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Overview

Background

Tardive dyskinesias (TDs) are involuntary movements of the tongue, lips, face, trunk, and extremities that occur in patients treated with long-term dopaminergic antagonist medications. Although they are associated with the use of neuroleptics, TDs apparently existed before the development of these agents. People with schizophrenia and other neuropsychiatric disorders are especially vulnerable to the development of TDs after exposure to conventional neuroleptics, anticholinergics, toxins, substances of abuse, and other agents.

TDs are most common in patients with schizophrenia, schizoaffective disorder, or bipolar disorder who have been treated with antipsychotic medication for long periods, but they occasionally occur in other patients as well. For example, people with fetal alcohol syndrome, other developmental disabilities, and other brain disorders are vulnerable to the development of TDs, even after receiving only 1 dose of the causative agent.

TD has been associated with polymorphisms of the dopamine receptor D2 (DRD2) gene,^[1]particularly TaqIA and TaqIB polymorphisms, and associated haplotypes,^[2]as well as polymorphisms of the dopamine receptor D3 (DRD3) gene.^{[1, 3]}Additionally, polymorphisms in the dopamine transporter (DAT) gene and the manganese superoxide dismutase (MnSOD) gene^[4]have also been implicated, though the evidence is less consistent

Dysfunction of the dopamine transporter has been hypothesized to play a role in the development of TD. However, Lafuente et al did not find evidence of involvement of a polymorphism with a variable number of tandem repeats (VNTD) in the DAT gene (SLC6A3) in dyskinesias induced by antipsychotics.^[5] Thus, further research is needed to investigate the role of the dopamine transporter in the development and maintenance of TD.

TDs may be differentiated from acute movement disorders that commonly occur in the same patient groups. The acute movement disorders that occur as manifestations of effects of neuroleptics and other dopamine antagonists include akathisia, acute dystonia, and other hyperkinetic dyskinesias.

Acute effects of dopamine antagonists also include parkinsonian syndromes manifested by bradykinesia, rigidity, and pill rolling tremor. The acute movement disorders resulting from exposure to dopamine antagonists are commonly termed extrapyramidal syndromes (EPS).

The occurrence of acute movement disorders on exposure to dopamine antagonists is increased in female patients and older patients. Use of potent dopamine antagonists, prolonged exposure to dopamine antagonists, and prior occurrence of acute movement disorders on exposure to dopamine antagonists are also associated with an increased risk for the occurrence of acute movement adverse effects.

Withdrawal dyskinesias may also occur as treatment with dopamine antagonists is decreased or withdrawn. They are often refractory to all therapeutic modalities. In addition to the prototypic orofacial dyskinesia, tardive syndromes also include a spectrum of hyperkinesias occurring during or after prolonged treatment with dopamine antagonists.

Next: Pathophysiology

Pathophysiology

Extrapyramidal dysfunction

For most of the past century, movement disorders (ie, abnormal adventitious movements) have been categorized as extrapyramidal side effects (EPS) caused by lesions of the extrapyramidal system of the central nervous system (CNS).

The pyramidal system, controlling voluntary movements, includes precise anatomic pathways from the cortex to muscle. Voluntary movements through the pyramidal systems are visible. An example of a classic disorder of the pyramidal system is a stroke, resulting in paralysis of an extremity.

Corticospinal lesions above the pyramidal decussation typically result in paralysis of volitional movements of the contralateral half of the body and a fixed posture with flexion of the upper extremity and extension of the lower extremity. Bilateral corticospinal lesions of the upper pons and midbrain typically cause extension of all four extremities and decerebrate rigidity with dorsiflexion of the cervical and thoracolumbar spine. Unilateral lesions of the upper pons and midbrain often result in extension of the ipsilateral arm and leg.

By contrast, extrapyramidal motor activities result in automatic movement and static, postural movement activities that are not noticeable (see Table 1 below). The extrapyramidal system includes theorized connections within the basal ganglia, the striatopallidonigral system, and other structures of the central nervous system that contribute to the regulation of movement, including related brainstem nuclei and the cerebellum.

Table 1. Classic Characterization of Pyramidal and Extrapyramidal Systems (Open Table in a new window)

Characteristic	Pyramidal	Extrapyramidal
Anatomy	Precisely demarcated pathways from cortex to muscle	Hypothesized pathways among basal ganglia and other structures of the central nervous system
Physiologic movements	Voluntary	Involuntary
Pathologic movements	Paralysis, paresis, hyperreflexia, and spasticity	Akathisia, athetosis, ballismus, chorea, dystonia, myoclonus, stereotypy, tic, and tremor

Classic disorders of the extrapyramidal system include a variety of involuntary movement disorders. Some of these movement disorders include dyskinesias such as akathisia, chorea, dystonia, myoclonus, stereotypy, tic, and tremor.

The pathophysiology of extrapyramidal disorders has been disputed on the grounds that some of these disorders may not involve lesions of the basal ganglia and, in addition, may not be involuntary. Because of the problems inherent in the concept of the extrapyramidal system, caution must be exercised in the classification of movement disorders as EPS, and new approaches to the classification of movement disorders may be helpful.

Bradykinesia versus hyperkinesia

Dyskinesia is a type of movement disorder that is subdivided into bradykinesias and hyperkinesias. Bradykinesias are characterized by abnormal slowness (eg, rigidity), difficulty initiating and terminating actions, and the masked facial expression of patients with Parkinson disease. Hyperkinesias are purposeless movements, including akathisia, chorea, dystonia, myoclonus, stereotypy, tic, and tremor.

This binary classification of movement disorders is based on the observed phenomenology, etiology, and topography. Practitioners and researchers may be confounded by this approach to classification and may prefer instead to use clinical impressions. Methods of data analysis, including linear and logistic regression, linear discriminant function analysis, factor analysis, inverted factor analysis, tree approaches, dynamic clusters analysis, and principal component analysis, may facilitate the classification of movement disorders.

Dopamine system

Although the pathophysiology of TD is not well understood, it is hypothesized that central dopamine blockade plays a role in the pathogenesis of this condition. It is also hypothesized that acute movement disorders result, in part, from the blockade of dopamine receptors by dopamine antagonists.

Several mechanisms have been proposed by which TD may develop, including the following:

Striatal dopamine receptor supersensitivity may be responsible
Chronic dopamine blockade may result in upregulation of dopamine receptor responsiveness
Compensatory supersensitivity of dopamine receptors may develop after long-term blockade; long-term blockade of dopamine D₂ receptors in the basal ganglia by dopamine D₂ antagonists (eg, neuroleptics) may produce TD
When dopamine D₂ -receptor blockade is reduced (even slightly), an exaggerated response of the postsynaptic dopamine D₂ -receptor (even to low concentrations of dopamine) may result
Striatal disinhibition of the thalamocortical pathway from imbalance of D₁ and D₂ receptors may be involved
Neurodegeneration secondary to lipid peroxidation or excitotoxic mechanisms may be responsible

Although the dopamine D₂ receptor has traditionally been implicated in the pathogenesis of TD, there is mounting evidence to indicate that in some individuals, the dopamine D₃, D₄, and D₅ receptors are involved.

Most likely, genetic traits produce a vulnerability to TD when a susceptible individual is exposed to particular agents. For example, the MscI polymorphism of the dopamine D₃ receptor gene has been associated with the development of TD. Support for the hypothesis that TD may result from blockade of postsynaptic dopamine receptors in the basal ganglia and other parts of the brain exists in the form of the beneficial effects of increasing doses of neuroleptics for some patients with TD. Thus, dopamine antagonists may mask TD.

Increased dopamine transport (DAT) uptake after treatment with quetiapine has been reported with the amelioration of TD in a 67-year-old woman.^[6]

Nicotine may play a role in the pathophysiology of TS. Cigarette smokers appear to have increased metabolism of dopamine D₂ antagonists. Nicotinic agonists appear to relieve dyskinesias in some people with Tourette syndrome, a condition characterized by the presence of motor and phonic tics. The relation between TD and the use of cigarettes and other nicotinic agonists remains to be clarified. The results of an animal study suggest the possibility that nicotine may be useful for improving the TD associated with antipsychotic use.^[7]

Tan et al reported an inverse correlation of plasma levels of brain-derived neurotrophic factor and dyskinetic movements in people with schizophrenia who had TD.^[8]Thus, brain-derived neurotrophic factor appears to have a protective effect in the nervous system against TD with people with schizophrenia.

Modestin et al observed that a fluctuating course of the illness characterizes people with TD. They also reported that length of illness is highly correlated with the development of TD.^[9]

Bishoi et al noted that curcumin, an antioxidant, may prevent the development of dyskinesias induced in animals by drugs that block dopamine receptors.^[10]

Adenosinergic receptor system

Bishnoi et al provided evidence of the involvement of the adenosinergic receptor system in the development of TD in rodents.^[11]Haloperidol induced vacuous chewing movements, orofacial movements, and facial stereotypies in rats. These changes were reversed after treatment with adenosine or caffeine. These findings provide evidence that adenosine, a major inhibitory neurotransmitter in the CNS, plays a role in TD. Additionally, these results suggest potential therapeutic agents for clinical trials.

Next: Pathophysiology

Etiology

Drugs

Tardive dyskinesia (TD) can be caused by long-term treatment with dopamine antagonists. It can also be caused by both high-potency and low-potency traditional neuroleptics, including long-acting depot formulations (eg, decanoate and enanthate). Greater D₂ dopamine receptor blockade at the trough levels of the neuroleptics may be associated with a greater degree of TD.^[12]Amisulpride has been associated with TD,^{[13, 14]}but in general, newer atypical antipsychotic agents, including olanzapine and risperidone (and its metabolite paliperidone^[15]), appear to carry less risk of TD.^[16]

The antiemetic metoclopramide, a potent D₂ dopamine receptor antagonist, may cause TD, particularly in elderly patients. TDs have also been reported with the use of antihistamines, fluoxetine, amoxapine (a tricyclic antidepressant), and other agents (see Table 2 below).

Table 2. Medications Causing Tardive Dyskinesia (Open Table in a new window)

Category	Agents
Antipsychotic agents (ie, neuroleptics)	Butyrophenones: droperidol, haloperidol, dibenzodiazepines, loxapine Diphenylbutylpiperidines: pimozide Indolones: molindone Phenothiazines: chlorpromazine, fluphenazine, mesoridazine, perphenazine, thioridazine, trifluoperazine Thioxanthenes: thiothixene
Newer atypical antipsychotic agents (sporadically linked to TDs)	Olanzapine Quetiapine Risperidone Paliperidone Amisulpride
TD = tardive dyskinesia.

A number of nonneuroleptic compounds are associated with dyskinesias that usually resolve with dose reduction or discontinuance (see Table 3 below).

Table 3. Nonneuroleptic Medications Linked to Dyskinesias (Open Table in a new window)

Category	Agents
Anticholinergics	Benzhexol Biperiden Ethopropazine Orphenadrine Procyclidine
Antidepressants	MAOIs: phenelzine SSRIs: fluoxetine, sertraline Trazodone TCAs: amitriptyline, amitriptyline-perphenazine, amoxapine, doxepin, imipramine
Antiemetics	Metoclopramide Prochlorperazine
Antiepileptic drugs	Carbamazepine Ethosuximide Phenobarbital Phenytoin
Antihistamines	Various
Antihistaminic decongestants	Combinations of antihistamines and sympathomimetics
Antimalarials	Chloroquine
Antiparkinson agents	Bromocriptine Carbidopa-levodopa Levodopa
Anxiolytics	Alprazolam
Biogenic amines	Dopamine
Mood stabilizers	Lithium
Oral contraceptives	Estrogens
Stimulants	Amphetamine Methylphenidate Caffeine
MAOI = monoamine oxidase inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.

Tardive dyskinesia and psychogenic movement disorders

Psychogenic movement disorders are often florid and bizarre (see Catatonia).^{[17, 18]}The motions of these disorders typically defy the boundaries that circumscribe neurologic disorders. They usually do not resemble classic TD. Psychogenic movement disorders generally represent conversion disorders, neurologic symptoms expressed by a patient who believes that the symptoms are present.^[19]The patient is apparently physically healthy. Conversion disorders are not well understood.^[19]

Often a stress, positive or negative, has occurred in the individual’s life. People with psychogenic movement disorders often have experienced a major life event (eg, failure to attain an expected promotion, death of a loved one).^[19]

Malingering disorders may occur when an individual seeks disability and other compensation. Specifically, malingering occurs when the patient seeks a tangible reward for being sick. A person who malingers may seek to be excused from work or school because of the feigned illness. A malingerer may seek compensation in the form of disability payments for the alleged illness.

Factitious disorder occurs when an individual feigns illness in order to assume the sick role. People with factitious disorders appear to seek the attention accorded to a patient. Like conversion disorders, factitious disorders are not well understood.

An extremely severe form of factitious disorder is manifested as Munchausen syndrome. Munchausen syndrome is characterized by the apparently deliberate feigning of symptoms and signs. People with Munchausen syndrome may fabricate elaborate and bizarre stories. They may agree to multiple operations in an attempt to diagnose and treat the fabricated illnesses.

Munchausen syndrome by proxy occurs when a parent seeks treatment for a child, typically an infant who cannot speak. The parent fabricates a history of false symptoms for the healthy child, which leads to unnecessary diagnostic and therapeutic interventions. Munchausen syndrome by proxy is a form of child abuse. Suspected cases of Munchausen syndrome by proxy merit report to child protective services.

Although people with psychogenic movement disorders may seek and demand medication and surgery, they are likely to experience severe adverse effects. Therefore, pharmacologic and surgical interventions should be avoided in patients with psychogenic movement disorders. These disorders must be differentiated from voluntary expressions of emotion characteristic of cultural and ethnic groups, such as zaghrouta.^{[20, 21]}Psychiatric consultation is indicated.

Genetic factors

A genetic basis for TD has not been identified. In particular, a functional polymorphism of the gene coding for human glutathione S-transferase P1 (GSTP1) does not appear to be associated with TD.^[22]Additionally, CYP3A4 and CYP2D6 gene polymorphisms are apparently unassociated with TD.^[23]TD has been associated with polymorphisms of the dopamine D₃ receptor Ser9Gly^[24]and of the serotonin 2A^[1]and 2C receptor genes.^{[24, 1]}

Reports of associations between TD and polymorphisms of nicotinamide adenine dinucleotide phosphate (NADPH) quinine oxidoreductase 1 (NQO1) and superoxide dismutase 2 (SOD2, MnSOD) genes have not consistently been confirmed by subsequent studies.^[25]

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms may be associated with the development of TD and the severity of TD in Whites.^[26]Thus, the enhancement of BDNF may be protective against the development of TD, particularly in Whites.^[26]

Next: Pathophysiology

Epidemiology

Frequency

In 1997, it was estimated that tardive dyskinesia (TD) occurs in approximately 15–30% of persons who receive long-term treatment with neuroleptics.^[27]TD is more likely to occur in individuals who have manifested acute adverse effects of exposure to dopamine antagonists. The prevalence of TD is higher in cigarette smokers.^[28]

The various subtypes of TD vary markedly in frequency. For example, orofacial, buccolingual, and masticatory dyskinesias are common, but only 1–2% of people treated with dopamine antagonists develop tardive dystonia.

Orofacial TDs differ from peripheral TDs with regard to the occurrence of comorbid acute movement disorders. Acute tremor, acute akathisia, and acute Parkinsonism are more common in people with peripheral TD. Distinguishing acute and TDs in an individual patient can represent a serious diagnostic challenge.

Age-, sex-, and race-related demographics

TD occurs in all ages. Connor et al found that 5.9% of 95 young people aged 7–21 years who received dopamine antagonist treatment for 3 months had TD.^[29]Advanced age is a major risk factor for TD.^[30]The prevalence of TD is 29% in elderly patients receiving dopamine antagonist treatment for 3 months and 26-67% in patients undergoing long-term treatment.

Elderly female patients appear to be particularly susceptible to the development of TD.^[30]Young men are prone to develop tardive blepharospasm and tardive dystonia.

TD occurs in persons of every race.^[30]Studies in different populations have identified overall prevalences ranging from 1% to 65%. Africans and African Americans appear to be especially vulnerable to TD after exposure to low doses of neuroleptics for short durations.

However, it is difficult to draw any firm conclusions from these findings, because the investigators conducted their studies in different settings. A number of other variables, such as therapeutic approaches, methodologic inconsistencies, diet, weather, and varied assessments, may also contribute to the differences reported in various racial groups.

Next: Pathophysiology

Patient Education

Fully inform the patient with tardive dyskinesia (TD) (or the legal surrogate if the patient is incompetent) of the possible courses of action. Discuss with the patient the advantages and disadvantages of dopamine antagonist treatment. A written treatment plan that documents agreement with the treatment course between the clinician and patient is helpful. Regularly review and revise the treatment plan as needed.

If a patient exhibits a movement disorder when taking a drug, then gradual discontinuance of the causative drug generally is a wise course if the patient can tolerate a reduction in dose.^[31]Advise the patient to avoid receiving dopamine-receptor blocking drugs. Advise the patient to obtain a medical alert bracelet to warn against the administration of dopamine-receptor blocking drugs.

For patient education resources, see the Sleep Disorders Center, as well as Restless Legs Syndrome.

Clinical Presentation

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Media Gallery

Diagnostic criteria for neuroleptic-induced tardive dyskinesia.
Tardive dyskinesia. Venn diagram of the classification of movement disorders.

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Table 1. Classic Characterization of Pyramidal and Extrapyramidal Systems

Characteristic	Pyramidal	Extrapyramidal
Anatomy	Precisely demarcated pathways from cortex to muscle	Hypothesized pathways among basal ganglia and other structures of the central nervous system
Physiologic movements	Voluntary	Involuntary
Pathologic movements	Paralysis, paresis, hyperreflexia, and spasticity	Akathisia, athetosis, ballismus, chorea, dystonia, myoclonus, stereotypy, tic, and tremor

Table 2. Medications Causing Tardive Dyskinesia

Category	Agents
Antipsychotic agents (ie, neuroleptics)	Butyrophenones: droperidol, haloperidol, dibenzodiazepines, loxapine Diphenylbutylpiperidines: pimozide Indolones: molindone Phenothiazines: chlorpromazine, fluphenazine, mesoridazine, perphenazine, thioridazine, trifluoperazine Thioxanthenes: thiothixene
Newer atypical antipsychotic agents (sporadically linked to TDs)	Olanzapine Quetiapine Risperidone Paliperidone Amisulpride
TD = tardive dyskinesia.

Table 3. Nonneuroleptic Medications Linked to Dyskinesias

Category	Agents
Anticholinergics	Benzhexol Biperiden Ethopropazine Orphenadrine Procyclidine
Antidepressants	MAOIs: phenelzine SSRIs: fluoxetine, sertraline Trazodone TCAs: amitriptyline, amitriptyline-perphenazine, amoxapine, doxepin, imipramine
Antiemetics	Metoclopramide Prochlorperazine
Antiepileptic drugs	Carbamazepine Ethosuximide Phenobarbital Phenytoin
Antihistamines	Various
Antihistaminic decongestants	Combinations of antihistamines and sympathomimetics
Antimalarials	Chloroquine
Antiparkinson agents	Bromocriptine Carbidopa-levodopa Levodopa
Anxiolytics	Alprazolam
Biogenic amines	Dopamine
Mood stabilizers	Lithium
Oral contraceptives	Estrogens
Stimulants	Amphetamine Methylphenidate Caffeine
MAOI = monoamine oxidase inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.

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Author

James Robert Brasic, MD, MPH, MS, MA Assistant Professor, Russell H Morgan Department of Radiology and Radiological Science and Neurology, Division of Nuclear Medicine and Molecular Imaging, Assistant Professor, Department of Neurology, Johns Hopkins University School of Medicine

James Robert Brasic, MD, MPH, MS, MA is a member of the following medical societies: American Academy of Child and Adolescent Psychiatry, American Academy of Neurology, International Parkinson and Movement Disorder Society, Society for Neuroscience, Society of Nuclear Medicine and Molecular Imaging

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Johns Hopkins University School of Medicine; New York City Health and Hospitals/Bellevue, New York University Langone Health Serve(d) as a speaker or a member of a speakers bureau for: Society of Nuclear Medicine and Molecular Imaging, Maryland Regional Council of Child and Adolescent Psychiatry Received research grant from: National Institutes of Health, Johns Hopkins University School of Medicine, Intellectual & Developmental Disabilities Research Center (U54 HD079123) at the Kennedy Krieger Institute Received income in an amount equal to or greater than $250 from: Gerson Lehrman Group; Guidepost Received royalty from Medscape for other.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Selim R Benbadis, MD Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida Morsani College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Association

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Bioserenity, Catalyst, Ceribell, Eisai, Jazz, LivaNova, Neurelis, Neuropace, SK Life Science Science, Sunovion, Takeda, UCB Serve(d) as a speaker or a member of a speakers bureau for: Catalyst, Jazz, LivaNova, Neurelis, SK Life Science, Stratus, UCB Received research grant from: Cerevel Therapeutics; Ovid Therapeutics; Neuropace; Jazz; SK Life Science, Xenon Pharmaceuticals, UCB, Marinus, Longboard.

Acknowledgements

Brian Bronson, MD Staff Physician, Department of Psychiatry, New York University Medical Center

Disclosure: Nothing to disclose.

Tristen T Chun Division of Nuclear Medicine, Russell H Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine

Disclosure: Nothing to disclose.

Nestor Galvez-Jimenez, MD, MSc, MHA Chairman, Department of Neurology, Program Director, Movement Disorders, Department of Neurology, Division of Medicine, Cleveland Clinic Florida

Nestor Galvez-Jimenez, MD, MSc, MHA is a member of the following medical societies: American Academy of Neurology, American College of Physicians, and Movement Disorders Society

Disclosure: Nothing to disclose.

Daniel H Jacobs MD, FAAN, Associate Professor of Neurology, University of Florida College of Medicine; Director for Stroke Services, Orlando Regional Medical Center

Daniel H Jacobs is a member of the following medical societies: American Academy of Neurology, American Society of Neurorehabilitation, and Society for Neuroscience

Disclosure: Teva Pharmaceutical Grant/research funds Consulting; Biogen Idex Grant/research funds Independent contractor; Serono EMD Royalty Speaking and teaching; Pfizer Royalty Speaking and teaching; Berlex Royalty Speaking and teaching

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Tardive Dyskinesia

Background

Pathophysiology

Extrapyramidal dysfunction

Bradykinesia versus hyperkinesia

Dopamine system

Adenosinergic receptor system

Etiology

Drugs

Tardive dyskinesia and psychogenic movement disorders

Genetic factors

Epidemiology

Frequency

Age-, sex-, and race-related demographics

Patient Education

References

Tables

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