Tardive dyskinesia
Encyclopedia
Tardive dyskinesia (ˈtɑrdɨv ˌdɪskɨˈniːʒə) is a difficult-to-treat form of dyskinesia
Dyskinesia
Dyskinesia is a movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or choreia. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but...

(disorder resulting in involuntary, repetitive body movements) that can be tardive (having a slow or belated onset). It frequently appears after long-term or high-dose use of antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...

 drugs,Compazine
Prochlorperazine
Prochlorperazine is a dopamine receptor antagonist that belongs to the phenothiazine class of antipsychotic agents that are used for the antiemetic treatment of nausea and vertigo. It is also a highly-potent typical antipsychotic, 10-20x more potent than chlorpromazine...

, Risperdal
Risperidone
Risperidone is a second generation or atypical antipsychotic, sold under the trade name . It is used to treat schizophrenia , schizoaffective disorder, the mixed and manic states associated with bipolar disorder, and irritability in people with autism...

or in children and infants as a side effect from usage of drugs for gastrointestinal disorders prevention.Propulsid
Cisapride
Cisapride is a gastroprokinetic agent, a drug which increases motility in the upper gastrointestinal tract. It acts directly as a serotonin 5-HT4 receptor agonist and indirectly as a parasympathomimetic. Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous...

, Reglan
Metoclopramide
Metoclopramide is an antiemetic and gastroprokinetic agent. It is commonly used to treat nausea and vomiting, to facilitate gastric emptying in people with gastroparesis, and as a treatment for the gastric stasis often associated with migraine headaches.-Medical uses:Metoclopramide is commonly...


Features

Tardive dyskinesia is characterized by repetitive, involuntary, purposeless movements, such as grimacing, tongue protrusion, lip smacking, puckering and pursing of the lips, and rapid eye blinking. Rapid movements of the extremities may also occur. Impaired movements of the fingers may also appear. For comparison, patients with Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...

 have difficulty moving, while patients with tardive dyskinesia have difficulty not moving.

Other closely related neurological disorders have been recognized as variants of tardive dyskinesia. Tardive dystonia
Dystonia
Dystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...

 is similar to standard dystonia
Dystonia
Dystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...

 but permanent. Tardive akathisia
Akathisia
Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...

 involves painful feelings of inner tension and anxiety and a compulsive drive to move the body. In the extreme, the individual undergoes internal torture and can no longer sit still. Tardive tourettism
Tourettism
Tourettism refers to the presence of Tourette-like symptoms in the absence of Tourette syndrome, as the result of other diseases or conditions, known as "secondary causes"....

 is a tic
Tic
A tic is a sudden, repetitive, nonrhythmic, stereotyped motor movement or vocalization involving discrete muscle groups. Tics can be invisible to the observer, such as abdominal tensing or toe crunching. Common motor and phonic tics are, respectively, eye blinking and throat clearing...

 disorder that can closely mimic Tourette Syndrome
Tourette syndrome
Tourette syndrome is an inherited neuropsychiatric disorder with onset in childhood, characterized by multiple physical tics and at least one vocal tic; these tics characteristically wax and wane...

, sometimes to the point where the two can only be distinguished by the details of their onsets. Tardive myoclonus
Myoclonus
Myoclonus is brief, involuntary twitching of a muscle or a group of muscles. It describes a medical sign and, generally, is not a diagnosis of a disease. Brief twitches are perfectly normal. The myoclonic twitches are usually caused by sudden muscle contractions; they also can result from brief...

, a rare disorder, presents as brief jerks of muscles in the face, neck, trunk, and extremities.

Tardive dyskinesia is often misdiagnosed as a mental illness
Mental illness
A mental disorder or mental illness is a psychological or behavioral pattern generally associated with subjective distress or disability that occurs in an individual, and which is not a part of normal development or culture. Such a disorder may consist of a combination of affective, behavioural,...

 rather than a neurological disorder
Neurological disorder
A neurological disorder is a disorder of the body's nervous system. Structural, biochemical or electrical abnormalities in the brain, spinal cord, or in the nerves leading to or from them, can result in symptoms such as paralysis, muscle weakness, poor coordination, loss of sensation, seizures,...

, and as a result patients are prescribed neuroleptic drugs
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...

 which enhance the probability that the patient will develop a severe and disabling case. In such cases, it is critical to properly identify the signs of the disorder and stop neuroleptic treatment as early as possible. The neuroleptic drugs have a tendency to suppress or mask the very symptoms they are causing, thus making disorder identification more difficult. The symptoms may then abruptly break out after drug usage is reduced or stopped.

Cause

Despite the fact that tardive dyskinesia was described 50 years ago, its mechanism is poorly understood. The most compelling line of evidence suggests that tardive dyskinesia may result primarily from neuroleptic-induced dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

 supersensitivity in the nigrostriatal pathway
Nigrostriatal pathway
The nigrostriatal pathway is a neural pathway that connects the substantia nigra with the striatum. It is one of the four major dopamine pathways in the brain, and is particularly involved in the production of movement, as part of a system called the basal ganglia motor loop.Loss of dopamine...

, with the D2 dopamine receptor being most affected. Neuroleptics act primarily on this dopamine system, and older neuroleptics, which have greater affinity for the D2 binding site, are associated with high risk for tardive dyskinesia. The D2 hypersensitivity hypothesis is also supported by evidence of a dose-response relationship, withdrawal effects, studies on D2 agonists and antagonists, animal studies, and genetic polymorphism research.

Given similar doses of the same neuroleptic, differences among individuals still exist in the likelihood of developing tardive dyskinesia. Such individual differences may be due to genetic polymorphisms, which code for D2 receptor binding site affinity, or prior exposure to environmental toxins. Decreased functional reserve or cognitive dysfunction, associated with aging, mental retardation, alcohol and drug abuse, or traumatic head injuries, has also been shown to increase risk of developing the disorder among those treated with neuroleptics. Antipsychotic drugs can sometimes camouflage the signs of tardive dyskinesia from occurring in the early stages; this can be from the individual having an increased dose of an antipsychotic drug, although when tardive dyskinesia worsens the signs become visible (Videbeck 2006).[citation needed]

Other dopamine antagonists and antiemetics can cause tardive dyskinesia, such as metoclopramide
Metoclopramide
Metoclopramide is an antiemetic and gastroprokinetic agent. It is commonly used to treat nausea and vomiting, to facilitate gastric emptying in people with gastroparesis, and as a treatment for the gastric stasis often associated with migraine headaches.-Medical uses:Metoclopramide is commonly...

 and promethazine
Promethazine
Promethazine is a first-generation antihistamine of the phenothiazine family. The drug has anti-motion sickness, antiemetic, and anticholinergic effects, as well as a strong sedative effect and in some countries is prescribed for insomnia when benzodiazepines are contraindicated...

, used to treat gastrointestinal disorders. While newer atypical antipsychotic
Atypical antipsychotic
The atypical antipsychotics are a group of antipsychotic tranquilizing drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...

s such as olanzapine
Olanzapine
Olanzapine is an atypical antipsychotic, approved by the FDA for the treatment of schizophrenia and bipolar disorder...

 and risperidone
Risperidone
Risperidone is a second generation or atypical antipsychotic, sold under the trade name . It is used to treat schizophrenia , schizoaffective disorder, the mixed and manic states associated with bipolar disorder, and irritability in people with autism...

 appear to have fewer dystonic effects, only clozapine
Clozapine
Clozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew...

 has been shown to have a lower risk of tardive dyskinesia than older antipsychotics. There has been a reported case of the anti-psychotic medication Aripiprazole, a partial agonist at D2 receptors, leading to tardive dyskinesia.

The available research seems to suggest that the concurrent prophylactic use of a neuroleptic and an antiparkinsonian drug is useless to avoid early extrapyramidal
Extrapyramidal system
In human anatomy, the extrapyramidal system is a neural network located in the brain that is part of the motor system involved in the coordination of movement. The system is called "extrapyramidal" to distinguish it from the tracts of the motor cortex that reach their targets by traveling through...

 side-effects and may render the patient more sensitive to tardive dyskinesia. Since 1973 the use of these drugs has been found to be associated with the development of tardive dyskinesia.
Since some of the symptoms of tardive dyskinesia can be interpreted as schizophrenia by doctors, they may prescribe additional neuroleptic drugs to treat it, leading to increased risk of more prevalent tardive dyskinesia.

Treatment

Primary prevention of tardive dyskinesia is achieved by using the lowest effective dose of a neuroleptic for the shortest time (Although, with diseases of chronic psychosis such as schizophrenia, this strategy must be balanced with the fact that increased dosages of neuroleptics are more beneficial in preventing recurrence of psychosis). If tardive dyskinesia is diagnosed, the causative drug should be discontinued. Tardive dyskinesia may persist after withdrawal of the drug for months, years or even permanently.

The dopamine-depleting drug tetrabenazine
Tetrabenazine
Tetrabenazine is a drug for the symptomatic treatment of hyperkinetic movement disorder and is marketed under the trade names Nitoman in Canada and Xenazine in New Zealand and some parts of Europe, and is also available in the USA as an orphan drug. On August 15, 2008 the U.S...

 has been used to treat tardive dyskinesia and other movement disorders.

Zofran has shown some benefit in experimental studies on tardive dyskinesia and a variety of anti-Parkinsonian medications are used such as Aricept, Baclofen
Baclofen
Baclofen is a derivative of gamma-aminobutyric acid . It is primarily used to treat spasticity and is under investigation for the treatment of alcoholism....

, Requip and Mirapex. Clonidine
Clonidine
Clonidine is a sympatholytic medication used to treat medical conditions, such as high blood pressure, some pain conditions, ADHD and anxiety/panic disorder...

 is used for dystonic spasms and can be of help. Botox injections are used for minor focal dystonia, but not in more advanced tardive dyskinesia. A review paper found Benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...

sBenzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...

 drugs e.g. Ativan
Lorazepam
Lorazepam is a high-potency short-to-intermediate-acting 3-hydroxy benzodiazepine drug that has all five intrinsic benzodiazepine effects: anxiolytic, amnesic, sedative/hypnotic, anticonvulsant, antiemetic and muscle relaxant...

, Valium
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...

, or Klonopin
Clonazepam
Clonazepamis a benzodiazepine drug having anxiolytic, anticonvulsant, muscle relaxant, and hypnotic properties. It is marketed by Roche under the trade name Klonopin in the United States and Rivotril in Australia, Brazil, Canada and Europe...

to be effective in alleviating the symptoms of tardive dyskinesia. However, like most anticonvulsants, benzodiazepines may cause tremors as well as benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...

 upon rapid discontinuation.

In males, the branched-chain amino acid formula Tarvil, containing the amino acids valine
Valine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...

, isoleucine
Isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....

, and leucine
Leucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...

 in a 3:3:4 ratio was reported as beneficial for motor symptoms in a small, non-blinded study.

Epidemiology

Tardive dyskinesia most commonly occurs in patients with psychiatric conditions who are treated with antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...

 medications for many years. One study reported that within the first four years of using antipsychotic medications, 18.5 percent of young adults develop symptoms. Furthermore, 31 percent of those over 55 years of age develop tardive dyskinesia symptoms in the same time frame. Other estimates suggest that it occurs in 15-30% of patients receiving treatment with antipsychotic neuroleptic medications for 3 months or longer.
“A study being conducted at the Yale University School of Medicine has estimated that 32% of patients develop persistent tics after 5 years on major tranquilizers, 57% by 15 years, and 68% by 25 years.”
Other estimates suggest that with each year of neuroleptic use, 5% of the patients will show signs of tardive dyskinesia, i.e., 5% after one year, 10% after two years, 15% after three years with no clear upper limit.
Eventually, according to these estimates, if on the drugs long enough, the majority of patients will develop the disorder. The incidence of tardive dyskinesia varies with the type of neuroleptic (e.g., haloperidol
Haloperidol
Haloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....

 (Haldol) more often than perphenazine
Perphenazine
Perphenazine is a typical antipsychotic drug. Chemically, it is classified as a piperazinyl phenothiazine. It has been in clinical use for decades....

 (Trilafon)), daily dose and duration of treatment (the higher the daily dose and the longer the duration of treatment, the higher the risk).

The elderly and female patients are more prone to develop tardive dyskinesia. Cigarette smokers also have a higher prevalence of tardive dyskinesia. Children and adolescents are much more sensitive to the early and late extrapyramidal side-effects of neuroleptics than adults. Because of this, treatment of youngsters with neuroleptics may be contraindicated, and many authorities believe that they should be initiated only as a last resort, using the lowest dose regime possible and the shortest duration of treatment in accordance with good patient management.

Tardive dyskinesia can become disabling socially and cause people to self isolate, due to the societal stigma as well. Patients and/or their families (guardians and/or caregivers/nurses) should receive full information about the neuroleptic before starting treatment (informed consent
Informed consent
Informed consent is a phrase often used in law to indicate that the consent a person gives meets certain minimum standards. As a literal matter, in the absence of fraud, it is redundant. An informed consent can be said to have been given based upon a clear appreciation and understanding of the...

). The benefits need to be weighed by the individual patient/guardian and their physician. However, the antipsychotic clozapine
Clozapine
Clozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew...

 is not known to cause tardive dyskinesia and can be an option and is not used on a more widespread basis because of blood dyscrasias as well as other side effects of concern..

The still hypothetical conditions tardive psychosis
Tardive Psychosis
Tardive psychosis is a form of psychosis distinct from schizophrenia and induced by the use of current antipsychotics by the depletion of dopamine and related to the known side effect caused by their long-term use, tardive dyskinesia....

, tardive dysphrenia
Tardive dysphrenia
The medical expression tardive dysphrenia, was proposed by the American neurologist Stanley Fahn, the head of the Division of Movements Disorders of the Neurological Institute of New York, in collaboration with the psychiatrist David V Forrest in the 1970s....

 and tardive dysmentia
Tardive dysmentia
Tardive Dysmentia is a rarely used term introduced in a 1983 paper to describe "changes in affect, activation level, and interpersonal interaction", and hypothesized to be caused by long-term exposure to neuroleptic drugs in the same way as the much better known syndrome of tardive dyskinesia...

 remain little understood and as yet unconfirmed.
New classes of antipsychotics in study such as glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...

 and other NMDA receptor modulators
NMDA Receptor Modulators
NMDA receptor modulators are a new form of antipsychotic that are in Phase II FDA study. The first compound studied was glycine which was hypothesized by Daniel Javitt after observation that people with phencyclidine-induced psychosis were lacking in glutamate transmission...

 in not affecting the dopaminergic system in Phase II FDA studies have been shown not to cause tardive dyskinesia and may, once realized as FDA approved antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...

s, be a new treatment modality that will not create this condition.

External links

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