OBJECTIVE: The aim of this study is to indirectly compare and rank the different drugs that have been studied in randomized clinical trials (RCTs) in patients with tardive dyskinesia (TD) in terms of their efficacy in ameliorating the symptoms of TD and safety.
METHODS: A network meta-analysis and a systematic review were registered prospectively on PROSPERO under the ID: CRD42023407823 and were conducted in accordance with the PRISMA-NMA guidelines.
METHODS: PubMed, Scopus, The Cochrane Central Register of Controlled Trials (CENTRAL), Web of Sciences, and Clinicaltrials.gov were searched to identify relevant records.
METHODS: Any parallel randomized blinded controlled clinical trials that studied the use of any medications in treating TD and assessed the symptoms using a functional scale that has been previously validated.
METHODS: The standardized mean difference of improvement along with the reported adverse events for each drug was extracted from each trial, and a network meta-analysis was conducted using a random-effects model.
RESULTS: One thousand eight hundred seventeen patients in 33 RCTs were included in the analysis. Twenty-three different drugs were compared to placebo in terms of reduction in TD symptoms. Among these, valbenazine 80 mg (SMD =  - 1.66, 95%CI = [- 2.55; - 0.78]), valbenazine 40 mg (- 1.00, [- 1.89; - 0.11]), and vitamin E (- 0.77, [- 1.45; - 0.1]) significantly reduced TD symptoms in comparison to placebo, while deutetrabenazine 36 mg (- 1.00, [- 2.12; 0.11]) and reserpine (- 0.54, [- 1.09; 0.02]) did not significantly reduce symptoms. Some serious adverse events were reported for valbenazine and deutetrabenazine, which included mainly psychiatric symptoms such as depression, worsening of schizophrenia, and suicidal ideation, while mild adverse events were reported for other drugs, and their incidence in the treatment arms was comparable to those in the placebo arm.
CONCLUSIONS: Valbenazine (80 and 40 mg) and vitamin E demonstrated efficacy in treating tardive dyskinesia. However, the significant side effects of valbenazine should prompt further investigation of alternative treatment modalities.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.

UNASSIGNED: Minimum clinically important difference (MCID) is the smallest change in an outcome measure that is considered clinically meaningful. Using validated MCID thresholds for outcomes powers trials adequately to detect meaningful treatment effects, aids in their interpretation and guides development of new outcome measures.
UNASSIGNED: To provide a comprehensive summary of MCID thresholds of various symptom severity scales reported in movement disorder.
UNASSIGNED: We conducted systematic review of the literature and included studies of one or more movement disorders, and reporting MCID scales.
UNASSIGNED: 2763 reports were screened. Final review included 32 studies. Risk of bias (RoB) assessment showed most studies were of good quality. Most commonly evaluated scale was Unified Parkinson\'s Disease Rating Scale (UPDRS) (11 out of 32). Four studies assessing MDS-UPDRS had assessed its different sub-parts, reporting a change of 2.64,3.05,3.25 and 0.9 points to detect clinically meaningful improvement and 2.45,2.51,4.63 and 0.8 points to detect clinically meaningful worsening, for the Part I, II, III and IV, respectively. For Parts II + III, I + II + III and I + II + III + IV, MCID thresholds reported for clinically meaningful improvement were 5.73, 4.9, 6.7 and 7.1 points respectively; while those for clinically meaningful worsening were 4.7, 4.2, 5.2 and 6.3 points, respectively. MCID thresholds reported for other scales included Abnormal Involuntary Movement Scale (AIMS), Toronto Western Spasmodic Torticollis Rating Scale (TWSRS), and Burke-Fahn-Marsden Dystonia Scale (BFMD).
UNASSIGNED: This review summarizes all the MCID thresholds currently reported in Movement disorders research and provides a comprehensive resource for future trials, highlighting the need for standardized and validated MCID scales in movement disorder research.

BACKGROUND: Dopamine antagonists induce dopamine receptor supersensitivity. This may manifest in late-appearing movement disorders (tardive dyskinesia (TD). VMAT-2 inhibitors reduce dopaminergic transmission but have limited activity at postsynaptic receptors and so may have antipsychotic activity with lower risk of tardive dyskinesia.
METHODS: We conducted a systematic database search from inception to September 2022 for articles describing the use of VMAT-2 inhibitors in psychosis. Inclusion criteria were as follows: Population: adults diagnosed with psychosis or schizophrenia; Intervention: treatment with tetrabenazine, deutetrabenazine or valbenazine; Comparison: comparison with placebo or/and antipsychotic drug; Outcomes: with efficacy outcomes (e.g. Brief Psychiatric Rating Scale (BPRS) change or clinician assessment) and adverse effects ratings (e.g. rating scale or clinician assessment or dropouts); and Studies: in randomised controlled trials and non-randomised studies.
RESULTS: We identified 4892 records relating to VMAT-2 inhibitor use of which 5 (173 participants) met our a priori meta-analysis inclusion criteria. VMAT-2 inhibitors were more effective than placebo for the outcome \'slight improvement\' (risk ratio (RR) = 1.77 (95% CI 1.03, 3.04)) but not for \'moderate improvement\' (RR 2.81 (95% CI 0.27, 29.17). VMAT-2 inhibitors were as effective as active comparators on both measures for-\'slight improvement\' (RR 1.05 (95% CI 0.6, 1.81)) and \'moderate improvement\' (RR 1.11 (95% CI 0.51, 2.42). Antipsychotic efficacy was also suggested by a narrative review of 37 studies excluded from the meta-analysis.
CONCLUSIONS: VMAT-2 inhibitors may have antipsychotic activity and may offer promise for treatment of psychosis with the potential for a reduced risk of TD.

Antipsychotics are the mainstay for the treatment of schizophrenia and other psychotic disorders; however, these agents are associated with an extensive side effect profile that may complicate treatment outcomes. We present the case of a 35-year-old woman with a history of schizoaffective disorder and five prior psychiatric hospitalizations. The patient first presented to the hospital for disorganized behavior, in addition to poor sleep, auditory hallucinations, and racing thoughts in the context of medication nonadherence. She received two loading doses of intra-muscular paliperidone with fair symptomatic improvement. After discharge, she was scheduled to receive a monthly dose of paliperidone, which she missed, resulting in decompensation, re-emergence of psychosis, and another hospitalization two months later. She was given the missed dose with no improvement and progressive deterioration, for which alternative agents were tried. She received olanzapine and was tried briefly on quetiapine and haloperidol as well, with no benefit, and she also developed abnormal perioral movements. She was reloaded with paliperidone, and her psychotic symptoms improved, although she developed akathisia and hyperprolactinemia. The patient returned to the hospital two days later after being discharged, due to disorganized behavior and multiple delusions. Clozapine was started and titrated to 100 mg qam and 200 mg qhs. While on clozapine, she developed profuse sialorrhea that was treated with sublingual atropine drops, and by the time of discharge psychotic symptoms had markedly improved, perioral movements diminished, and prolactin level trended down. The patient maintained stability for over a year after the last admission. Identifying antipsychotics to successfully treat refractory psychosis and managing their multiple potential side effects is challenging but can result in better quality of life for patients as well as improved treatment adherence. This case report is unique in the way it illustrates this point, while discussing different approaches to managing multiple side effects that can happen simultaneously.

UNASSIGNED: Two vesicular monoamine transporter 2 (VMAT2) inhibitors are approved in the United States (US) for the treatment of tardive dyskinesia (TD). There is a paucity of information on the impact of VMAT2 inhibitor treatment on patient social and physical well-being. The study objective was to elucidate clinician-reported improvement in symptoms and any noticeable changes in social or physical well-being in patients receiving VMAT2 inhibitors.
UNASSIGNED: A web-based survey was offered to physicians, nurse practitioners, and physician assistants based in the US who prescribed valbenazine for TD within the past 24 months. Clinicians reported data from the charts of patients who met the inclusion criteria and were allowed to recall missing information.
UNASSIGNED: Respondents included 163 clinicians who reviewed charts of 601 VMAT2-treated patients with TD: 47% had TD symptoms in ≥2 body regions, with the most common being in the head or face and upper extremities. Prior to treatment, 93% of patients showed impairment in ≥1 social domain, and 88% were impaired in ≥1 physical domain. Following treatment, among those with improvement in TD symptoms (n = 540), 80% to 95% showed improvement in social domains, 90% to 95% showed improvement in physical domains, and 73% showed improvement in their primary psychiatric condition.
UNASSIGNED: In VMAT2-treated patients with TD symptom improvement, clinicians reported concomitant improvement in psychiatric disorder symptoms and in social and physical well-being. Regular assessment of TD impact on these types of domains should occur simultaneously with movement disorder ratings when evaluating the value of VMAT2 inhibitor therapy.

The Extrapyramidal Symptom Rating Scale - Abbreviated (ESRS-A) is an abbreviated version of the Extrapyramidal Symptom Rating Scale (ESRS) with instructions, definitions, and a semi-structured interview that follows clinimetric concepts of measuring clinical symptoms. Similar to the ESRS, the ESRS-A was developed to assess four types of drug-induced movement disorders (DIMD): parkinsonism, akathisia, dystonia, and tardive dyskinesia (TD).
The present review of the literature provides the most relevant clinimetric properties displayed by the ESRS and ESRS-A in clinical studies. Comprehensive ESRS-A definitions, official scale, and basic instructions are provided. ESRS inter-rater reliability was evaluated in two pivotal studies and in multicenter international studies. Inter-rater reliability was high for assessing both antipsychotic-induced movement disorders and idiopathic Parkinson\'s disease. Guidelines were also established for inter-rater reliability and the rater certification processes. The ESRS showed good concurrent validity with 96% agreement between Abnormal Involuntary Movement Scale (AIMS) for TD-defined cases and ESRS-defined cases. Similarly, concurrent validity for ESRS-A total and subscores for parkinsonism, akathisia, dystonia, and dyskinesia ranged from good to very good. The ESRS was particularly sensitive for detecting DIMD-related movement differences following treatment with placebo, antipsychotics, and antiparkinsonian and antidyskinetic medications. ESRS measurement of drug-induced extrapyramidal symptoms was shown to discriminate extrapyramidal symptoms from psychiatric symptoms.
The ESRS and ESRS-A are valid clinimetric indices for measuring DIMD. They can be valuably implemented in clinical research, particularly in trials testing antipsychotic medications, and in clinics to detect the presence, severity, and response to treatment of movement disorders.

Antipsychotic-associated movement disorders remain common and disabling. Their screening and assessment are challenging due to clinical heterogeneity and different use of nomenclature between psychiatrists and neurologists.
An International Parkinson and Movement Disorder Society subcommittee aimed to rate psychometric quality of severity and screening instruments for antipsychotic-associated movement disorders.
Following the methodology adopted by previous International Parkinson and Movement Disorders Society subcommittee papers, instruments for antipsychotic-associated movement disorders were reviewed, applying a classification as \"recommended,\" \"recommended with caveats,\" \"suggested,\" or \"listed.\"
Our review identified 23 instruments. The highest grade of recommendation reached is \"recommended with caveats,\" assigned to seven severity rating instruments (Extrapyramidal Symptoms Rating Scale, Barnes Akathisia Rating Scale, Abnormal Involuntary Movements Scale, Drug-Induced Extra-Pyramidal Symptoms Scale, Maryland Psychiatric Research Centre involuntary movements scale, Simpson Angus Scale, and Matson Evaluation of Drug Side effects). Only three of these seven (Drug-Induced Extra-Pyramidal Symptoms Scale, Maryland Psychiatric Research Centre, Matson Evaluation of Drug Side effects) were also screening instruments. Their main caveats are insufficient demonstration of psychometric properties (internal consistency, skewing, responsiveness to change) and long duration of administration. Eight \"suggested\" instruments did not meet requirements for the \"recommended\" grade also because of insufficient psychometric validation. Other limitations shared by several instruments are lack of comprehensiveness in assessing the spectrum of antipsychotic-associated movement disorders and ambiguous nomenclature.
The high number of instruments \"recommended with caveats\" does not support the need for developing new instruments for antipsychotic-associated movement disorders. However, addressing the caveats with new psychometric studies and revising existing instruments to improve the clarity of their nomenclature are recommended next steps. © 2023 International Parkinson and Movement Disorder Society.

The inadequate efficacy and adverse effects of antipsychotics severely affect the recovery of patients with schizophrenia spectrum disorders (SSD). We report the evidence for associations between pharmacogenetic (PGx) variants and antipsychotics outcomes, including antipsychotic response, antipsychotic-induced weight/BMI gain, metabolic syndrome, antipsychotic-related prolactin levels, antipsychotic-induced tardive dyskinesia (TD), clozapine-induced agranulocytosis (CLA), and drug concentration level (pharmacokinetics) in SSD patients. Through an in-depth systematic search in 2010-2022, we identified 501 records. We included 29 meta-analyses constituting pooled data from 298 original studies over 69 PGx variants across 39 genes, 4 metabolizing phenotypes of CYP2D9, and 3 of CYP2C19. We observed weak unadjusted nominal significant (p < 0.05) additive effects of PGx variants of DRD1, DRD2, DRD3, HTR1A, HTR2A, HTR3A, and COMT (10 variants) on antipsychotic response; DRD2, HTR2C, BDNF, ADRA2A, ADRB3, GNB3, INSIG2, LEP, MC4R, and SNAP25 (14 variants) on weight gain; HTR2C (one variant) on metabolic syndrome; DRD2 (one variant) on prolactin levels; COMT and BDNF (two variants) on TD; HLA-DRB1 (one variant) on CLA; CYP2D6 (four phenotypes) and CYP2C19 (two phenotypes) on antipsychotics plasma levels. In the future, well-designed longitudinal naturalistic multi-center PGx studies are needed to validate the effectiveness of PGx variants in antipsychotic outcomes before establishing any reproducible PGx passport in clinical practice.

Tardive dyskinesia (TD) is a movement disorder that can develop with the use of dopamine receptor-blocking agents and is most commonly caused by antipsychotics. The use of antipsychotics is expanding, which may lead to an increased number of patients experiencing TD. To summarise the current knowledge of the epidemiology and risk factors for TD in Japan, we reviewed articles related to the current state of knowledge around TD identified through a PubMed search, and held a roundtable discussion of experts in Japan on 9 September 2021 to form the basis of the opinion presented within this review. The true prevalence of TD among patients treated with antipsychotics is not well characterised; it is reported to be between 15% and 50% globally and between 6.5% and 7.7% in Japan. Potential barriers to timely treatment of TD include the stigma surrounding mental health issues and the lack of data regarding TD in Asian patients. This review summarises the current knowledge of the epidemiology, challenges to TD diagnosis and risk factors for TD in Japan. Recent strategies for symptom monitoring and early diagnosis, as well as consensus recommendations are included. Achieving a high level of awareness of TD among physicians who treat patients with psychiatric disorders is of great importance and physicians should ensure that patients with psychiatric disorders receiving antipsychotics are proactively monitored for signs of TD.
UNASSIGNED: Plain Language Summary (In Japanese).
UNASSIGNED: Visual Summary (In Japanese).