Volume 17 | September 2024

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

EXPERT COMMENTARY
Expert Commentary With Gus Alva, MD, DFAPA
Expert Commentary With Gus Alva, MD, DFAPA
This newsletter is produced by Teva Pharmaceuticals, and Dr Alva was compensated by Teva for his insights.
Q1.
Why are patients with mood disorders at a greater risk for developing tardive dyskinesia (TD)?

The American Psychiatric Association recognizes several risk factors for TD, including long-term exposure to antipsychotic drugs, or APDs, mood disorder, substance use disorder, prior development of drug-induced parkinsonism, treatment for drug-induced parkinsonism with anticholinergics, age, and female sex. Thus, patients with mood disorders can have multiple risk factors for TD. For example, substance abuse is common in patients with mood disorders and confers additional risk for developing TD in patients with major depressive disorder and bipolar disorder.

Q2.
How has the use of atypical APDs to treat patients with mood disorders changed over the last decade?

The use of atypical APDs continues to rise, primarily driven by their use in the treatment of mood disorders. Although the prevalence of TD is lower with atypical agents, patients are still at risk and the increased use of these drugs is a significant contributor to the corresponding rise in the number of patients with TD. In a meta-analysis that examined the prevalence of TD, 1 in 14 patients without prior typical APD use had TD, compared with 1 in 3 patients treated with typical APDs. Additionally, 1 in 5 patients treated with atypical APDs, but with unknown previous exposure to typical agents, had TD.

In the United States, an estimated 41 million people suffer from depression and bipolar disorder. Many of these patients will receive long-term treatment with atypical APDs. Therefore, it is important for clinicians to recognize that these agents carry specific safety warnings not only for cardiovascular disease, neuroleptic malignant syndrome, and metabolic syndromes but also for development of TD. As mental health clinicians, we not only manage the brain, but we must also protect our patients’ hearts, be conscious of their metabolic health, and screen for development of TD.

Q3.
Why is it important to keep TD top of mind when treating patients with mood disorders?

The diagnosis of TD can be easily missed in patients with mood disorders, as movements from TD can manifest in a subtle manner and be perceived as minor or insignificant. However, the impact of even subtle TD on the patient can be severe. Small orofacial movements can result in changes in speech and painful biting of the cheeks and tongue. TD can also be a source of embarrassment, leading to the avoidance of social encounters and cause patients to become reclusive.

Patients with mood disorders may often be high functioning, live active lives, and have greater sensitivity to even mild movements when compared with schizophrenia patients, who frequently lack the same degree of insight. TD movements, no matter how subtle, can undermine the stability of a patient’s mood disorder, resulting in worsening of their mental health.

Q4.
What best practices have been identified for screening and assessing the impact of TD on patients with mood disorders?

Patients with TD who are undiagnosed far outnumber those who are diagnosed. Even when diagnosed, only a small percentage receive appropriate treatment with a vesicular monoamine transporter 2, or VMAT2, inhibitor. This, in part, may be the result of missing TD symptoms or misdiagnosing them as another type of movement disorder. Fortunately, there are protocols that can help clinicians recognize and assess TD.

Every clinical encounter should be used as an opportunity to visually screen patients and ask them if they have experienced any involuntary movements. If there is suspicion of TD, clinicians should more formally evaluate the patient’s movements using the Abnormal Involuntary Movement Scale, or AIMS. AIMS, a 12-item scale scored from 0 to 4, is widely used to screen for and monitor TD symptoms, measure the overall severity of symptoms, and assess the global impact of TD on the patient. A minimum score of 2 on any AIMS items 1-7 confirms TD movements and justifies assessing the impact of TD on the patient. Performing an AIMS examination is uncomplicated and should be part of the standard mental health professional tool kit.

Q5.
How do you explain a diagnosis of TD and discuss treatment with a patient who has a mood disorder?

Explaining to patients why they have developed TD can be difficult. Educating patients is essential to help them make informed treatment decisions as they may not understand that TD is an iatrogenic disease resulting from exposure to APDs. It is important for clinicians to have an open dialogue with their patients when initiating treatment with an atypical APD, to make them aware that, although low, there is a chance of developing TD. Encouraging patients to ask questions can improve clinician-patient relationships. Patients should know that they will be periodically assessed, and if they develop TD, they can be treated with a VMAT2 inhibitor.

Patients may often feel overburdened with their current treatment regimens or may have an emotional reaction to the abnormal movements they are experiencing and may not want to receive treatment for TD. TD movements initially tolerated by patients at diagnosis can begin to impact new aspects of their lives over time and shift their desire to initiate treatment. During patient follow-up appointments, clinicians should continue to assess and discuss the impact of TD on the patient and reoffer appropriate treatment.

Motivational interviewing techniques can also help clinicians address treatment hesitancy by highlighting the challenges they face, prompting them to reconsider their stance, and supporting the achievement of their goals. Clinicians can encourage patients to consider how they would advise others facing similar challenges, emphasizing the importance of treatment in improving their symptoms.

Q6.
What has been your experience with AUSTEDO XR, a VMAT2 inhibitor for the treatment of TD, in patients with mood disorders?

Polypharmacy regimens for neuropsychiatric patients are now more the rule than the exception. With each additional medication added to a patient’s treatment regimen their risk for drug-drug interactions increases. Clinicians should consider the metabolic pathways of the concomitant medications and select a VMAT2 inhibitor that is appropriate for each specific patient. AUSTEDO XR has no contraindications for use with medications that are strong CYP3A4 inducers or inhibitors and has 5 doses up to 36 mg/day that may be used concomitantly with strong CYP2D6 inhibitors.

It is important for clinicians to understand that each patient can be titrated to a specific dose that suitably manages their TD. AUSTEDO XR is available in a one pill, once-daily treatment option that provides clinicians the flexibility to choose a dose that is effective and achieves tolerable symptom control.

Q7.
What must clinicians consider when managing a patient with a mood disorder and TD?

It is essential for clinicians to realize that APDs are, increasingly, a routine choice for clinicians treating patients with mood disorders. The use of these agents creates a clinical dilemma as atypical APDs still carry the risk of causing TD. Therefore, it is crucial to have a discussion with patients and assess movements at every clinical encounter. Even subtle movements of TD can affect patients with mood disorders, as these individuals often lead active lives, are highly functional, and are more aware of and sensitive to involuntary movements. It is important to maintain a high index of suspicion in these cases and take the time to thoroughly screen for TD and evaluate its impact on patients so that clinicians can make appropriate treatment decisions for their patients.

Suggested Reading
  • American Psychiatric Association. The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia. 3rd ed. Washington, DC: American Psychiatric Association; 2021.
  • AUSTEDO® XR (deutetrabenazine) extended-release tablets/AUSTEDO® current Prescribing Information. Parsippany, NJ: Teva Neuroscience, Inc.
  • Butler M, Urosevic S, Desai P, et al. Treatment for bipolar disorder in adults: a systematic review. Comparative effectiveness review No. 208. Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-2012-00016-I. Rockville, MD: Agency for Healthcare Research and Quality; August 2018. AHRQ Publication No. 18-EHC012-EF.
  • 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.
  • 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):19cs12983.
  • 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.
  • Gelenberg AJ, Freeman MP, Markowitz JC, et al. Practice guideline for the treatment of patients with major depressive disorder, third edition. Accessed June 11, 2024. http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf
  • Gulko C. Tardive dyskinesia: tips on conducting patient-focused exams. Tardive Dyskinesia: Contemporary Approaches. Accessed June 11, 2024. https://www.medpagetoday.com/resource-centers/tardive-dyskinesia-contemporary-approaches/tardive-dyskinesia-tips-conducting-patient-focused-exams/3347
  • Guy W. ECDEU Assessment Manual for Psychopharmacology: Revised. Rockville, MD: US Department of Health, Education and Welfare, Public Health Service, Alcohol, Drug Abuse and Mental Health Administration, NIMH Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976:534-537. DHEW publication number ADM 76-338.
  • Halli-Tierney AD, Scarbrough C, Carroll D. Polypharmacy: evaluating risks and deprescribing. Am Fam Physician. 2019;100(1):32-38.
  • 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. 2022;27(2):208-217.
  • 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.
  • Jain R, Ayyagari R, Goldschmidt D, et al. 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.
  • Lane RD, Glazer WM, Hansen TE, Berman WH, Kramer SI. Assessment of tardive dyskinesia using the abnormal involuntary movement scale. J Nerv Ment Dis. 1985;173(6):353-357.
  • 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.
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  • National Institutes of Mental Health. Any mood disorder. Accessed June 11, 2024. https://www.nimh.nih.gov/health/statistics/any-mood-disorder.shtml
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  • Zyprexa® (olanzapine) Prescribing Information. Indianapolis, IN: Eli Lilly and Company; 2009.
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Once-Daily AUSTEDO XR: Considerations for Patients 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.