Continuing Education Activity
Tardive dyskinesia is a syndrome that includes a group of iatrogenic movement disorders caused by the 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. This activity reviews tardive dyskinesia and highlights the role of the interprofessional team in the recognition and management of patients affected by this condition.
- Describe the pathophysiology of tardive dyskinesia.
- Describe exam findings consistent with tardive dyskinesia.
- Ascertain management strategies for tardive dyskinesia.
- Incorporate strategies to educate interprofessional teams on common etiologies of tardive dyskinesia as well as common presentations, so that efforts can be made to prevent it from developing in the first place and stop it from progressing if it has already developed.
Tardive dyskinesia (TD) is a syndrome that encompasses a constellation of iatrogenic movement disorders caused by antagonism of dopamine receptors. The movement disorders include akathisia, dystonia, buccolingual stereotypy, chorea, tics, and other abnormal involuntary movements. Most often, these dyskinetic disorders precipitate following chronic antipsychotic administration, 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 that persists despite discontinuation or change of the medications. As per DSM-V, to confirm a diagnosis of tardive dyskinesia, symptoms must persist for at least one month after discontinuation of the medication. 
TD is most common in schizophrenics and bipolar patients treated with antipsychotic medications but can occur in the setting of any disorder. In addition, the medications that precipitate TD can also induce parkinsonian symptoms. Although the precise pathogenesis continues to elude researchers, there are data suggestive that TD is induced by aberrant dopamine transporters.
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 inducing tardive dyskinesia. Atypical antipsychotics have been associated with a decreased TD diathesis--as well as 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.
Metoclopramide can also cause TD, especially in older individuals. TD may also occur with certain antihistamines, amoxapine, and fluoxetine.
The average prevalence of tardive dyskinesia is estimated to be at least 20% of all patients who are 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. Other factors increasing TD diathesis include the duration of exposure to the neuroleptic agent, the manifestation of EPS, using first-generation antipsychotics--instead of second-generation antipsychotics. Of note, the long-term use of anticholinergic medications may increase the risk of tardive dyskinesia.
First-generation antipsychotics bind more 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. 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 substantial nigra--results in the manifestation of tardive dyskinesia. Evidence also suggests that antipsychotic medications and their metabolites can also be directly toxic to neurons 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.
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 a 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. The onset of TD is insidious and can be difficult to distinguish as the nascent stages demonstrate only subtle deviant motion. TD can manifest as early as 1 to 6 months following the initiation of a dopamine receptor antagonist. 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.
Specific TD that can occur with anti-dopaminergic agents include:
- Tardive akathisia
- Tardive Orofacial dyskinesia
- Tardive dystonia
- Tardive blepharospasm
- Tardive tics
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 with a follow-up screening performed no longer than 3 months later. 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 volitional 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's disease, Wilson's disease, or a central nervous system tumor. 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. Tardive dyskinesia should be distinguished from withdrawal dyskinesias as these 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 ruling out other conditions such as Huntington's disease where atrophy of the caudate nucleus is seen, and Fahr syndrome where calcification is noted in the basal ganglia.
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. To date, treatment options remain sparse. The American Academy of Neurology only recommends a few treatment options, which include including clonazepam and Ginkgo Biloba. 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, the best treatment option is primary prevention. 
- Complex seizure
- Essential tremor
- Tourette syndrome
- Tic disorder
- Wilson disease
- Sydenham chorea
Unfortunately, TD is considered a chronic and unremitting disorder. Nothing has yet proven to resolve TD but as mentioned previously, supportive measures can attenuate the severity.
Mostly, TD is a progressive disturbance that causes unmeasurable discomfort and potential embarrassment. Fortunately, it is generally not life-threatening, however severe TD of the larynx and diaphragm may prove fatal.
- Ophthalmologist to assess the eye for Wilson disease
- Movement disorder specialist
- Psychiatrist consult
Deterrence and Patient Education
The best means of obviating TD is primary prevention. Primary prevention of tardive dyskinesia includes using the lowest effective dose of an antipsychotic agent for the shortest period possible. 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.
Enhancing Healthcare Team Outcomes
The diagnosis and management of TD are best done with an interprofessional team. In most cases, the diagnosis may be suspected by the primary clinician during follow-up.
Movement disorders like tardive dyskinesias are 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. The caregiver should be informed about the possibility of this adverse effect and what the alternatives are.
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 that warns against the administration of such drugs. Once the patient is started on a neuroleptic, close monitoring is essential, because with early diagnosis, the drug may be discontinued or the dose lowered to prevent full-blown TD.(Level V)
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 persists. 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. (Level V)