Abnormal Involuntary Movement Scale Total Score Research Articles

Sustained Treatment Response and Global Improvements With Long-term Valbenazine in Patients With Tardive Dyskinesia.

Using data from KINECT® 4, a phase 3, 48-week study of valbenazine, post hoc analyses were conducted to assess long-term outcomes that are relevant to the real-world management of tardive dyskinesia (TD). Post hoc analyses of the participants of the KINECT 4 study who completed 48 weeks of open-label valbenazine (40 or 80 mg) treatment were conducted. Valbenazine effects on TD were evaluated using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD (CGI-TD), and Patient Global Impression of Change (PGIC). Of 103 participants completing 48 weeks of treatment, 55% experienced clinically meaningful improvement (defined as ≥2-point reduction in AIMS total score [sum of items 1-7, evaluated by site raters]) by week 4; at week 48, 97% met this threshold. The percentage of completers who achieved AIMS total score response thresholds of ≥10% to ≥90% increased over time, with 86% of completers reaching ≥50% improvement. Of the 40 (39%) completers with AIMS ≥50% response at week 8, 38 (95%) sustained this response at week 48; 81% of those who did not meet this threshold at week 8 had achieved it by week 48. At week 48, more than 85% of completers achieved CGI-TD and PGIC ratings of "much improved" or "very much improved." The majority of participants who completed 48 weeks of treatment with once-daily valbenazine experienced substantial clinically meaningful and sustained TD improvements. These findings indicate that valbenazine can be a highly effective long-term treatment in patients with TD.

Sex difference in association between tardive dyskinesia and cognitive deficits in patients with chronic schizophrenia.

Tardive dyskinesia (TD), a side effect due to long-term use of antipsychotic medication, is associated with cognitive impairment. Several studies have found sex differences in cognitive impairment in schizophrenia patients, while whether there are sex differences in cognitive performance in schizophrenia patients with TD has not been reported. A total of 496 schizophrenia inpatients and 362 healthy controls were recruited for this study. We used the Positive and Negative Syndrome Scale (PANSS) to assess patients' psychopathological symptoms and the Abnormal Involuntary Movement Scale (AIMS) to assess the severity of TD. Cognitive function was measured in 313 of these inpatients and 310 of healthy controls using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS). Patients with schizophrenia performed worse in all cognitive domains than healthy controls(all p<0.001). Compared to patients without TD, patients with TD had higher PANSS total, PANSS negative symptom subscale and AIMS scores (all p<0.001), while RBANS total, visuospatial/constructional and attention subscale scores were significantly lower (all p<0.05). In addition, the visuospatial/constructional and attention indices remained significantly lower in male patients with TD than those without TD (both p<0.05), but these results were not observed in female patients. Moreover, visuospatial/constructional and attention indices were negatively correlated with total AIMS scores only in male patients (both p<0.05). Our results suggest that there may be sex differences in cognitive impairment in schizophrenia patients with comorbid TD, indicating that female gender may have a protective effect on cognitive impairment in schizophrenia patients caused by TD.

Sustained Treatment Response With Long-Term Valbenazine in Patients With Tardive Dyskinesia

AbstractBackgroundValbenazine is a once-daily VMAT2 inhibitor approved for the treatment of tardive dyskinesia (TD), a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotics, antiemetics, and other dopamine receptor blocking agents. The efficacy, safety, and tolerability of valbenazine has been established in several phase 3 trials, including a long-term study (KINECT 4 [NCT02405091]) in which participants received open-label valbenazine (40 or 80 mg) for 48 weeks. Post hoc analyses of KINECT 4 data were conducted to assess patterns of treatment response.MethodsData from KINECT 4 treatment completers (participants who reached the Week 48 visit and had the longest duration of treatment) were analyzed post hoc. TD was assessed using the Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1–7, as rated by the study investigator), the Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD), and the Patient Global Impression of Change (PGIC). Analyses were conducted at Week 8 (first study visit after the valbenazine dose-optimization period) and Week 48 using the following definitions of response: ≥50% and ≥70% improvement from baseline in AIMS total score; rating of “much improved” or “very much improved” (score ≤2) on the CGI-TD and PGIC.ResultsOf the 167 participants who entered KINECT 4, 103 (62%) were treatment completers and included for analysis. Of these 103 participants, 39% and 86% met the ≥50% AIMS response threshold at Weeks 8 and 48, respectively. The percentages of participants who met the highly rigorous AIMS ≥70% response threshold at Weeks 8 and 48 were 17% and 52%, respectively. Of the 40 participants with AIMS ≥50% total score improvement at Week 8, 95% also met this threshold at Week 48 (“sustained response”). Of the 63 participants with &lt;50% AIMS improvement at Week 8, 81% achieved the ≥50% response threshold by end of treatment at Week 48. The proportion of participants meeting the threshold for CGI-TD response also increased over time, from 50% at Week 8 to 92% at Week 48. PGIC results were similar, with response rates of 53% and 88% at Weeks 8 and 48, respectively.ConclusionsPost hoc analyses of data from a 48-week, open-label study of once-daily valbenazine showed that the proportion of participants meeting rigorous treatment response thresholds increased over time. By the end of treatment at Week 48, &gt;80% of participants demonstrated robust improvements in TD, as assessed using the AIMS (≥50% improvement), CGI-TD (score ≤2), and PGIC (score ≤2).FundingNeurocrine Biosciences, Inc.

Minimal clinically important change in Abnormal Involuntary Movement Scale score in tardive dyskinesia as assessed in pivotal trials of deutetrabenazine

IntroductionDeutetrabenazine is approved by the US Food and Drug Administration to treat tardive dyskinesia (TD) based on 2 pivotal, 12-week, placebo-controlled studies (ARM-TD and AIM-TD) evaluating safety and efficacy in patients with baseline total motor Abnormal Involuntary Movement Scale (AIMS) score ≥6. This analysis estimated the minimal clinically important change (MCIC) in total motor AIMS score in TD patients treated with deutetrabenazine. MethodsThe pooled analysis population included all patients in ARM-TD and AIM-TD who received study drug and had ≥1 postbaseline AIMS assessment. MCIC analyses were performed using Patient Global Impression of Change (PGIC) and Clinical Global Impression of Change (CGIC) as anchors. MCIC was defined as the mean change from baseline in total motor AIMS score in patients treated with deutetrabenazine who were rated minimally improved on PGIC or CGIC at Week 12. ResultsThis analysis included 295 patients (deutetrabenazine, n = 197; placebo, n = 98). At Week 12, the MCIC in deutetrabenazine-treated patients was −2.4 based on the PGIC and −2.1 based on the CGIC. Mean change from baseline in total motor AIMS score for placebo-treated patients rated minimally improved was −1.4 based on the PGIC and −1.5 based on the CGIC. The proportion of deutetrabenazine-treated patients who achieved improvement in total motor AIMS score by ≥2 and ≥3 points was 66% and 55%, respectively. ConclusionUsing anchor-based methodology, the MCIC on the AIMS for deutetrabenazine in patients with TD was approximately −2, suggesting that a reduction in total motor AIMS score of ∼2 is associated with clinically meaningful improvement in TD symptoms.

Long-Term Deutetrabenazine Treatment for Tardive Dyskinesia Is Associated With Sustained Benefits and Safety: A 3-Year, Open-Label Extension Study.

BackgroundDeutetrabenazine is a vesicular monoamine transporter 2 inhibitor approved for the treatment of tardive dyskinesia (TD) in adults. In two 12-week pivotal studies, deutetrabenazine demonstrated statistically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores, with favorable safety/tolerability in TD patients. This study reports long-term efficacy and safety of deutetrabenazine in a 3-year, single-arm, open-label extension (OLE) study.MethodsPatients who completed the pivotal studies could enroll in this single-arm OLE study, titrating up to 48 mg/day based on dyskinesia control and tolerability. Efficacy was assessed based on change from baseline in total motor AIMS score, Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC), and quality of life (QOL) assessments. Safety evaluation included adverse event (AE) incidence, reported using exposure-adjusted incidence rates, and safety scales.Results343 patients enrolled in the study (6 patients were excluded). At Week 145 (mean dose: 39.4 ± 0.83 mg/day), mean ± SE change from baseline in total motor AIMS score was −6.6 ± 0.37 and 67% of patients achieved ≥50% improvement in total motor AIMS score. Based on CGIC and PGIC, 73% and 63% of patients achieved treatment success, respectively. QOL improvements were also observed. Deutetrabenazine was generally well tolerated, with low rates of mild-to-moderate AEs and no new safety signals; most safety scales remained unchanged over time.ConclusionsLong-term deutetrabenazine treatment was associated with sustained improvement in AIMS scores, indicative of clinically meaningful long-term benefit, and was generally well tolerated. Results suggest deutetrabenazine may provide increasing benefit over time without increases in dose.

Long-Term Safety and Efficacy of Deutetrabenazine in Younger and Older Patients With Tardive Dyskinesia

To assess long-term safety and efficacy of deutetrabenazine in younger (<55 years) and older (≥55 years) adult participants with tardive dyskinesia (TD). Three-year, single-arm, open-label extension (OLE) study enrolling participants who completed the 12-week, pivotal ARM-TD or AIM-TD studies. Seventy-six centers in the United States and Europe. A total of 337 participants with TD (119 younger and 218 older). Deutetrabenazine was initiated at 12 mg/day and titrated once weekly by 6 mg/day using a response-driven dosing regimen until adequate dyskinesia control was reached or a clinically significant adverse event occurred. This post hoc analysis assessed change and percent change from baseline in total motor Abnormal Involuntary Movement Scale (AIMS) score, response rates for ≥50% AIMS improvement, Clinical Global Impression of Change (CGIC), Patient Global Impression of Change (PGIC), and safety in younger and older participants with TD. After 3 years of open-label treatment, mean deutetrabenazine dose was ∼39.5 mg/day in both groups. Mean±SE changes from baseline in total motor AIMS score were -6.7 ± 0.62 and -6.5 ± 0.47 in younger and older participants, respectively (percent changes: -61.4% ± 4.10% and -54.6% ± 3.01%); 76% of younger and 62% of older participants achieved ≥50% AIMS response. Most younger and older participants achieved treatment success per CGIC (67% and 76%) and PGIC (64% and 63%). Deutetrabenazine was generally well tolerated in both groups. Deutetrabenazine treatment was associated with sustained improvements in total motor AIMS score, treatment success, and improved quality of life, and was well tolerated in younger and older adults with TD in this 3-year OLE study.

Deutetrabenazine Reduces Severe Tardive Dyskinesia Movements in a 3-year Open-Label Extension Trial

There are no established treatment guidelines for tardive dyskinesia (TD) based on movement severity. The 12-week ARM-TD and AIM-TD studies in TD patients with baseline Abnormal Involuntary Movement Scale (AIMS) total score (items 1-7) ≥6 showed clinically significant improvements in AIMS score with deutetrabenazine versus placebo. Patients who completed these studies were eligible for the open-label extension (OLE) trial. This post-hoc analysis evaluated deutetrabenazine in TD patients with severe movements. Subgroups were defined by upper quartile of baseline total AIMS score (local rating). Endpoints were: change and percent change from baseline in AIMS score, and percent of patients achieving ≥50% AIMS reduction from baseline. 337 patients were analyzed. The upper quartile of baseline total AIMS score was 14. Subgroups were defined as >14 and ≤14 at baseline, respectively (n=64 vs 273); data are presented at Week 145 (n=40 vs 120). Mean treatment duration was 880.5 and 760.8 days. Mean±SE daily doses were 41.1±1.6mg and 38.9±1.0mg. Mean±SE change from baseline in AIMS score was -11.0±0.8 versus -5.1±0.3; percent change from baseline was -60.1%±3.6% versus -55.9%±3.0%. More patients with AIMS score >14 had ≥50% AIMS reduction (73% vs 65%). Less patients discontinued (38% vs 51%); reasons included withdrawal by subject (16% vs 25%), adverse event (3% vs 11%), and lost to follow-up (6% vs 7%). Withdrawal due to lack of efficacy was uncommon (5% vs 2%). Patients with baseline total AIMS score >14 had clinically meaningful reductions in AIMS score, suggesting deutetrabenazine has long-term benefit in these patients. Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel.

Tardive Dyskinesia: Assessing and Treating a Debilitating Side Effect of Prolonged Antipsychotic Exposure

Tardive Dyskinesia: Assessing and Treating a Debilitating Side Effect of Prolonged Antipsychotic Exposure

Abnormal functional connectivity of motor circuit in the schizophrenic patients with tardive dyskinesia: A resting-state fMRI study

BackgroundAnimal and neuroimaging studies suggest that the volume of the motor-circuit region decreases in tardive dyskinesia (TD). This study examined the differences in functional connectivity within the motor circuit of patients with schizophrenia with and without TD to further clarify how the dysfunction is related to the pathogenesis of TD. MethodsFunctional magnetic resonance images were taken of 56 schizophrenic patients with TD (TD group), 64 without TD (non-TD group), and 68 healthy controls (HC group). The motor-circuit area was selected as the seed region for a whole brain resting-state functional connectivity (rsFC) analysis. Psychopathological symptoms and TD severity were assessed with the Positive and Negative Syndrome Scale (PANSS) and Abnormal Involuntary Movement Scale (AIMS), respectively. Group differences and correlations among 18 brain regions of interest (e.g., the global strength of connectivity between two regions) were analyzed. ResultsThe analysis of variance results were as follows: The three groups exhibited rsFC losses in the left primary motor cortex, bilateral parietal cortices, right postcentral gyrus, right putamen, right superior parietal lobule, right supplementary motor area and bilateral thalami (false discovery rate,p < 0.05). The TD group showed a significant rsFC loss between the right postcentral gyrus and the inferior frontal gyrus of the left triangular part when compared with the non-TD group (AlphaSim, p < 0.001), which was negatively correlated with the AIMS total score (r=-0.259, p = 0.03). ConclusionsThese findings may suggest dysfunction of the postcentral and inferior frontal gyri of the triangular part in patients with schizophrenia and TD.

Association between the IL10 rs1800896 Polymorphism and Tardive Dyskinesia in Schizophrenia.

ObjectiveInterleukin-10 (IL-10) is a major immunoregulatory cytokine and its gene plays a fundamental role in anti-inflammatory and immunosuppressive activity. This study aimed to examine the association between the IL10 gene promoter -1082G/A polymorphism (rs1800896) and tardive dyskinesia (TD) in schizophrenia. MethodsTwo hundred and eighty unrelated Korean schizophrenic patients participated in this study (105 TD and 175 non-TD patients). TD was diagnosed using the Research Diagnostic Criteria for TD and Abnormal Involuntary Movement Scale (AIMS). Genotyping was performed by RT-PCR and high-resolution melting curve analysis. ResultsThe distributions of genotypic frequencies did not differ between patients with and without TD (χ2=4.33, p=0.115). However, allelic frequencies of the two groups were different (χ2=4.45, p=0.035); the A allele frequency was higher in TD. The total AIMS scores of the three genotypes were not different (F=1.33, p=0.266). However, the total AIMS scores of the A allele carrier and the A allele non-carrier were significantly different (t=5.79, p<0.001). Logistic regression analaysis showed that IL10 -1082G/A genotype significantly predicts presence of TD (p=0.045) after adjusting for covariates such as age and treatment duration. ConclusionThis finding suggests that the A allele of rs1800896 may be associated with TD development following a low IL-10 function.

Correlates of the Abnormal Involuntary Movement Scale in Veterans With Tardive Dyskinesia.

To add to limited evidence on the Abnormal Involuntary Movement Scale (AIMS) as a measure of tardive dyskinesia (TD) in clinical practice settings, the characteristics and correlates of AIMS scores were assessed. Veterans with schizophrenia/schizoaffective, bipolar, or major depressive disorders receiving antipsychotics and at least 1 AIMS score during October 1, 2014, to September 30, 2015, were identified. Tardive dyskinesia was determined by the International Classification of Diseases, Ninth Revision, Clinical Modification, codes. Correlates of AIMS scores were examined using χ or t tests. Odds ratios and β parameters with 95% confidence intervals for categorical and continuous variables associated with AIMS scores were derived from a multivariate logistic and linear regression, respectively. Among 7985 veterans receiving antipsychotics, only 4706 (58.9%) had at least 1 AIMS examination. Of these, 229 (4.9%) were diagnosed with possible TD. The mean total AIMS scores and AIMS awareness/incapacitation scores were significantly higher for patients with TD (both P < 0.0001). Comparing diagnostic threshold criteria of AIMS ratings, only 17.5% to 37.1% of veterans with TD were successfully identified. Among TD patients, 21.4% had a total score of moderate-severe and 15.3% had ratings of at least mild movements in 2 or more body regions. In the regression analyses, being older, African-American, having schizophrenia/schizoaffective disorder, and receiving antipsychotics or benztropine significantly increased the severity of AIMS scores. Higher AIMS scores were not predictive of outcomes other than marital status in socioeconomic or healthcare domains. Although the AIMS is essential for TD research, its value in clinical practice without training and oversight remains unclear. Efforts to adapt screening procedures to clinical needs may be worthwhile.

EFFECTS OF LONG-TERM VALBENAZINE IN KINECT 4: POST HOC RESPONSE AND SHIFT ANALYSES IN YOUNGER AND OLDER ADULTS WITH TARDIVE DYSKINESIA

Introduction Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with prolonged antipsychotic exposure. Compared to younger patients, older patients have a higher risk of TD and may develop symptoms earlier during antipsychotic treatment. Valbenazine, a novel and highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor, is approved to treat TD in adults of all ages, with no dose adjustment required for older patients. The long-term effects of valbenazine on TD were evaluated in KINECT 4 (NCT02405091), an open-label study in which participants received up to 48 weeks of once-daily treatment with valbenazine. Abnormal Involuntary Movement Scale (AIMS) data from this study were analyzed post hoc to evaluate treatment responses in older (≥55 to 85 years) and younger (18 to Methods KINECT 4 included participants who met the following criteria: ages 18 to 85 years; DSM-IV diagnosis of schizophrenia, schizoaffective disorder, or mood disorder; neuroleptic-induced TD for ≥3 months prior to screening; stable psychiatric status (Brief Psychiatric Rating Scale score Results Of 163 participants in the safety/efficacy population, 103 (63.2%) had an available AIMS assessment at Week 48. At Week 48, the percentages of patients who met the criteria for minimal response (≥10% AIMS total score improvement from baseline) or clinically meaningful (≥30% improvement) response were similar between the older and younger subgroups (≥55 years; Conclusions After 48 weeks of treatment with once-daily valbenazine, >95% of all KINECT 4 participants (older and younger) had a minimal AIMS total score response (≥10% improvement), >90% had a clinically meaningful response (≥30% improvement), and >80% had a robust response (≥50% improvement). Older patients seemed more likely than younger patients to achieve a maximal response, including 100% improvement, although these results may be limited by smaller sample sizes. Shift analyses based on AIMS item scores were supportive of AIMS total score responses. Together, the results presented in this post hoc analysis suggest that valbenazine is an appropriate long-term treatment for both older and younger adults with TD. This research was funded by: This study was sponsored by Neurocrine Biosciences, Inc.

77 Long-term Valbenazine Treatment in Patients with Schizophrenia/Schizoaffective Disorder or Mood Disorder and Tardive Dyskinesia

AbstractBackgroundPatients treated with antipsychotics, regardless of psychiatric diagnosis, are at risk for developing tardive dyskinesia (TD), a potentially debilitating drug-induced movement disorder. Valbenazine (INGREZZA; VBZ) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor approved to treat TD in adults. Data from KINECT 4 (NCT02405091) were analyzed to evaluate the long-term effects of VBZ in adults with schizophrenia/schizoaffective disorder (SZD) or mood disorder (MD) and moderate or severe TD.MethodsKINECT 4 included open-label treatment (48weeks) followed by washout (4weeks). Entry requirements included: moderate or severe TD, qualitatively assessed at screening by a blinded, external reviewer; DSM diagnosis of SZD or MD; psychiatric stability (Brief Psychiatric Rating Scale score &lt;50). Stable concomitant psychiatric medications were allowed. Dosing was initiated at 40mg, with escalation to 80mg at Wk4 if participants had a Clinical Global Impression of Change-TD score of ≥3 (minimally improved to very much worse) and tolerated 40mg. A reduction to 40mg was allowed if 80mg was not tolerated (80/40mg); participants unable to tolerate 40mg were discontinued. Safety was the primary focus, but the Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1–7) was used to evaluate changes in TD. Mean changes from baseline (BL) in AIMS total score (rated by on-site investigators) were analyzed descriptively. Safety assessments included treatment-emergent adverse events (TEAEs) and psychiatric scales (Positive and Negative Syndrome Scale [PANSS], Calgary Depression Scale for Schizophrenia [CDSS], Montgomery-Åsberg Depression Rating Scale [MADRS], Young Mania Rating Scale [YMRS], and Columbia-Suicide Severity Rating Scale [C SSRS]).ResultsOf 163 participants in the analyses, 103 completed the study. Adverse events (n=26) was the most common reason for discontinuation. Analyses included 119 participants with SZD (40mg=37; 80mg=76; 80/40mg=6) and 44 with MD (40mg=8; 80mg=31; 80/40mg=5). At Wk48, mean improvements from BL in AIMS total score were: SZD (40mg, –10.1; 80mg,–10.7); MD (40mg, 10.2; 80mg: –11.6). AIMS total scores at Wk52 (end of washout) indicated a return toward BL levels. Compared to SZD, the MD subgroup had a higher incidence of any TEAE (84% vs 61% [all doses]) but fewer TEAEs leading to discontinuation (7% vs 18%). Urinary tract infection was the most common TEAE in the MD subgroup (18%); somnolence and headache were most common in the SZD subgroup (7% each). Psychiatric status remained stable from BL to Wk48: SZD (PANSS positive, –0.7, PANSS negative, –0.6; CDSS, –0.7); MD (MADRS, –0.3; YMRS, –0.3). Most participants (95%) had no change in C-SSRS score during the study.ConclusionSustained and clinically meaningful TD improvements were observed with VBZ, regardless of primary psychiatric diagnosis. VBZ was generally well tolerated and no notable changes in psychiatric status were observed.Funding Acknowledgements: Supported by Neurocrine Biosciences, Inc.

Characterizing Treatment Effects of Valbenazine for Tardive Dyskinesia: Additional Results From the KINECT 3 Study.

In the KINECT 3 (NCT02274558; October 2014 to September 2015) study, valbenazine efficacy in tardive dyskinesia (TD) was demonstrated based on mean changes from baseline in the Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1-7). Data from this study were analyzed further to provide a more clinically meaningful interpretation of the primary AIMS results. The study included adults who had a DSM-IV diagnosis of schizophrenia, schizoaffective disorder, or any mood disorder and also met DSM-IV criteria for neuroleptic-induced TD. Study participants received 6 weeks of double-blind treatment with valbenazine (40 or 80 mg/d) or placebo. Post hoc AIMS analyses, based on available data, included Cohen d effect sizes, response analyses with odds ratios (ORs) and numbers needed to treat (NNTs), and shift analyses. At week 6 (N = 202), medium-to-high effect sizes were found for mean improvements in AIMS total score (40 mg/d, d = 0.52; 80 mg/d, d = 0.89). For AIMS total score responses of ≥ 10% to ≥ 70% improvement from baseline, statistical significance was found for valbenazine 80 mg/d versus placebo (P ≤ .01), with ORs (range, 3.0-10.3) and NNTs (range, 3-9) indicating clinical relevance. For response per AIMS item (score ≤ 1 at week 6), significant differences between valbenazine (both doses or 80 mg/d) and placebo were found in the lips, jaw, tongue, and upper extremities. In participants who had an AIMS item score ≥ 1 at baseline, the percentage with a ≥ 1-point improvement at week 6 (shift) was significantly higher with valbenazine (40 and/or 80 mg/d) versus placebo in all 7 body regions. Consistent with primary published results for KINECT 3, these supplemental analyses indicate that participants treated with valbenazine (40 or 80 mg/d) had statistically significant and clinically relevant improvements in TD severity both overall and in specific body regions. ClinicalTrials.gov identifier: NCT02274558.

The effects of valbenazine on tardive dyskinesia in patients with a primary mood disorder.

Few studies have assessed the treatment of tardive dyskinesia (TD) in patients with primary mood disorders who are managed with antipsychotics. The effects of once-daily valbenazine on TD were evaluated in adults with a bipolar or depressive disorder. Data were pooled from two 6-week double-blind placebo-controlled trials (KINECT 2 and KINECT 3; 114 mood participants) and a long-term blinded extension study (KINECT 3 extension; 77 mood participants) of valbenazine in adults with TD. Efficacy assessments included Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1-7), Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD), and Patient Global Impression of Change (PGIC). Safety assessments included treatment-emergent adverse events (TEAEs), Young Mania Rating Scale, and Montgomery-Åsberg Depression Rating Scale. At Week 6, mean improvements in AIMS total score were significantly greater with valbenazine versus placebo (40 mg/day, -3.1 [P < 0.01]; 80 mg/day, -3.5 [P < 0.001]; placebo, -0.9). Significant differences between valbenazine (80 mg/day) and placebo were also found for Week 6 AIMS response (≥50% total score improvement) and CGI-TD response ("much improved" or "very much improved"), but not PGIC response. Sustained improvements in AIMS, CGI-TD, and PGIC were found through 48 weeks. Valbenazine was generally well tolerated, with no unexpected TEAEs, worsening in psychiatric symptoms, or emergence of suicidality. Pooled analyses were conducted post hoc, and neither study was designed to focus solely on mood disorder patients. In participants with primary mood disorders, once-daily treatment with valbenazine was generally well tolerated and resulted in 6-week and sustained TD improvements.

Resting-state Brain Activity Changes Associated with Tardive Dyskinesia in Patients with Schizophrenia: Fractional Amplitude of Low-frequency Fluctuation Decreased in the Occipital Lobe

We explored resting-state brain activity and its potential links to clinical parameters in schizophrenic patients with tardive dyskinesia (TD) using fractional amplitude of low-frequency fluctuations (fALFF). Resting-state functional magnetic resonance imaging data were acquired from 32 schizophrenic patients with TD (TD group), 31 without TD (NTD group), and 32 healthy controls (HC group). Clinical parameters including psychopathological symptoms, severity of TD, and cognitive function were assessed using the Positive and Negative Syndrome Scale, Abnormal Involuntary Movement Scale (AIMS), and Repeatable Battery for the Assessment of Neuropsychological Status, respectively. Pearson correlation analyses were performed to determine the relationship between the regions with altered fALFF values and clinical parameters in TD patients. The TD group showed decreased fALFF in the left middle occipital gyrus (MOG) and the right calcarine sulcus (CAL) compared to the HC group, and decreased fALFF in the left cuneus compared to the NTD group. In the TD group, fALFF values in the left MOG and the right CAL were correlated separately with the delayed memory score (r = 0.44, p = 0.027; r = 0.43, p = 0.028, respectively). The AIMS total score was negatively correlated to the visuospatial/constructional score (r = −0.53, p = 0.005). Our findings suggested that resting-state brain activity changes were associated with TD in schizophrenic patients. There was an association between the decreased brain activity in the occipital lobe and the delayed memory cognition impairment in this population.

Switching antipsychotic treatment to aripiprazole in psychotic patients with neuroleptic-induced tardive dyskinesia: a 24-week follow-up study.

Aripiprazole is a second-generation antipsychotics, acting as a partial dopamine D2 receptor agonist. Previous studies on aripiprazole for tardive dyskinesia (TD) treatment were limited and inconclusive. This study was aimed to examine the effectiveness of aripiprazole in psychotic patients with a pre-existing TD. This was an open-label 24-week prospective cohort study conducted in a public mental hospital in Northern Taiwan from January 2009 to February 2010. Psychotic patients were cross-titrated of prior antipsychotics with aripiprazole, and the severity of TD was assessed at baseline and at weeks 2, 4, 8, 12, 16, 20, and 24. The primary study outcome was the change of TD severity, assessed by Abnormal Involuntary Movement Scale (AIMS) total score. Responder was defined as the reduction of AIMS total scores of no less than 50% from baseline to the study endpoint (24 weeks). Thirty psychotic patients with neuroleptic-induced TD were recruited. The AIMS total scores significantly decreased from baseline to the study endpoint (-7.17±5.55). The significant decrease of AIMS total scores started at week 2 (P<0.0001), and the change remained significant throughout the entire study period (P<0.0001). A greater severity of TD (adjusted odds ratio: 1.35, 95% confidence interval: 1.04-1.76, P=0.03) or a lower severity of parkinsonism (adjusted odds ratio: 0.78, 95% confidence interval: 0.61-0.99, P=0.04) at baseline was significantly associated with treatment responders. Our findings implicated that aripiprazole can be a promising treatment for clinicians considering drug switch in psychotic patients with TD. Further large randomized, controlled trials are warranted to confirm our findings.

Treatment of tardive dyskinesia with VMAT-2 inhibitors: a systematic review and meta-analysis of randomized controlled trials.

AimThe aim of this study was to summarize the characteristics, efficacy, and safety of vesicular monoamine transporter-2 (VMAT-2) inhibitors for treating tardive dyskinesia (TD).Materials and methodsWe conducted a literature search in PubMed, Cochrane Database, and ClinicalTrials.gov, screening for systematic reviews, meta-analyses or double-blind, randomized, placebo-controlled trials (DBRPCTs) reporting efficacy or safety data of VMAT-2 inhibitors (tetrabenazine, deutetrabenazine, and valbenazine) in patients with TD. A random effects meta-analysis of efficacy and safety data from DBRPCTs was performed.ResultsTwo acute, 12-week DBRPCTs with deutetrabenazine 12–48 mg/day (n=413) and 4 acute, 4–6-week double-blind trials with valbenazine 12.5–100 mg/day (n=488) were meta-analyzable, without meta-analyzable, high-quality data for tetrabenazine. Regarding reduction in total Abnormal Involuntary Movement Scale (AIMS) scores (primary outcome), both deutetrabenazine (k=2, n=413, standardized mean difference [SMD] =−0.40, 95% confidence interval [CI] =−0.19, −0.62, p<0.001; weighted mean difference (WMD) =−1.44, 95% CI =−0.67, −2.19, p<0.001) and valbenazine (k=4, n=421, SMD =−0.58, 95% CI =−0.26, −0.91, p<0.001; WMD =−2.07, 95% CI =−1.08, −3.05, p<0.001) significantly outperformed placebo. Results were confirmed regarding responder rates (≥50% AIMS total score reduction; deutetrabenazine: risk ratio [RR] =2.13, 95% CI =1.10, 4.12, p=0.024, number-needed-to-treat [NNT] =7, 95% CI =3, 333, p=0.046; valbenazine: RR =3.05, 95% CI =1.81, 5.11, p<0.001, NNT =4, 95% CI =3, 6, p<0.001). Less consistent results emerged from patient-rated global impression-based response (p=0.15) and clinical global impression for deutetrabenazine (p=0.088), and for clinical global impression change for valbenazine (p=0.67). In an open-label extension (OLE) study of deutetrabenazine (≤54 weeks) and a dose-blinded valbenazine study (≤48 weeks), responder rates increased over time. With valbenazine, discontinuation effects were studied, showing TD symptom recurrence towards baseline severity levels within 4 weeks after valbenazine withdrawal. No increased cumulative or specific adverse (AEs) events versus placebo (acute trials) in extension versus acute trial data were observed.ConclusionThe 2 VMAT-2 inhibitors, valbenazine and deutetrabenazine, are effective in treating TD, both acutely and long-term, without concerns about increased risk of depression or suicide in the TD population. No head-to-head comparison among VMAT-2 inhibitors and no high-quality, meta-analyzable data are available for tetrabenazine in patients with TD.

A Cross-Sectional Study on the Characteristics of Tardive Dyskinesia in Patients with Chronic Schizophrenia.

BackgroundTardive dyskinesia (TD) is an abnormal involuntary movement disorder caused by patients’ long-term use of antipsychotic medication. It diminishes the social functioning of patients with mental disorders, thereby affecting their compliance with antipsychotic medication. The cause and nosogenesis of TD remains unclear; furthermore, because the presentation differs greatly among individuals it often goes undiagnosed or can be easily misdiagnosed. The present study aims to evaluate the abnormal movement patterns in patients with TD, and analyze the differences among different TD patterns, in order to seek effective methods of preventing, diagnosing and treating TD.AimsTo describe the movement patterns of patients with chronic schizophrenia with TD, and analyze their clinical characteristics and risk factors.MethodsA cross-sectional study was carried out on a psychiatric unit of the Xuhui Mental Health Center with inpatients who had chronic schizophrenia as participants. Abnormal Involuntary Movement Scale (AIMS) was employed to screen for patients with schizophrenia who also had TD. These patients’ movement disorders were evaluated, and they were divided into groups based on their movement patterns. Positive and Negative Syndrome Scale (PANSS) was used to assess the psychotic symptoms of patients, collect clinical information, compare the differences between the two groups and analyze the clinical characteristics and risk factors of TD.Results(1) A total of 448 patients met the inclusion criteria for chronic schizophrenia with 46 in the TD group and 402 in the control group. After the TD group and the control group was compared, significant differences were seen between the two groups in gender, age, total duration of illness, age of onset, dosage of antipsychotic medication (daily chlorpromazine equivalent), factor scores of negative symptoms on PANSS and PANSS total scores. (2) It was possible that age, factor scores of negative symptoms in PANSS, the amount of antipsychotic medication used (daily chlorpromazine equivalent) and gender are correlated with the occurrence of TD. (3) There were significant differences among the number of TD patients with movement disorders in facial and oral areas (67.4%), limbs (58.7%) and torso (37%). The AIMS scores corresponding with movement disorders in different parts of the body were also significantly different. (4) Comparing TD patients with single affected area and those with multiple affected areas, we found that they had significant differences in gender, age of onset, AIMS total scores, severity scores of abnormal movements and loss of range due to abnormal movements.Conclusion(1) Compared to the control group, the TD group had more men, was older, had a longer duration of illness, later age of onset, generally took a higher dosage of antipsychotic medication and presented with more severe negative symptoms. It is possible that age, factor scores of negative symptoms on PANSS, dosage of antipsychotic medication (daily chlorpromazine equivalent) and gender are correlated with the occurrence of TD. (2) The occurrence of movement disorders in facial and oral areas for patients with chronic schizophrenia with TD was the most frequent, and the symptoms were the most severe. (3) Compared to TD patients with a single affected area, TD patients with multiple affected areas may have an earlier age of onset, more severe movement disorders, and more setbacks in their movement and functioning.

SA17. Response to Treatment With Valbenazine (NBI-98854) in Subjects With Tardive Dyskinesia

Abstract Background: Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder resulting from exposure to dopamine receptor-blocking agents (DRBAs), such as antipsychotics. Valbenazine is a novel and highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor that is being evaluated for the treatment of TD and other movement disorders. Clinical studies include a Phase 3 trial of valbenazine in adults who had TD and underlying schizophrenia/schizoaffective disorder or mood disorder (KINECT 3; NCT02274558). The primary end point of this trial was met as demonstrated by a significant difference between valbenazine 80 mg/day and placebo for the Abnormal Involuntary Movement Scale (AIMS) dyskinesia total score (Items 1–7) change from baseline. Additional analyses of AIMS data from this trial were conducted to assess treatment response in subjects with TD. Methods: In this 6-week, double-blind, placebo-controlled trial, subjects were randomized 1:1:1 to once-daily treatment with valbenazine 80 mg, valbenazine 40 mg, or placebo. Treatment response was defined as ≥50% reduction in the AIMS total score. AIMS responders were analyzed by study visit (Weeks 2, 4, and 6) in the intent-to-treat (ITT) population and in subgroups categorized by underlying psychiatric diagnosis (schizophrenia/schizoaffective disorder or mood disorder). Numbers needed to treat (NNTs) were calculated for AIMS responders (valbenazine vs placebo) at Week 6. Significance testing was not conducted in the subgroups. Results: At Week 6 in the ITT population (N = 225), AIMS responder rates were significantly higher with valbenazine than with placebo: 80 mg, 40.0% (P < .0001; NNT = 4); 40 mg, 23.8% (P = .0200; NNT=7); placebo, 8.7%. Treatment with valbenazine 80 mg versus placebo also resulted in significantly higher responder rates at Week 2 (23.4% vs 5.3%, P = .0016) and Week 4 (28.8% vs 9.7%, P = 0.0039). Subjects treated with valbenazine 40 mg also had higher response rates at Week 2 (14.3% vs 5.3%) and Week 4 (15.6% vs 9.7%) relative to placebo-treated subjects, but the differences were not statistically significant. In subjects with schizophrenia/schizoaffective disorder (n = 148) or mood disorder (n = 77), AIMS responder rates were higher with valbenazine than placebo at all study visits. The highest responder rates were found at Week 6 and similar in the schizophrenia subgroup (80 mg, 40.9%, NNT = 4; 40 mg, 26.2%, NNT = 6; placebo, 9.3%) and mood subgroup (80 mg, 38.5%, NNT = 4; 40 mg, 19.0%, NNT=9; placebo, 7.7%). Conclusion: These study results, based on a rigorous definition of treatment response, indicate that substantial TD improvements occurred more frequently with valbenazine than placebo in adults diagnosed with schizophrenia/schizoaffective disorder or mood disorder. A significant difference between the 80-mg dose and placebo for the AIMS response was observed as early as 2 weeks of treatment.