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Guidance for Diagnosing and Managing Tardive Dyskinesia

Released: June 08, 2023

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Key Takeaways
  • Prevention, regular screening, and patient/caregiver education are the best strategies to avoid development of tardive dyskinesia (TD).
  • Risk factors for TD development include long duration and/or high dose of dopamine receptor–blocking agents, older age, baseline use of anticholinergic medication, and baseline or treatment-emergent extrapyramidal symptoms.
  • When treating TD with a vesicular monoamine transporter-2 (VMAT2) inhibitor, it is important to be aware of possible drug-drug interactions and their impact on VMAT2 inhibitor dosing.

Tardive dyskinesia (TD) is a known potential adverse event of dopamine receptor‒blocking agents (DRBAs), such as antipsychotics and metoclopramide. TD presents as an involuntary, repetitive but irregular movement disorder consisting of several different movement types. Movements associated with TD may be choreiform (ie, rapid, jerky, and nonrepetitive), athetoid (ie, slow, sinuous, and continual), and semirhythmic (ie, stereotypies). These movements are seen most often in the oral, lingual, and buccal regions, and less often in the hands, legs, feet, and torso. In relation to its severity, frequency and location, TD can have a serious impact on mental and physical quality of life and functionality. Therefore, quick, effective identification and treatment are paramount to preserving patients’ wellbeing and social, as well as educational/vocational, functioning.

Prevention is the best strategy to avoid TD, but—as we all are well aware—DRBAs, such as antipsychotics, cannot always be avoided. What we can do to optimize safety is confirm and document the true indication for treatment with a DRBA after having considered alternative options, use conservative maintenance doses that are below the threshold for akathisia or other extrapyramidal adverse events (ie, parkinsonism), keep an eye out for risk factors, and screen patients regularly. Unmodifiable risk factors include age older than 55 years, female sex, and illness qualities (ie, longer duration, mood disorders, prior brain damage). Modifiable risk factors include substance abuse, high DRBA dose, and use of first-generation antipsychotics. In addition, healthcare professionals (HCPs) should be aware of baseline and treatment-emergent extrapyramidal symptoms or cotreatment with anticholinergic medications, as these also increase the risk of TD development with DRBA use.

Screening for TD should be done prior to initiating treatment with a DRBA and periodically after, depending on patient risk level. The Abnormal Involuntary Movement Scale exam is a standard-of-care structured exam to screen for TD that assesses 7 body areas and impact on the patient’s life. Between these exams, HCPs still should be alert for any abnormal movements seen during routine patient visits, performing an “informal” screening at each visit. Of note, patients with ill-fitting dentures should remove them prior to examination, because oral movements to adjust the placement of dentures can be confused with TD movements.

Before making a diagnosis of TD, however, there needs to be a differential diagnosis, because it is a diagnosis of exclusion. First, we need to rule out other movement disorders or involuntary movements that are not related to TD. These include mannerisms, which are semipurposeful movements, and stereotypies, which are repetitive complex movements, and those too can be part of catatonia and schizophrenia or mood disorders. Other examples to consider in differential diagnosis are tics, which are quick, repetitive movements and can be part of Tourette syndrome; myoclonic jerks, which are quick and may be irregular; dystonic movements, which are sustained or repetitive muscle contractions; and akathisia, which is internal or external restlessness. Symptoms associated with parkinsonism also must be carefully assessed, as TD is commonly misdiagnosed as drug-induced parkinsonism. These symptoms include akinesia, rigidity, and tremor. However, tremors are rhythmic and regular, which is a feature not shared by the irregular, arrhythmic TD movements.

HCPs also need to be aware of medical conditions that can give rise to abnormal involuntary movements that are choreoathetoid in nature. These include Huntington disease, benign familial chorea, metabolic conditions, such as electrolyte imbalances, hypo- or hyperparathyroidism, vitamin B12 deficiency and uremia, Sydenham chorea, systemic lupus erythematosus, and substance induced TD like movements.

When TD is identified, it is important to initiate treatment quickly to preserve the patient’s quality of life. We have a few treatments in our toolbox, but only 2 of them have FDA approval for use in TD—the VMAT2 inhibitors deutetrabenazine and valbenazine. Agents with less evidence for their benefit in TD include branched chain amino acids, amantadine, antioxidants or radical scavengers, such as vitamin E, vitamin B6, ginkgo biloba or fish oil, as well as clonazepam, and even tetrabenazine, which is approved for the treatment of Huntington chorea but not approved for TD.

Before going to the potential treatment with a VMAT2 inhibitor, one could try to modify the dose of the potentially causative agent, but TD often persists despite antipsychotic dose reduction, increase, or discontinuation. Furthermore, reducing or discontinuing the dose increases the risk of worsening a patient’s psychiatric condition; this action is riskier in primary psychotic disorders but worsening may also occur in mood disorders with or without psychosis.

In the older population, it is necessary to adjust our approach to TD treatment. For example, in older patients, a slower titration of VMAT2 inhibitors may improve tolerability. This approach also may help identify a lower effective dose for patients and can help balance efficacy with tolerability. In addition, polypharmacy is common in older patients; therefore, HCPs need to watch out for drug‒drug interactions. Fortunately, most antipsychotic medications can be continued without adjustment with use of a VMAT2 inhibitor.

However, medications that induce or inhibit the cytochrome P450 2D6 and/or 3A4 system have been noted to have drug interactions with the VMAT2 inhibitors, as this system is involved in the breakdown of valbenazine and deutetrabenazine. For patients concurrently using cytochrome P450 inducers, such as carbamazepine or phenytoin, the dose of the VMAT2 inhibitor needs to be increased. If patients are concurrently receiving strong cytochrome P450 2D6 inhibitors (eg, fluoxetine, risperidone, aripiprazole, and bupropion), the dose of deutetrabenazine and valbenazine needs to be reduced. In the case of valbenazine, patients concurrently receiving strong cytochrome P450 3A4 inhibitors (eg, ketoconazole) will need a reduced dose of valbenazine.

The dose adjustment of the VMAT2 inhibitor depends not only on the individual patient, but also on the magnitude of the dose of the cytochrome P450 system‒inhibiting medication. If relatively high doses of the cytochrome P450 inhibiting medication are used and necessary, a rule of thumb would be to try to half the dose of the VMAT2 inhibitor. If efficacy is insufficient, one could then slowly increase the dose further.

In summary, even mild TD can have a severe impact on patients’ lives, making prevention, early identification, and adequate treatment paramount to preserving quality of life and functionality. The VMAT2 inhibitors deutetrabenazine and valbenazine offer valuable options for managing TD, but only if HCPs know how to properly prescribe them to individual patients.

Your Thoughts?
Even mild TD can have a severe impact on patients’ lives, making early identification and adequate treatment paramount to preserving quality of life. The VMAT2 inhibitors deutetrabenazine and valbenazine offer valuable options for managing TD, but only if HCPs know how to properly prescribe them to individual patients. Have you prescribed either of these agents for your patients with TD? Answer the poll and join the discussion in the comments.

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Have you prescribed the VMAT2 inhibitors deutetrabenazine and valbenazine for your patients with TD?

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