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Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotics and other dopamine receptor blocking agents. Valbenazine is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of TD in adults. Using data from a long-term study (KINECT 3; NCT02274558), the effects of once-daily valbenazine (40 mg, 80 mg) on TD were assessed using the Abnormal Involuntary Movement Scale (AIMS) in participants who were early responders based on subjective measures, including patient self-report (Patient Global Impression of Change [PGIC]) or clinician judgment (Clinical Impression of Change-Tardive Dyskinesia [CGI-TD]).
Data from KINECT 3 (6-week double-blind, placebo-controlled [DBPC] period; 42-week double-blind extension) were analyzed post hoc. Long-term outcomes included mean change from baseline to Week 48 in AIMS total score (sum of items 1-7) and AIMS response (≥50% total score improvement from baseline) at Week 48. These AIMS outcomes were assessed in participants who achieved early improvement, defined as a PGIC or CGI-TD score of ≤3 (“minimally improved” or better) at Week 2 (first post-baseline visit of the DBPC period). Participants who initially received placebo were not included in the analyses.
In participants who received only valbenazine (40 or 80 mg) during KINECT 3 and had available Week 2 assessment, 50% (72/143) had early PGIC improvement (score ≤3) and 43% (61/142) had early CGI-TD improvement (score ≤3). Baseline characteristics were generally similar between participants who achieved early PGIC or CGI-TD improvement and those who did not. Based on available assessments at Week 48, mean AIMS total score change from baseline in participants with early PGIC improvement was similar to those who did not reach the early PGIC improvement threshold (-4.1 [n=35] vs -3.5 [n=41]). Mean AIMS total score change from baseline in participants with early CGI-TD improvement was similar to those who did not achieve early CGI-TD improvement (-4.2 [n=31] vs -3.5 [n=45]). AIMS response at Week 48 was also similar in those who achieved early PGIC and CGI-TD improvement (40% and 42%, respectively) compared to those who did not achieve early PGIC and CGI-TD improvement (39% and 38%, respectively).
Results from this long-term valbenazine trial indicate that many participants achieved at least minimal patient- and clinician-reported improvement at Week 2. AIMS outcomes at Week 48 demonstrated long-term reductions in TD severity regardless of early response. More research is needed to understand the association between early improvement and long-term treatment effects, but early non-improvement based on subjective measures may not be predictive of long-term treatment failure.
International Congress of Parkinson’s Disease and Movement Disorders; September 22-26, 2019; Nice, France.
This study was sponsored by Neurocrine Biosciences, Inc.
To Evaluate the impact of mild-to-moderate orofacial tardive dyskinesia (TD) symptoms on the people and social lives of people with TD.
TD, a movement disorder affecting the face and extremities, may arise in patients taking antipsychotics. The impact of stigma on the professional and social lives of people with moderate-to-severe TD was previously examined, but has not been investigated in those with mild-to-moderate TD.
This study is an experimental, randomized digital survey of a general population sample. Three component surveys corresponding to employment, dating, and friendship domains were adopted from a prior study. For each domain, participants were randomized 1:1 into either a test group (who viewed a video of a scripted interview with an actor depicting mild-to-moderate TD movements) or a control group (who viewed the same actor but without TD movements) and asked about their impressions of the video subject. Actor simulations of the TD symptoms were validated by physicians familiar with TD and rehearsed to simulate orofacial movements with a total Abnormal Involuntary Movement Scale (AIMS) score of 3–6. Statistical comparison was made using Wilcoxon signed-rank or chi-squared tests for continuous and categorical variables.
A total of 800 respondents completed each survey. In all domains, respondents had more negative perceptions of actors portraying mild-to-moderate TD movements than of the same actors without movements. For employment, 41% fewer respondents in the test group versus the control group agreed that the actor would be suitable for client-facing jobs (P<0.001). For dating, the proportions of respondents who agreed that they would like to continue talking to the actor and who would be interested in meeting them for a coffee/drink were 23.2% and 26.0% lower, respectively, in the test group than in the control group (P<0.001). For friendship, the proportions of respondents who rated the actor as interesting and who would be interested in friendship with them were 13.0% and 12.2% lower in the test group than in the control group (P<0.001).
This study addresses the stigma faced by those with mild-to-moderate TD in professional and social situations. Consistent with previous results for moderate-to-severe TD, actors simulating mild-to-moderate orofacial TD movements were perceived to be less likely to move forward in a job interview, be considered as a potential romantic partner, or be a new friend.
This study was funded by Teva Pharmaceuticals, Petach Tikva, Israel.
Evaluate the impact of orofacial tardive dyskinesia (TD) symptoms on the professional and social lives of patients with TD.
TD, a movement disorder affecting the face and extremities, may arise in patients taking antipsychotics. The impact of social stigma on the professional and social lives of patients with orofacial manifestations of TD has not been thoroughly examined.
This study is an experimental, randomized digital survey of a general population sample. Three component surveys were developed, corresponding to employment, dating, and friendship domains. For each domain, participants were randomized 1:1 into either a test group (who viewed a video of a scripted interview with a standardized patient actor depicting TD movements) or a control group (who viewed the same actors but without TD movements), and asked about their impressions of the video subject. Actor simulations were validated by physicians familiar with TD and rehearsed to simulate a total Abnormal Involuntary Movement Scale score between 6 and 10. Statistical comparison was made using Wilcoxon sign-rank or chi-squared tests for continuous and categorical variables, respectively.
A total of 800 respondents completed each survey. In all domains, respondents had more-negative perceptions of actors portraying TD movements than of the same actors without movements. Regarding employment, 34.8% fewer respondents in the test group versus the control group agreed that the actor would be suitable for client-facing jobs (P<0.001). Regarding dating, the proportions of respondents who agreed that they would like to continue talking to the actor and who would be interested in meeting them for coffee/drink were 25.0% and 27.2% lower, respectively, in the test group than in the control group (P<0.001). Regarding friendship, the proportions of respondents who rated the actor as interesting and who would be interested in friendship with them were 18.8% and 16.5% lower, respectively, in the test group than in the control group (P<0.001).
Actors simulating orofacial TD movements were perceived to be statistically significantly less likely to move forward in a job interview, be considered as a potential romantic partner, or be a new friend. This is the first study to quantify the stigma faced by people with TD in a variety of professional and social situations.
This study was funded by Teva Pharmaceuticals, Petach Tikva, Israel.
Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with prolonged antipsychotic use. RE KINECT, a real-world screening study of antipsychotic-treated outpatients, included patients with movements that were clinician-confirmed as possible TD (Cohort 2) and patients with no involuntary movements (Cohort 1). Baseline data from the patient rated EuroQoL 5-Dimension 5-Level questionnaire (EQ-5D-5L) and Sheehan Disability Scale (SDS) were analyzed to evaluate health related quality of life (Cohort 2 vs. Cohort 1) and the effects of possible TD on quality of life (Cohort 2).
Assessments included EQ-5D-5L utility score (0=equivalent to death to 1=perfect health); SDS total score (0=no impact to 30=highest impact); patient- and clinician-rated severity of possible TD in 4 body regions (0=none, 1=some, and 2=a lot; summary score, 0 to 8); and patient-rated impact of possible TD in 7 daily activities (0=none, 1=some, and 2=a lot; summary score, 0 to 14). Populations included Cohort 1 (N=450); full Cohort 2 (N=204); and limited Cohort 2 (N=111, patients who self-reported “some” or “a lot” of TD severity in ≥1 body region). Mean differences between Cohort 2 and Cohort 1 in EQ-5D-5L utility and SDS total scores were analyzed using a generalized linear regression model that was adjusted for potentially confounding factors (e.g., age, sex, psychiatric diagnosis). Associations between TD summary scores (severity, impact) and quality of life (EQ-5D-5L utility, SDS total) were analyzed using a regression model.
The mean score difference between full Cohort 2 (N=204) and Cohort 1 (N=450) was significant for EQ-5D-5L utility (-0.037; P<0.05 [adjusted analysis]) but not SDS total (0.267; P>0.05). However, when limited to Cohort 2 patients who self-reported “a lot” of TD severity (n=53) or impact (n=33), both EQ 5D 5L utility and SDS total scores were significantly worse than in Cohort 1 (P<0.05). Regression coefficients indicated significant associations between patient-rated impact and EQ 5D-5L utility in the full Cohort 2 (-0.021, P<0.001) and limited Cohort 2 (-0.024, P<0.001). A significant association was also found with patient rated severity in limited Cohort 2 (P<0.05), but not with clinician-rated severity. Similar results were found for SDS total score.
RE-KINECT patients were consistent in evaluating the severity and impact of TD, whether based on subjective assessments or standardized patient-reported instruments (EQ-5D-5L, SDS). Clinician-rated severity of TD may not always correlate with patient perceptions of the significance of TD. Patient self-assessments (focused on symptom impact) can be clinically relevant; incorporating such measures into everyday practice may provide a more comprehensive approach to TD assessment and management.
Tardive dyskinesia (TD) is a hyperkinetic movement disorder associated with antipsychotic treatment. RE KINECT (NCT03062033), a real-world study of outpatients prescribed antipsychotics, was designed to identify the presence of possible TD and characterize the impact of involuntary movements on functioning and quality of life. Data from RE-KINECT were used to compare the impact of possible TD in patients with schizophrenia/schizoaffective disorder [SZD] versus mood/other psychiatric disorders [Mood].
Adults with ≥3months of lifetime exposure to antipsychotics and ≥1 psychiatric disorder were recruited. The presence of possible TD was based on clinicians’ observation of involuntary movements in 4 body regions (head, trunk, upper extremities, and lower extremities). Baseline outcomes included demographics, medication history, location/severity of abnormal movements, impact of abnormal movements on daily activities, the Sheehan Disability Scale (SDS), and the EuroQoL 5-Dimensional questionnaire (EQ-5D-5L).
Of 204 patients with clinician-confirmed possible TD, 111 (54.4%) had a SZD diagnosis and 93 (45.6%) had a mood/other psychiatric diagnosis. Significant differences found between groups (Mood vs SZD) included: mean age (56.9 vs 52.7 years; P=0.0263); male sex (33.3% vs 62.2%; P<0.0001); African-American race (7.5% vs 26.1%; P=0.0005); mean lifetime exposure to antipsychotics (9.5 vs 19.5 years; P<0.0001); and percentage of patients currently taking ≥2 psychiatric medications (93.5% vs 79.3%; P=0.0093). Based on clinician observation, there were no significant differences between diagnosis groups in the number of body regions impacted by abnormal movements, maximum severity score across all 4 regions, or patient awareness of possible TD. Over 30% of patients in both groups reported that involuntary movements had “some” or “a lot” of impact on their ability to continue usual activities, be productive, and socialize. No significant differences between the diagnosis groups (Mood vs SZD) were found for mean SDS total score (12.8 vs 10.8), SDS domain scores (work/school [4.1 vs 4.2], social life [4.3 vs 3.7], family life [4.1 vs 3.5]), EQ-5D-5L utility score (0.68 vs 0.74), or EQ-5D-5L health state VAS (64.8 vs 68.5).
In this cohort of outpatients with possible TD, those with Mood disorders were more likely to be older, female, and white than patients with SZD. The ability to function and quality of life were equally impaired in both groups. Further studies on the impact of TD are needed.
Funding Acknowledgements: Neurocrine Biosciences, Inc.
Vesicular monoamine transporter 2 (VMAT2) inhibitors are the first class of drugs approved to treat tardive dyskinesia (TD). With the recent approval of these medications, a modified Delphi process was implemented to address the need for updated clinical guidelines for TD screening, diagnosis, and treatment.
A Steering Committee of 11 TD experts met in a Nominal Group meeting format to discuss/prioritize questions to be addressed about TD and identify individuals to be invited to serve as Delphi survey panelists. Two survey rounds were conducted anonymously; responses were collected, collated, and analyzed. Respondent agreement was defined a priori by the Steering Committee 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 (deemed unlikely to achieve consensus) and some questions that already achieved consensus (>75% agreement).
Online surveys were sent to 60 individuals; 29 agreed to participate as panelists (23 psychiatrists; 6 neurologists). Respondents unanimously agreed (100%) that all patients currently taking dopamine receptor blocking agents (DRBAs) should be screened for TD, and that the Abnormal Involuntary Movement Scale (AIMS) is the standard structured assessment for monitoring severity of TD. There was consensus (76%) that a semi-structured assessment could be used for more frequent routine TD screening. Respondents unanimously agreed that treatment with first generation antipsychotics, older age, and longer cumulative exposure to antipsychotics were risk factors for TD. For TD diagnosis, consensus (89%) was reached that a patient with an AIMS score >2 (mild) affecting 1 body area should be considered as having possible TD; consensus (93%) was also reached that TD was most often evident in orofacial musculature, although other body areas may be affected and should not be neglected. Consensus was not reached on minimum cumulative duration of DRBA exposure for TD diagnosis, but a majority (70%) agreed that minimum cumulative exposure of 1month may be sufficient. For TD treatment, unanimity or consensus was reached on 4 strategies to consider: discussion of treatment options with patients/caregivers (100%), modification of antipsychotic regimen (100%), treatment with VMAT2 inhibitor (100%), and modification of anticholinergic regimen (86%).
Using a Nominal Group and modified Delphi process, consensus was reached within 1−2 rounds on several key aspects of TD screening, diagnosis, and treatment. This process may offer an expedient method to identify gaps in agreement and facilitate updated management guidelines.
Funding Acknowledgements: Sponsored by Neurocrine Biosciences,Inc.
Tardive dyskinesia (TD) is associated with prolonged exposure to dopamine receptor blockers including antipsychotics. This registry describes the prevalence and impact of involuntary movements (possible TD) in a real-world population of patients taking antipsychotics.
RE-KINECT (NCT03062033) aims to enroll 1,000 patients from 70 US psychiatric practices. Adults with ≥3 months lifetime exposure to antipsychotic(s) and ≥1 psychiatric disorder are eligible for two-tier screening: informal observation, and then clinician observation of abnormal involuntary movements in general body regions (head/face, neck/trunk, upper/lower limbs) and confirmation of possible TD. Based on clinician assessment, patients are assigned to Cohort 1 or Cohort 2 (without or with abnormal involuntary movements, respectively). In both cohorts, the following baseline assessments are included: clinician’s assessment of clinical psychiatric severity, patient perceived health‐related quality of life (EuroQOL 5-Dimensions), social burden/disability questionnaire (Sheehan Disability Scale), and 12-month retrospective chart review ofmedical and treatment history. Cohort 2 also participate in 12-month longitudinal evaluation. Interim baseline data are available from four sites.
Baseline data are currently available for 116 patients—mean age, 49.6 years; female, 60.3%; schizophrenia/schizoaffective disorder, 32.8%; at least 1 mood disorder, 84.5%, and 10.4 years mean cumulative lifetime exposure to antipsychotic(s). The most concerning health condition for both cohorts is their mental health (69.0%), followed by physical activity and nutrition (33.6%). 32.8% of subjects had clinician confirmation of possible TD.
This novel registry aims to evaluate the real-world potential impact/burden of TD. Preliminary analyses suggest that TD is common in patients with schizophrenia and mood disorders taking antipsychotics. Further analyses will explore the burden of illness in this population.
This study was funded by Neurocrine Biosciences, Inc.
Tardive dyskinesia (TD), an often-irreversible movement disorder, develops in patients treated withantipsychotics. Although antipsychotic dose reduction has been utilized in the management of TD, the benefits and risks of lowering doses have not been well studied and could cause additional burden to patients.
To analyze the healthcare burden of antipsychotic dose reduction in patients with schizophrenia.
Medical claims from six US states spanning 6 years are retrospectively analyzed for ≥10% or ≥30% antipsychotic dosereductions and compared with those from patients receiving stable doses. Outcomes measured include inpatient admissions and emergency room (ER) visits for schizophrenia, all psychiatric disorders, and all causes.
Baseline analysis revealed 17,984 patients with ≥10% and 14,029 patients with ≥30% dose reduction. Patients with≥10% dose reduction and matched controls were similar in age (mean 45.5 years), gender (51% male) and healthcare plan type. Preliminary analyses indicate that ≥10% dose reduction is associated with increased risk of admission or ER visit for schizophrenia (hazard ratio [HR] 1.26; 95% confidence interval [CI] 1.18, 1.35; P<0.001) and all psychiatric disorders (HR 1.18; 95% CI 1.11, 1.25; P<0.001) versus controls, which may be even greater with ≥30% dose reduction. Final updated results of ongoing analyses will be presented at the meeting.
Patients with antipsychotic dose reductions may be at risk for significant increases in hospital utilization rates. This suggests that dose reductions may increase overall healthcare burden in some schizophrenia patients, and highlights the need for alternative strategies in the management of TD.
Presented at: Psych Congress; September 16–19, 2017; New Orleans, Louisiana, USA.
This study was funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.
The CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) schizophrenia study sought to compare the effectiveness and cost-effectiveness of four second-generation antipsychotics and one first-generation antipsychotic in the treatment of schizophrenia. This study design posed several challenges for statistical analysis. The authors describe the stratified Phase 1/1A randomization, and explain the steps for comparing treatment groups within the stratified randomization structure. They describe strategies to perform treatment group comparisons that control the inflation of Type 1 error due to multiple pair-wise testing, and focus on the evaluation of multiple outcomes. The authors examine the advantages of using all-cause treatment discontinuation as the primary effectiveness outcome and the specific statistical issues for its analysis, and address the impact of missing data due to phase discontinuation on analysis of the secondary outcomes. The authors contrast the statistical methods employed to address this issue, and consider further methods.
There are claims that second-generation antipsychotics produce fewer
extrapyramidal side-effects (EPS) compared with first-generation
To compare the incidence of treatment-emergent EPS between
second-generation antipsychotics and perphenazine in people with
Incidence analyses integrated data from standardised rating scales and
documented use of concomitant medication or treatment discontinuation for
EPS events. Mixed model analyses of change in rating scales from baseline
were also conducted.
There were no significant differences in incidence or change in rating
scales for parkinsonism, dystonia, akathisia or tardive dyskinesia when
comparing second-generation antipsychotics with perphenazine or comparing
between second-generation antipsychotics. Secondary analyses revealed
greater rates of concomitant antiparkinsonism medication among
individuals on risperidone and lower rates among individuals on
quetiapine, and lower rates of discontinuation because of parkinsonism
among people on quetiapine and ziprasidone. There was a trend for a
greater likelihood of concomitant medication for akathisia among
individuals on risperidone and perphenazine.
The incidence of treatment-emergent EPS and change in EPS ratings
indicated that there are no significant differences between
second-generation antipsychotics and perphenazine or between
second-generation antipsychotics in people with schizophrenia.
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