Analysis of Antipsychotic Dosage in Patients With Tardive Dyskinesia: A Case-Control Study Using the Claims Database of the Corporate Health Insurance Association.

PURPOSE: This study aimed to assess the association between antipsychotic doses and the risk of tardive dyskinesia (TD) in clinical practice using a Japanese claims database from 2010 to 2020. METHODS: The study population included patients 15 years or older with a diagnosis record of schizophrenia, depression, or bipolar disorder who were prescribed antipsychotics. Using a case-control design, we categorized patients newly diagnosed with TD as cases, with corresponding 1:10 matching in the control group. The primary endpoint was the relative risk of TD in the >median dose and ≤median dose groups, as determined using conditional logistic regression analysis adjusted for age. RESULTS: The analysis population included 58,452 patients, and the median daily antipsychotic dose was 75 mg/d of chlorpromazine equivalent (CPZE). Of these, 80 were identified as TD cases, and doses >75 mg/d were associated with a significantly increased risk of TD at the last prescription and the maximum dose, respectively, before the date of the first diagnosis of TD. Post-hoc analysis further showed a significant association between doses ≥300 mg/d and the risk of TD compared to doses ≤75 mg/d and doses >75 to <300 mg/d. Comparing ≥300 mg/d versus >75 to <300 mg/d, the odd ratios at the last prescription and maximum dose before the first diagnosis of TD were 3.40 and 3.50, respectively. CONCLUSIONS: In the Japanese medical claims database of patients receiving relatively low doses of antipsychotics, doses >75 mg/d were associated with an increased risk of TD in a dose-dependent manner.

Deutetrabenazine Provides Long-Term Benefit for Tardive Dyskinesia Regardless of Underlying Condition and Dopamine Receptor Antagonist Use: A Post Hoc Analysis of the 3-Year, Open-Label Extension Study.

BACKGROUND: Deutetrabenazine is approved for adults with tardive dyskinesia (TD). Data based on underlying psychiatric condition and baseline dopamine receptor antagonist (DRA) use are limited. METHODS: Patients with TD who completed parent studies ARM-TD or AIM-TD were eligible for the 3-year, open-label extension study (RIM-TD; NCT02198794). In RIM-TD, deutetrabenazine was titrated based on dyskinesia control and tolerability. In this post hoc analysis of RIM-TD, total motor Abnormal Involuntary Movement Scale (AIMS) score and adverse events (AEs) were analyzed by underlying condition and DRA use at parent study baseline. RESULTS: Of 343 patients enrolled in RIM-TD, 336 were included in the analysis by underlying condition, and 337 were included in the analysis by DRA use. One hundred eighty-nine of 205 (92%) patients with psychotic disorders (schizophrenia/schizoaffective disorder) and 65 of 131 (50%) with mood and other disorders (depression/bipolar disorder/other) were receiving a DRA. Mean (SE) deutetrabenazine doses at week 145 were 40.4 (1.13), 38.5 (1.21), 39.9 (1.00), and 38.5 (1.48) mg/d for patients with psychotic disorders, those with mood and other disorders, and those receiving DRAs or not, respectively. Mean (SD) changes in total motor AIMS score from this study baseline to week 145 were -6.3 (4.53), -7.1 (4.92), -6.1 (4.42), and -7.5 (5.19). Exposure-adjusted incidence rates (number of AEs/patient-years) of AEs were similar across groups: any (1.02, 1.71, 1.08, 1.97), serious (0.10, 0.12, 0.10, 0.12), and leading to discontinuation (0.07, 0.05, 0.06, 0.05). CONCLUSIONS: Long-term deutetrabenazine provided clinically meaningful improvements in TD-related movements, with a favorable benefit-risk profile, regardless of underlying condition or DRA use.

Mining and analysis of security alert signals of valbenazine based on the Food and Drug Administration Adverse Event Reporting System database.

BACKGROUND: Valbenazine is used for tardive movement disorders in adults. Current studies on its safety are mostly from clinical trials and small case reports, limiting information on rare adverse reactions. This study investigated valbenazine-related adverse event (AE) risk signals using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: Valbenazine AEs data were collected from the FAERS database from 2017 Q2 to 2023 Q1, employing methods like reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network, and empirical Bayesian geometric mean. RESULTS: After data cleaning and drug screening, there were 20,837 AEs primarily suspecting valbenazine, involving 26 system organ classes and 125 AEs related to valbenazine at the preferred terms level. AEs related to valbenazine were mainly concentrated in nervous system disorders, general disorders and administration site conditions, and psychiatric disorders. Eye disorders and gastrointestinal disorders are new AEs not labeled in the valbenazine instructions. In addition, some new potential AE signals were found, such as Tardive dyskinesia and eyelid function disorder. CONCLUSION: The common AEs of valbenazine in the real world are consistent with the instructions, but there are some newly discovered suspicious AEs.

Comparative Analysis of Deutetrabenazine and Valbenazine as VMAT2 Inhibitors for Tardive Dyskinesia: A Systematic Review.

Background: Tardive Dyskinesia (TD) is a neurological disorder characterized by involuntary movements, often caused by dopamine receptor antagonists. Vesicular Monoamine Transporter 2 (VMAT2) inhibitors, such as valbenazine and deutetrabenazine, have emerged as promising therapies for TD and several clinical trials have shown their efficacy. This study aims to compare the efficacy and safety profile of VMAT2 inhibitors, focusing on a recent trial conducted in the Asian population. Methods: We reviewed the PubMed, Cochrane Library, Embase database, and clinicaltrials.gov between January 2017 and October 2023, using the keywords "tardive dyskinesia" AND ("valbenazine" [all fields] OR " deutetrabenazine " [all fields]) AND "clinical trial". The reviewed articles were studied for efficacy and side effects. Results: An initial search yielded 230 articles, of which 104 were duplicates. Following the title and abstract screening, 25 additional articles were excluded. A full-text review resulted in the exclusion of 96 more articles. Ultimately, four double-blind clinical trials met the inclusion criteria. The deutetrabenazine studies demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores compared to placebo, with no difference in adverse events. The valbenazine studies showed favorable results in reducing TD symptoms and were well-tolerated. Discussion: The studies reviewed in this analysis underscore the potential of deutetrabenazine and valbenazine as valuable treatment options for TD in diverse populations. Both medications demonstrated significant improvements in AIMS scores, suggesting their effectiveness in managing TD symptoms. Additionally, they exhibited favorable safety profiles, with low rates of serious adverse events and no significant increase in QT prolongation, parkinsonism, suicidal ideation, or mortality. Conclusion: The studies reviewed highlight the promising efficacy and tolerability of deutetrabenazine and valbenazine as treatments for Tardive Dyskinesia, providing new hope for individuals affected by this challenging condition.

An Evidence-Based Update on Anticholinergic Use for Drug-Induced Movement Disorders.

Drug-induced movement disorders (DIMDs) are associated with use of dopamine receptor blocking agents (DRBAs), including antipsychotics. The most common forms are drug-induced parkinsonism (DIP), dystonia, akathisia, and tardive dyskinesia (TD). Although rare, neuroleptic malignant syndrome (NMS) is a potentially life-threatening consequence of DRBA exposure. Recommendations for anticholinergic use in patients with DIMDs were developed on the basis of a roundtable discussion with healthcare professionals with extensive expertise in DIMD management, along with a comprehensive literature review. The roundtable agreed that "extrapyramidal symptoms" is a non-specific term that encompasses a range of abnormal movements. As such, it contributes to a misconception that all DIMDs can be treated in the same way, potentially leading to the misuse and overprescribing of anticholinergics. DIMDs are neurobiologically and clinically distinct, with different treatment paradigms and varying levels of evidence for anticholinergic use. Whereas evidence indicates anticholinergics can be effective for DIP and dystonia, they are not recommended for TD, akathisia, or NMS; nor are they supported for preventing DIMDs except in individuals at high risk for acute dystonia. Anticholinergics may induce serious peripheral adverse effects (e.g., urinary retention) and central effects (e.g., impaired cognition), all of which can be highly concerning especially in older adults. Appropriate use of anticholinergics therefore requires careful consideration of the evidence for efficacy (e.g., supportive for DIP but not TD) and the risks for serious adverse events. If used, anticholinergic medications should be prescribed at the lowest effective dose and for limited periods of time. When discontinued, they should be tapered gradually.

Efficacy and Safety of Valbenazine in Japanese Patients With Tardive Dyskinesia and Schizophrenia/Schizoaffective Disorder or Bipolar Disorder/Depressive Disorder: Primary Results and Post Hoc Analyses of the J-KINECT Study.

PURPOSE: This post hoc analysis investigated whether a patient's underlying psychiatric disease (schizophrenia/schizoaffective disorder [SCHZ] or bipolar disorder/depressive disorder [MOOD]) influenced the efficacy or safety of valbenazine for tardive dyskinesia (TD) in an Asian population. METHODS: We analyzed data from J-KINECT, a multicenter, phase II/III, randomized, double-blind study, which consisted of a 6-week placebo-controlled period followed by a 42-week extension where Japanese patients with TD received once-daily 40- or 80-mg valbenazine. We compared the change from baseline in Abnormal Involuntary Movement Scale total score and Clinical Global Impression of TD score between patients with SCHZ and those with MOOD, and incidence of treatment-emergent adverse events. RESULTS: Of 256 patients included in the placebo-controlled period, 211 continued to the long-term extension. The mean change from baseline in Abnormal Involuntary Movement Scale total score at week 6 (95% confidence interval) was -1.8 (-3.2 to -0.5) and -3.3 (-4.7 to -1.9) in the valbenazine 40- and 80-mg groups, respectively (SCHZ group), and -2.4 (-3.9 to -0.9) and -3.5 (-5.1 to -1.9) in the valbenazine 40- and 80-mg groups, respectively (MOOD group), demonstrating improvement at either dose level over placebo, regardless of the underlying disease. These results were maintained to week 48, and improvements of Clinical Global Impression of TD scores were similar. There were no notable differences in the incidence of serious or fatal treatment-emergent adverse events by underlying disease; differences in the incidence of worsening schizophrenia and depression were attributed to underlying disease progression. CONCLUSIONS: Safety and efficacy of long-term valbenazine therapy for TD did not vary according to underlying psychiatric disease.

The Clinician's Tardive Inventory (CTI): A New Clinical Tool for Documenting and Rating Tardive Dyskinesia.

Objective: Current clinician-rated tardive dyskinesia (TD) symptom scales have not addressed the expanding clinical signs and functional impact of TD. The study objective was to develop and test the reliability of a new integrated instrument.Methods: A movement disorder neurologist devised the outline of the rating scale. A Steering Committee (5 neurologists and 2 psychiatrists) provided revisions until consensus was reached. The Clinician's Tardive Inventory (CTI) assesses abnormal movements of the eye/eyelid/face, tongue/mouth, jaw, and limb/trunk; complex movements defined as complicated movements different from simple patterned movements or postures; and vocalizations. The CTI rates frequency of symptoms from 0 to 3 (ranging from absent to constant). Functional impairments, including activities of daily living (ADL), social impairment, symptom distress, and physical harm, are rated 0-3 (ranging from unawareness to severe impact). The CTI underwent interrater and test-retest reliability testing between February and June 2022 based on videos and accompanying vignettes, which were reviewed by 2 movement disorder specialists to determine adequacy. Four clinicians rated each video/vignette. Interrater agreement was analyzed via 2-way random-effects intraclass correlation (ICC), and test-retest agreement was assessed utilizing the Kendall tau-b.Results: Forty-five video/vignettes were assessed for interrater reliability and 16 for test-retest reliability. The most prevalent movements were those of the tongue and mouth (77.8%) and jaw (55.6%). ICCs for movement frequency for anatomic symptoms were as follows: anatomic symptom summary score 0.92, abnormal eye movement 0.89, abnormal tongue/mouth movement 0.91, abnormal jaw movement 0.89, abnormal limb movement 0.76, complex movement 0.87, and abnormal vocalization 0.77; ICCs for functional impairments were as follows: total impairment score 0.92, physical harm 0.82, social embarrassment 0.88, ADLs 0.83, and symptom bother 0.92; Retests were conducted a mean (SD) of 15 (3) days later with correlation coefficients ranging from 0.66 to 0.87.Conclusions: The CTI is a new integrated instrument with proven reliability in assessing TD signs and functional impacts. Future validation study is warranted.