Physician’s Weekly interviews Joseph McEvoy, MD, Professor Emeritus of Psychiatry and Behavioral Sciences, at Duke University School of Medicine, and Jonathan Meyer, MD, Clinical Professor of Psychiatry at University of California, San Diego, and a Psychopharmacology Consultant for California State Department of Health, about the basics of tardive dyskinesia.

 

Joseph McEvoy, MD, of Augusta University in Georgia and Duke University Medical Center in Durham, North Carolina

 

Jonathan Meyer, MD, Clinical Professor of Psychiatry, University of California San Diego

 

 

 


 

PW: What is the clinical definition of tardive dyskinesia (TD)?

Dr. McEvoy: The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) defines tardive dyskinesia (TD) as “involuntary athetoid or choreiform movements (lasting at least a few weeks) generally of the tongue, lower face and jaw, and extremities (but sometimes involving the pharyngeal, diaphragmatic, or trunk muscles) developing in association with the use of a neuroleptic medication for at least a few months.”1

PW: What are the symptoms of TD?

Dr. McEvoy: As summarized in the DSM-5, TD is characterized by abnormal and involuntary movements, often in the orofacial region (tongue, lips, facial muscles, jaw) but also in the upper extremities (arms, hands, fingers), lower extremities (legs, feet, toes), and trunk.2-4 These movements have been described as choreiform (irregular, dance-like) and athetoid (slow, writhing).4  Although assessing and reducing the severity of TD symptoms is crucial for clinical management, it is important to note that impact on patients (e.g., impaired physical and social function, embarrassment) can significantly reduce quality of life for both patients and their caregivers.5 For example, highly functioning patients who are aware of their symptoms (e.g., those with mood disorders) may be very bothered by their TD movements, even if those movements are “mild” in terms of amplitude and frequency.

PW: What is the difference between orofacial dyskinesia or oro-bucco-lingual dyskinesia?

Dr. McEvoy: Oral-buccal-lingual dyskinesia is the repetitive, chewing movement of the mouth and/or jaw, often with tongue protrusion and lip pursing or smacking, which is considered to be the “classic” manifestations of TD. Oral‑buccal-lingual dyskinesia accounts for many TD cases and can lead to difficulty speaking, swallowing, and eating, lip/tongue biting, and the cracking or grinding down of teeth.4 Orofacial dyskinesia includes oral-buccal-lingual movements of the mouth/jaw, as well as irregular facial movements (e.g., grimacing) and increased eye blinking or blepharospasm.4

PW: What other parts of the body can be affected by TD?

Dr. McEvoy: TD may also present in the upper extremities as “piano-playing” movements of the fingers/hands, in the lower extremities as tapping of the toes/feet, or in the neck or trunk as rocking or thrusting. In severe cases, balance and/or ambulation can be impaired by excessive movements in the arms, legs, or trunk.4 In milder cases, TD may not be easily apparent during the visual assessment (e.g., toe or foot tapping may not be visible if patient’s feet are covered by shoes/socks). In addition, some patients may not be aware of their abnormal movements due to cognitive impairment from underlying severe schizophrenia, while others may not report TD symptoms due to embarrassment or greater concern with other medical or psychiatric conditions.4 Therefore, caregivers and/or family members should be encouraged to participate in the patient’s assessments, as they can provide useful information about the location and severity of any abnormal movements, as well as the impact of those movements on the patient’s functioning and quality of life.

PW: What are the causes and risk factors for TD?

Dr. Meyer: The major cause of TD is exposure to a dopamine-receptor blocking agent (DRBA). This class includes first- and second-generation antipsychotics (FGAs, SGAs), the motility agent metoclopramide, and chronic exposure to weak dopamine antagonists used as antiemetics (e.g. prochlorperazine). With the expanding use of SGAs, the number of patients at risk for TD continues to rise. In addition to the treatment of schizophrenia, SGAs are approved for mood disorders (e.g., bipolar mania or bipolar depression, unipolar major depression, Tourette’s disorder, irritability associated with Autistic disorder) and are often used off‑label for behavioral issues (e.g., agitation, irritability, aggression) in individuals with psychiatric, neuropsychiatric, or neurodevelopmental disorders (e.g., dementia, intellectual disability).6-8 SGAs are less likely to cause TD than FGAs, but evidence indicates that the risk associated with both classes is substantial. In a 2017 meta-analysis, the prevalence of TD was 30% in patients receiving FGAs and 21% for SGAs; in FGA-naïve patients who had only received SGAs, the prevalence was still 7%.9 According to DSM-5, TD usually develops after at least a few months of antipsychotic treatment, or even sooner in older patients.1 The risk of TD increases with longer treatment, but in some patients TD can appear within weeks or even days.10

In addition to DRBA exposure, studies have shown that older age is the greatest source of risk for TD, with incidence rates 5-fold greater than those among younger patients.11 Additional potential risk factors are female sex, psychiatric diagnosis, higher ratings of negative symptoms in schizophrenia, greater cognitive impairment, diabetes, substance abuse, and prior adverse reaction to DRBAs (e.g., parkinsonism, akathisia, dystonia, or treatment- or withdrawal-emergent dyskinesia).11,12

 

References

1. 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.

2. Waln O, Jankovic J. An update on tardive dyskinesia: from phenomenology to treatment. Tremor Other Hyperkinet Mov (NY). 2013;3.

3. Savitt D, Jankovic J. Tardive syndromes. J Neurol Sci. 2018;389:35-42.

4. Hauser RA, Meyer JM, Factor SA, et al. Differentiating tardive dyskinesia: a video-based review of antipsychotic-induced movement disorders in clinical practice. CNS Spectr. 2020:1-10.

5. McEvoy J, Gandhi SK, Rizio AA, et al. Effect of tardive dyskinesia on quality of life in patients with bipolar disorder, major depressive disorder, and schizophrenia. Qual Life Res. 2019;28(12):3303-3312.

6. Carton L, Cottencin O, Lapeyre-Mestre M, et al. Off-label prescribing of antipsychotics in adults, children and elderly Individuals: a systematic review of recent prescription trends. Curr Pharm Des. 2015;21(23):3280-3297. 7. Lunsky Y, Khuu W, Tadrous M, Vigod S, Cobigo V, Gomes T. Antipsychotic use with and without comorbid psychiatric diagnosis among adults with intellectual and developmental disabilities. Can J Psychiatry. 2018;63(6):361-369.

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8. Loy JH, Merry SN, Hetrick SE, Stasiak K. Atypical antipsychotics for disruptive behaviour disorders in children and youths. Cochrane Database Syst Rev. 2017;8:CD008559.

9. Carbon M, Hsieh CH, Kane JM, Correll CU. Tardive dyskinesia prevalence in the period of second-generation antipsychotic use: a meta-analysis. J Clin Psychiatry. 2017;78(3):e264-e278.

10. Frei K, Truong DD, Fahn S, Jankovic J, Hauser RA. The nosology of tardive syndromes. J Neurol Sci. 2018;389:10-16.

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13. Abnormal Involuntary Movement Scale (117-AIMS). In: Guy W, ed. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: National Institute of Mental Health; 1976:534-537.

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15. 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).

16. 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.

17. Meyer JM. Future directions in tardive dyskinesia research. J Neurol Sci. 2018;389:76-80.

18. Bhidayasiri R, Jitkritsadakul O, Friedman JH, Fahn S. Updating the recommendations for treatment of tardive syndromes: A systematic review of new evidence and practical treatment algorithm. J Neurol Sci. 2018;389:67-75.

19. Schneider F, Bradbury M, Baillie TA, et al. Pharmacokinetic and metabolic profile of deutetrabenazine (TEV-50717) compared with tetrabenazine in healthy volunteers. Clin Transl Sci. 2020;13(4):707-717.

20. Stahl SM. Comparing pharmacologic mechanism of action for the vesicular monoamine transporter 2 (VMAT2) inhibitors valbenazine and deutetrabenazine in treating tardive dyskinesia: does one have advantages over the other? CNS Spectr. 2018;23(4):239-247.

21. Grigoriadis DE, Smith E, Hoare SR, Madan A, Bozigian H. Pharmacologic characterization of valbenazine (NBI-98854) and its metabolites. -J Pharmacol Exp Ther. 2017;361(3):454-461.

22. Skor H, Smith EB, Loewen G, O’Brien CF, Grigoriadis DE, Bozigian H. Differences in dihydrotetrabenazine isomer concentrations following administration of tetrabenazine and valbenazine. Drugs in R&D. 2017;17(3):449-459.

23. Luo R, Bozigian H, Jimenez R, Loewen G, O’Brien CF. Single dose and repeat once-daily dose safety, tolerability and pharmacokinetics of valbenazine in healthy male subjects. Psychopharmacol Bull. 2017;47(3):44-52.

24. Harriott ND, Williams JP, Smith EB, Bozigian HP, Grigoriadis DE. VMAT2 Inhibitors and the Path to Ingrezza (Valbenazine).Prog Med Chem. 2018;57(1):87-111.

25. Marder SR, Singer C, Lindenmayer JP, et al. A phase 3, 1-year, open-label trial of valbenazine in adults with tardive dyskinesia. J Clin Psychopharmacol. 2019;39(6):620-627.

26. Stacy M, Sajatovic M, Kane JM, et al. Abnormal Involuntary Movement Scale in tardive dyskinesia: minimal clinically important difference. Mov Disord. 2019;34(8):1203-1209.

27. Correll CU, Carmack T, Shah C, Lundt L. Patterns of improvement in tardive dyskinesia: post-hoc analysis of a long-term study with valbenazine (KINECT 4) [poster]. Presented virtually at the American Psychatric Association annnual meeting; May 1-3, 2021.

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31. Yassa R. Functional impairment in tardive dyskinesia: medical and psychosocial dimensions. Acta Psychiatr Scand. 1989;80(1):64-67.

32. Yassa R, Lal S. Respiratory irregularity and tardive dyskinesia. A prevalence study. Acta Psychiatr Scand. 1986;73(5):506-510.

33. Lundt L, Franey E, Yonan C. Real-world use and impact of VMAT2 inhibitors in patients with tardive dyskinesia [poster]. Presented virtually at the International Parkinson and Movement Diosrder Society annual congress; Sep 12-16, 2020.