Jonathan Meyer, MD
Clinical Professor of Psychiatry
University of California San Diego
Because the introduction of second-generation antipsychotics has reduced but not eliminated the risk for tardive dyskinesia, recognizing and treating TD are extremely important. To minimize the risk of patients’ involuntary movements becoming permanent, they must be detected early and treated.
To improve the early recognition and diagnosis of TD, clinicians must know the risk factors, understand the functional impairment, regularly and systematically assess their patients, and appropriately apply diagnostic criteria. Identifying patients with TD is difficult and often goes unnoticed, presenting insidiously over months to years. Some patients may not even recognize abnormal movements, even when of moderate or greater severity, and some may be aware but do not feel compelled to seek treatment.
Risk factors for developing TD include older age (older than 65 years), history of extrapyramidal symptoms during antipsychotic treatment, and exposure to antipsychotics and other dopamine-blocking agents. Higher rates of TD are associated with first-generation antipsychotics vs second-generation agents (30% vs 20%, respectively).2 Early recognition of signs and symptoms potentially associated with TD can lead to improved understanding of the diagnosis, consideration of treatment options, and better long-term patient outcomes.
All patients with known or suspected exposure to antipsychotics or other DRBAs should be monitored for the development of TD. The Abnormal Involuntary Movement Scale (AIMS)13 is used clinically and in research to assess the severity of TD movements and changes in severity over time. However, it is not a diagnostic tool for TD. Diagnosis of TD is based on psychiatric and medical history, including known or suspected exposure to DRBAs, as well as the clinical presentation of its characteristic movement phenomenology.
The common manifestations of TD include writhing movements (athetosis), jerking movements (chorea), tic-like movements (eg, eye blinking), and stereotypic movements (eg, lip pursing, cheek puffing).
Conditions to Rule Out
- Spontaneous dyskinesias occurring in the elderly, including in patients with schizophrenia
- Oral movements from ill-fitting dentures and other dental problems
- Chronic motor tic disorder
- Huntington’s disease
- Meige’s syndrome
- Restless legs syndrome
- Rett’s syndrome
- Senile chorea
- Syndeham’s chorea
- Tourette syndrome
- Wilson’s disease
As presented in the real-world RE-KINECT study, these informal assessments could be based on a quick visual observation of the four major body regions (head/face, neck/trunk, upper extremities, lower extremities) and simple descriptors of severity (“none”, “some”, or “a lot”). Ideally, patients should be assessed prior to initiating or modifying an antipsychotic treatment to establish baseline “normal” movements and then screened regularly during treatment for any changes. TD assessments can be incorporated into routine protocols that are already in place in many clinical practices, which are used to monitor other antipsychotic-associated adverse events (e.g., orthostatic hypotension, hyperprolactinemia, weight gain).
FDA-Approved Drugs for Tardive Dyskinesia
The only medications approved for the treatment of TD are vesicular monoamine transporter 2 (VMAT2) inhibitors, with valbenazine and deutetrabenazine both approved in 2017.17 According to to Dr. Meyer, results based on a well-controlled clinical trials of these VMAT2 inhibitors, authors of the 2018 American Academy of Neurology (AAN) guidelines for TD designated both medications as having “Level A” evidence for efficacy, and the APA guidelines for schizophrenia recommend them as first-line treatment for moderate-to-severe or disabling TD due to antipsychotic therapy.14,18 “According to the APA guidelines, valbenazine and deutetrabenazine can also be considered in patients with mild TD based on factors such as patient preference, impairment due to TD, and the impact of TD on psychosocial functioning,” he says.
“Valbenazine is the valine ester of the [+] alpha dihydrotetrabenazine isomer; thus, its pharmacologic actions are mediated solely by [+]-alpha. Valbenazine is rapidly absorbed and metabolized slowly to the [+]-alpha metabolite, with a half-life of ~20 hours.23 This pharmacokinetic profile supports once-daily dosing, with specificity/selectivity for the VMAT2 enzyme and negligible affinity for other receptors potentially limiting off-target effects. In addition, there is no requirement to administer with food,” says Dr. Meyer
Deutetrabenazine, on the other hand, is a deuterated form of tetrabenazine, which is approved for chorea in Huntington’s disease and TD in adults. “Incorporating deuterium in place of specific hydrogen atoms is thought to slow metabolism and prolong half-life compared to tetrabenazine, which allows for twice-daily administration of deutetrabenazine with food,” says Dr. Meyers. “While results have not been reported for deutetrabenazine specifically, its pharmacologic activity is thought to be similar to tetrabenazine, in that it is mediated by a blend of 4 isomeric dihydrotetrabenazine metabolites ([+]-alpha, [-]-alpha, [+]-beta, and [-]-beta) that inhibit VMAT2.20,21 While circulating levels of the 4 individual isomers of deutetrabenazine have not been published, it is likely that they are similar to those of tetrabenazine with most VMAT2 inhibition being mediated somewhat by a [+]-beta isomer and some by the more VMAT2-selective and potent isomer ([+]-alpha dihydrotetrabenazine).”
- Kremens DE. Earlier Diagnosis of Tardive Dyskinesia. J Clin Psychiatry. 2019 Dec 10;81(1):NU18041BR1C. doi: 10.4088/JCP.NU18041BR1C. PMID: 31846242.
- American Psychiatric Association. DSM-5 Task Force. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. 5th ed. Washington, D.C.: American Psychiatric Association; 2013.
- Keepers GA, Fochtmann LJ, Anzia JM, et al. The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia. Am J Psychiatry. 2020;177(9):868-872.
- Caroff SN, Citrome L, Meyer J, et al. A modified delphi consensus study of the screening, diagnosis, and treatment of tardive dyskinesia. J Clin Psychiatry. 2020;81(2).
- Caroff SN, Yeomans K, Lenderking WR, et al. RE-KINECT: a prospective study of the presence and healthcare burden of tardive dyskinesia in clinical practice settings. J Clin Psychopharmacol. 2020;40(3):259-268.
- Meyer JM. Future directions in tardive dyskinesia research. J Neurol Sci. 2018;389:76-80.
- ement Diosrder Society annual congress; Sep 12-16, 2020.