Volume 17 | September 2024

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

Treatment
Once-Daily AUSTEDO XR: Considerations for Patients With a Mood Disorder
Once-Daily AUSTEDO XR: Considerations for Patients With a Mood Disorder

Tardive dyskinesia (TD), a disorder characterized by abnormal involuntary hyperkinetic movements, can occur in patients receiving treatment with antipsychotic drugs (APDs).1-3 TD of any severity can have a profound impact on many aspects of a patient’s life, whether physical, social, psychological, or vocational.4-7 The American Psychiatric Association (APA) describes the presence of mood disorders as an independent risk factor for the development of TD.8 Therefore, patients being treated with an APD for a mood disorder may have a compounded risk of developing TD.

Additionally, several studies have indicated that patients with mood disorders have greater awareness of TD, which may add to the impact of the disorder.7,9,10 APA guidelines recommend vesicular monoamine transport type 2 (VMAT2) inhibitors as first-line treatment for TD, irrespective of severity, if it has an impact on the patient.8

AUSTEDO XR is a VMAT2 inhibitor approved in the US for the treatment of adults with TD.11 This article highlights key findings from the 2 pivotal trials of AUSTEDO. It also provides insights from RIM-TD, an open-label, long-term study designed to evaluate AUSTEDO as a maintenance therapy. Additionally, the article discusses dosing options for AUSTEDO XR and explains how clinicians can get their patients started on AUSTEDO XR using the 4-week Titration Kit.

ARM-TD and AIM-TD Clinical Trials

The efficacy and safety profile of AUSTEDO was established in 2 pivotal clinical trials, ARM-TD (Aim to Reduce Movements in Tardive Dyskinesia) and AIM-TD (Addressing Involuntary Movements in Tardive Dyskinesia).12,13

ARM-TD (N=113) was a 12-week, randomized, double-blind, placebo-controlled flexible-dose clinical trial in which doses were titrated to an individualized dosage that reduced abnormal movements and was tolerated.12

AIM-TD (N=222) was a 12-week, fixed-dose trial in which patients were randomized 1:1:1:1 to 12 mg AUSTEDO, 24 mg AUSTEDO, 36 mg AUSTEDO, or placebo per day.11,13

The primary efficacy endpoint in both studies was the change in Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1 through 7) from baseline (defined for each patient as the value from the day 0 visit) to Week 12, as assessed by 2 blinded central video ratings.11-14

Patients in the ARM-TD study showed a significant improvement in AIMS total score from baseline (P=0.019) at Week 12 vs placebo (3.0-point reduction vs 1.6-point reduction) (Figure 1).12,14 Results were consistent with those observed in AIM-TD at Week 12.11,13

Figure 1. Change in AIMS total score from baseline to Week 12 in ARM-TD and AIM-TD trials11-14,*,†
Figure 1
*Higher AIMS scores are indicative of more severe TD.11
†Patients in the clinical trials received the AUSTEDO BID formulation.12,13
Safety and Tolerability Profile

The most commonly reported adverse events (AEs) by patients treated with AUSTEDO (>3% and greater than placebo) in the placebo-controlled studies were nasopharyngitis (4%) and insomnia (4%) (Table 1).11 Discontinuation due to AEs occurred in 4% of patients taking AUSTEDO vs 3% of patients taking placebo.13 Dose reduction due to AEs was required in 4% of patients taking AUSTEDO vs 2% of patients taking placebo.11 Once patients were titrated to their maintenance dose, the following AEs were no longer reported: dry mouth, nausea, and hypertension in AIM-TD and somnolence and dry mouth in ARM-TD.14 Adverse reactions with AUSTEDO XR are expected to be similar to those with AUSTEDO BID.

Table 1. Placebo-Controlled TD Studies: Adverse Reactions Reported in ≥2% of Patients Treated With AUSTEDO11,*
Table 1
*Patients in the clinical trials received the AUSTEDO BID formulation.12,13
RIM-TD, An Open-Label, Long-Term Maintenance Study

RIM-TD (Reducing Involuntary Movements in Participants With Tardive Dyskinesia) was an open-label, long-term maintenance study in patients who successfully completed ARM-TD or AIM-TD.15 They discontinued AUSTEDO for 1 week and then started at a dose of 12 mg/day, which was titrated for up to 6 weeks.15 The dose was increased in a response-driven manner on a weekly basis by 6 mg/day until the maximum allowable dose was reached, a clinically significant AE occurred, or adequate dyskinesia control was achieved.15 Patients were followed for approximately 3 years.15

Among the patients evaluated, 337 received treatment at baseline and 163 continued treatments through the end of Week 145.15 During the overall treatment period, patients generally experienced an improvement in AIMS total score.15 There was a gradual reduction in the mean AIMS total scores beginning at Week 2, with the mean change in AIMS total score from baseline at Week 145 of −6.6.15

Of the patients who received treatment at baseline, 205 had a psychotic disorder (167 patients had schizophrenia, while 38 patients had schizoaffective disorder) and 131 patients had a mood disorder (59 patients had depression, 57 patients had bipolar disorder) or another diagnosis (15 patients) (Figure 2).14

Figure 2. Concurrent Diagnoses of RIM-TD Patient Population at Baseline14
Figure 2

When stratified by the underlying mental health disorder, the mean change in total motor AIMS score from baseline at Week 145 was −6.3 for patients with psychotic disorders and −7.1 for patients with mood and other disorders.14 Although there was a greater improvement in the mood and other disorders group, the difference between the subgroups was not significant at any of the assessed time points.14

Figure 3. Sustained Reduction in AIMS Total Score Observed Through ~3 Years Regardless of Underlying Condition14,†
Figure 3
*Mean total daily dose.
†Patients in the RIM-TD study received the AUSTEDO BID formulation.15

At Week 145, 67% of patients in both subgroups achieved ≥50% improvement in AIMS total score.14 Preexisting psychiatric scores remained stable throughout the treatment period, and AEs were comparable to those seen in the clinical trials.14 The mean overall adherence rate was nearly 90% at 3 years.14

Consider Pathways of Drug Metabolism of Concomitant Medications

Often, patients with mood disorders are treated with multiple concomitant medications. Therefore, clinicians should consider the metabolic pathways of these medications when choosing a treatment for TD. AUSTEDO XR is the only FDA-approved VMAT2 inhibitor with no recommendations against concomitant use with strong CYP3A4 inducers or inhibitors.11,16 For a treatment regimen that includes a strong CYP2D6 inhibitor, or if the patient is genetically a poor CYP2D6 metabolizer, the maximum daily dose of AUSTEDO XR should not exceed 36 mg.11 For these patients, the FDA has approved 5 different dose options of AUSTEDO XR.11

One Pill, Once-Daily for All Doses

AUSTEDO XR is a one pill, once-daily treatment option available in 8 strengths from 12 mg to 48 mg, providing flexibility for effective and tolerable symptom control.14 The recommended starting dose of AUSTEDO XR for patients with TD is 12 mg/day. Titration should be continued by 6 mg/day each week until symptom control is achieved, or the maximum recommended daily dose of 48 mg is reached (Figure 4).11,14 The average daily dose in clinical trials was >36 mg/day.12,13 At Week 145 in RIM-TD, over half of the patients received a dose between 36 and 48 mg/day.15

Figure 4. AUSTEDO XR Dosing Options11,¶
Figure 4
Tablets not shown at actual size.
Once-daily AUSTEDO XR may be taken at any time of day with or without food. AUSTEDO XR tablets should be swallowed whole and not chewed, crushed, or broken.11
Getting Your Patients Started on AUSTEDO XR

Patients can start on AUSTEDO XR at no cost with the easy-to-use Titration Kit, which brings them to 30 mg/day within the first 4 weeks and is available through sample or prescription (Figure 5).14

The 4-week patient Titration Kits were evaluated in the START Study, a phase 4, non-interventional, 2- cohort (TD and Huntington's disease [HD]), real-world study assessing 4-week Titration Kit utilization and treatment success in 53 patients with TD and 17 patients with HD chorea, both of similar demographics to the AUSTEDO TD pivotal studies.14 In this study, >90% of patients adhered to the Titration Kit, and a majority of patients reached a clinically therapeutic dose range (24-48 mg/day) by Week 4.14

Patients and providers reported overall satisfaction with the Titration Kit and ease of following titration schedule.14

Figure 5. The 4-week Titration Kit is available through sample or prescription*
Figure 5
Image shown is not an actual 4-week Titration Kit. Tablets not shown at actual size.

Eligible patients can start at no cost with the 4-week Titration Kit. Exclusions and limitations apply. Refer to: AUSTEDOCARDFORM.com.

*Prescription should not include refills; provide a separate prescription for maintenance dose.

For patients currently on AUSTEDO BID, transitioning to once-daily AUSTEDO XR is straightforward. Simply write once-daily AUSTEDO XR for their next refill at the same total daily dose as AUSTEDO BID.11

Summary

Patients with a mood disorder are at an increased risk for TD and may experience a high degree of awareness of the impact of the disorder on their lives.7-10 APA guidelines recommend VMAT2 inhibitors, such as AUSTEDO XR, as first-line treatment for TD, irrespective of severity, if it has an impact on the patient.8

The two pivotal trials of AUSTEDO demonstrated a statistically significant greater improvement in AIMS total score compared with placebo.12,13 In addition, long-term results from the RIM-TD study established TD symptom control in patients with mood disorders, which was sustained for three years.14

AUSTEDO XR is a one-pill, once-daily treatment for TD that provides flexibility to titrate until effective and tolerable symptom control is achieved.11,14 AUSTEDO XR is available in 6 mg, 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg, and 48 mg extended-release tablets.11,14

References
1. 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. 2. Fahn S, Jankovic J, Hallett M, eds. Principles and Practice of Movement Disorders. 2nd ed. Elsevier Saunders; 2011. 3. Zutshi D, Cloud LJ, Factor SA. Tardive syndromes are rarely reversible after discontinuing dopamine receptor blocking agents: experience from a university-based movement disorder clinic. Tremor Other Hyperkinet Mov (N Y). 2014;4:266. 4. 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. 5. 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. 6. 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. 7. 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. 8. American Psychiatric Association. The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia. 3rd ed. Washington, DC: American Psychiatric Association; 2021. 9. McCutcheon RA, Keefe RSE, McGuire PK. Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment. Mol Psychiatry. 2023;28(5):1902-1918. 10. Yassa R. Functional impairment in tardive dyskinesia: medical and psychosocial dimensions. Acta Psychiatr Scand. 1989;80(1):64-67. 11. AUSTEDO® XR (deutetrabenazine) extended-release tablets/AUSTEDO® current Prescribing Information. Parsippany, NJ: Teva Neuroscience, Inc. 12. Fernandez HH, Factor SA, Hauser RA, et al. Randomized controlled trial of deutetrabenazine for tardive dyskinesia: the ARM-TD study. Neurology. 2017;88(21):2003-2010. 13. Anderson KE, Stamler D, Davis MD, et al. Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Psychiatry. 2017;4(8):595-604. 14. Data on file. Teva Neuroscience, Inc. Parsippany, NJ. 15. Hauser RA, Barkay H, Fernandez HH, et al. Long-term deutetrabenazine treatment for tardive dyskinesia is associated with sustained benefits and safety: a 3-year, open-label extension study. Front Neurol. 2022;13:773999. 16. Ingrezza® (valbenazine) capsules Prescribing Information. San Diego, CA: Neurocrine Biosciences, Inc.
Prev ARTICLE
Case Study
Management of Tardive Dyskinesia in a Patient With a Mood Disorder
Next ARTICLE
Expert Commentary
Expert Commentary With Gus Alva, MD, DFAPA
Past Volumes
Volume 16
Consideration of Possible Drug-Drug Interactions Is a Critical Step in the Treatment of Tardive Dyskinesia (TD)
Read more
Volume 15
Classifying TD and DIP as EPS Leads to Misdiagnosis and Inappropriate Use of Anticholinergics in TD
Read more
Volume 14
Understanding the Long-Term Nature of TD and Its Impact on the Underlying Mental Health Condition
Read more
Volume 13
Exploring the Nurse Practitioner's Role in the Screening and Assessment of Patients for Tardive Dyskinesia
Read more
Scroll Top
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.