Tardive Dyskinesia


Article Author:
Sarayu Vasan


Article Editor:
Ranjit Padhy


Editors In Chief:
Rhonda Coffman
Lindsay Iverson
Heather Templin


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
2/4/2019 4:00:48 PM

Introduction

Tardive dyskinesia is a syndrome which includes a group of iatrogenic movement disorders caused due to a blockade of dopamine receptors. The movement disorders include akathisia, dystonia, buccolingual stereotypy, myoclonus, chorea, tics and other abnormal involuntary movements which are commonly caused by the long-term use of typical antipsychotics. However, several other medications are also associated with tardive dyskinesia. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM V) defines tardive dyskinesia as a medication-induced movement disorder and persists despite discontinuation or change of the medications. As per DSM-V, to confirm a diagnosis of tardive dyskinesia, symptoms must persist for a month after discontinuation of the medication. [1][2][3]

Etiology

Tardive dyskinesia is caused due to long-term exposure to first and second generation neuroleptics, certain antidepressants, lithium and some antiemetic medications. Typically, the first-generation antipsychotics with increased dopamine D2 receptor affinity are affiliated with a higher risk of causing permanent abnormal involuntary movements. Atypical antipsychotics have fewer extrapyramidal side effects compared to typical antipsychotics due to their lower affinity for dopamine D2 receptors in the dorsal striatum and concomitant blockade of serotonin 5-HT2A/2C receptors.[4][5]

Epidemiology

The average prevalence of tardive dyskinesia is estimated to be at least 20% of all patients who were treated with first-generation neuroleptics. However, other medications that are responsible for tardive dyskinesia have been less studied, and published data indicate a prevalence ranging from 1% to 10%. Women are at higher risk of developing tardive dyskinesia than men especially in middle-aged to senior patients. Post-menopausal women have incidence rates as high as 30% after almost a year of exposure to antipsychotic medications suggesting estrogen may have an antioxidant effect protecting against tardive dyskinesia. Elderly patients are more likely to develop tardive dyskinesia due to age-related changes in the brain and body. Several studies indicate African Americans are more likely to develop tardive dyskinesia after long-term exposure to dopamine-blocking agents compared to whites.[6]

Pathophysiology

First-generation antipsychotics bind tightly to dopamine D2 receptors in comparison to second-generation antipsychotics, and for this reason, the typical antipsychotics have a higher tendency to cause tardive dyskinesia. There is some evidence that suggests the presence of extrapyramidal symptoms during neuroleptic treatment predicts the development of tardive dyskinesia. Also, the long-term use of anticholinergic medications may increase the risk of tardive dyskinesia. In addition to dopamine, the other neurotransmitter receptors that may be involved in causing tardive dyskinesia include 5-hydroxytryptophan receptors that are found in the striatum. These receptors interact with dopaminergic neurons and considered to be involved in regulating motor activity. Upregulation of dopamine receptors due to chronic dopamine blockade can result in an exaggerated response to the post-synaptic receptors to dopamine causing tardive dyskinesia. Another hypothesis is the resulting oxidative stress due to antidepressants blocking dopamine receptors which cause an increase in dopamine metabolism and this subsequently results in free radical production. The consequential oxidative stress on the basal ganglia, striatum and substantia nigra results in the manifestation of tardive dyskinesia. Evidence also suggests that the antipsychotic medications and their metabolites can also be directly toxic to neuron through oxidative stress. It is known that removing the agent that causes tardive dyskinesia can exacerbate the symptoms, and this is defined as withdrawal dyskinesia. It is theorized that this is due to dopamine D2 receptor upregulation and postsynaptic receptor super sensitivities. However, this does not explain why tardive dyskinesia remains for many years after the offending drug has been discontinued.[3]

History and Physical

Physicians should examine all patients for any movement disorders before initiating treatment with dopamine D2 receptor antagonists. Tardive dyskinesia presents clinically as stereotypical involuntary movements of the tongue, neck and facial muscles, truncal musculature, and limbs. Buccolingual movements including masticatory muscles are characterized by lip smacking, tongue protrusion, perioral movements, chewing movements or puffing of cheeks. Sometimes these movements may be hard to distinguish from stereotype posturing seen in chronic psychotic patients. However, tardive dyskinesia is seen in patients who have had chronic exposure to dopamine D2 receptor blockade and rarely seen in patients who have been exposed to antipsychotics less than three to six months. Diagnosis of acute or chronic dyskinesias may be challenging without a careful history. A thorough history of movement disorders and medication history will aid in making an accurate diagnosis of tardive dyskinesia. A diagnosis of antipsychotic-induced tardive dyskinesia is made after the symptoms have persisted for at least one month and required exposure to neuroleptics for at least three months.

Evaluation

There are numerous rating scales to determine the presence and severity of tardive dyskinesia. The most widely used instrument is the Abnormal Involuntary Movement Scale (AIMS). It is recommended to administer the AIMS at baseline before initiating antipsychotic medications and then at least three months after that while on treatment. Upon evaluation of the patient, it can be noted that tardive dyskinesia is present at rest and somewhat diminished when there is any form of movement. For example, tongue dyskinesias reduce when the patient is asked to protrude their tongue. If tardive dyskinesia is present in conjunction with dementia, one should consider Huntington disease, Wilson disease, or a central nervous system tumor. Tardive dyskinesia should be distinguished from withdrawal dyskinesias as this most likely remits soon after the termination of the antipsychotic.

Workup for tardive dyskinesia may include selected laboratory studies and imaging. Typically, brain CT and MRI are normal in patients with tardive dyskinesia. However, they may assist in ruing out other conditions such as Huntington disease where atrophy of the caudate nucleus is seen and Fahr syndrome where calcification is noted in the basal ganglia.[1][5][7]

Treatment / Management

Dopamine receptor antagonists should be avoided whenever possible by selecting other medications that have a lower potential to cause tardive dyskinesia. Furthermore, chronic use of first-generation antipsychotics should be avoided whenever possible. There have been very few treatment options including clonazepam and ginkgo biloba as recommended by the American Academy of Neurology. Valbenazine, a vesicular monoamine transport type 2 (VMAT2) inhibitor was approved by the FDA on April 11, 2017, for the treatment of tardive dyskinesia. The KINECT 3 trial results revealed valbenazine improved tardive dyskinesia when compared to the placebo drug. However primary prevention of tardive dyskinesia includes using the lowest effective dose of antipsychotic agent for the shortest period possible. However, if tardive dyskinesia develops, it is recommended to decrease the dose or even discontinue the offending agent and switch to clozapine. Clozapine is recommended in patients with tardive dyskinesia who continue to require antipsychotics as the incidence of tardive dyskinesia with clozapine is significantly less than other antipsychotics.[8][9][10]

Differential Diagnosis

  • Chorea
  • Complex seizure
  • Essential tremor
  • Tourette syndrome
  • Tic disorder
  • Wilson disease
  • Sydenham chorea

Consultations

  • Ophthalmologist to assess the eye for Wilson disease
  • Neurologist
  • Movement disorder specialist
  • Psychiatrist consult

Enhancing Healthcare Team Outcomes

Movement disorders like tardive dyskinesias is frequently aggravated by the use of drugs that block dopamine. In susceptible patients, even a single dose of an anti-dopaminergic drug can lead to the instant development of disabling movement disorders. Thus, besides the physician, the role of the pharmacist is key. Patients vulnerable to tardive dyskinesia include schizophrenics and those with developmental disabilities who may develop the movement disorder when administered a dopamine blocking agent. The pharmacist must keep a note of these patients and on what medications they are treated with. Physicians should be advised not to start such medications if there are other options. Plus the pharmacist must educate the patient about wearing an alert bracelet which warns against the administration of such drugs. [11][12](Level V)

Outcomes

Data on the management of TD are inconsistent and difficult to understand. Some studies show an improvement when the antipsychotic drug is decreased in dose or discontinued, and other studies show no change. Long-term studies suggest that in at least 10-30% of patients, TD persist. Recent studies show that the outcomes of TD are improved in younger patients treated with low doses for shorter periods. Switching to low potency antipsychotics drugs has been shown to lower the risk of TDs. Recently the FDA approved the drug Valbenazine to treat TDs. Early data from the clinical trial reveals that the drug is effective in abolishing TDs and is safe. However, the study was conducted by many physicians who also received some type of compensation from the pharmaceutical companies- so one has to take this data with a grain of salt until more long-term data are available. [2][13](Level V)

 

 


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Tardive Dyskinesia - Questions

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Which medication is most likely to cause tardive dyskinesia?



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Which of the following may prevent tardive dyskinesia?



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Which of the following is the best treatment for symptoms of tardive dyskinesia (TD) after the use of antipsychotic drugs?



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Which of the following statements does NOT describe tardive dyskinesia induced by neuroleptics?



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Which is not a clinical feature of tardive dyskinesias?



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Blockade of which of the following receptors can cause tardive dyskinesia?



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Select the medication that can cause tardive dyskinesia.



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A patient with schizophrenia presents with involuntary and repetitive movements of her tongue, face, trunk, and extremities. She admits to complying with her prescribed medication. What is the best treatment?



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Which of the following antipsychotic drug has the highest incidence of tardive dyskinesia?



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A 32 year old patient is being evaluated for hip pain by a physical therapist. The patient is noted to have a shuffling gait, tremors, and facial grimacing. Select the most likely cause of these findings.



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Which medications are least associated with tardive dyskinesia?



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A 33-year old female with a history of schizophrenia presents with uncontrolled movements of her tongue and jaw. The mother claims these movements started several weeks ago and have gotten worse. You also note that the patient has writhing movements of her arms and neck and she is not able to stand still. She was started on a new neuroleptic 6 weeks ago. The mother would like to try something natural rather than a prescription medication to treat the movement disorder. What would you recommend based on current evidence?



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Tardive Dyskinesia - References

References

D'Abreu A,Friedman JH, Tardive Dyskinesia-like Syndrome Due to Drugs that do not Block Dopamine Receptors: Rare or Non-existent: Literature Review. Tremor and other hyperkinetic movements (New York, N.Y.). 2018     [PubMed]
Kim DD,Barr AM,Chung Y,Yuen JWY,Etminan M,Carleton BC,White RF,Honer WG,Procyshyn RM, Antipsychotic-Associated Symptoms of Tourette Syndrome: A Systematic Review. CNS drugs. 2018 Aug 18     [PubMed]
Ward KM,Citrome L, Antipsychotic-Related Movement Disorders: Drug-Induced Parkinsonism vs. Tardive Dyskinesia-Key Differences in Pathophysiology and Clinical Management. Neurology and therapy. 2018 Jul 19     [PubMed]
Erbe S, [Prevention and Treatment of Antipsychotic-induced Tardive Dyskinesia]. Fortschritte der Neurologie-Psychiatrie. 2018 Jul 11     [PubMed]
Walther S,Stegmayer K, [Diagnosis and treatment of motor phenomena in schizophrenia spectrum disorders]. Therapeutische Umschau. Revue therapeutique. 2018 Jun     [PubMed]
Correll CU, Epidemiology and Prevention of Tardive Dyskinesia. The Journal of clinical psychiatry. 2017 Nov/Dec     [PubMed]
Jain R,Correll CU, Tardive Dyskinesia: Recognition, Patient Assessment, and Differential Diagnosis. The Journal of clinical psychiatry. 2018 Mar/Apr     [PubMed]
Kane JM,Correll CU,Nierenberg AA,Caroff SN,Sajatovic M, Revisiting the Abnormal Involuntary Movement Scale: Proceedings From the Tardive Dyskinesia Assessment Workshop. The Journal of clinical psychiatry. 2018 May/Jun     [PubMed]
Kim AP,Baker DE,Levien TL, VMAT2 Inhibitors: New Drugs for the Treatment of Tardive Dyskinesia. The Consultant pharmacist : the journal of the American Society of Consultant Pharmacists. 2018 Apr 1     [PubMed]
Caroff SN,Aggarwal S,Yonan C, Treatment of tardive dyskinesia with tetrabenazine or valbenazine: a systematic review. Journal of comparative effectiveness research. 2018 Feb     [PubMed]
Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the treatment of schizophrenia and related disorders. The Australian and New Zealand journal of psychiatry. 2005 Jan-Feb     [PubMed]
Munetz MR,Benjamin S, How to examine patients using the Abnormal Involuntary Movement Scale. Hospital     [PubMed]
Essali A,Soares-Weiser K,Bergman H,Adams CE, Calcium channel blockers for antipsychotic-induced tardive dyskinesia. The Cochrane database of systematic reviews. 2018 Mar 26     [PubMed]

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