Abstract

Introduction

Tardive dyskinesia (TD) is an involuntary, hyperkinetic movement disorder associated with prolonged exposure to dopamine receptor-blocking agents, such as antipsychotics and metoclopramide.¹ The symptoms of TD often persist after discontinuing the offending drug and typically include excessive blinking, grimacing, lip puckering and smacking, or twisting and writhing in the upper and lower trunk and extremities.^1,2 The clinical burden of TD symptoms is associated with impaired social and physical capabilities, leading to negative outcomes such as social withdrawal, shame, embarrassment, and helplessness.^3,4 TD symptoms can also increase the stigma associated with mental illness and reduce patients’ quality of life (QOL).^5,6 Vesicular monoamine transporter 2 (VMAT2) inhibitors show clinically meaningful improvement in TD symptoms regardless of underlying psychiatric diagnosis or patient characteristics and are considered the standard of care for TD.^7-10 Valbenazine and deutetrabenazine are the 2 reversible VMAT2 inhibitors approved by the United States (US) Food and Drug Administration (FDA) for managing TD symptoms.^11,12 Although the phase 2 and 3 clinical studies for these 2 agents showed statistically significant improvements in TD severity using the Abnormal Involuntary Movement Scale (AIMS)¹³ score (items 1-7), none of the clinical trials showed statistically significant improvement in patient-reported health-related QOL or indicators of social or physical well-being, as QOL was not consistently measured throughout the trials.^8,14-18

Reduction in severity of TD motor symptoms represents one aspect of treatment-related changes, but additional measures of social and physical well-being help capture the broader extent of patient benefit. Published case reports note that VMAT2 inhibitors provide improvement not only in clinical disease severity, but also in social and physical well-being.^19,20 Unfortunately, there is limited information on this topic from the prospective clinical trials of the new VMAT2 inhibitors. Additionally, retrospective data regarding the social and/or physical impact of the symptoms of TD or potential effect of treatment on social and physical capabilities are challenging to locate in electronic medical records or insurance claim databases.

To expand the understanding of this issue, Neurocrine Biosciences, Inc. sponsored the present hybrid study composed of a clinician survey and chart review by treating clinicians. The primary objective of this study was to assess if patients who showed improvement in TD movement-associated symptoms showed changes in 3 other aspects: (1) social capabilities, with individual domains of socialization and engagement with family and friends and ability to work or go to school; (2) physical capabilities, with individual domains of mobility, eating and speech, and activities of daily living; and (3) primary psychiatric condition. The goal was to provide real-world clinician-reported data to supplement the extant clinical trial data on VMAT2 inhibitors and to inform clinicians, patients, payers, and regulatory bodies about the overall potential benefits of VMAT2 inhibitors for the treatment of TD.

Methods

The survey instrument was jointly developed by IQVIA and Neurocrine Biosciences, Inc. and was administered by IQVIA, who invited physicians, nurse practitioners, and physician assistants based in the US to complete the study. These clinicians who had prescribed valbenazine for TD within the past 24 months were asked to complete a web-based survey consisting of specific data of interest for VMAT2-treated patients. They may have also prescribed deutetrabenazine or off-label tetrabenazine for TD, as determined by IQVIA. Invitations were sent to 2359 individuals, and 240 responses were received for a 10.2% response rate. Survey participants had to provide consent to participate and were compensated for completing the survey. The survey participants were blinded to the sponsor, and the sponsor was blinded to the survey participants.

In this hybrid methodology, the clinician was asked to input data from the chart with recall allowed to complete items not directly found within the chart. Clinicians provided patient-specific information of interest consisting of both pre-VMAT2 inhibitor treatment and post-VMAT2 inhibitor treatment data. For testing clarity and clinical relevance of the survey, IQVIA obtained feedback from 4 clinicians in a pilot interview (via phone) that was used to improve the clarity and content of the survey before it was extended to all survey participants.

Clinicians provided data from up to 10 patient charts for adult patients (aged ≥18 years) who started at least 1 VMAT2 inhibitor (valbenazine, deutetrabenazine, or off-label tetrabenazine) for TD on or after January 1, 2018, and completed at least 2 months of treatment. The study focused on the impact of TD symptom improvement on social and/or physical capabilities. Data provided by the clinicians were reviewed for quality (logic) and completeness before inclusion in the final analysis. The database contains no patient-identifiable data beyond age and gender. All patient-related data were protected in compliance with HIPAA rules on patient confidentiality.

Clinicians participating in the survey logged into a secure website to complete a survey (1 per patient), which included items related to TD symptom presentation (body location and severity), impact of TD on social and physical capabilities prior to treatment, and any improvements after VMAT2 inhibitor treatment. Clinician responses to the multiple-choice questions were based on their chart review of any documented patient-specific disease impact, clinician recall from patient interactions, and clinician judgment. Clinicians described characteristics of patient symptoms by identifying the body regions with TD symptoms, duration of TD symptoms, and awareness of symptoms. Disease severity was categorized as “asymptomatic,” “mild,” “moderate,” or “severe” based on their clinical perception. Clinicians categorized the pretreatment impact of TD symptoms on patient social and physical well-being into one of the following ratings: “no impact,” “somewhat impacted,” and “significantly impacted.” Likewise, clinicians categorized patient TD symptom improvements posttreatment into one of the following ratings: “none,” “somewhat improved,” and “significantly improved.” These defined categories allowed understanding of the observed impact of the disease before treatment compared to TD symptom improvements after treatment with a VMAT2 inhibitor. The study also collected information related to noticeable changes in psychiatric conditions based on clinician judgment as “none,” “somewhat improved,” or “significantly improved” after treatment with VMAT2 inhibitors. The survey was approved by the Western Institutional Review Board. Data, collected from July 24, 2019, to August 30, 2019, were analyzed and summarized with descriptive statistics. Statistics for frequencies of responses and measures of central tendency as means were reported.

Results

Location and Severity of TD Symptoms

The most commonly reported regions where TD symptoms were present included the head or face (82%) and upper extremities (42%), and 47% of the patients had symptoms in ≥2 body regions (Figure 1). More than half (61%) of patients experienced TD symptoms for 1 to 5 years, and 6% experienced symptoms for ≥11 years. Clinicians rated TD symptom severity to be mild (111/601; 18%), moderate (328/601; 55%), or severe (160/601; 27%). Clinician-reported patient awareness of TD symptoms was highest for lips (79%) and tongue (77%) and lowest for ankles (55%) and toes (55%).

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Impact of TD Symptoms

Clinicians reported that nearly all patients had social or physical impacts from their TD symptoms (Figure 2). Most patients (93%; 560/601) were impacted in at least 1 social domain, and 88% (528/601) were impacted in at least 1 physical domain. Clinicians rated social domains as “significantly impacted” or “somewhat impacted” in 84% (504/601) of patients. In the social domains, clinicians most frequently reported “significantly impacted” or “somewhat impacted” for socializing (504/601; 84%) and engagement with family and friends (461/601; 77%). Clinicians rated physical domains as “significantly impacted” or “somewhat impacted” in 71% (427/601) of patients. In the physical domains, clinicians most frequently reported “significantly impacted” or “somewhat impacted” for speech and communication (429/601; 71%) and eating (403/601; 67%).

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Impact of TD Symptom Improvement on Social and Physical Domains

If clinicians reported improvement in TD symptoms, the survey sought to understand if there was a commensurate improvement in the social and physical domains that were negatively impacted by TD symptoms. For example, there were 142 patients in the study where TD symptoms “significantly improved” following VMAT2 treatment. Of those 142 patients with “significant improvement” in TD symptoms, there were 125 where TD symptoms impacted the socializing domain. For this subset of patients, clinicians indicated that 90 (72% of 125) had improved “significantly” in socializing after their TD symptoms improved following VMAT2 inhibitor treatment, 28 (22%) patients improved “somewhat,” and the remaining 7 (6%) had no observed improvement (Figure 3).

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Patients with “Significantly Improved” TD Symptoms

Many of the patients for whom clinicians reported “significant improvement” in TD symptoms with a VMAT2 inhibitor were also reported to have improvement in social and physical well-being, as well as psychiatric condition improvement. Of this group (n = 142), 96.5% (137/142) improved in at least 1 social domain, and 94% (134/142) improved in at least 1 physical domain. Psychiatric conditions were rated as improved in 73% (74/142) of these patients (Figure 3). Engagement with family and friends (89/116; 77%), engagement in outside function (82/109; 75%), mobility (63/83; 76%), and speech and communication (79/108; 73%) had the largest number of patients rated by clinicians as “significantly improved” in the social and physical domains.

Patients with “Much Improved” TD Symptoms

Among 230 patients in the “much improved” TD symptoms category, 98% (226/230) showed improvement in at least 1 social domain, and 97% (224/230) in at least 1 physical domain while 70% were rated as having improvement in their primary psychiatric condition (Figure 4). Socializing, engagement with family and friends, eating, and mobility were rated by clinicians as “significantly improved” in nearly half of the patients (47%-48%).

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Patients with “Somewhat Improved” TD Symptoms

Of the 168 patients categorized as “somewhat improved” in TD symptoms, few (3%-9%) showed “significant improvement” in any of the social or physical well-being domains (Figure 5). Likewise, a smaller proportion of patients (16%; 27/168) were categorized as having “significant improvement” in their psychiatric conditions. These data support the linkage between TD symptom improvement and well-being change.

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Discussion

This retrospective real-world study describes clinician perceptions of clinical improvement in TD symptoms along with concurrent improvement in social and/or physical well-being in patients receiving VMAT2 inhibitors. Changes in AIMS score are often tracked during VMAT2 inhibitor treatment, but they do not reflect changes in social or physical impairment associated with TD²¹ or its treatment. Given the potential impact of TD on social and physical functioning, it is important for clinicians to assess social and physical well-being function in patients on VMAT2 inhibitors as part of a holistic approach to gauging the impact of treating TD. While this survey was descriptive and retrospective in nature, the results are consistent with the data on functional improvement after TD treatment published in case studies.^19,20

In this survey, clinicians reported that 90% (n = 540) of patients on VMAT2 inhibitors showed improvement in TD symptoms and in their ability to socialize, engage with family and friends, work, or attend school. More than 90% reportedly showed improvements in the ability to perform physical activities such as speaking, eating, moving, or carrying out activities of daily living. In general, patients who were reported to have “significantly improved” TD symptoms with VMAT2 inhibitor treatment had a greater frequency of significant improvement in each domain, while patients who were reported to have “somewhat improved” had a lower frequency of significant improvement in each domain (compare Figures 3-5). The patients included in this study had similar characteristics to what has been observed in a real-world population of patients treated with antipsychotics and possible TD diagnosis. In the 204 patients with clinician-reported possible TD, 55% of patients had a mood disorder or other psychiatric condition (eg, anxiety disorder, major depressive disorder), and 83% had been exposed to an SGA.²² In the current study, 40% of patients had bipolar disorder (29%) or major depressive disorder (11%), and 74% had been exposed to a SGA. This further supports that TD can occur in other psychiatric conditions and with exposure to SGAs.

Inherent limitations exist for this study, partially due to the retrospective nature and use of the survey study design. The clinician sample is not necessarily representative of all those who treat TD patients, as only clinicians who had prescribed a VMAT2 inhibitor in the past 24 months based on pharmacy claims data were invited to participate, and the charts reviewed by the clinicians were prone to selection bias based on perceived treatment success. Second, improvements and outcomes were only captured by clinicians based on chart review and clinician recall. While standardized scales such as AIMS that prospectively measure TD signs are available, the survey did not capture clinicians’ use of the scale. Clinicians could have used AIMS-related data if it was recorded in the patient’s chart, but it was not a requirement for this study. As this study was a retrospective chart review, only data that were available in the charts could be used to complete the survey responses. Also, improvements in social and physical well-being reported in the study were not captured in a standardized manner; in order to reduce bias, a sample of qualified physicians pretested the survey before fieldwork, and the team designed the survey with close-ended responses to all of the questions. Finally, because this was intended to be a responder analysis, the survey did not collect information related to antipsychotic or VMAT2 inhibitor discontinuations or dose reductions due to adverse events or worsening TD symptoms. Only use of FGAs or SGAs were recorded and not the use of a specific antipsychotic.

This hybrid study was conducted to gather data that are not systematically captured in this population nor part of clinical trial endpoints. Therefore, given the limited information on functional outcomes from VMAT2 inhibitor therapy, more prospective clinical data are needed to investigate patient improvements in well-being related to improvements in TD symptom severity to reinforce the understanding that TD is a disorder that potentially impacts multiple aspects of patient well-being.

Conclusions

This retrospective clinician survey study provides preliminary real-world evidence suggesting that improvements in TD symptom severity with VMAT2 inhibitor treatment may be accompanied by improvements in social and physical well-being. Future prospective studies evaluating this relationship would further strengthen the value of VMAT2 inhibitors in treating TD. Therefore, a holistic approach to treating patients with TD that includes assessment of social and physical functioning is warranted. Such assessments should include patient perspective on impact of TD and subsequent improvements after VMAT2 inhibitor treatment initiation to appreciate the true value of these therapies.