Profiling deutetrabenazine extended-release tablets for tardive dyskinesia and chorea associated with Huntington's disease.

INTRODUCTION: Tardive dyskinesia (TD) and Huntington's disease (HD)-associated chorea are persistent and disabling hyperkinetic disorders that can be treated with vesicular monoamine transporter type 2 (VMAT2) inhibitors, including the recently approved once-daily (QD) formulation of deutetrabenazine (DTBZ ER). While its efficacy and safety profile have not been directly investigated, currently available data confirms bioequivalence and similar bioavailability to the twice-daily formulation (DTBZ BID). AREAS COVERED: The authors briefly review the pivotal trials establishing efficacy of DTBZ for TD and HD-associated chorea, the pharmacokinetic data for bioequivalence between QD and BID dosing of DTBZ, as well as dose proportionality evidence, titration recommendations, and safety profile for DTBZ ER. EXPERT OPINION: Long-term data show that DTBZ is efficacious and well tolerated for the treatment of TD and HD-associated chorea. DTBZ ER likely demonstrates therapeutic equivalence with no new safety signals. Due to the lack of comparative clinical trial data, no evidence-based recommendation about choice of VMAT2 inhibitor or switching between VMAT2 inhibitors can be made about best practice. Ultimately, QD dosing may offer the chance of improved medication adherence, an important consideration in patients with complex treatment regimens and/or patients with cognitive decline.

Efficacy and safety of different pharmacological interventions in the treatment of tardive dyskinesia: a systematic review and network meta-analysis.

OBJECTIVES: 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. DESIGN: 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. DATA SOURCES: PubMed, Scopus, The Cochrane Central Register of Controlled Trials (CENTRAL), Web of Sciences, and Clinicaltrials.gov were searched to identify relevant records. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: 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. DATA EXTRACTION: 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.

Molecular Dynamic Simulations to Determine Individualized Therapy: Tetrabenazine for the GNAO1 Encephalopathy E246K Variant.

INTRODUCTION: GNAO1 encephalopathy is characterized by severe hypotonia, psychomotor retardation, epilepsy, and movement disorders. Genetic variations in GNAO1 have been linked to neurological symptoms including movement disorders like dystonia. The correlation between the E246K mutation in the Gα subunit and aberrant signal transduction of G proteins has been established but no data are reported regarding the efficacy of medical treatment with tetrabenazine. METHODS: Molecular modeling studies were performed to elucidate the molecular mechanisms underlying this mutation. We developed drug efficacy models using molecular dynamic simulations that replicated the behavior of wild-type and mutated proteins in the presence or absence of ligands. RESULTS AND DISCUSSION: We demonstrated that the absence of the mutation leads to normal signal transduction upon receptor activation by the endogenous ligand, but not in the presence of tetrabenazine. In contrast, the presence of the mutation resulted in abnormal signal transduction in the presence of the endogenous ligand, which was corrected by the drug tetrabenazine. Tetrabenazine was identified as a promising therapeutic option for pediatric patients suffering from encephalopathy due to an E246K mutation in the GNAO1 gene validated through molecular dynamics. This is a potential first example of the use of this technique in a rare neurological pediatric disease.

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

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

Meta-analysis and systematic review of vesicular monoamine transporter (VMAT-2) inhibitors in schizophrenia and psychosis.

RATIONALE: 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.

Crushing the Contents of Valbenazine Capsules for Potential Addition to Soft Foods or Administration via Gastrostomy Tube.

PURPOSE: One-capsule, once-daily valbenazine is approved for tardive dyskinesia and under evaluation for chorea associated with Huntington's disease, conditions in which patients often experience dysphagia. In vitro studies were conducted to assess the suitability of crushing the contents of valbenazine capsules (40 and 80 mg) for mixing with soft foods or liquids or administration via a gastrostomy tube (G-tube). METHODS: In study 1, the dissolution of whole valbenazine capsules and crushed capsule contents were measured serially for 1 hour. In study 2, valbenazine recovery was evaluated after crushed contents were mixed with soft foods, buffer solutions (pH range, 1.2-6.8), and fed-state simulated gastric fluid. In study 3, valbenazine recovery was evaluated after crushed contents were dispersed in water and delivered via a G-tube. In studies 2 and 3, acceptable valbenazine recovery was 90% to 110%. FINDINGS: Study 1 indicated rapid and complete drug release for whole valbenazine capsules and crushed capsule contents, with similar release at 10 minutes (whole, 94%-99%; crushed, 98%-100%) and 60 minutes (whole, 101%-103%; crushed, 101%-102%). Study 2 found acceptable valbenazine recovery within 2 hours of adding crushed capsule contents to tested foods, buffers, or fed-state simulated gastric fluid (recovery, 92%-102%). Study 3 found acceptable valbenazine recovery when crushed contents were added to cold or hot water and delivered via G-tube, with a water cup rinse to capture residual contents (recovery, 91%-97%). IMPLICATIONS: These studies indicate the potential viability of valbenazine formulation(s) that can be added to soft foods or liquids or delivered via G-tube. Such formulations will be important for individuals who require treatment with a vesicular monoamine transporter 2 inhibitor but cannot swallow whole pills.

Systematic review of drug therapy for chorea in NXK2-1-related disorders: Efficacy and safety evidence from case studies and series.

BACKGROUND: The NKX2-1-related disorders (NKX2-1-RD) is a rare disorder characterized by choreiform movements along with respiratory and endocrine abnormalities. The European Reference Network of Rare Neurological Disorders funded by the European Commission conducted a systematic review to assess drug treatment of chorea in NKX2-1-RD, aiming to provide clinical recommendations for its management. METHODS: A systematic pairwise review using various databases, including MEDLINE, Embase, Cochrane, CINAHL, and PsycInfo, was conducted. The review included patients diagnosed with chorea and NKX2-1-RD genetic diagnosis, drug therapy as intervention, no comparator, and outcomes of chorea improvement and adverse events. The methodological quality of the studies was assessed, and the study protocol was registered in PROSPERO. RESULTS: Of the 1417 studies examined, 28 studies met the selection criteria, consisting of 68 patients. The studies reported 22 different treatments for chorea, including carbidopa/levodopa, tetrabenazine, clonazepam, methylphenidate, carbamazepine, topiramate, trihexyphenidyl, haloperidol, propranolol, risperidone, and valproate. No clinical improvements were observed with carbidopa/levodopa, tetrabenazine, or clonazepam, and various adverse effects were reported. However, most patients treated with methylphenidate experienced improvements in chorea and reported only a few negative effects. The quality of evidence was determined to be low. CONCLUSIONS: The management of chorea in individuals with NKX2-1-RD presents significant heterogeneity and lack of clarity. While the available evidence suggests that methylphenidate may be effective in improving chorea symptoms, the findings should be interpreted with caution due to the limitations of the studies reviewed. Nonetheless, more rigorous and comprehensive studies are necessary to provide sufficient evidence for clinical recommendations.

[Tardive dyskinesia]. / Tardivnaya diskineziya.

Tardive dyskinesia (TD) is a delayed, often irreversible iatrogenic movement disorder caused by long-term use of that dopamine receptors blocking drugs. Prevention of TD is paramount, and clinicians should follow best practice recommendations for prescribing antipsychotics, as well as reduction the using of dopamine receptor blocking drugs for non-psychiatric prescriptions. Replacement of antipsychotics with lower affinity for D2 receptors drugs, addition of VMAT2 (tetrabenazine), botulinum therapy, amantadine may be effective. In detection and incurable cases, the possibility of neuromodulation of brain structures should be considered. Most methods for testing TD currently have an insufficient level of evidence, although they include recommendations from professional communities. There is a great need for new clinical trials.

Real-world experience with VMAT2 inhibitors in Tourette syndrome.

OBJECTIVES: We aimed to review our "real-world" experience with the vesicular monoamine transporter 2 (VMAT2) inhibitors tetrabenazine, deutetrabenazine, and valbenazine for treatment of Tourette syndrome, focusing on therapeutic benefits, side effect profile, and accessibility for the off-label use of these drugs. METHODS: We performed a retrospective chart review, supplemented with a telephone survey, of all our patients treated for their tics with VMAT2 inhibitors over a period of 4 years from January 2017 until January 2021. RESULTS: We identified 164 patients treated with the various VMAT2 inhibitors (tetrabenazine, n = 135; deutetrabenazine, n = 71; valbenazine, n = 20). Data on the mean treatment duration and daily dosages were collected. The response to VMAT2 inhibitors was assessed by a Likert scale by comparing the symptom severity before initiation and while on treatment. Side effects were mild and mostly consisted of depression as the major side effect but there was no suicidality reported. CONCLUSION: VMAT2 inhibitors are effective and safe in the treatment of tics associated with Tourette syndrome but are not readily accessible by patients in the United States, partly because of lack of approval by the Food and Drug Administration.

The effects of sigma-1 agonist fluvoxamine on experimental induced tardive dyskinesia model in rats.

Tardive dyskinesia (TD) is a persistent involuntary complex movement disorder that is known to occur with long-term antipsychotic treatment. Despite being a well-recognized complication of this treatment, its symptoms are often masked by the antipsychotic agents, only to become apparent upon reducing or terminating the treatment. In an effort to advance our understanding of TD pathophysiology and to identify potential therapies, the current study aimed to establish an animal model of TD by administering haloperidol to rats and to evaluate the efficacy of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), in ameliorating TD symptoms. The study compared the behavioral and biochemical parameters of rats that were treated with either fluvoxamine, tetrabenazine, haloperidol, or saline (control group). The biochemical parameters of interest included the brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), superoxide dismutase (SOD), and malondialdehyde (MDA). To achieve the study objectives, 32 male Wistar Albino rats were assigned to four different groups. The control group received physiological saline for six weeks. The haloperidol group received 1 mg/kg/ip haloperidol for the first three weeks, followed by two weeks of saline. The haloperidol+fluvoxamine group received 1 mg/kg/ip haloperidol for the first three weeks, followed by 30 mg/kg/ip fluvoxamine. The haloperidol+tetrabenazine group was administered 1 mg/kg/ip haloperidol for the first three weeks, followed by 5 mg/kg/ip tetrabenazine. Behavioral assessments of the rats were performed by measuring vacuous chewing movements. Subsequently, samples were collected from the hippocampus, striatum, and frontal lobe tissues of the rats, and BDNF, NGF, SOD, and MDA levels were measured. The results of the study demonstrated significant differences between the groups with respect to behavioral observations. Furthermore, SOD levels in the hippocampus, as well as BDNF, NGF, and SOD levels in the striatum of the haloperidol+fluvoxamine group were significantly higher than those observed in the haloperidol group. Conversely, MDA levels in the hippocampus were significantly lower in the haloperidol+fluvoxamine group than in the haloperidol group. These findings provide evidence of the beneficial effects of fluvoxamine, acting as a sigma-1 agonist, in treating TD symptoms induced experimentally. The observed benefits were supported by the biochemical investigations performed on brain tissue samples. Therefore, fluvoxamine may be considered as a potential alternative treatment for TD in clinical practice, although further research is needed to corroborate these findings.

Computational insights into missense mutations in HTT gene causing Huntington's disease and its interactome networks.

BACKGROUND: Huntington's disease is a rare neurodegenerative illness of the central nervous system that is inherited in an autosomal dominant pattern. Mutant huntingtin protein is produced as a result of enlargement of CAG repeat in the N-terminal of the polyglutamine tract. AIM OF THE STUDY: Herein, we aim to investigate the mutations and their effects on the HTT gene and its genetic variants. Additionally, the protein-protein interaction of HTT with other proteins and receptor-ligand interaction with the three-dimensional structure of huntingtin protein were identified. METHODS: A comprehensive analysis of the HTT interactome and protein-ligand interaction has been carried out to provide a global picture of structure-function analysis of huntingtin protein. Mutations were analyzed and mutation verification tools were used to check the effect of mutation on protein function. RESULTS: The results showed, mutations in a single gene are not only responsible for causing a particular disease but may also cause other hereditary disorders as well. Moreover, the modification at the nucleotide level also cause the change in the specific amino acid which may disrupt the function of HTT and its interacting proteins contributing in disease pathogenesis. Furthermore, the interaction between MECP2 and BDNF lowers the rate of transcriptional activity. Molecular docking further confirmed the strong interaction between MECP2 and BDNF with highest affinity. Amino acid residues of the HTT protein, involved in the interaction with tetrabenazine were N912, Y890, G2385, and V2320. These findings proved, tetrabenazine as one of the potential therapeutic agent for treatment of Huntington's disease. CONCLUSION: These results give further insights into the genetics of Huntington's disease for a better understanding of disease models which will be beneficial for the future therapeutic studies.

[Late-Onset Dyskinesia Occurring During Antipsychotic Treatment for Schizophrenia: Treatments for Tardive Dyskinesia].

Tardive dyskinesia is recognized as buccolingual dyskinesia, but also includes various involuntary movements, such as chorea, dystonia, myoclonus, and tremor. Tardive dyskinesia can be treated depending on the type of movement disorder present. Antipsychotics causing tardive dyskinesia should be reduced in dosage or should be discontinued. However, the treatment of schizophrenia is important, and neurologists must treat tardive dyskinesia in collaboration with psychiatrists taking care of patients with tardive dystonia. Various treatments, such as VMAT-2 inhibitors or tetrabenazine, reserpine, dopamine receptor antagonists, botulinum toxin therapy, anticholinergic agents, or deep brain stimulation, are trialed, depending on the type of movement disorder and the degree of severity of the disorder.

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

INTRODUCTION: Deutetrabenazine 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. METHODS: The 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. RESULTS: This 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. CONCLUSION: Using 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.

Recent developments in the management of Huntington's disease.

Huntington's disease (HD) is a rare, incurable, inheritedneurodegenerative disorder manifested by chorea, hyperkinetic, and hypokinetic movements. The FDA has approved only two drugs, viz. tetrabenazine, and deutetrabenazine, to manage the chorea associated with HD. However, several other drugs are used as an off-label to manage chorea and other symptoms such as depression, anxiety, muscle tremors, and cognitive dysfunction associated with HD. So far, there is no disease-modifying treatment available. Drug repurposing has been a primary drive to search for new anti-HD drugs. Numerous molecular targets along with a wide range of small molecules and gene therapies are currently under clinical investigation. More than 200 clinical studies are underway for HD, 75% are interventional, and 25% are observational studies. The present review discusses the small molecule clinical pipeline and molecular targets for HD. Furthermore, the biomarkers, diagnostic tests, gene therapies, behavioral and observational studies for HD were also deliberated.

An MDS Evidence-Based Review on Treatments for Huntington's Disease.

BACKGROUND: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off-label treatments. OBJECTIVES: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for HD gene expansion carriers. METHODS: We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible randomized controlled trials were identified via an electronic search of the CENTRAL, MEDLINE, and EMBASE databases. All eligible trials that evaluated one or more of 33 predetermined clinical questions were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool. A framework was adapted to allow for efficacy and safety conclusions to be drawn from the balance between the GRADE level of evidence and the importance of the benefit/harm of the intervention. RESULTS: Twenty-two eligible studies involving 17 interventions were included, providing data to address 8 clinical questions. These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea. The data did not support a disease-modifying effect for premanifest and manifest HD. There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality. Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments. CONCLUSIONS: Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms. © 2021 International Parkinson and Movement Disorder Society.

Pimozide and pancreatic cancer in diabetic chorea: a case report.

PURPOSE/AIM: Diabetic chorea is a rare movement disorder associated with diabetes mellitus. We report the case of a patient that benefited from pimozide and died of pancreatic cancer. CASE REPORT: A 70-year-old woman presented with pollakiuria and involuntary movements of left limbs since three months. Laboratory tests revealed high serum levels of glycemia and glycated haemoglobin. She was admitted to internal medicine department and discharged one week later: insulin was administered with normalization of blood glucose levels and the involuntary movements gradually disappeared. Three weeks later she was admitted to neurological department due to the recurrence of the involuntary movements. Glycemia and other routine laboratory tests were normal. Neurological examination showed choreic movements involving left limbs. MRI showed a hyperintensity on T1- and T2-weighted sequences of right putamen and caudate nucleus head. Haloperidol was administered without improvement, it was successively substituted with tetrabenazine and the patient was discharged with an unvaried clinical picture. Two months later tetrabenazine was discontinued because of inefficacy and pimozide was started. The choreic movements considerably diminished after few days. Four months later, a pancreatic cancer was diagnosed and the patient died in the same month. CONCLUSION: Clinical and radiological features were suggestive of diabetic chorea. Our patient benefited exclusively from pimozide, it could be reasonable to use pimozide in resistant form and also propose it as first choice treatment. Another important element is the diagnosis of pancreatic cancer some months after chorea onset: a causal link could exist.

Digging Deeper: Advancements in Visualization of Inhibitory Synapses in Neurodegenerative Disorders.

Recent research has provided strong evidence that neurodegeneration may develop from an imbalance between synaptic structural components in the brain. Lately, inhibitory synapses communicating via the neurotransmitters GABA or glycine have come to the center of attention. Increasing evidence suggests that imbalance in the structural composition of inhibitory synapses affect deeply the ability of neurons to communicate effectively over synaptic connections. Progressive failure of synaptic plasticity and memory are thus hallmarks of neurodegenerative diseases. In order to prove that structural changes at synapses contribute to neurodegeneration, we need to visualize single-molecule interactions at synaptic sites in an exact spatial and time frame. This visualization has been restricted in terms of spatial and temporal resolution. New developments in electron microscopy and super-resolution microscopy have improved spatial and time resolution tremendously, opening up numerous possibilities. Here we critically review current and recently developed methods for high-resolution visualization of inhibitory synapses in the context of neurodegenerative diseases. We present advantages, strengths, weaknesses, and current limitations for selected methods in research, as well as present a future perspective. A range of new options has become available that will soon help understand the involvement of inhibitory synapses in neurodegenerative disorders.

Efficacy and Safety of Fixed-Dose Deutetrabenazine in Children and Adolescents for Tics Associated With Tourette Syndrome: A Randomized Clinical Trial.

Importance: Tourette syndrome is a neurodevelopmental disorder characterized by childhood onset of motor and phonic tics, often accompanied by behavioral and psychiatric comorbidities. Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor approved in the US for the treatment of chorea associated with Huntington disease and tardive dyskinesia. Objective: To report results of the ARTISTS 2 (Alternatives for Reducing Tics in Tourette Syndrome 2) study examining deutetrabenazine for treatment of Tourette syndrome. Design, Setting, and Participants: This phase 3, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study was conducted over 8 weeks with a 1-week follow-up (June 21, 2018, to December 9, 2019). Children and adolescents aged 6 to 16 years with a diagnosis of Tourette syndrome and active tics causing distress or impairment were enrolled in the study. Children were recruited from 52 sites in 10 countries. Data were analyzed from February 4 to April 22, 2020. Interventions: Participants were randomized (1:1:1) to low-dose deutetrabenazine (up to 36 mg/d), high-dose deutetrabenazine (up to 48 mg/d), or a matching placebo, which were titrated over 4 weeks to the target dose followed by a 4-week maintenance period. Main Outcomes and Measures: The primary efficacy end point was change from baseline to week 8 in the Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS) for high-dose deutetrabenazine. Key secondary end points included changes in YGTSS-TTS for low-dose deutetrabenazine, Tourette Syndrome Clinical Global Impression score, Tourette Syndrome Patient Global Impression of Impact score, and Child and Adolescent Gilles de la Tourette Syndrome-Quality of Life Activities of Daily Living subscale score. Safety assessments included incidence of treatment-emergent adverse events, laboratory parameters, vital signs, and questionnaires. Results: The study included 158 children and adolescents (mean [SD] age, 11.7 [2.6] years). A total of 119 participants (75%) were boys; 7 (4%), Asian; 1 (1%), Black; 32 (20%), Hispanic; 4 (3%), Native American; 135 (85%), White; 2 (1%), multiracial; 9 (6%), other race; and 1 (0.6%), of unknown ethnic origin. Fifty-two participants were randomized to the high-dose deutetrabenazine group, 54 to the low-dose deutetrabenazine group, and 52 to the placebo group. Baseline characteristics for participants were similar between groups. Of the total 158 participants, 64 (41%) were aged 6 to 11 years, and 94 (59%) were aged 12 to 16 years at baseline. Mean time since Tourette syndrome diagnosis was 3.3 (2.8) years, and mean baseline YGTSS-TTS was 33.8 (6.6) points. At week 8, the difference in YGTSS-TTS was not significant between the high-dose deutetrabenazine and placebo groups (least-squares mean difference, -0.8 points; 95% CI, -3.9 to 2.3 points; P = .60; Cohen d, -0.11). There were no nominally significant differences between groups for key secondary end points. Treatment-emergent adverse events were reported for 34 participants (65%) treated with high-dose deutetrabenazine, 24 (44%) treated with low-dose deutetrabenazine, and 25 (49%) treated with placebo and were generally mild or moderate. Conclusions and Relevance: In this fixed-dose randomized clinical trial of deutetrabenazine in children and adolescents with Tourette syndrome, the primary efficacy end point was not met. No new safety signals were identified. Trial Registration: ClinicalTrials.gov Identifier: NCT03571256.