Volume 17 | September 2024

When Patients With Mood Disorders Develop TD: Considerations for Assessment and Treatment

TD and Mood Disorders
Tardive Dyskinesia (TD) and Its Impact on Patients With a Mood Disorder
Tardive Dyskinesia (TD) and Its Impact on Patients With a Mood Disorder
TD and Associated Risk Factors

Patients treated with both first- and second-generation antipsychotic drugs (APDs) are at risk for developing TD,1,2  an often persistent and potentially debilitating disorder characterized by involuntary hyperkinetic movements of the face, trunk, and extremities.3  In a meta-analysis that examined the prevalence of TD in patients with APDs, approximately 1 in 3 patients treated with typical APDs and up to 1 in 5 patients treated with atypical APDs had developed TD.1 Besides exposure to APDs, other factors that increase the risk of TD include age (older than 55 years), female sex (especially postmenopausal women), substance use disorder, intellectual disabilities or central nervous system injury, clinically significant parkinsonism or akathisia, and mood disorder (Figure 1).4,5

Figure 1. Several Factors Increase the Risk of Developing TD
Figure 1

Mood disorders comprise a broad group of psychiatric conditions, including major depressive disorder and bipolar disorder, that affect the individual's emotional state and may include periods of excessive joy or sadness.6

In the United States, an estimated 43 million people suffer from schizophrenia and mood disorders, for which APDs are widely prescribed.7-13 From 2017 to 2022, the number of patients treated with atypical APDs increased by 22%, a rise primarily driven by its increasing use in patients with a mood disorder.2,14

Impact of TD on Patients' Lives

Understanding the impact of TD is important for improving patient outcomes. Based on the underlying mental health disorder, patients may perceive the impact of TD differently. For example, patients with schizophrenia, who are more likely to have severe cognitive impairments, are often unaware of or unconcerned about abnormal movements of TD. Conversely, patients with a mood disorder, who otherwise may be highly functional and live active lives, can be bothered by even subtle TD symptoms and find them extremely disruptive.15,16

Irrespective of severity, TD can have a profound impact on many aspects of patients' lives.17 In a recent online survey of 269 patients with TD, 3 of 4 patients reported that the impact of TD was severe.18  Patients reported the impact of TD across 4 key domains (Figure 2)17:

  • Social

  • Physical

  • Psychological/psychiatric

  • Vocational/educational/recreational

Figure 2. TD Can Impact Many Aspects of Patients' Lives
Figure 2

No clinical studies have been conducted to evaluate the effects of treating TD on the outcomes listed.

The audio and video clips shown in Figure 3 are of a patient with depression and posttraumatic stress disorder who has been treated with an atypical antipsychotic for several years. They illustrate how subtle symptoms of TD can have a substantial impact on the patient. In Video 3a, when only hearing about the impact that TD symptoms are having on the patient, one would expect TD symptoms to be severe and obvious. However, when watching Video 3b, the symptoms are subtle and can be easily missed if the clinician is not observing the patient carefully. In Video 3c, the absence of sound makes TD movements more obvious, as the focus here is on seeing versus listening to the patient. This example underscores the importance of observation, even in the psychiatry setting, where patients and clinicians are largely focused on dialogue.

Figure 3. Impact of TD Symptoms, Regardless of Severity, Can Be Substantial

Video 3a

audio only

Video 3b

video with sound

Video 3c

video without sound
Assessing Impact of TD

In 2020, an advisory panel of 7 experts assembled by Teva developed consensus recommendations on the need to assess the impact of TD on various domains in a patient’s life. A total of 6 recommendations were developed, of which 4 were related to assessing the impact of TD.19

Impact recommendation 1: importance of assessing19

Assess the impact of TD on the patient's life to guide TD treatment recommendations and aid TD treatment.

  • The impact of TD should not be based solely on the severity of abnormal movements

  • The degree of impact determines the level of treatment urgency

  • Information should be garnered from multiple sources, including staff and caregivers, all of whom may have valuable insights into how the patient is affected

Impact recommendation 2: key domains19

Assess the overall impact of TD on the individual's life and functioning in the social, physical, vocational, and psychological/psychiatric domains.

Impact recommendation 3: time points for assessing19

Assess the impact of TD at every patient visit because the impact varies over time and can affect treatment decisions.

Impact recommendation 4: approaches to assessing19

Utilize the key domains identified in recommendation 2 to assess the social, physical, vocational, and psychological/psychiatric impact of TD.

  • Consult with the patient directly and/or obtain input from caregivers/family/friends

  • Ask the patient questions related to disability; this can be especially helpful for understanding the impact of TD in patients with subtle symptoms, in whom abnormal movements may not be so obvious20

Assessment of impact should be a routine part of clinical practice.
Treatment Guidelines for TD and Initiating Treatment in Patients With a Mood Disorder

APA guidelines recommend that regardless of severity, TD symptoms that have an impact on the patient should be managed with a VMAT2 (vesicular monoamine transporter 2) inhibitor.4

Clinicians may, however, face several challenges in initiating treatment for TD and managing the underlying condition following a diagnosis of TD, especially in patients with a mood disorder who are highly functional. After learning that TD is an iatrogenic movement disorder (caused by their existing antipsychotic treatment), patients may make decisions that are counter to their well-being. These include becoming nonadherent or completely stopping their existing medication, discontinuing visits to their treating clinician, and advising others to not take their antipsychotic medication.18 In addition, these patients may be hesitant to consider taking a medication to treat TD, knowing that the condition was caused by their antipsychotic medication.

To address these issues, it is important that clinicians establish a dialogue with their patients at an appropriate time to educate on the need for, and safety and efficacy of, APDs in treating mood disorders or other underlying conditions. This also provides an opportunity to discuss the potential risks of TD as a side effect and the treatment options available to address the symptoms of TD.

TD that has an impact on the lives of patients with a mood disorder should be treated, irrespective of severity
Summary

Patients with a mood disorder may be more aware of their TD; therefore, it can have a significant impact, even when the movements are subtle. It is important to fully assess the impact of TD at every visit in patients with a mood disorder so that they can receive appropriate treatment.

References
1. 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. 2. McIntyre RS, Calabrese JR, Nierenberg AA, et al. The effects of valbenazine on tardive dyskinesia in patients with a primary mood disorder. J Affect Disord. 2019;246:217-223. 3. Waln O, Jankovic J. An update on tardive dyskinesia: from phenomenology to treatment. Tremor Other Hyperkinet Mov (N Y). 2013;3:tre-03-161-4138-1. 4. American Psychiatric Association. The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia. 3rd ed. Washington, DC: American Psychiatric Association; 2021. Accessed May 17, 2024. https://psychiatryonline.org/doi/pdf/10.1176/appi.books.9780890424841 5. Yassa R, Jeste DV. Gender differences in tardive dyskinesia: a critical review of the literature. Schizophr Bull. 1992;18(4):701-715. 6. Merck Manual Professional Version. Overview of mood disorders. Accessed May 23, 2024. https://www.merckmanuals.com/professional/psychiatric-disorders/mood-disorders/overview-of-mood-disorders 7. US Census Bureau. U.S. and world population clock. Accessed April 19, 2024. https://www.census.gov/popclock/ 8. National Institute of Mental Health. Schizophrenia. Accessed April 19, 2024. https://www.nimh.nih.gov/health/statistics/schizophrenia.shtml 9. National Institute of Mental Health. Any mood disorder. Accessed April 19, 2024. https://www.nimh.nih.gov/health/statistics/any-mood-disorder.shtml 10. National Institute of Mental Health. Bipolar disorder. Accessed April 19, 2024. https://www.nimh.nih.gov/health/statistics/bipolar-disorder 11. Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161(2 suppl):1-56. 12. Hirschfeld RM, Bowden CL, Gitlin MJ, et al. Practice guideline for the treatment of patients with bipolar disorder, second edition. Accessed April 19, 2024. http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/bipolar.pdf 13. Gelenberg AJ, Freeman MP, Markowitz JC, et al. Practice guideline for the treatment of patients with major depressive disorder, third edition. Accessed April 19, 2024. http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf 14. Data on file. Teva Neuroscience, Inc. Parsippany, NJ. 15. 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. 16. McCutcheon RA, Keefe RS, McGuire PK. Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment. Mol Psychiatry. 2023;28(5):1902-1918. 17. Jackson R, Brams MN, Carlozzi NE, et al. Impact-Tardive Dyskinesia (Impact-TD) scale: a clinical tool to assess the impact of tardive dyskinesia. J Clin Psychiatry. 2022;84(1):22cs14563. 18. Jain R, Ayyagari R, Goldschmidt D, Zhou M, Finkbeiner S, Leo S. Impact of tardive dyskinesia on physical, psychological, social, and professional domains of patient lives: a survey of patients in the United States. J Clin Psychiatry. 2023;84(3):22m14694. 19. Jackson R, Brams MN, Citrome L, et al. Assessment of the impact of tardive dyskinesia in clinical practice: consensus panel recommendations. Neuropsychiatr Dis Treat. 2021;17:1589-1597.20. Caroff SN. Overcoming barriers to effective management of tardive dyskinesia. Neuropsychiatr Dis Treat. 2019;15:785-794.
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Management of Tardive Dyskinesia in a Patient With a Mood Disorder
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IMPORTANT SAFETY INFORMATION
Depression and Suicidality in Patients with Huntington's Disease: AUSTEDO XR and AUSTEDO can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington's disease. Balance the risks of depression and suicidality with the clinical need for treatment of chorea. Closely monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior. Inform patients, their caregivers, and families of the risk of
IMPORTANT SAFETY INFORMATION
Depression and Suicidality in Patients with Huntington's Disease: AUSTEDO XR and AUSTEDO can increase the risk of depression
INDICATIONS AND USAGE

AUSTEDO XR® (deutetrabenazine) extended-release tablets and AUSTEDO® (deutetrabenazine) tablets are indicated in adults for the treatment of chorea associated with Huntington's disease and for the treatment of tardive dyskinesia.

IMPORTANT SAFETY INFORMATION
Depression and Suicidality in Patients with Huntington's Disease: AUSTEDO XR and AUSTEDO can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington's disease. Balance the risks of depression and suicidality with the clinical need for treatment of chorea. Closely monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior. Inform patients, their caregivers, and families of the risk of depression and suicidality and instruct them to report behaviors of concern promptly to the treating physician. Exercise caution when treating patients with a history of depression or prior suicide attempts or ideation. AUSTEDO XR and AUSTEDO are contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression.
Contraindications AUSTEDO XR and AUSTEDO are contraindicated in patients with Huntington's disease who are suicidal, or have untreated or inadequately treated depression. AUSTEDO XR and AUSTEDO are also contraindicated in: patients with hepatic impairment; patients taking reserpine or within 20 days of discontinuing reserpine; patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of discontinuing MAOI therapy; and patients taking tetrabenazine or valbenazine.
Clinical Worsening and Adverse Events in Patients with Huntington's Disease: AUSTEDO XR and AUSTEDO may cause a worsening in mood, cognition, rigidity, and functional capacity. Prescribers should periodically re-evaluate the need for AUSTEDO XR or AUSTEDO in their patients by assessing the effect on chorea and possible adverse effects.
QTc Prolongation: AUSTEDO XR and AUSTEDO may prolong the QT interval, but the degree of QT prolongation is not clinically significant when AUSTEDO XR or AUSTEDO is administered within the recommended dosage range. AUSTEDO XR and AUSTEDO should be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.
Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex reported in association with drugs that reduce dopaminergic transmission, has been observed in patients receiving tetrabenazine. The risk may be increased by concomitant use of dopamine antagonists or antipsychotics. The management of NMS should include immediate discontinuation of AUSTEDO XR and AUSTEDO; intensive symptomatic treatment and medical monitoring; and treatment of any concomitant serious medical problems.
Akathisia, Agitation, and Restlessness: AUSTEDO XR and AUSTEDO may increase the risk of akathisia, agitation, and restlessness. The risk of akathisia may be increased by concomitant use of dopamine antagonists or antipsychotics. If a patient develops akathisia, the AUSTEDO XR or AUSTEDO dose should be reduced; some patients may require discontinuation of therapy.
Parkinsonism: AUSTEDO XR and AUSTEDO may cause parkinsonism in patients with Huntington's disease or tardive dyskinesia. Parkinsonism has also been observed with other VMAT2 inhibitors. The risk of parkinsonism may be increased by concomitant use of dopamine antagonists or antipsychotics. If a patient develops parkinsonism, the AUSTEDO XR or AUSTEDO dose should be reduced; some patients may require discontinuation of therapy.
Sedation and Somnolence: Sedation is a common dose-limiting adverse reaction of AUSTEDO XR and AUSTEDO. Patients should not perform activities requiring mental alertness, such as operating a motor vehicle or hazardous machinery, until they are on a maintenance dose of AUSTEDO XR or AUSTEDO and know how the drug affects them. Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence.
Hyperprolactinemia: Tetrabenazine elevates serum prolactin concentrations in humans. If there is a clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing should be done and consideration should be given to discontinuation of AUSTEDO XR and AUSTEDO.
Binding to Melanin-Containing Tissues: Deutetrabenazine or its metabolites bind to melanin-containing tissues and could accumulate in these tissues over time. Prescribers should be aware of the possibility of long-term ophthalmologic effects.
Common Adverse Reactions: The most common adverse reactions for AUSTEDO (>8% and greater than placebo) in a controlled clinical study in patients with Huntington's disease were somnolence, diarrhea, dry mouth, and fatigue. The most common adverse reactions for AUSTEDO (4% and greater than placebo) in controlled clinical studies in patients with tardive dyskinesia were nasopharyngitis and insomnia. Adverse reactions with AUSTEDO XR extended-release tablets are expected to be similar to AUSTEDO tablets.
Please see accompanying full Prescribing Information, including Boxed Warning.
INDICATIONS AND USAGE

AUSTEDO XR® (deutetrabenazine) extended-release tablets and AUSTEDO® (deutetrabenazine) tablets are indicated in adults for the treatment of chorea associated with Huntington's disease and for the treatment of tardive dyskinesia.

IMPORTANT SAFETY INFORMATION
Depression and Suicidality in Patients with Huntington's Disease: AUSTEDO XR and AUSTEDO can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington's disease. Balance the risks of depression and suicidality with the clinical need for treatment of chorea. Closely monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior. Inform patients, their caregivers, and families of the risk of depression and suicidality and instruct them to report behaviors of concern promptly to the treating physician. Exercise caution when treating patients with a history of depression or prior suicide attempts or ideation. AUSTEDO XR and AUSTEDO are contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression.
Contraindications AUSTEDO XR and AUSTEDO are contraindicated in patients with Huntington's disease who are suicidal, or have untreated or inadequately treated depression. AUSTEDO XR and AUSTEDO are also contraindicated in: patients with hepatic impairment; patients taking reserpine or within 20 days of discontinuing reserpine; patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of discontinuing MAOI therapy; and patients taking tetrabenazine or valbenazine.
Clinical Worsening and Adverse Events in Patients with Huntington's Disease: AUSTEDO XR and AUSTEDO may cause a worsening in mood, cognition, rigidity, and functional capacity. Prescribers should periodically re-evaluate the need for AUSTEDO XR or AUSTEDO in their patients by assessing the effect on chorea and possible adverse effects.
QTc Prolongation: AUSTEDO XR and AUSTEDO may prolong the QT interval, but the degree of QT prolongation is not clinically significant when AUSTEDO XR or AUSTEDO is administered within the recommended dosage range. AUSTEDO XR and AUSTEDO should be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.
Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex reported in association with drugs that reduce dopaminergic transmission, has been observed in patients receiving tetrabenazine. The risk may be increased by concomitant use of dopamine antagonists or antipsychotics. The management of NMS should include immediate discontinuation of AUSTEDO XR and AUSTEDO; intensive symptomatic treatment and medical monitoring; and treatment of any concomitant serious medical problems.
Akathisia, Agitation, and Restlessness: AUSTEDO XR and AUSTEDO may increase the risk of akathisia, agitation, and restlessness. The risk of akathisia may be increased by concomitant use of dopamine antagonists or antipsychotics. If a patient develops akathisia, the AUSTEDO XR or AUSTEDO dose should be reduced; some patients may require discontinuation of therapy.
Parkinsonism: AUSTEDO XR and AUSTEDO may cause parkinsonism in patients with Huntington's disease or tardive dyskinesia. Parkinsonism has also been observed with other VMAT2 inhibitors. The risk of parkinsonism may be increased by concomitant use of dopamine antagonists or antipsychotics. If a patient develops parkinsonism, the AUSTEDO XR or AUSTEDO dose should be reduced; some patients may require discontinuation of therapy.
Sedation and Somnolence: Sedation is a common dose-limiting adverse reaction of AUSTEDO XR and AUSTEDO. Patients should not perform activities requiring mental alertness, such as operating a motor vehicle or hazardous machinery, until they are on a maintenance dose of AUSTEDO XR or AUSTEDO and know how the drug affects them. Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence.
Hyperprolactinemia: Tetrabenazine elevates serum prolactin concentrations in humans. If there is a clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing should be done and consideration should be given to discontinuation of AUSTEDO XR and AUSTEDO.
Binding to Melanin-Containing Tissues: Deutetrabenazine or its metabolites bind to melanin-containing tissues and could accumulate in these tissues over time. Prescribers should be aware of the possibility of long-term ophthalmologic effects.
Common Adverse Reactions: The most common adverse reactions for AUSTEDO (>8% and greater than placebo) in a controlled clinical study in patients with Huntington's disease were somnolence, diarrhea, dry mouth, and fatigue. The most common adverse reactions for AUSTEDO (4% and greater than placebo) in controlled clinical studies in patients with tardive dyskinesia were nasopharyngitis and insomnia. Adverse reactions with AUSTEDO XR extended-release tablets are expected to be similar to AUSTEDO tablets.
Please see accompanying full Prescribing Information, including Boxed Warning.