Tardive Dyskinesia

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 inducing tardive dyskinesia. Atypical antipsychotics have been associated with a decreased tardive dyskinesia 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.[4][5]

Metoclopramide can also cause tardive dyskinesia, especially in older individuals. The condition may also occur with certain antihistamines, amoxapine, and fluoxetine.

Epidemiology

The average prevalence of tardive dyskinesia is estimated at least 20% of all patients treated with first-generation neuroleptics. However, other medications responsible for tardive dyskinesia have been less studied, and published data indicate a prevalence ranging from 1% to 10%. Women risk developing tardive dyskinesia more 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 than White-race individuals.[6] 

Other factors increasing tardive dyskinesia diathesis include the duration of exposure to the neuroleptic agent, the manifestation of EPS, and 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. 

Pathophysiology

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. Some evidence 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 found in the striatum. These receptors interact with dopaminergic neurons and are 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 postsynaptic receptors to dopamine, causing tardive dyskinesia. Another hypothesis is the resulting oxidative stress due to antidepressants blocking dopamine receptors which causes 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.[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 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 with chronic exposure to dopamine D2 receptor blockade.

The onset of tardive dyskinesia is insidious and can be difficult to distinguish as the nascent stages demonstrate only subtle deviant motion. Tardive dyskinesia 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 diagnosing tardive dyskinesia accurately. 

Specific conditions that can occur with anti-dopaminergic agents include:

• Tardive akathisia
• Tardive orofacial dyskinesia
• Tardive dystonia
• Tardive blepharospasm
• Tardive tics

Evaluation

Numerous rating scales 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 three 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 remit 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.[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. To date, treatment options remain sparse. The American Academy of Neurology only recommends a few treatment options, which include clonazepam and ginkgo biloba. Valbenazine, a vesicular monoamine transport type 2 (VMAT2) inhibitor, was approved by the FDA on April 11, 2017, to treat 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.[8][9][10](B2)

Differential Diagnosis

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

Prognosis

Unfortunately, tardive dyskinesia is considered a chronic and unremitting disorder. Nothing has yet been proven to resolve tardive dyskinesia, but as mentioned previously, supportive measures can attenuate the severity.

Complications

Tardive dyskinesia is primarily a progressive disturbance that causes unmeasurable discomfort and potential embarrassment. Fortunately, it is generally not life-threatening. However, severe tardive dyskinesia of the larynx and diaphragm may prove fatal.