discontinuation of the offending drug. (See "Tardive dyskinesia: Prevention, treatment, and prognosis".)

DIFFERENTIAL DIAGNOSIS — Although the diagnosis of TD is usually straightforward, other causes of involuntary movements should be considered, especially for patients presenting with manifestations other than classic oro-bucco-lingual dyskinesia and those with an atypical exposure history (eg, relatively brief duration of dopamine receptor-blocking agent therapy, or exposure to a medication that rarely causes TD).

Other drug-induced movement disorders — It is important to distinguish TD from drug-induced movement disorders, particularly drug-induced parkinsonism and drug-induced tremor. Patients who experience drug-induced movement disorders from antipsychotic drugs are at increased risk for later development of TD. (See 'Risk factors' above.)

Acute dyskinesia – Acute dyskinesias, more commonly known as acute dystonic reactions, typically occur immediately after introduction of a dopamine receptor-blocking agent and resolve within a month of its discontinuation. Acute dyskinesias are often dystonic in nature, including oculogyric crisis, cervical dystonia, and oromandibular dystonia [66]. Risk factors for acute dystonic reactions include young age, male sex, use of cocaine, and a previous history of an acute dystonic reaction to a dopamine receptor-blocking agent.

The temporal relationship between involuntary movements and the initiation of a dopamine receptor-blocking agent is usually sufficient to distinguish between acute and tardive dyskinesia. However, acute dyskinesia can sometimes occur late in treatment after switching from a milder to a more potent antipsychotic drug or can occur episodically during treatment with long-acting injectable antipsychotic drugs.

Management of acute dystonic reactions is reviewed separately. (See "Schizophrenia in adults: Maintenance therapy and side effect management", section on 'Dystonia'.)

Akathisia – Akathisia occurs both early and late in antipsychotic drug treatment and, in the case of tardive akathisia, may persist after cessation of the causative agent [61]. The distinction depends primarily on the temporal relationship between symptoms and drug exposure, as it may be difficult to differentiate acute from tardive akathisia based solely on phenomenology.

Acute akathisia includes 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 such 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," which is often not accompanied by a subjective feeling of motor restlessness and should be considered a manifestation of TD.

Parkinsonism and tremor – Tremor is a common manifestation of drug-induced parkinsonism and only very rarely an isolated manifestation of TD, when it tends to be more of a large-amplitude postural rather than resting tremor [67,68]. Drug-induced tremor is nearly always reversible and is usually associated with rigidity and akinesia due to drug-induced parkinsonism. By definition, parkinsonism is never a tardive phenomenon: parkinsonism persisting after the discontinuation of a dopamine-blocking agent is either due to slow resolution of a drug-induced effect or due to an unrelated underlying primary parkinsonian syndrome. (See "Drug-induced parkinsonism".)

Levodopa-related dyskinesia that arises in patients with idiopathic Parkinson disease is discussed separately. (See "Medical management of motor fluctuations and dyskinesia in Parkinson disease".)

Perioral tremor – 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. The oral tremor in rabbit syndrome often does not involve the tongue, which may help differentiate it from classic tardive orolingual movements [69].

Stereotypies and mannerisms — TD should be distinguished from stereotypies and psychotic mannerisms associated with chronic schizophrenia, autism, and severe intellectual disability. Stereotypies in schizophrenia are usually less rhythmic, more stereotyped, and more complex in appearance than the stereotyped but simpler, repetitive, and often rhythmic involuntary movements associated with TD. (See "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis" and "Autism spectrum disorder: Clinical features", section on 'Stereotyped behaviors'.)

Spontaneous or idiopathic dyskinesias — A significant background level of spontaneous orofacial dyskinesia occurs in the general population, especially in older adults with edentulism or dementia. Among individuals with no history of exposure to dopamine receptor-blocking agents, the mean prevalence of spontaneous dyskinesia has been estimated to be 5 percent [70]. The prevalence in edentulous patients has been estimated to be approximately 15 percent. (See "Overview of chorea", section on 'Edentulous dyskinesia'.)

Meige syndrome refers to 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. (See "Etiology, clinical features, and diagnostic evaluation of dystonia", section on 'Blepharospasm'.)

Isolated dystonia — Idiopathic focal or segmental dystonia of adulthood can be indistinguishable phenotypically from tardive dystonia, and a thorough medication history may be the only discerning factor. Blepharospasm, jaw and lingual dystonia, and retrocollis are particularly common isolated dystonias when they occur due to TD. (See "Etiology, clinical features, and diagnostic evaluation of dystonia", section on 'Adult-onset focal or segmental isolated dystonia'.)

Isolated dystonia occurring early in life (childhood or adolescence) is usually genetic in origin. As an example, DYT-THAP1 is a genetic isolated dystonia that causes prominent craniocervical involvement [71]. Genetic testing or a careful family history may identify family members with similar symptoms that raise suspicion for a familial disorder. However, the absence of a positive family history does not rule out isolated dystonia, as many mutations have incomplete penetrance. (See "Etiology, clinical features, and diagnostic evaluation of dystonia", section on 'Early-onset isolated dystonia'.)

Primary movement disorders — A variety of primary neurologic disorders can manifest with prominent dyskinesia, typically in combination with other abnormalities. Patients with undiagnosed primary movement disorders may occasionally be misidentified as having TD if there is a history of exposure to a dopamine receptor-blocking agent and dyskinesia is prominent. However, in most cases there are additional clues to an underlying movement disorder based on the presence of additional neurologic symptoms and signs, progression over time, a family history, imaging or laboratory abnormalities, or onset of symptoms early in life.

Huntington disease – Advanced Huntington disease is readily identified clinically by a positive family history, marked gait abnormality, dementia, and disproportionate caudate atrophy on brain imaging. Genetic testing confirms the diagnosis. It must be noted that many patients with advanced Huntington disease develop psychosis and are prescribed antipsychotic drugs. Early-stage Huntington disease can be harder to differentiate from TD because involuntary choreiform movements may be subtle and can be the only manifestation. (See "Huntington disease: Clinical features and diagnosis".)

Wilson disease – Wilson disease should be considered in younger patients with unexplained dystonia, tremor, chorea, or other neurologic symptoms, especially in the presence of liver dysfunction, psychiatric abnormalities, history of consanguinity, or a positive family history. While the majority of patients diagnosed with Wilson disease are between the ages of 5 and 35 years, Wilson disease has been diagnosed in patients in their 70s. Initial testing consists of liver biochemical tests, complete blood count, and serum ceruloplasmin. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history".)

Tourette syndrome – Tourette syndrome is a cause of motor and vocal tics that is easily identified by a history of fluctuating motor and vocal tics before 18 years of age. (See "Tourette syndrome: Pathogenesis, clinical features, and diagnosis".)

Autoimmune encephalitis – Some of the autoimmune encephalitis syndromes can manifest with prominent dyskinesia as well as psychiatric disturbances that might lead to treatment with an antipsychotic drug. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, in particular, frequently features prominent orofacial dyskinesia and other movement abnormalities. (See "Paraneoplastic and autoimmune encephalitis", section on 'Anti-NMDA receptor encephalitis'.)

Structural disorders of the basal ganglia (eg, stroke, hemorrhage, tumor) – Ischemic and hemorrhagic stroke involving the basal ganglia (particularly the subthalamic nucleus) can manifest with unilateral chorea or hemiballismus in the acute or chronic phase. Vascular disease should be considered when hemichorea develops acutely and is maximal at onset, particularly in older patients with hypertension or other risk factors. (See "Overview of chorea", section on 'Vascular'.)

Other disorders of the basal ganglia – A variety of neurogenetic disorders have a predilection for the basal ganglia and can manifest with hyperkinetic movements, along with other abnormalities. Examples include neuroacanthocytosis, neuroferritinopathy, and other forms of neurodegeneration with brain iron accumulation. (See "Overview of chorea", section on 'Hereditary causes of chorea'.)

These and other causes of abnormal movements in children and adults are reviewed in more detail separately. (See "Hyperkinetic movement disorders in children" and "Bradykinetic movement disorders in children" and "Etiology, clinical features, and diagnostic evaluation of dystonia" and "Overview of chorea".)

Systemic causes of hyperkinetic movements — 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 associated with antiphospholipid antibody syndrome (see "Clinical manifestations of antiphospholipid syndrome", section on 'Neurologic involvement')

Chorea due to hyperthyroidism or hypoparathyroidism (see "Neurologic manifestations of hyperthyroidism and Graves' disease", section on 'Movement disorders' and "Hypoparathyroidism", section on 'Extrapyramidal disorders')

Rheumatic or lupus chorea (see "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus", section on 'Chorea')

Sydenham chorea (primarily in children) (see "Sydenham chorea")

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 education: Tardive dyskinesia (The Basics)")

SUMMARY AND RECOMMENDATIONS

Definition – Tardive dyskinesia (TD) is a medication-induced hyperkinetic movement disorder caused by exposure to dopamine receptor-blocking agents that persists for at least a month after discontinuation of the offending agent. (See 'Definitions' above.)

Causative agents – All dopamine receptor-blocking agents have the potential to cause TD. First- and second-generation antipsychotic drugs and metoclopramide are the most common culprits. Although other medications with different mechanisms of action have very rarely been implicated in TD, convincing evidence of a causal relationship is lacking. (See 'Causative agents' above and 'Pathophysiology' above.)

Risk factors – Older age and duration of exposure to dopamine receptor-blocking agents, particularly first-generation antipsychotics (FGAs), are the most important risk factors for TD (table 1). (See 'Risk factors' above.)

The estimated annual risk of TD with continuous exposure to an FGA is 5 to 6 percent overall and 10 to 25 percent among older adults. For second-generation antipsychotics (SGAs), the estimated annual risk is approximately 4 percent overall and 5 to 7 percent among older adults. (See 'Antipsychotic drugs' above.)

Clinical features – Oral, facial, and lingual dyskinesia are the most common manifestations of TD (movie 1). They are observed in nearly three-quarters of patients, very often in association with manifestations of dyskinesia, dystonia, chorea, and tics in other body parts (movie 2). (See 'Clinical spectrum' above.)

The onset of TD is insidious and may be difficult to recognize initially because movements are often initially subtle and fluctuating. Symptoms very often first appear after a reduction in dose, after switching to a less potent antipsychotic drug, or following discontinuation of an antipsychotic drug or other dopamine receptor-blocking agent. (See 'Clinical course' above.)

Screening – All patients receiving long-term antipsychotic drugs or metoclopramide should be regularly screened for the development of TD (form 1). It is important to identify TD as early as possible, since the potential for remission appears to be related to the duration of symptoms before discontinuation of the offending drug. (See 'Screening' above.)

Diagnosis – TD is a clinical diagnosis based upon the presence of typical dyskinetic or dystonic involuntary movements, a history of at least one month of dopamine receptor-blocking agent exposure, and the exclusion of other causes of abnormal movements. (See 'Evaluation' above and 'Diagnosis' above.)

Differential diagnosis – Although the diagnosis of TD is usually straightforward, other causes of involuntary movements should be considered, especially for patients presenting with manifestations other than classic oro-bucco-lingual dyskinesia and those with an atypical drug exposure history. (See 'Differential diagnosis' above.)

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