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Tardive dyskinesia and dystonia are intractable extrapyramidal symptoms caused by the blockade of dopamine receptors by antipsychotic drugs. In addition to the reduction or discontinuation of the causative drug, valbenazine for tardive dyskinesia and botulinum toxin for tardive dystonia have been reported to be effective. However, their efficacy has not been fully demonstrated. In this study, we report the case of a female patient with bipolar disorder, valbenazine-resistant tardive dystonia, and tardive dyskinesia who achieved improvement in extrapyramidal symptoms with electroconvulsive therapy. Additionally, we conducted a narrative literature review on the safety and efficacy of electroconvulsive therapy for tardive dyskinesia and dystonia. [ABSTRACT FROM AUTHOR]

Valbenazine is a highly potent and selective inhibitor of synaptic vesicular monoamine transporter 2. The current therapeutic doses of valbenazine for tardive dyskinesia (TD) are 40, 60, or 80 mg capsules, given orally, once daily (QD). While 40 and 80 mg were investigated in phase 3 KINECT® 3 trial and initially approved, the approval of valbenazine 60 mg was based on the analysis utilizing the Model‐informed drug development (MIDD) approach, facilitated through the US Food and Drug Administration's MIDD Pilot Program. This study aimed to demonstrate the efficacy of 60 mg QD dose through model simulations using an established exposure‐response (E‐R) relationship between valbenazine active metabolite [+]‐α‐dihydrotetrabenazine exposure and the change from baseline in Abnormal Involuntary Movement Scale total score (AIMS‐CFB). A longitudinal E–R model was constructed based on the 40 and 80 mg data from the KINECT 3 trial. The final Emax model adequately predicted dose‐dependent improvement in the primary endpoint and was used to interpolate AIMS‐CFB for 60 mg at week 6. The efficacy of the unstudied 60 mg dose regimen is expected to be within the range of doses studied clinically with predicted mean AIMS‐CFB (95% confidence interval) of −2.69 (−3.30, −2.13) between observed mean AIMS‐CFB for 40 mg of −1.92 and 80 mg of −3.39. Results from this analysis provided the key evidence to establish efficacy of 60 mg QD without the need for an additional clinical trial. The availability of valbenazine 60 mg dose fills an existing medical need for patients with TD who could benefit from this third effective dose. [ABSTRACT FROM AUTHOR]

Valbenazine is commonly used to treat tardive dyskinesia, and we conducted a pharmacovigilance analysis using the Food and Drug Administration Adverse Event Reporting System (FAERS) to evaluate neurological safety signals associated with valbenazine. Data was collected in FAERS from the second quarter of 2017 to the fourth quarter of 2023 for data cleaning. Neurological adverse event (AE) signals of valbenazine were mined by calculating reporting odds ratios (ROR), information component (IC) and empirical Bayesian geometric mean (EBGM). The serious and non-serious cases and signals were prioritized using a rating scale. The number of neurological AE reports where the primary suspect (PS) drug was 8981 for valbenazine. Significant AE signals were identified by the preferred term (PT) analysis for valbenazine, including somnolence (ROR 19.69), tremor (ROR 15.17), and tardive dyskinesia (ROR 236.91), among which 18 AEs were identified as new signals. Patient age (p < 0.009) and sex (p = 0.197) might be associated with an increased risk of neurological AE severity. Notably, the association between valbenazine and neurological disorders remained when stratified by sex, age, and reporter type. AE timing analysis was performed for the drug and four moderate clinical priority signals [i.e., somnolence, balance disorder, parkinsonism, and akathisia (priorities 7)], showing the same early failure type profiles. The increase in neurological safety signals is identified in the post-marketing research of valbenazine. Clinicians need to pay attention to not only common AEs but also be alert to new neurological AE signals when using valbenazine. • This study provides the latest valbenazine-related neurological safety profiles, and eighteen AEs were identified as new signals. • Neurological AEs most commonly identified for valbenazine were somnolence, tremor, dizziness, drooling, dyskinesia, and balance disorder. • Our findings could potentially prompt improved awareness of valbenazine-related toxicities and help healthcare professionals mitigate the risk of neurological events. [ABSTRACT FROM AUTHOR]

The crystal structure of valbenazine has been solved and refined using synchrotron X-ray powder diffraction data and optimized using density functional theory techniques. Valbenazine crystallizes in space group P212121 (#19) with a = 5.260267(17), b = 17.77028(7), c = 26.16427(9) Å, V = 2445.742(11) Å3, and Z = 4 at 295 K. The crystal structure consists of discrete molecules and the mean plane of the molecules is approximately (8,−2,15). There are no obvious strong intermolecular interactions. There is only one weak classical hydrogen bond in the structure, from the amino group to the ether oxygen atom. Two intramolecular and one intermolecular C–H⋯O hydrogen bonds also contribute to the lattice energy. The powder pattern has been submitted to ICDD for inclusion in the Powder Diffraction File™ (PDF®) [ABSTRACT FROM AUTHOR]

Background: Valbenazine is used for tardive movement disorders in adults. Current studies on its safety are mostly from clinical trials and small case reports, limiting information on rare adverse reactions. This study investigated valbenazine-related adverse event (AE) risk signals using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods: Valbenazine AEs data were collected from the FAERS database from 2017 Q2 to 2023 Q1, employing methods like reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network, and empirical Bayesian geometric mean. Results: After data cleaning and drug screening, there were 20,837 AEs primarily suspecting valbenazine, involving 26 system organ classes and 125 AEs related to valbenazine at the preferred terms level. AEs related to valbenazine were mainly concentrated in nervous system disorders, general disorders and administration site conditions, and psychiatric disorders. Eye disorders and gastrointestinal disorders are new AEs not labeled in the valbenazine instructions. In addition, some new potential AE signals were found, such as Tardive dyskinesia and eyelid function disorder. Conclusion: The common AEs of valbenazine in the real world are consistent with the instructions, but there are some newly discovered suspicious AEs. [ABSTRACT FROM AUTHOR]

Introduction: 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. Methods: 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. Results: 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. Discussion: 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.

Huntington's Disease (HD) is a severely debilitating neurodegenerative disorder in which sufferers exhibit different combinations of movement disorders, dementia, and behavioral or psychiatric abnormalities. The disorder is a result of a trinucleotide repeat expansion mutation that is inherited in an autosomal dominant manner. While there is currently no treatment to alter the course of HD, there are medications that lessen abnormal movement and psychiatric symptoms. ClinicalTrials.gov was searched to identify drugs that are currently in or have completed phase III drug trials for the treatment of HD. The described phase III trials were further limited to interventional studies that were recruiting, active not recruiting, or completed. In addition, all studies must have posted an update within the past year. PubMed was used to gather further information on these interventional studies. Of the nine clinical trials that met these criteria, eight involved the following drugs: metformin, dextromethorphan/quinidine, deutetrabenazine, valbenazine, Cellavita HD, pridopidine, SAGE-718, and RO7234292 (RG6042). Of these drug treatments, four are already FDA approved. This systematic review provides a resource that summarizes the present therapies for treating this devastating condition that are currently in phase III clinical trials in the United States. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A simple, specific, rapid, sensitive reversed‐phase high‐performance liquid chromatography method was developed and validated for the determination of Valbenazine, impurities, and its degradation products. The proposed high‐performance liquid chromatography method showed optimum separation in 60 min using potassium dihydrogen phosphate buffer and ACN in the ratio of 90:10 (V/V) as mobile phase‐A whereas ACN and methanol in the ratio of 60:40 (V/V) as mobile phase‐B. YMC‐Pack ODS‐AQ (150 × 4.6 mm, 3.0 μm), column used along with security guard cartridge C18, (4.0 × 3.0 mm) at 1.1 ml/min flow. The injection volume was 10 μl and detection was carried out at 285 nm. The drug was degraded under different stress conditions and the method was validated as per International Conference on Harmonization guidelines on the basis of accuracy, precision, linearity, and robustness. A degradation study indicates that Valbenazine is prone to oxidative degradation. The method was linear over the concentration range of limit of quantitation to 200% for impurities and drug substances. The method was found robust and was studied by the design of experiments. The proposed method is applicable for the determination of the stability of Valibenazine and was successfully used in the quality control of bulk drug manufacturing and pharmaceuticals. [ABSTRACT FROM AUTHOR]

Valbenazine and deutetrabenazine are vesicular monoamine transporter 2 (VMAT2) inhibitors approved for tardive dyskinesia. The clinical activity of valbenazine is primarily attributed to its only dihydrotetrabenazine (HTBZ) metabolite, [+]‐α‐HTBZ. Deutetrabenazine is a deuterated form of tetrabenazine and is metabolized to four deuterated HTBZ metabolites: [+]‐α‐deuHTBZ, [+]‐β‐deuHTBZ, [−]‐α‐deuHTBZ, and [−]‐β‐deuHTBZ. An open‐label, crossover study characterized the pharmacokinetic profiles of the individual deuHBTZ metabolites, which have not been previously reported. VMAT2 inhibition and off‐target interactions of the deuHTBZ metabolites were evaluated using radioligand binding. The only valbenazine HTBZ metabolite, [+]‐α‐HTBZ, was a potent VMAT2 inhibitor, with negligible affinity for off‐target dopamine, serotonin, and adrenergic receptors. Following deutetrabenazine administration, [−]‐α‐deuHTBZ represented 66% of circulating deuHTBZ metabolites and was a relatively weak VMAT2 inhibitor with appreciable affinity for dopamine (D2S, D3) and serotonin (5‐HT1A, 5‐HT2B, 5‐HT7) receptors. [+]‐β‐deuHTBZ was the most abundant deuHTBZ metabolite that potently inhibited VMAT2, but it represented only 29% of total circulating deuHTBZ metabolites. The mean half‐life of [+]‐α‐HTBZ (22.2 hours) was ∼3× longer than that of [+]‐β‐deuHTBZ (7.7 hours). These findings are similar to studies with tetrabenazine, in that deutetrabenazine is metabolized to four deuHTBZ stereoisomers, the most abundant of which has negligible interaction with VMAT2 in vitro and appreciable affinity for several off‐target receptors. In contrast, valbenazine's single HTBZ metabolite is a potent VMAT2 inhibitor in vitro with no discernible off‐target activity. Determination of the effects of intrinsic/extrinsic variables on deutetrabenazine's safety/efficacy profile should incorporate assessment of the effects on all deuHTBZ metabolites. [ABSTRACT FROM AUTHOR]

Huntington’s Disease (HD) is a severely debilitating neurodegenerative disorder in which sufferers exhibit different combinations of movement disorders, dementia, and behavioral or psychiatric abnormalities. The disorder is a result of a trinucleotide repeat expansion mutation that is inherited in an autosomal dominant manner. While there is currently no treatment to alter the course of HD, there are medications that lessen abnormal movement and psychiatric symptoms. ClinicalTrials.gov was searched to identify drugs that are currently in or have completed phase III drug trials for the treatment of HD. The described phase III trials were further limited to interventional studies that were recruiting, active not recruiting, or completed. In addition, all studies must have posted an update within the past year. PubMed was used to gather further information on these interventional studies. Of the nine clinical trials that met these criteria, eight involved the following drugs: metformin, dextromethorphan/quinidine, deutetrabenazine, valbenazine, Cellavita HD, pridopidine, SAGE-718, and RO7234292 (RG6042). Of these drug treatments, four are already FDA approved. This systematic review provides a resource that summarizes the present therapies for treating this devastating condition that are currently in phase III clinical trials in the United States.

Aim: Valbenazine is approved in the US for treatment of tardive dyskinesia (TD); however, efficacy/safety data in Asian populations are lacking. We assessed the efficacy/safety of valbenazine in Japanese patients. Methods: This phase II/III, multicenter, randomized, double‐blind, placebo‐controlled study (NCT03176771) included adult psychiatric patients with TD, who were randomly allocated to receive placebo or valbenazine (once‐daily 40‐ or 80‐mg) for a 6‐week, double‐blind period, after which the placebo group was switched to valbenazine for a 42‐week extension. The primary endpoint was change from baseline in Abnormal Involuntary Movement Scale (AIMS) total score at Week 6; clinical global impression of improvement of TD (CGI‐TD) was also assessed. Results: Of 256 patients, 86, 85, and 85 were allocated to the 40‐mg valbenazine, 80‐mg valbenazine, and placebo groups, respectively. Least‐squares mean (95% confidence interval) change from baseline in AIMS score at Week 6 was −2.3 (−3.0 to −1.7) in the valbenazine 40‐mg group, −3.7 (−4.4 to −3.0) in the 80‐mg group, and −0.1 (−0.8 to 0.5) in the placebo group; both treatment groups showed statistically significant improvements vs. placebo. Patients switched to valbenazine at Week 6 showed similar improvements in AIMS scores, which were maintained to Week 48. Improvements in CGI‐TD scores were observed for both treatment groups vs. placebo. Incidence of adverse events was highest in the 80‐mg group; common events included nasopharyngitis, somnolence, schizophrenia worsening, hypersalivation, insomnia, and tremor. Conclusion: The efficacy/safety profile of valbenazine was similar to that of previous clinical trials, supporting its use for TD treatment in Japanese patients. [ABSTRACT FROM AUTHOR]

Tardive dyskinesia and dystonia are intractable extrapyramidal symptoms caused by the blockade of dopamine receptors by antipsychotic drugs. In addition to the reduction or discontinuation of the causative drug, valbenazine for tardive dyskinesia and botulinum toxin for tardive dystonia have been reported to be effective. However, their efficacy has not been fully demonstrated. In this study, we report the case of a female patient with bipolar disorder, valbenazine-resistant tardive dystonia, and tardive dyskinesia who achieved improvement in extrapyramidal symptoms with electroconvulsive therapy. Additionally, we conducted a narrative literature review on the safety and efficacy of electroconvulsive therapy for tardive dyskinesia and dystonia.

Tardive dyskinesia (TD) is a movement disorder associated with dopamine receptor blocking medications. Recommended treatments for TD include discontinuing the causative agent, adding vesicular monoamine transporter 2 (VMAT2) inhibitors, or adding vitamin B6. We present a 66-year-old Caucasian male with bipolar I disorder who developed TD while on lithium and quetiapine having been euthymic on this regimen for three years. He was initially treated with 1200 mg B6 daily. This failed to improve his TD and was associated with a depressive episode. He switched to valbenazine 40 mg daily which improved his TD and concurrently his mood, but months later the TD symptoms worsened again. Our case adds to the literature by demonstrating that some patients with TD will not respond to vitamin B6. To our knowledge, ours is the first case suggesting association of high dose vitamin B6 with depression. This case also demonstrates that response to valbenazine may not last and further studies are needed.

Tardive dyskinesia (TD) is a potentially irreversible movement disorder characterized by involuntary, repetitive movements, most commonly affecting the face, tongue, and extremities. It is primarily associated with the long-term use of first-generation (typical) antipsychotics but can also occur with second-generation (atypical) antipsychotics such as aripiprazole. Despite its lower risk profile, aripiprazole can induce TD, as illustrated by a 45-year-old woman with schizophrenia who developed severe involuntary movements after five years of stable treatment with this medication. Her symptoms, including facial grimacing and choreiform movements, were assessed using the Abnormal Involuntary Movement Scale (AIMS), scoring 18, indicative of moderate to severe TD. Following a switch to clozapine and the addition of valbenazine, a VMAT2 inhibitor, the patient experienced significant symptom reduction and improved quality of life. This case emphasizes the need for ongoing monitoring of TD in patients on long-term antipsychotic therapy, even with atypical agents. Effective management strategies, including medication adjustment and the use of VMAT2 inhibitors, are crucial for optimizing patient outcomes and quality of life. Continued research is needed to better understand and address TD in clinical practice., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Mulla et al.)

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., Competing Interests: Dr. Khashayar Dashtipour’s conflict of interest: Amneal, Teva, Neurocrine, Abbvie, Supernus, Ipsen, Acadia, Acorda, Sunovion. The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

Aim: To separate and evaluate 9-cyclopropylmethoxy-dihydrotetrabenazine (13a) and its stereoisomers for their high affinity for vesicular monoamine transporter-2 (VMAT2). Method: Stereoisomers of 13a were separated and configurations were ascertained by chiral chromatography and crystal diffraction combined with 1 H- 1 H NOESY assay. Possible binding modes of eight stereoisomers and VMAT2 were explored by molecular docking assays. The VMAT2 affinity of the stereoisomers, inhibition in vivo  and pharmacokinetics in rats were evaluated. Results: Three stereoisomers were obtained: P1, P2 and P3, and all had similar VMAT2 binding modes. P2 [(2 R , 3 R , 11b R )-13a] showed the highest potential VMAT2 binding activity ( K i  = 0.75 nM), decreased locomotor activity in rats and had an oral absolute bioavailability of 92.0%. Conclusion: P2 has good efficacy and pharmacokinetic properties and warrants further development to treat tardive dyskinesia.