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.

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.
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.
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.
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.

OBJECTIVE: 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.

Neuronal degeneration and apoptosis may play an important role in the pathogenesis of tardive dyskinesia (TD). Previous studies suggested brain structural and functional abnormalities in patients with TD. We investigated changes in cerebral regional homogeneity (ReHo) in patients with TD using resting-state functional magnetic resonance imaging (rs-fMRI). Imaging data were collected from schizophrenia patients with TD (TD group, n=58) and without TD (non-TD group, n=66) and healthy controls (HC group, n=67), processed with SPM, and evaluated at a corrected threshold. Psychopathology and severity of TD were assessed with the Positive and Negative Syndrome Scale (PANSS) and Abnormal Involuntary Movement Scale (AIMS), respectively. Results: TD vs. non-TD group showed significantly higher ReHo in the Left Inferior Semilunar Lobule and Right Fusiform Gyrus and lower ReHo in Left Supramarginal Gyrus, Right Inferior Tempotal Gyrus, and Left Medial Frontal Gyrus. The ReHo value in the Left Inferior Semilunar Lobule was negatively correlated with AIMS upper limbs scores. Conclusions: The findings suggest altered regional neural connectivities in association with TD and may inform research of the etiology and monitor the course of TD in patients with schizophrenia and potentially other psychotic disorders.

暂无摘要。

Previous studies have shown that transcranial direct current stimulation(tDCS) led to an improvement of cognitive function in patients with schizophrenia, but rare study has explored the effect of tDCS on long-term hospitalized chronic schizophrenia with tardive dyskinesia (TD). The present research explored if cognitive function in patients with long-term hospitalized chronic schizophrenia with TD could be improved through tDCS.
This study is a randomized, double-blind, sham-controlled clinical trial. Of the 52 patients, 14 dropped out, and 38 completed the experiment. Thirty-eight patients on stable treatment regimens were randomly assigned to receive active tDCS(n = 21) or sham stimulation(n = 17) on weekdays of the first, third, and fifth weeks of treatment. Patients performed the Pattern Recognition Memory (PRM) and the Intra/Extradimensional Set Shift (IED) from the Cambridge Neuropsychological Test Automated Battery (CANTAB) at baseline and the end of week 3, week 5. Clinical symptoms were also measured at the baseline and the fifth week using the Scale for the Assessment of Negative Symptoms (SANS) and the Positive and Negative Syndrome Scale (PANSS). Side effects of tDCS were assessed with an experimenter-administered open-ended questionnaire during the whole experiment.
There were no significant differences in PRM and IED performance metrics, SANS total score and PANSS total score between active and sham tDCS groups at the end of week 5 (p > 0.05). Furthermore, there was a significant difference in the adverse effects of the tingling sensation between the two groups (p < 0.05), but there was no significant difference in other side effects (p > 0.05).
According to these findings, no evidence supports using anodal stimulation over the left dorsolateral prefrontal cortex to improve cognitive function in patients with long-term hospitalized chronic schizophrenia with TD.

Tardive dyskinesia (TD) develops in 20-30% of schizophrenia patients and up to 50% in patients > 50 years old. DNA methylation may play an important role in the development of TD.
DNA methylation analyses in schizophrenia with TD.
We conducted a genome-wide DNA methylation analysis in schizophrenia with TD using methylated DNA immunoprecipitation coupled with next-generation sequencing (MeDIP-Seq) in a Chinese sample including five schizophrenia patients with TD and five without TD (NTD), and five healthy controls. The results were expressed as the log2FC, fold change of normalized tags between two groups within the differentially methylated region (DMR). For validation, the pyrosequencing was used to quantify DNA methylation levels of several methylated genes in an independent sample (n = 30).
Through genome-wide MeDIP-Seq analysis, we identified 116 genes that were significantly differentially methylated in promotor regions in comparison of TD group with NTD group including 66 hypermethylated genes (top 4 genes are GABRR1, VANGL2, ZNF534, and ZNF746) and 50 hypomethylated genes (top 4 genes are DERL3, GSTA4, KNCN, and LRRK1). Part of these genes (such as DERL3, DLGAP2, GABRR1, KLRG2, LRRK1, VANGL2, and ZP3) were previously reported to be associated with methylation in schizophrenia. Gene Ontology enrichment and KEGG pathway analyses identified several pathways. So far, we have confirmed the methylation of 3 genes (ARMC6, WDR75, and ZP3) in schizophrenia with TD using pyrosequencing.
This study identified number of methylated genes and pathways for TD and will provide potential biomarkers for TD and serve as a resource for replication in other populations.

Genetic etiology of schizophrenia is poorly understood despite large genome-wide association data. Long non-coding RNAs (lncRNAs) with a probable regulatory role are emerging as important players in neuro-psychiatric disorders including schizophrenia. Prioritising important lncRNAs and analyses of their holistic interaction with their target genes may provide insights into disease biology/etiology. Of the 3843 lncRNA SNPs reported in schizophrenia GWASs extracted using lincSNP 2.0, we prioritised n = 247 based on association strength, minor allele frequency and regulatory potential and mapped them to lncRNAs. lncRNAs were then prioritised based on their expression in brain using lncRBase, epigenetic role using 3D SNP and functional relevance to schizophrenia etiology. 18 SNPs were finally tested for association with schizophrenia (n = 930) and its endophenotypes-tardive dyskinesia (n = 176) and cognition (n = 565) using a case-control approach. Associated SNPs were characterised by ChIP seq, eQTL, and transcription factor binding site (TFBS) data using FeatSNP. Of the eight SNPs significantly associated, rs2072806 in lncRNA hsaLB_IO39983 with regulatory effect on BTN3A2 was associated with schizophrenia (p = 0.006); rs2710323 in hsaLB_IO_2331 with role in dysregulation of ITIH1 with tardive dyskinesia (p < 0.05); and four SNPs with significant cognition score reduction (p < 0.05) in cases. Two of these with two additional variants in eQTL were observed among controls (p < 0.05), acting likely as enhancer SNPs and/or altering TFBS of eQTL mapped downstream genes. This study highlights important lncRNAs in schizophrenia and provides a proof of concept of novel interactions of lncRNAs with protein-coding genes to elicit alterations in immune/inflammatory pathways of schizophrenia.

Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with antipsychotic use. Data from RE-KINECT, a real-world study of antipsychotic-treated outpatients, were analyzed to assess the effects of possible TD on patient health and social functioning.
Analyses were conducted in Cohort 1 (patients with no abnormal involuntary movements) and Cohort 2 (patients with possible TD per clinician judgment). Assessments included: EuroQoL\'s EQ-5D-5L utility (health); Sheehan Disability Scale (SDS) total score (social functioning); patient- and clinician-rated severity of possible TD (\"none\", \"some\", \"a lot\"); and patient-rated impact of possible TD (\"none\", \"some\", \"a lot\"). Regression models were used to analyze the following: associations between higher (worse) severity/impact scores and lower (worse) EQ-5D-5L utility (indicated by negative regression coefficients); and associations between higher (worse) severity/impact scores and higher (worse) SDS total score (indicated by positive regression coefficients).
In Cohort 2 patients who were aware of their abnormal movements, patient-rated TD impact was highly and significantly associated with EQ-5D-5L utility (regression coefficient: - 0.023, P < 0.001) and SDS total score (1.027, P < 0.001). Patient-rated severity was also significantly associated with EQ-5D-5L utility (- 0.028, P < 0.05). Clinician-rated severity was moderately associated with both EQ-5D-5L and SDS, but these associations were not statistically significant.
Patients were consistent in evaluating the impacts of possible TD on their lives, whether based on subjective ratings (\"none\", \"some\", \"a lot\") or standardized instruments (EQ-5D-5L, SDS). Clinician-rated severity of TD may not always correlate with patient perceptions of the significance of TD.

BACKGROUND: Drug-induced movement disorders (DIMDs) form an important subgroup of secondary movement disorders, which despite conferring a significant iatrogenic burden, tend to be under-recognized and inappropriately managed.
OBJECTIVE: We aimed to look into phenomenology, predictors of reversibility, and its impact on the quality of life of DIMD patients.
METHODS: We conducted the study in the Department of Neurology at a tertiary-care centre in India. The institutional ethics-committee approved the study. We assessed 55-consecutive DIMD patients at presentation to our movement disorder clinic. Subsequently, they followed up to evaluate improvement in severity-scales (UPDRS, UDRS, BARS, AIMS) and quality of life (EuroQol-5D-5L). Wilcoxan-signed-rank test compared the scales at presentation and follow-up. Binary-logistic-regrerssion revealed the independent predictors of reversibility.
RESULTS: Fourteen patients (25.45%) had acute-subacute DIMD and 41 (74.55%) had tardive DIMD. Tardive-DIMD occurred more commonly in the elderly (age 50.73±16.92 years, p<0.001). Drug-induced-Parkinsonism (DIP) was the most common MD, followed by tardivedyskinesia. Risperidone and levosulpiride were the commonest culprit drugs. Patients in both the groups showed a statistically significant response to drug-dose reduction /withdrawal based on follow-up assessment on clinical-rating-scales and quality of life scores (EQ-5D-5L). DIMD was reversible in 71.42% of acute-subacute DIMD and 24.40% of patients with chronic DIMD (p=0.001). Binary-logistic-regression analysis showed acute-subacute DIMDs and DIP as independent predictors of reversibility.
CONCLUSIONS: DIP is the commonest and often reversible drug-induced movement disorder. Levosulpiride is notorious for causing DIMD in the elderly, requiring strict pharmacovigilance.