Investigating Real-World Benztropine Usage Patterns in Movement Disorders: Claims Analysis and Health Care Provider Survey Results.

Objective: To evaluate real-world treatment patterns for patients initiating benztropine and to understand treatment approaches in patients with drug-induced movement disorders from a health care provider perspective.Methods: A retrospective claims analysis was conducted among patients with evidence of benztropine initiation from January 2017 through March 2020 to assess treatment patterns and patient health care resource utilization. Subsequently, a 30-minute, United States-based online survey fielded from December 2021 to January 2022 was sent to physicians, nurse practitioners, and physician assistants who reported a primary care or psychiatry specialty currently treating drug-induced movement disorders and prescribed benztropine.Results: The health care claims analysis included 112,542 patients. Polypharmacy and multiple comorbidities were frequent characteristics in this population; 54.1% of patients had ≥ 2 comorbidities at baseline, and 59.1% had claims for > 10 medications. Benztropine was used for > 3 months in > 50% of the population. Health care costs and resource utilization were high, with mean all-cause pharmacy and outpatient costs totaling $11,755. Survey results from 349 primary care or psychiatry health care providers indicated that benztropine is often used in non-tardive dyskinesia drug-induced movement disorders but frequently continued for > 3 months or used in tardive dyskinesia. In this study, psychiatry providers prescribed benztropine in line with guideline recommendations more often than primary care providers; however, < 40% indicated familiarity with 2020 American Psychiatric Association Practice Guideline for the Treatment of Patients with Schizophrenia.Conclusions: These complementary analyses suggest that benztropine is used long-term in non-tardive dyskinesia drug-induced movement disorders and in tardive dyskinesia despite risks of worsening tardive dyskinesia or adverse effects.Prim Care Companion CNS Disord 2023;25(4):22m03472. Author affiliations are listed at the end of this article.

The Clinical and Economic Burden of Tardive Dyskinesia in Israel: Real-World Data Analysis.

PURPOSE/BACKGROUND: Tardive dyskinesia (TD) is a hyperkinetic movement disorder caused by exposure to dopamine-receptor blockers. Data on TD burden in Israel are scarce. This analysis assesses the clinical and economic burden of TD in Israeli patients. METHODS/PROCEDURES: This retrospective analysis used a national health plan database (Maccabi Healthcare Services), representing 25% of the Israeli population. The study included adults alive at index date with an International Classification of Diseases, Ninth Revision, Clinical Modification TD diagnosis before 2018 and more than or equal to 1-year enrollment before diagnosis. Tardive dyskinesia patients were matched to non-TD patients (1:3) by underlying psychiatric condition, birth year, and sex. Treatment patterns and 2018 annual health care resource utilization and costs were assessed. FINDINGS/RESULTS: Of 454 TD patients alive between 2013 and 2018, 333 alive on January 1, 2018, were matched to 999 non-TD patients. At baseline, TD patients had lower socioeconomic status and higher proportion of chronic kidney disease and antipsychotic medication use; all analyses were adjusted accordingly. Tardive dyskinesia patients had significantly more visits to general physicians, neurologists, psychiatrists, physiotherapists, and emergency departments versus non-TD patients (all P < 0.05). Tardive dyskinesia patients also had significantly longer hospital stays than non-TD patients ( P = 0.003). Total healthcare and medication costs per patient were significantly higher in the TD versus non-TD population (US $11,079 vs US $7145, P = 0.018). IMPLICATIONS/CONCLUSIONS: Israeli TD patients have higher clinical and economic burden than non-TD patients. Understanding real-world health care resource utilization and costs allows clinicians and decision makers to quantify TD burden and prioritize resources for TD patients' treatment.

Cost-effectiveness of valbenazine compared with deutetrabenazine for the treatment of tardive dyskinesia.

AIMS: To evaluate clinical and economic outcomes associated with valbenazine compared with deutetrabenazine in patients with tardive dyskinesia (TD) using a model that accounts for multiple dimensions of patient health status. MATERIALS AND METHODS: A discretely integrated condition event model was developed to evaluate the cost-effectiveness of treatment with valbenazine and deutetrabenazine in a synthetic cohort of 1,000 patients with TD who were receiving antipsychotic medication to treat an underlying psychiatric disorder. Clinical inputs were derived from relevant clinical trials or from publicly available sources. Patients were assessed over 1 year using ≥50% improvement from baseline in Abnormal Involuntary Movement Scale (AIMS) total score as the primary definition of response. Response at 1 year using Clinical Global Impression of Change (CGIC) score ≤2 was also assessed. Health outcomes included quality-adjusted life years (QALYs), life years, proportion responding to treatment at 1 year, and number of psychiatric relapses. RESULTS: Regardless of the definition used for response, patients treated with valbenazine were more likely to have responded to treatment at 1 year, lived longer, and accrued more QALYs than patients who received deutetrabenazine. Using the AIMS response criterion, the incremental cost-effectiveness ratio was $9,951/QALY for valbenazine compared with deutetrabenazine. By comparison, using the CGIC response criterion valbenazine dominated deutetrabenazine with valbenazine-treated patients accumulating more QALYs (3.4 vs 3.3 years) and incurring lower lifetime costs ($252,311 vs $283,208) than deutetrabenazine-treated patients. LIMITATIONS: There are no head-to-head trials of valbenazine and deutetrabenazine, so probabilities of response used in the model were calculated based on an indirect treatment comparison of results from individual trials with one drug or the other, using only those metrics reported across trials. CONCLUSIONS: In patients with TD, treatment with valbenazine is highly cost-effective compared with deutetrabenazine.

Expanding phenomenologic heterogeneity of tardive syndromes: Time for an updated assessment tool.

Tardive syndromes (TDS) are a group of hyperkinetic and hypokinetic movement disorders that occurs after exposure to dopamine receptor blocking agents such as antipsychotic and antiemetic drugs. The Abnormal Involuntary Movement Scale (AIMS) is a widely used instrument that has become the standard for assessment of tardive dyskinesia (TDD), the most common form of TDS. However, the AIMS has a number of clinimetric limitations and was designed primarily to assess the anatomic distribution and severity of involuntary movements without regard to phenomenology. To build on recent advances in understanding and treatment of TDS, re-evaluation and revision of the AIMS that could aid both clinical practice and research may be worthwhile. Challenges, such as retaining the efficiency of the current AIMS, incorporating evaluation of impairment in daily activities, and re-training clinicians for a revised examination procedure and rating instrument, are very likely surmountable.

A Modified Delphi Consensus Study of the Screening, Diagnosis, and Treatment of Tardive Dyskinesia.

OBJECTIVE: A nominal group process followed by a modified Delphi method was used to survey expert opinions on best practices for tardive dyskinesia (TD) screening, diagnosis, and treatment and to identify areas lacking in clinical evidence. PARTICIPANTS: A steering committee of 11 TD experts met in nominal group format to prioritize questions to be addressed and identify core bibliographic materials and criteria for survey panelists. Of 60 invited experts, 29 (23 psychiatrists and 6 neurologists) agreed to participate. EVIDENCE: A targeted literature search of PubMed (search term: tardive dyskinesia) and recommendations of the steering committee were used to generate core bibliographic material. Inclusion criteria were as follows: (1) review articles, meta-analyses, guidelines, or clinical trials; (2) publication in English between 2007 and 2017; (3) > 3 pages in length; and (4) publication in key clinical journals with impact factors ≥ 2.0. Of 29 references that met these criteria, 18 achieved a score ≥ 5 (calculated as the number of steering committee votes multiplied by journal impact factor and number of citations divided by years since publication) and were included. CONSENSUS PROCESS: Two survey rounds were conducted anonymously through electronic media from November 2017 to January 2018; responses were collected, collated, and analyzed. Respondent agreement was defined a priori as unanimous (100%), consensus (75%-99%), or majority (50%-74%). For questions using a 5-point Likert scale, agreement was based on percentage of respondents choosing ≥ 4 ("agree completely" or "agree"). Round 1 survey included questions on TD screening, diagnosis, and treatment. Round 2 questions were refined per panelist feedback and excluded Round 1 questions with < 25% agreement and > 75% agreement (unless feedback suggested further investigation). CONCLUSIONS: Consensus was reached that (1) a brief, clinical assessment for TD should be performed at every clinical encounter in patients taking antipsychotics; (2) even mild movements in 1 body area may represent possible TD; (3) management requires an overall evaluation of treatment, including reassessment of antipsychotics and anticholinergics as well as consideration of vesicular monoamine transporter 2 (VMAT2) inhibitors; and (4) informed discussions with patients/caregivers are essential.

Medication Options and Clinical Strategies for Treating Tardive Dyskinesia.

Valbenazine and deutetrabenazine are FDA-approved as treatment for tardive dyskinesia (TD). Both medications are vesicular monoamine transporter type 2 (VMAT2) inhibitors, and both are effective for reducing TD symptoms. Clinicians need to be aware of the adverse effects of valbenazine and deutetrabenazine, as well as other key differences between the two, in order to individualize treatment. Using the Abnormal Involuntary Movement Scale assists clinicians in assessing progress for each patient. Treating TD effectively with these new medications will reduce the burden of the condition for patients.

Cumulative Burden of Illness in Veterans With Tardive Dyskinesia and Serious Mental Disorders.

PURPOSE/BACKGROUND: To inform cost-benefit decisions for veterans, the risk of tardive dyskinesia (TD) and its impact on comorbidities and outcomes were assessed. METHODS/PROCEDURES: In a retrospective study, veterans with schizophrenia/schizoaffective, and bipolar and major depressive disorders receiving antipsychotics during the period October 1, 2014, to September 30, 2015, were identified. Tardive dyskinesia was determined by International Classification of Diseases, Ninth Revision, Clinical Modification codes. Correlates of TD were examined using χ or t tests. Odds ratios (ORs) and ß parameters with 95% confidence intervals (CIs) for categorical and continuous variables associated with TD were derived from a multivariate logistic and linear regression, respectively. FINDINGS/RESULTS: Among 7985 veterans, 332 (4.2%) were diagnosed as having possible TD. The odds of having TD were higher for older veterans (OR, 1.04; 95% CI, 1.03-1.05; P < 0.0001) and veterans with schizophrenia/schizoaffective disorder (OR, 1.54; 95% CI, 1.23-1.91; P < 0.0001) or diabetes (OR, 1.64; 95% CI, 1.30-2.06; P < 0.0001). Veterans with TD received more antipsychotic prescriptions (mean ± SD, 18.4 ± 30.3 vs 13.3 ± 26.4; P = 0.003) and days of supply (233.9 ± 95.4 vs 211.4 ± 102.0; P < 0.0001). They were more likely to have received 2 or more antipsychotics (27.1% vs 19.7%, P = 0.0009) and benztropine (OR, 2.25: 95% CI 1.73-2.91; P < 0.0001). Veterans with TD had a higher Charlson Comorbidity Index score (ß = 0.32; SE, 0.09; 95% CI, 0.14-0.49; P = 0.0003) and higher odds of any medical hospitalization (OR, 1.45; 95% CI, 1.07-1.95; P = 0.001). IMPLICATIONS/CONCLUSIONS: The diagnosis of possible TD was associated with older age, schizophrenia/schizoaffective disorder, medical comorbidity, and hospitalization. Tardive dyskinesia may be a marker for patients at risk of adverse health care outcomes and diminished quality of life.

Risk assessment and prediction of TD incidence in psychiatric patients taking concomitant antipsychotics: a retrospective data analysis.

BACKGROUND: Tardive dyskinesia (TD) is a serious, often irreversible movement disorder caused by prolonged exposure to antipsychotics; identifying patients at risk for TD is critical to preventing it. Predictive models for the occurrence of TD can improve patient monitoring and inform implementation of counteractive interventions. This study aims to identify risk factors associated with TD and to develop a model using a retrospective data analysis to predict the incidence of TD among patients taking antipsychotic medications. METHODS: Adult patients with schizophrenia, major depressive disorder, or bipolar disorder taking oral antipsychotics were identified in a Medicaid claims database (covering six US states from 1997 to 2016) and divided into cohorts based on whether they developed TD within 1 year after the first observed claim for antipsychotics. Patient characteristics between cohorts were compared, and univariate Cox analyses were used to identify potential TD risk factors. A cross-validated version of the least absolute shrinkage and selection operator regression method was used to develop a parsimonious multivariable Cox proportional hazards model to predict diagnosis of TD. RESULTS: A total of 189,415 eligible patients were identified. Potential TD risk factors were identified based on the cohort analysis within a sample of 151,280 patients with at least 1 year of continuous eligibility. The prediction model had a clinically meaningful concordance of 70% and was well calibrated (P = 0.32 for Hosmer-Lemeshow goodness-of-fit test). Age (hazard ratio [HR] = 1.04, P < 0.001), diagnosis of schizophrenia (HR = 1.99, P < 0.001), antipsychotic dosage (up to 100 mg/day chlorpromazine equivalent; HR = 1.65, P < 0.01), and comorbid bipolar and related disorders (HR = 1.39, P < 0.01) were significantly associated with an increased risk of TD. Other potential risk factors included history of extrapyramidal symptoms (HR = 1.35), other movement disorders (parkinsonism, HR = 1.43; bradykinesia, HR = 1.44; tremors, HR = 2.12, and myoclonus, HR = 2.33), and diabetes (HR = 1.13). A modest reduction in the risk of TD was associated with the use of second-generation antipsychotics (HR = 0.85) versus first-generation drugs. CONCLUSIONS: This study identified factors associated with development of TD among patients taking antipsychotics. The prediction model described herein can enable physicians to better monitor patients at high risk for TD and recommend appropriate treatment plans to help maintain quality of life.

Health Care Resource Utilization and Costs for Patients with Tardive Dyskinesia.

BACKGROUND: Tardive dyskinesia (TD) is an often-irreversible movement disorder affecting any part of the body. Patients experience debilitating symptoms that lower quality of life and increase mortality. Prolonged exposure to dopamine antagonists, which are frequently prescribed for psychiatric disorders as neuroleptic (antipsychotic) drugs, is a common cause of TD. The estimated prevalence of TD is 20%-50% among patients on antipsychotics, and the reported incidence of TD ranges from < 1% to 42%, depending on the antipsychotics studied. However, there are few real-world studies examining health care utilization and the economic burden of TD. OBJECTIVE: To assess health care utilization and costs in a sample of patients with TD from the commercially insured and Medicare supplemental U.S. METHODS: A retrospective analysis was conducted using Truven MarketScan Commercial and Medicare administrative claims data. Patients were included in the TD group if they had the first TD diagnosis (index date) between January 1, 2008, and September 30, 2014, with ≥ 1 inpatient or ≥ 2 outpatient nondiagnostic claims for TD (ICD-9-CM code 333.85). Patients without TD were randomly assigned an index date. Further inclusion criteria for all patients were ≥ 12 months of pre- and post-index medical and pharmacy continuous enrollment and no evidence of TD claims during the pre-index period. Patients with TD were directly matched to patients without TD within subgroups for schizophrenia, major depressive disorder, bipolar disorder, and other psychiatric disorders and propensity matched on other demographic and clinical factors. Descriptive statistics on the incidence of resource utilization and costs of health care were reported. RESULTS: Of 3,397 patients with TD, 834 met the selection criteria and were matched to 834 non-TD controls. Patients with TD generally had significantly greater utilization during the 12 months after TD diagnosis than in the 12 months before TD diagnosis. Their rates for health care utilization and costs were also substantially higher than for those without TD. During the post-TD-diagnosis time, inpatient admissions (55.5% vs. 26.1%; P < 0.001) and emergency room visits (61.5% vs. 50.6%; P < 0.001) occurred more for patients with TD than for patients without TD. Total health care costs were significantly greater for patients with TD than for those without TD ($54,656 vs. $28,777; P < 0.001). CONCLUSIONS: Patients diagnosed with TD demonstrate significantly higher health care utilization and costs compared with non-TD patients. DISCLOSURES: This study was funded by Teva Pharmaceuticals (Petach Tikva, Israel). Truven Health Analytics, an IBM Watson Health Company, received payment from Teva Pharmaceuticals for the analysis in this study. Carroll is employed by Teva Pharmaceuticals and Irwin is employed by Truven Health Analytics, an IBM Watson Health Company.

Antipsychotic-induced tardive dyskinesia: update on epidemiology and management.

PURPOSE OF REVIEW: To provide an update on the frequency of antipsychotic-induced tardive dyskinesia and its management in patients with schizophrenia spectrum disorders in studies published since the last systematic review in 2008. RECENT FINDINGS: Recent data about antipsychotic-induced tardive dyskinesia in patients with schizophrenia underscore the superiority of newer generation antipsychotics (21%) over first-generation antipsychotics (30%) with respect to prevalence and incidence rates. Regarding recently tested management strategies, the new vesicular monoamine transporter 2 inhibitors valbenazine and deutetrabenazine have been found to be effective and may be considered as first-line pharmacotherapy for tardive dyskinesia. Owing to quality issues of randomized controlled trials and/or small sample sizes, limited and conflicting evidence remains for most treatment strategies. SUMMARY: The reviewed literature reveals lower prevalence rates of antipsychotic-induced tardive dyskinesia in patients treated with newer generation compared with first-generation antipsychotics. The evidence of vesicular monoamine transporter 2 inhibitors as a first-line therapy for tardive dyskinesia is well supported by several controlled clinical trials.

Prevalence of and Risk Factors for Extrapyramidal Side Effects of Antipsychotics: Results From the National FACE-SZ Cohort.

BACKGROUND: Extrapyramidal side effects (EPS) have been identified as a complication of antipsychotic treatment. Previous meta-analyses have investigated EPS prevalence and risk factors in randomized clinical trials with highly selected patients, but studies in real-world schizophrenia are missing. OBJECTIVE: To examine the prevalence and clinical correlates associated with EPS in a nonselected national multicenter sample of stabilized patients with schizophrenia. METHODS: Between 2010 and 2016, patients suffering from schizophrenia (DSM-IV-TR criteria) were recruited through the FondaMental Academic Centers of Expertise for Schizophrenia (FACE-SZ) network and data were collected during a comprehensive 1-day-long standardized evaluation. The Simpson-Angus Scale and the Abnormal Involuntary Movement Scale were used to assess drug-induced parkinsonism (DIP) and tardive dyskinesia, respectively. RESULTS: The overall prevalence of DIP and tardive dyskinesia was 13.2% and 8.3%, respectively, in this community-dwelling sample of 674 patients. DIP was associated with negative symptoms (Positive and Negative Syndrome Scale [PANSS] subscore) (adjusted odds ratio [aOR] = 1.102, P < .001), first-generation antipsychotic prescription (aOR = 2.038, P = .047), and anticholinergic drug administration (aOR = 2.103, P = .017) independently of sex, age, disorganization (PANSS disorganized factor), and antipsychotic polytherapy. Tardive dyskinesia was associated with PANSS disorganized factor (aOR = 1.103, P = .049) independently of sex, age, negative symptoms, excitation, first-generation antipsychotic prescription, and benzodiazepine and anticholinergic drug administration. CONCLUSIONS: Our results indicate the high prevalence of EPS in a nonselected community-dwelling clinically stable sample of outpatients with schizophrenia. In the monitoring of antipsychotic treatment, EPS should be systematically evaluated, especially when negative symptoms and disorganization or cognitive alteration are present. Monotherapy with a second-generation antipsychotic should be preferentially initiated for patients with these side effects.

Revisiting the Abnormal Involuntary Movement Scale: Proceedings From the Tardive Dyskinesia Assessment Workshop.

OBJECTIVE: To provide an historic overview of the Abnormal Involuntary Movement Scale (AIMS) in clinical trials of tardive dyskinesia (TD), with current recommendations for analyzing and interpreting AIMS data. PARTICIPANTS: Seven psychiatrists and 1 neurologist were selected by the workshop sponsor based on each individual's clinical expertise and research experience. EVIDENCE: Using PubMed entries from January 1970 to August 2017, participants selected studies that used the AIMS to evaluate TD treatments. The selections were intended to be representative rather than prescriptive or exhaustive, and no specific recommendations for TD treatment are implied. CONSENSUS PROCESS: The Working Group met in October 2016 to discuss the AIMS as an assessment tool, outline the challenges of translating clinical trial results into everyday clinical practice, and propose different methods for reporting AIMS data in clinically relevant terms. Recommendations for selecting TD studies for review, analyzing and interpreting AIMS data, and synthesizing discussions among the participants were initiated during the onsite workshop and continued remotely throughout development of this report. Disagreements were resolved via group e-mails and teleconferences. Consensus was based on final approval of this report by all workshop participants. CONCLUSIONS: For both research and clinical practice, the AIMS is a valid measure for assessing TD and the effects of treatment, but alternative analyses of AIMS data (eg, effect size, minimal clinically important difference, response analyses, category shifts) may provide broader evidence of clinical effectiveness. No single analysis of AIMS data can be considered the standard of clinical efficacy; multiple analytic approaches are recommended.

Tardive Dyskinesia: Recognition, Patient Assessment, and Differential Diagnosis.

Tardive dyskinesia (TD) is an involuntary movement disorder associated with antipsychotic treatment. Because of the serious and potentially irreversible nature of TD, accurate diagnosis is crucial. However, diagnosing TD can be challenging, since the subtle and often fluctuating symptoms can be easily mistaken for symptoms of mental illness or other side effects. Although the risk of developing TD in relation to treatment with second-generation antipsychotics is lower than that associated with first-generation antipsychotics, the risk still exists and may be greater than once believed. Clinicians prescribe antipsychotics for a variety of illnesses and may underestimate the possibility of a patient developing TD, thus missing early signs of the disorder. In this ACADEMIC HIGHLIGHTS, experts review the prevalence, phenomenology, risk factors, and impact of TD, illustrated by case examples, and provide valuable clinical information to guide early recognition and accurate diagnosis.

Tardive Dyskinesia Associated with Atypical Antipsychotics: Prevalence, Mechanisms and Management Strategies.

All antipsychotics, including the atypical antipsychotics (AAPs), may cause tardive dyskinesia (TD), a potentially irreversible movement disorder, the pathophysiology of which is currently unknown. The prevention and treatment of TD remain major challenges for clinicians. We conducted a PubMed search to review the prevalence and etiology of and management strategies for TD associated with AAPs. TD prevalence rates varied substantially between studies, with an estimated prevalence of around 20% in patients using AAPs. The risk of TD is lower with AAPs than with typical antipsychotics (TAPs) but remains a problem because AAPs are increasingly being prescribed. Important risk factors associated with TD include the duration of antipsychotic use, age, and ethnicity other than Caucasian. Theories about the etiology of TD include supersensitivity of the dopamine receptors and oxidative stress, but other neurotransmitters and factors are probably involved. Studies concerning the management of TD have considerable methodological limitations. Thus, recommendations for the management of TD are based on a few trials and clinical experience, and no general guidelines for the management of TD can be established. The best management strategy remains prevention. Caution is required when prescribing antipsychotics, and regular screening is needed for early detection of TD. Other strategies may include reducing the AAP dosage, switching to clozapine, or administering vesicular monoamine transporter (VMAT)-2 inhibitors. In severe cases, local injections of botulinum toxin or deep brain stimulation may be considered. More clinical trials in larger samples are needed to gather valid information on the effect of interventions targeting TD.

Two New Drugs for Tardive Dyskinesia Hit the Market.

Ingrezza and Austedo were approved last year. ICER calculations raise questions about their price.

Epidemiology, Prevention, and Assessment of Tardive Dyskinesia and Advances in Treatment.

​​ Tardive dyskinesia (TD) is a disorder characterized by involuntary movements, typically of the orofacial muscles and also of the extremities and other muscle groups. The condition is associated with exposure to dopamine receptor blocking agents, including antipsychotics. Because the indications and off-label uses for these agents have expanded over the last 2 decades, a larger number of patients are receiving antipsychotic medications than in the past. While evidence suggests that patients being treated with second-generation antipsychotics have less risk for developing TD than those treated with first-generation antipsychotics, the decreased risk is not as great as was originally expected. In addition, patients with chronic psychiatric conditions often require long-term use of antipsychotics, putting them at risk for TD. This article addresses the prevalence, risk factors, and prevention of TD; assessment strategies including diagnostic criteria and rating scales; and evidence for TD treatments, including 2 newly approved medications: deutetrabenazine and valbenazine. ​​​.