valbenazine and Tardive-Dyskinesia

The purpose of this review is to summarize the current evidence for valbenazine and deutetrabenazine use for the treatment of tardive dyskinesia (TD).. A literature search was conducted to gather relevant data regarding the use of valbenazine and deutetrabenazine for TD management. PubMed, MEDLINE, and ClinicalTrials.gov were searched using the following keywords and MeSH terms: valbenazine, deutetrabenazine, tardive dyskinesia, VMAT2 inhibitors, and vesicular monoamine transporter 2 inhibitors. Randomized, double-blind, placebo-controlled trials and meta-analyses published in English from April 2015 to August 2019 were included. Valbenazine 40-80 mg and deutetrabenazine 12-36 mg per day have been evaluated for the treatment of TD. Abnormal Involuntary Movement Scale (AIMS) scores decline similarly (by 2-5 points) with use of either agent. AIMS response rates, defined by a 50% decline in symptoms, range from 33% to 50%. Both agents are well tolerated, with somnolence and akathisia reported most frequently (at low rates). Agent selection may be guided by manufacturer labeling recommendations for special populations and cost considerations.. Valbenazine and deutetrabenazine were demonstrated to be effective in decreasing AIMS scores and were well tolerated in randomized controlled trials. These treatments may be considered as a next-line option when traditional strategies are not feasible or are ineffective. Head-to-head studies are warranted to decipher if either agent is preferable in terms of efficacy or tolerability.

Topics: Humans; Randomized Controlled Trials as Topic; Tardive Dyskinesia; Tetrabenazine; Treatment Outcome; Valine; Vesicular Monoamine Transport Proteins

Tardive dyskinesia (TD) is an iatrogenic condition that encompasses a wide phenomenological spectrum of movement disorders caused by exposure to dopamine receptor blocking agents (DRBAs). TD may cause troublesome or disabling symptoms that impair quality of life. Due to frequent, often inappropriate, use of DRBAs, TD prevalence rates among patients exposed to DRBAs continue to be high. The judicious use of DRBAs is key to the prevention of TD, reduction of disease burden, and achieving lasting remission. Dopamine-depleting vesicular monoamine transporter type 2 inhibitors are considered the treatment of choice of TD.

Topics: Antipsychotic Agents; Botulinum Toxins; Deep Brain Stimulation; Electroconvulsive Therapy; Humans; Muscarinic Antagonists; Neuromuscular Agents; Tardive Dyskinesia; Tetrabenazine; Trihexyphenidyl; Valine; Vesicular Monoamine Transport Proteins

Tardive dyskinesia (TD) is caused by exposure to medications with dopamine antagonism, mainly antipsychotics. It often distresses individuals, physically and emotionally and affects their quality of life. We evaluated peer-reviewed recently published articles with a goal of providing a critically appraised update on the latest advancements in this field.. In 2017, FDA approved VMAT2 inhibitors, deutetrabenazine and valbenazine. They have demonstrated efficacy in several class 1 studies. Also there have been update in the evidence-based guidelines for treatment for tardive dyskinesia. Various medication classes are being used for treatment of TD with VMAT2 inhibitors to be first FDA-approved medications. Their use should be tailored to the individual patient. Long-term studies will further guide us in how to optimize treatment, especially in the real-world setting. As clinicians, we need to take into consideration all aspects of symptomatology, etiology, potential side effects of the medications, to find the best possible "match" for our patients.

Topics: Antipsychotic Agents; Dopamine Antagonists; Drug-Related Side Effects and Adverse Reactions; Humans; Quality of Life; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins

Tardive dyskinesia (TD), a condition characterized by involuntary movements, is found in patients taking antipsychotics or other agents that block dopamine receptors. Symptoms of TD are associated with reduced quality of life, psychosocial problems, and medication nonadherence. Few agents tested in the treatment of TD had sufficient data to support or refute their use, until recently. A review of new evidence was combined with the existing guideline to provide new treatment recommendations. This activity provides an overview of treatments for patients with TD, including valbenazine and deutetrabenazine, which both received FDA approval for the treatment of TD.

Topics: Humans; Medication Adherence; Practice Guidelines as Topic; Tardive Dyskinesia; Tetrabenazine; Valine

Tardive dyskinesia is a potentially irreversible, debilitating, hyperkinetic movement disorder that can result from dopamine receptor antagonists. Prompt recognition and resolution of symptoms are instrumental in preventing disease irreversibility, though current treatment options have fallen short of robust, effective, and long-term symptom control. In April 2017, the Food and Drug Administration (FDA) approved 2 new vesicular monoamine transporter 2 (VMAT2) inhibitors, deutetrabenazine and valbenazine, for chorea related to Huntington's disease and tardive dyskinesia, respectively. These agents were pharmacologically modified from tetrabenazine, a VMAT2 inhibitor used off-label in the treatment of tardive dyskinesia. Despite FDA-labeled indications of deutetrabenazine and valbenazine, each agent was explored as a treatment option for those with tardive dyskinesia. In this study, the pharmacologic modifications of the 2 new VMAT2 inhibitors are described, with detailed explanation as to how these may impact clinical practice. The associated case series, observational studies, and clinical trials exploring their use in the treatment of tardive dyskinesia are reported with expert opinion on practice implication.

Topics: Adrenergic Uptake Inhibitors; Dopamine Antagonists; Drug Labeling; Humans; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins

Tardive dyskinesia is a movement disorder characterised by irregular, stereotyped, and choreiform movements associated with the use of antipsychotic medication. We aim to provide recommendations on the treatment of tardive dyskinesia.. We performed a systematic review of studies of the treatment of tardive dyskinesia. Studies were rated for methodological quality using the American Academy of Neurology Risk of Bias Classification system. Overall level of evidence classifications and grades of recommendation were made using the Scottish Intercollegiate Guidelines Network framework.. Preventing tardive dyskinesia is of primary importance, and clinicians should follow best practice for prescribing antipsychotic medication, including limiting the prescription for specific indications, using the minimum effective dose, and minimising the duration of therapy. The first-line management of tardive dyskinesia is the withdrawal of antipsychotic medication if clinically feasible. Yet, for many patients with serious mental illness, the discontinuation of antipsychotics is not possible due to disease relapse. Switching from a first-generation to a second-generation antipsychotic with a lower D2 affinity, such as clozapine or quetiapine, may be effective in reducing tardive dyskinesia symptoms. The strongest evidence for a suitable co-intervention to treat tardive dyskinesia comes from tests with the new VMAT inhibitors, deutetrabenazine and valbenazine. These medications have not been approved for use in Canada.. Data on tardive dyskinesia treatment are limited, and the best management strategy remains prevention. More long-term safety and efficacy data are needed for deutetrabenazine and valbenazine, and their routine availability to patients outside of the USA remains in question.

Topics: Adrenergic Uptake Inhibitors; Antipsychotic Agents; Humans; Tardive Dyskinesia; Tetrabenazine; Valine

Up to 30% of patients taking antipsychotics may develop tardive dyskinesia (TD). Recent evidence-based recommendations demonstrate an unmet need for effective TD management. This systematic review was designed to update the evidence for TD treatment, comparing two vesicular monoamine transporter 2 (VMAT2) inhibitors, tetrabenazine and valbenazine. Of 487 PubMed/Embase search results, 11 studies met the review criteria. Valbenazine efficacy was demonstrated in rigorously designed clinical trials that meet the guidelines for AAN Class I evidence. Due to differences in study designs and a lack of standardized and controlled trials with tetrabenazine, a formal meta-analysis comparing the agents was not possible. However, valbenazine appears to have fewer side effects and a more favorable once-daily dosing regimen for the treatment of TD.

Topics: Adrenergic Uptake Inhibitors; Antipsychotic Agents; Clinical Trials as Topic; Drug Administration Schedule; Humans; Research Design; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins

Valbenazine is a selective VMAT2 inhibitor that the FDA approved in April 2017 for the specific treatment of tardive dyskinesia (TD), a movement disorder commonly caused by dopamine blocking agents. Valbenazine acts to decrease dopamine release, reducing excessive movement found in TD. Areas covered: This drug profile reviews the development of valbenazine and the clinical trials that led to its approval as the first treatment specific to TD. The literature search was performed with the PubMed online database. Expert commentary: Two clinical trials assessing the efficacy of valbenazine have shown the reduction of antipsychotic-induced involuntary movement. No life threatening adverse effects were found. Data from a 42-week extension study demonstrated sustained response.

Topics: Adult; Animals; Antipsychotic Agents; Dopamine; Drug Approval; Humans; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins

Tardive dyskinesia (TD) encompasses the spectrum of iatrogenic hyperkinetic movement disorders following exposure to dopamine receptor-blocking agents (DRBAs). Despite the advent of atypical or second- and third-generation antipsychotics with a presumably lower risk of complications, TD remains a persistent and challenging problem. Prevention is the first step in mitigating the risk of TD, but early recognition, gradual withdrawal of offending medications, and appropriate treatment are also critical. As TD is often a persistent and troublesome disorder, specific antidyskinetic therapies are often needed for symptomatic relief. The vesicular monoamine transporter 2 (VMAT2) inhibitors, which include tetrabenazine, deutetrabenazine, and valbenazine, are considered the treatment of choice for most patients with TD. Deutetrabenazine-a deuterated version of tetrabenazine-and valbenazine, the purified parent product of one of the main tetrabenazine metabolites, are novel VMAT2 inhibitors and the only drugs to receive approval from the US FDA for the treatment of TD. VMAT2 inhibitors deplete presynaptic dopamine and reduce involuntary movements in many hyperkinetic movement disorders, particularly TD, Huntington disease, and Tourette syndrome. The active metabolites of the VMAT2 inhibitors have high affinity for VMAT2 and minimal off-target binding. Compared with tetrabenazine, deutetrabenazine and valbenazine have pharmacokinetic advantages that translate into less frequent dosing and better tolerability. However, no head-to-head studies have compared the various VMAT2 inhibitors. One of the major advantages of VMAT2 inhibitors over DRBAs, which are still being used by some clinicians in the treatment of some hyperkinetic disorders, including TD, is that they are not associated with the development of TD. We also briefly discuss other treatment options for TD, including amantadine, clonazepam, Gingko biloba, zolpidem, botulinum toxin, and deep brain stimulation. Treatment of TD and other drug-induced movement disorders must be individualized and based on the severity, phenomenology, potential side effects, and other factors discussed in this review.

Topics: Antipsychotic Agents; Drug Approval; Humans; Huntington Disease; Tardive Dyskinesia; Tetrabenazine; Tourette Syndrome; United States; United States Food and Drug Administration; Valine; Vesicular Monoamine Transport Proteins

Tardive dyskinesia (TD) is an iatrogenic movement disorder caused by exposure to dopamine receptor blocking agents. Two vesicular monoamine transporter type 2 (VMAT2) inhibitors for the treatment of TD were approved by the US Food and Drug Administration in 2017: valbenazine and deutetrabenazine. Areas covered: A brief review of TD and its identification, as well as a review of older treatment interventions is provided, followed by a detailed synthesis regarding the clinical utility of valbenazine and deutetrabenazine. Expert commentary: As evidenced from well-designed clinical trials, both valbenazine and deutetrabenazine are efficacious and tolerable. They differ in terms of labeled instructions for frequency of administration (twice daily for deutetrabenazine vs. once daily for valbenazine), titration requirements (dose to efficacy/tolerability for deutetrabenazine vs. titrate to target dose of 80 mg/day for valbenazine), need for food (administer deutetrabenazine with food), drug-drug interactions (consider CYP2D6 modulators for deutetrabenazine vs. both CYP2D6 and CYP3A4 for valbenazine), contraindications (hepatic impairment for deutetrabenazine), and minor differences in adverse event profile.

Topics: Adrenergic Uptake Inhibitors; Dopamine Antagonists; Humans; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins

To provide a review of tardive dyskinesia (TD) symptoms, etiology, pathophysiology, and treatments.. PubMed, Web of Science, ClinicalTrials. gov, and Google Scholar were searched for relevant literature using a combination of the following terms: tardive dyskinesia, treatment, management, guidelines, tetrabenazine, deutetrabenazine, and valbenazine. Sources were limited to human data.. Articles were reviewed for relevance to TD therapy. Reference lists were manually searched for other relevant articles. Selected literature was published between 1968 and 2017.. This article reviews treatment options available for patients with TD. Many agents have been tried off-label to manage symptoms, with limited evidence of benefit. The Food and Drug Administration approved the first drug to treat TD valbenazine on April 11, 2017.. TD is largely iatrogenic. Valbenazine's approval by the Food and Drug Administration was followed by the approval of deutetrabenazine, a drug with similar mechanism of action. Further data from postmarketing studies will be needed to verify that valbenazine's adverse effect profile is different from the profiles of tetrabenazine and deutetrabenazine.

Topics: Drug Approval; Humans; Practice Guidelines as Topic; Tardive Dyskinesia; Tetrabenazine; United States; United States Food and Drug Administration; Valine; Vesicular Monoamine Transport Proteins

The aim of this study was to summarize the characteristics, efficacy, and safety of vesicular monoamine transporter-2 (VMAT-2) inhibitors for treating tardive dyskinesia (TD).. We conducted a literature search in PubMed, Cochrane Database, and ClinicalTrials.gov, screening for systematic reviews, meta-analyses or double-blind, randomized, placebo-controlled trials (DBRPCTs) reporting efficacy or safety data of VMAT-2 inhibitors (tetrabenazine, deutetrabenazine, and valbenazine) in patients with TD. A random effects meta-analysis of efficacy and safety data from DBRPCTs was performed.. Two acute, 12-week DBRPCTs with deutetrabenazine 12-48 mg/day (n=413) and 4 acute, 4-6-week double-blind trials with valbenazine 12.5-100 mg/day (n=488) were meta-analyzable, without meta-analyzable, high-quality data for tetrabenazine. Regarding reduction in total Abnormal Involuntary Movement Scale (AIMS) scores (primary outcome), both deutetrabenazine (k=2, n=413, standardized mean difference [SMD] =-0.40, 95% confidence interval [CI] =-0.19, -0.62,. The 2 VMAT-2 inhibitors, valbenazine and deutetrabenazine, are effective in treating TD, both acutely and long-term, without concerns about increased risk of depression or suicide in the TD population. No head-to-head comparison among VMAT-2 inhibitors and no high-quality, meta-analyzable data are available for tetrabenazine in patients with TD.

Topics: Antipsychotic Agents; Humans; Randomized Controlled Trials as Topic; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins

Topics: Humans; Tardive Dyskinesia; Tetrabenazine; Treatment Outcome; Valine

The two approved treatments for tardive dyskinesia both inhibit the vesicular monoamine transporter type 2 (VMAT2) yet have pharmacologic properties that distinguish one from the other. Knowing these differences may help optimize which treatment to select for individual patients.

Topics: Adrenergic Uptake Inhibitors; Animals; Humans; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins

Drug-induced parkinsonism (DIP) and tardive dyskinesia (TD) are iatrogenic consequences of antidopaminergic drugs. Both are particularly prevalent among the elderly and those with dementia. However, despite their prevalence, these disorders are often overlooked. Both entities share risk factors, physiopathological mechanisms and, to some degree, therapeutic approaches. Withdrawing the causal agent, reducing the dose or switching to a less potent antidopaminergic drug should be the first therapeutic options. Here we review both entities and emerging therapies including the recently approved drugs deutetrabenazine and valbenazine. We discuss relevant aspects for clinical practice such as new diagnostic techniques and the latest advances in the understanding of DIP and TD.

Topics: Aged; Dementia; Dyskinesia, Drug-Induced; Humans; Parkinsonian Disorders; Risk Factors; Tardive Dyskinesia; Tetrabenazine; Valine

The objective of this systematic review was to describe the efficacy, tolerability, and safety of valbenazine for the treatment of tardive dyskinesia (TD).. The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/ and http://www.clinicaltrials.gov, for the search terms 'valbenazine' OR 'NBI-98854', and by also querying the EMBASE (Elsevier) commercial database for clinical poster abstracts, and by asking the manufacturer for copies of posters presented at congresses. Product labeling provided additional information.. All available clinical reports of studies were identified.. Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the available study reports and other sources of information.. Valbenazine, a reversible inhibitor of Vesicular Monoamine Transporter Type 2 (VMAT2), received approval for the treatment of TD in adults based on a clinical trial development programme that included three 6-week parallel group, randomised, placebo-controlled studies, including one Phase III trial described in product labeling. The recommended dose for valbenazine is 80 mg/d. The percentage of responders in the Phase III acute study, as defined by ≥50% reduction from baseline in the Abnormal Involuntary Movement Scale dyskinesia score was 40.0% for valbenazine 80 mg/d vs 8.7% for placebo, yielding a NNT of 4 (95% CI 3-6). As pooled from available data, discontinuation rates because of an adverse event were 2.9% for valbenazine-treated patients vs 1.6% for placebo-treated patients, resulting in a NNH of 76 (ns). The only adverse event that met the threshold of incidence ≥5% for valbenazine and a rate of ≥2 times than that observed with placebo was somnolence (somnolence, fatigue, sedation), with rates of 10.9% for valbenazine (all doses) vs 4.2% for placebo, resulting in a NNH of 15 (95% CI 9-52). An additional warning and precaution is that valbenazine can prolong the ECG QT interval, however, the valbenazine product label does not contain any bolded boxed warnings or contraindications.. Valbenazine is presently the only US Food and Drug Administration-approved agent specifically indicated for the treatment of TD. Valbenazine is about 15 times more likely to result in a response than in a discontinuation because of an adverse event. Head-to-head comparisons with other VMAT2 inhibitors among patients with TD in the 'real world' are needed.

Topics: Central Nervous System Agents; Humans; Numbers Needed To Treat; Tardive Dyskinesia; Tetrabenazine; Treatment Outcome; Valine

Valbenazine (Ingrezza™) is an orally bioavailable, selective, vesicular monoamine transporter 2 (VMAT2) inhibitor being developed by Neurocrine Biosciences for the treatment of various central nervous system disorders. Valbenazine has been approved in the USA for the treatment of adults with tardive dyskinesia (TD), is at various stages of development in other countries for TD and is in phase 2 development in the USA for Tourette syndrome. This article summarizes the milestones in the development of valbenazine leading to its first global approval in the USA for the treatment of adults with TD.

Topics: Adult; Clinical Trials as Topic; Drug Approval; Humans; Tardive Dyskinesia; Tetrabenazine; Tourette Syndrome; United States; United States Food and Drug Administration; Valine; Vesicular Monoamine Transport Proteins

Chronic intake of typical neuroleptics or centrally acting dopamine receptor blocking antiemetics may cause onset of tardive syndromes. Various types exist. One of them is tardive dyskinesia, characterised by often stigmatising, purposeless, rapid, repetitive, stereotypic, involuntary movements of face, limbs or trunk. Effective symptomatic drug treatment options beyond application of tetrabenazine are rare. Tetrabenazine is usually administered three times daily due to the short half life of this agent. Areas covered: This narrative review discusses the value of valbenazine for the treatment of tardive dyskinesia as a therapeutic alternative to tetrabenazine. Expert commentary: Valbenazine is a selective inhibitor of vesicular monoamine transporter 2, which is metabolized to (+)-alpha-dihydrotetrabenazine. Valbenazine and particularly its metabolite inhibit vesicular monoamine transporter 2 function. Once daily intake of valbenazine ameliorated the severity of tardive dyskinesia. The chiral purity of valbenazine circumvents generation of the (-)alpha and (+) and (-)beta dihydrotetrabenazine metabolites of tetrabenazine or deutetrabenazine. Valbenazine and its metabolite do not antagonize postsynaptic monoamine receptors in contrast to the tetrabenazine formulations. Therefore one may hypothesize that fewer and less severe motor and psychopathological side effects will occur during valbenazine long term application compared with tetrabenazine or deutretrabenazine.

Topics: Adrenergic Uptake Inhibitors; Humans; Tardive Dyskinesia; Tetrabenazine; Valine

The broad use of atypical antipsychotics was expected to dramatically reduce the prevalence and incidence of tardive dyskinesia (TD), but data show that TD remains an important challenge due the persistent nature of its symptoms and resistance to numerous treatment modalities, including antipsychotic discontinuation. Recent insights on genetic risk factors and new concepts surrounding pathophysiology have spurred interest in the possibility of targeted treatment for TD. As will be reviewed in this article, the number of evidence-based strategies for TD treatment is small: only clonazepam, amantadine, ginkgo biloba extract, and the vesicular monoamine transporter 2 (VMAT2) inhibitor tetrabenazine have compelling data. Using new insights into the metabolism of tetrabenazine and the properties of its active metabolites, 2 modifications of tetrabenazine have been synthesized to improve the kinetic profile, and are currently involved in double-blind placebo controlled studies aimed at U.S. Food and Drug Administration (FDA) regulatory approval. The possible availability of these new agents, deuterated tetrabenazine and valbenazine, significantly widens the range of treatment choices for patients with TD. For clinicians with patients at risk for TD due to dopamine antagonist exposure, experience has shown that the problem of TD will be an ongoing issue in modern psychiatry, and that an appreciation of new developments in the pathophysiology of, risk factors for, and treatment of TD is crucial to managing this condition.

Topics: Adrenergic Uptake Inhibitors; Amantadine; Antipsychotic Agents; Clonazepam; Dopamine Agents; Dopamine Antagonists; GABA Modulators; Ginkgo biloba; Humans; Plant Extracts; Risk Factors; Tardive Dyskinesia; Tetrabenazine; Valine

Valbenazine (NBI-98854, Ingrezza) is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor that modulates dopamine release during nerve communication. The pharmacological target VMAT2 may play an important role in the treatment of tardive dyskinesia (TD), an iatrogenic condition associated with the administration of antipsychotic medication for long periods and characterized by rapid, repetitive, stereotypic, involuntary movements of the face and extremities. There are currently no Food and Drug Administration (FDA)-approved drugs for the treatment of TD. Results of clinical trials have shown a distinctive improvement in TD symptoms during valbenazine administration and a new drug application submitted to the FDA in August 2016 is undergoing priority review with a decision expected in April 2017.

Topics: Animals; Dopamine; Humans; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins

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.. 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.. 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.. The efficacy/safety profile of valbenazine was similar to that of previous clinical trials, supporting its use for TD treatment in Japanese patients.

Topics: Adult; Antipsychotic Agents; Double-Blind Method; Humans; Japan; Tardive Dyskinesia; Tetrabenazine; Treatment Outcome

To evaluate the effects of once-daily valbenazine (40 or 80 mg/d) in older and younger adults with tardive dyskinesia (TD).. Data were pooled from three 6-week, randomized, double-blind, placebo-controlled (DBPC) studies (KINECT [NCT01688037], KINECT 2 [NCT01733121], and KINECT 3 [NCT02274558]) and two long-term studies (KINECT 3 extension and KINECT 4 [NCT02405091]). Outcomes analyzed in older and younger participants (55 years or older and younger than 55 years, respectively) included Abnormal Involuntary Movement Scale (AIMS) response (threshold of greater than or equal to 50% improvement from baseline in total score [items 1 to 7]) and Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD) response (score 2 or less ["very much improved" or "much improved"]). Safety assessments included treatment-emergent adverse events (TEAEs).. At week 6 (end of DBPC treatment), the percentage of participants who met the AIMS response threshold was higher with valbenazine versus placebo in both subgroups: 55 years or older (80 mg/d, 39.7% [P < .001]; 40 mg/d, 28.6% [P < .01]; placebo, 9.7%); younger than 55 years (80 mg/d, 39.5% [P < .001]; 40 mg/d, 20.0% [P > .05]; placebo, 10.8%). The percentage of participants with CGI-TD response was also higher with valbenazine versus placebo: 55 years or older (80 mg/d, 41.3% [P < .01]; 40 mg/d, 30.2% [P > .05]; placebo, 19.4%); younger than 55 years (80 mg/d, 39.5% [P < .05]; 40 mg/d, 35.3% [P < .05]; placebo, 18.5%). Responses at week 48 (end of long-term treatment, combined doses) were as follows: 55 years or older (AIMS, 70.7%; CGI-TD, 82.8%); younger than 55 years (AIMS, 58.7%; CGI-TD, 72.3%). No significant differences between older and younger subgroups were found for AIMS or CGI-TD response. No new safety signals or TEAEs of clinical concern were found in older participants who received long-term treatment.. Valbenazine improved TD and was generally well tolerated in older and younger adults.

Topics: Adult; Age Factors; Aged; Double-Blind Method; Female; Humans; Male; Middle Aged; Tardive Dyskinesia; Tetrabenazine; Treatment Outcome; Valine

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

Topics: Antipsychotic Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Mood Disorders; Tardive Dyskinesia; Tetrabenazine; Valine

A minimal clinically important difference has not been established for the Abnormal Involuntary Movement Scale in patients with tardive dyskinesia. Valbenazine is a vesicular monoamine transporter 2 inhibitor approved for the treatment of tardive dyskinesia in adults. Efficacy in randomized, double-blind, placebo-controlled trials was defined as the change from baseline in Abnormal Involuntary Movement Scale total score (sum of items 1-7).. To estimate an minimal clinically important difference for the Abnormal Involuntary Movement Scale using valbenazine trial data and an anchor-based method.. Data were pooled from three 6-week double-blind, placebo-controlled trials: KINECT (NCT01688037), KINECT 2 (NCT01733121), and KINECT 3 (NCT02274558). Valbenazine doses were pooled for analyses as follows: "low dose," which includes 40 or 50 mg/day; and "high dose," which includes 75 or 80 mg/day. Mean changes from baseline in Abnormal Involuntary Movement Scale total score were analyzed in all participants (valbenazine- and placebo-treated) with a Clinical Global Impression of Change-Tardive Dyskinesia or Patient Global Impression of Change score of 1 (very much improved) to 3 (minimally improved).. The least squares mean improvement from baseline to week 6 in Abnormal Involuntary Movement Scale total score was significantly greater with valbenazine (low dose: -2.4; high dose: -3.2; both, P < 0.001) versus placebo (-0.7). An minimal clinically important difference of 2 points was estimated based on least squares mean changes in Abnormal Involuntary Movement Scale total score in participants with a Clinical Global Impression of Change-Tardive Dyskinesia score ≤3 at week 6 (mean change: -2.2; median change: -2) or Patient Global Impression of Change score ≤3 at week 6 (mean change: -2.0; median change: -2).. Results from an anchor-based method indicate that a 2-point decrease in Abnormal Involuntary Movement Scale total score may be considered clinically important. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Topics: Aged; Antipsychotic Agents; Female; Humans; Male; Middle Aged; Minimal Clinically Important Difference; Mood Disorders; Psychotic Disorders; Schizophrenia; Tardive Dyskinesia; Tetrabenazine; Treatment Outcome; Valine; Vesicular Monoamine Transport Proteins

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

Topics: Adrenergic Uptake Inhibitors; Affective Disorders, Psychotic; Antipsychotic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Least-Squares Analysis; Outcome Assessment, Health Care; Schizophrenia; Tardive Dyskinesia; Tetrabenazine; Valine

Tardive dyskinesia is a persistent movement disorder induced by dopamine receptor blockers, including antipsychotics. Valbenazine (NBI-98854) is a novel, highly selective vesicular monoamine transporter 2 inhibitor that demonstrated favorable efficacy and tolerability in the treatment of tardive dyskinesia in phase 2 studies. This phase 3 study further evaluated the efficacy, safety, and tolerability of valbenazine as a treatment for tardive dyskinesia.. This 6-week, randomized, double-blind, placebo-controlled trial included patients with schizophrenia, schizoaffective disorder, or a mood disorder who had moderate or severe tardive dyskinesia. Participants were randomly assigned in a 1:1:1 ratio to once-daily placebo, valbenazine at 40 mg/day, or valbenazine at 80 mg/day. The primary efficacy endpoint was change from baseline to week 6 in the 80 mg/day group compared with the placebo group on the Abnormal Involuntary Movement Scale (AIMS) dyskinesia score (items 1-7), as assessed by blinded central AIMS video raters. Safety assessments included adverse event monitoring, laboratory tests, ECG, and psychiatric measures.. The intent-to-treat population included 225 participants, of whom 205 completed the study. Approximately 65% of participants had schizophrenia or schizoaffective disorder, and 85.5% were receiving concomitant antipsychotics. Least squares mean change from baseline to week 6 in AIMS dyskinesia score was -3.2 for the 80 mg/day group, compared with -0.1 for the placebo group, a significant difference. AIMS dyskinesia score was also reduced in the 40 mg/day group (-1.9 compared with -0.1). The incidence of adverse events was consistent with previous studies.. Once-daily valbenazine significantly improved tardive dyskinesia in participants with underlying schizophrenia, schizoaffective disorder, or mood disorder. Valbenazine was generally well tolerated, and psychiatric status remained stable. Longer trials are necessary to understand the long-term effects of valbenazine in patients with tardive dyskinesia.

Topics: Abnormal Involuntary Movement Scale; Adult; Aged; Antipsychotic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Mood Disorders; Psychotic Disorders; Schizophrenia; Tardive Dyskinesia; Tetrabenazine; Treatment Outcome; Valine

Valbenazine (VBZ) is a vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of tardive dyskinesia. The safety, tolerability and pharmacokinetics of VBZ following single and repeat once-daily (QD) dosing were evaluated in 2 randomized, single-center, double-blind studies in healthy male subjects. In the first study, 2 cohorts of 8 subjects were administered single doses (SD) of placebo (PBO; N = 2/period) or VBZ (N = 6/period; 1, 2, 5, or 12.5 mg for Cohort 1 and 12.5, 25, 50, or 75 mg for Cohort 2) using a sequential escalation scheme. The second study consisted of 2 phases. In the initial phase, subjects were administered SD PBO (N = 2/period) or VBZ (N = 6/period; 75, 100, 125 or 150 mg) with sequential escalation. In the second phase, subjects received PBO, or 50 or 100 mg VBZ (N = 4:8:8) QD for 8 days (Cohort 1) or PBO or 50 mg VBZ (N = 6:6) QD for 8 days (Cohort 2). For both studies, plasma concentrations of VBZ and its active metabolite, NBI-98782, were determined. Safety was assessed throughout the studies. PK parameters were determined using noncompartmental methods. In both studies, VBZ was rapidly absorbed with peak concentrations typically observed within 1.5 hours. Peak NBI-98782 concentrations were typically observed at 4.0 to 9.0 hours. Terminal elimination half-life for both VBZ and NBI-98782 was ~20 hours. Across the 1 to 150 mg SD range evaluated across the studies, VBZ and NBI-98782 C

Topics: Adrenergic Uptake Inhibitors; Adult; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Healthy Volunteers; Humans; Male; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins

Valbenazine (VBZ, NBI-98854) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of tardive dyskinesia (TD). The KINECT 3 study (NCT02274558) evaluated the effects of VBZ on TD in subjects with mood disorder or schizophrenia/schizoaffective disorder (SCHZ, presented separately) who received up to 48 weeks of treatment.. KINECT 3 included: 6-week, double-blind, placebo (PBO)-controlled (DBPC) period (205 completers); 42-week VBZ extension (VE) period (124 completers); 4-week washout period (121 completers). Subjects entering the DBPC were randomized 1:1:1 to once-daily VBZ 80 mg, VBZ 40 mg, or PBO; stable concomitant antipsychotic medication regimens were allowed. Subjects completing the DBPC and entering the VE period were re-randomized (blinded) from PBO to VBZ (80 or 40 mg) or continued VBZ treatment at the same dose. Efficacy assessments included: mean changes from baseline in Abnormal Involuntary Movement Scale (AIMS) total score (items 1-7); mean Clinical Global Impression of Change (CGI-TD) scores; AIMS responders (subjects with ≥50% score reduction from baseline); and CGI-TD responders (subjects with score ≤2 ["much improved" or "very much improved"]). Treatment effect sizes (Cohen's d) and numbers needed to treat (NNTs) were analyzed for DBPC outcomes.. Efficacy analyses were conducted in 77 subjects (DBPC) and 73 subjects (VE) with a mood disorder. At Week 6 (end of DBPC), AIMS mean score improvements were greater in the VBZ groups (in a dose-related pattern) than in the PBO group (80 mg, -3.6, d = 0.94; 40 mg, -2.4, d = 0.55; PBO, -0.7). AIMS mean score changes at Week 48 (end of VE) showed continued TD improvement during long-term VBZ treatment (80 mg, -5.8; 40 mg, -4.2). By Week 52 (end of washout), AIMS mean scores in both dose groups were returning toward baseline levels, indicating re-emergence of TD. CGI-TD scores showed a similar pattern: Week 6 (80 mg, 2.7, d = 0.64; 40 mg, 2.9, d = 0.39; PBO, 3.2), Week 48 (80 mg, 2.0; 40 mg, 2.2), Week 52 (80 mg, 3.6; 40 mg, 2.8). AIMS responder rates (≥50% score reduction) were greater with VBZ vs PBO at Week 6 (80 mg, 38.5%, NNT = 4; 40 mg, 19.0%, NNT = 9; PBO, 7.7%), were increased at Week 48 (80 mg, 56.0%; 40 mg, 33.3%), and lower after VBZ washout (Week 52 80 mg, 16.7%; 40 mg, 27.8%). CGI-TD responder rates followed a similar pattern: Week 6 (80 mg, 34.6%, NNT = 6; 40 mg, 28.6%, NNT = 8; PBO, 15.4%), Week 48 (80 mg, 80.0%; 40 mg, 61.1%), Week 52 (80 mg, 25.0%; 40 mg, 44.4%).. Sustained TD improvements were found in subjects with a mood disorder who received up to 48 weeks of VBZ, with TD reverting toward baseline severity when assessed 4 weeks after treatment withdrawal. Together with results from SCHZ subjects and the long-term safety profile (presented separately), these results indicate that long-term VBZ can be beneficial for managing TD regardless of psychiatric diagnosis.

Topics: Adrenergic Uptake Inhibitors; Adult; Aged; Antipsychotic Agents; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Mood Disorders; Outcome Assessment, Health Care; Psychotic Disorders; Schizophrenia; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins

The short-term safety profile of once-daily valbenazine (NBI-98854) has been evaluated in several double-blind, placebo-controlled (DBPC) trials in adults with tardive dyskinesia (TD) who had a diagnosis of schizophrenia/schizoaffective (SCHZ) disorder or mood disorder. Studies with longer treatment duration (up to 48 weeks) were conducted to evaluate the long-term safety of this novel drug in subjects with TD.. The pooled long-term exposure (LTE) population included valbenazine-treated subjects from 3 studies: KINECT (NCT01688037: 6-week DBPC, 6-week open-label); KINECT 3 (NCT02274558: 6-week DBPC, 42-week blinded extension, 4-week drug-free follow-up); KINECT 4 (NCT02405091: 48-week open-label, 4-week drug-free follow-up). Safety assessments included adverse events (AEs), laboratory tests, vital signs, electrocardiograms (ECGs), and extrapyramidal symptom (EPS) scales. Psychiatric stability was monitored using the Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS) (SCHZ subgroup), as well as the Montgomery-Åsberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) (mood subgroup). All data were analyzed descriptively.. The LTE population included 430 subjects (KINECT, n = 46; KINECT 3, n = 220; KINECT 4, n = 164), 71.7% with SCHZ and 28.3% with a mood disorder; 85.5% were taking an antipsychotic (atypical only, 69.8%; typical only or typical + atypical, 15.7%). In the LTE population, treatment-emergent AEs (TEAEs) and discontinuations due to AEs were reported in 66.5% and 14.7% of subjects, respectively. The TEAE incidence was lower in the SCHZ subgroup (64.4%) than in the mood subgroup (71.9%). The 3 most common TEAEs in the SCHZ subgroup were urinary tract infection (UTI, 6.1%), headache (5.8%), and somnolence (5.2%). The 3 most common TEAEs in the mood subgroup were headache (12.4%), UTI (10.7%), and somnolence (9.1%). Mean score changes from baseline to end of treatment (Week 48) indicated that psychiatric stability was maintained in the SCHZ subgroup (PANSS Total, -3.4; PANSS Positive, -1.1; PANSS Negative, -0.1; PANSS General Psychopathology, -2.2; CDSS total, -0.4) and the mood subgroup (MADRS Total, 0.0; YMRS Total, -1.2). These scores remained generally stable during the 4-week drug-free follow-up periods. In the LTE population, mean changes in laboratory parameters, vital signs, ECG, and EPS scales were generally minimal and not clinically significant.. Valbenazine appeared to be well tolerated in adults with TD who received up to 48 weeks of treatment. In addition to long-term efficacy results (presented separately), these results suggest that valbenazine may be appropriate for the long-term management of TD regardless of underlying psychiatric diagnosis (SCHZ disorder or mood disorder).

Topics: Adrenergic Uptake Inhibitors; Adult; Aged; Antipsychotic Agents; Double-Blind Method; Female; Follow-Up Studies; Humans; Long Term Adverse Effects; Male; Middle Aged; Mood Disorders; Outcome Assessment, Health Care; Psychotic Disorders; Schizophrenia; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins

Valbenazine (VBZ, NBI-98854) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of tardive dyskinesia (TD). The KINECT 3 study (NCT02274558) evaluated the effects of VBZ on TD in subjects with schizophrenia/schizoaffective disorder (SCHZ) or mood disorder (mood disorder presented separately) who received up to 48 weeks of treatment.. KINECT 3 included: 6-week, double-blind, placebo (PBO)-controlled (DBPC) period (205 completers); 42-week VBZ extension (VE) period (124 completers): 4-week washout period (121 completers). Subjects entering the DBPC were randomized 1:1:1 to once-daily VBZ 80 mg, VBZ 40 mg, or PBO; stable concomitant antipsychotic medication regimens were allowed. Subjects completing the DBPC and entering the VE period were re-randomized (blinded) 1:1 from PBO to VBZ (80 or 40 mg) or continued VBZ treatment at the same dose. Efficacy assessments included: mean changes from baseline in Abnormal Involuntary Movement Scale (AIMS) total score (items 1-7); mean Clinical Global Impression of Change (CGI-TD) scores; AIMS responders (subjects with ≥50% score reduction from baseline): and CGI-TD responders (subjects with score ≤2 ["much improved" or "very much improved"]). Treatment effect sizes (Cohen's d) and numbers needed to treat (NNTs) were analyzed for DBPC outcomes.. Efficacy analyses were conducted in 148 subjects (DBPC) and 125 subjects (VE) with SCHZ. At Week 6 (end of DBPC), AIMS mean score improvements were greater in the VBZ groups (in a dose-related pattern) than in the PBO group (80 mg, -2.9, d = 0.88; 40 mg, -1.6, d = 0.52; PBO, +0.3). AIMS score changes at Week 48 (end of VE) showed continued TD improvement during long-term VBZ treatment (80 mg, -4.2; 40 mg, -2.5). By Week 52 (end of washout), AIMS scores were returning toward baseline levels, indicating re-emergence of TD. CGI-TD mean scores were as follows: Week 6 (80 mg, 3.0, d = 0.11; 40 mg, 2.9, d = 0.23; PBO, 3.2), Week 48 (80 mg, 2.2; 40 mg, 2.4), Week 52 (80 mg, 3.4; 40 mg, 3.3). AIMS responder rates (≥50% score reduction) were greater with VBZ than with PBO at Week 6 (80 mg, 40.9%, NNT = 4; 40 mg, 26.2%, NNT = 6; PBO, 9.3%), were increased at Week 48 (80 mg, 50.0%; 40 mg, 26.2%), and decreased after VBZ washout (80 mg, 21.6%; 40 mg, 9.5%). CGI-TD responder rates followed a similar pattern: Week 6 (80 mg, 29.5%, NNT = 17; 40 mg, 33.3%, NNT = 10; PBO, 23.3%), Week 48 (80 mg, 73.7%; 40 mg, 58.1%), Week 52 (80 mg, 29.7%; 40 mg, 33.3%).. Sustained TD improvements were found in subjects with SCHZ who received up to 48 weeks of VBZ, with TD reverting toward baseline when assessed 4 weeks after treatment withdrawal. Together with results from mood disorder subjects and the long-term safety profile (presented separately), these results indicate that long-term VBZ can be beneficial for managing TD regardless of psychiatric diagnosis category.

Topics: Adrenergic Uptake Inhibitors; Adult; Aged; Antipsychotic Agents; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Psychotic Disorders; Schizophrenia; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins

Individuals with tardive dyskinesia (TD) who completed a long-term study (KINECT 3 or KINECT 4) of valbenazine (40 or 80 mg/day, once-daily for up to 48 weeks followed by 4-week washout) were enrolled in a subsequent study (NCT02736955) that was primarily designed to further evaluate the long-term safety of valbenazine.. Participants were initiated at 40 mg/day (following prior valbenazine washout). At week 4, dosing was escalated to 80 mg/day based on tolerability and clinical assessment of TD; reduction to 40 mg/day was allowed for tolerability. The study was planned for 72 weeks or until termination due to commercial availability of valbenazine. Assessments included the Clinical Global Impression of Severity-TD (CGIS-TD), Patient Satisfaction Questionnaire (PSQ), and treatment-emergent adverse events (TEAEs).. At study termination, 85.7% (138/161) of participants were still active. Four participants had reached week 60, and none reached week 72. The percentage of participants with a CGIS-TD score ≤2 (normal/not ill or borderline ill) increased from study baseline (14.5% [23/159]) to week 48 (64.3% [36/56]). At baseline, 98.8% (158/160) of participants rated their prior valbenazine experience with a PSQ score ≤2 (very satisfied or somewhat satisfied). At week 48, 98.2% (55/56) remained satisfied. Before week 4 (dose escalation), 9.4% of participants had ≥1 TEAE. After week 4, the TEAE incidence was 49.0%. No TEAE occurred in ≥5% of participants during treatment (before or after week 4).. Valbenazine was well-tolerated and persistent improvements in TD were found in adults who received once-daily treatment for >1 year.

Topics: Adrenergic Uptake Inhibitors; Aged; Double-Blind Method; Female; Humans; Male; Middle Aged; Patient Satisfaction; Tardive Dyskinesia; Tetrabenazine; Treatment Outcome; Valine

Topics: Adrenergic Uptake Inhibitors; Adult; Affective Disorders, Psychotic; Aged; Antipsychotic Agents; Female; Humans; Male; Parkinson Disease, Secondary; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins

This letter to the editor acknowledges the contribution of Akbar et al. to the field of tardive dyskinesia (TD) and provides important regulatory information about the potential for parkinson-like symptoms in patients with TD who are treated with valbenazine.

Topics: Antipsychotic Agents; Humans; Parkinsonian Disorders; Tardive Dyskinesia; Tetrabenazine; Valine

​​​​Early Recognition and Treatment of Tardive Dyskinesia in Patients With Mood Disorders and Schizophrenia Click to enlarge page​​.

Topics: Antipsychotic Agents; Diagnosis, Differential; Drug Monitoring; Early Diagnosis; Humans; Membrane Transport Modulators; Mood Disorders; Patient Care; Patient Education as Topic; Psychology; Risk Assessment; Schizophrenia; Tardive Dyskinesia; Tetrabenazine; Valine

Valbenazine and deutetrabenazine are FDA-approved as treatment for tardive dyskinesia (TD). Both medications are vesicular monoamine transporter type 2 (VMAT2) inhibitors, and both are effective for reducing TD symptoms. Clinicians need to be aware of the adverse effects of valbenazine and deutetrabenazine, as well as other key differences between the two, in order to individualize treatment. Using the Abnormal Involuntary Movement Scale assists clinicians in assessing progress for each patient. Treating TD effectively with these new medications will reduce the burden of the condition for patients.

Topics: Drug Monitoring; Humans; Medication Therapy Management; Membrane Transport Modulators; Neurologic Examination; Patient Care Management; Psychiatry; Tardive Dyskinesia; Tetrabenazine; Treatment Outcome; Valine; Vesicular Monoamine Transport Proteins

The use of second-generation antipsychotics has not eliminated tardive dyskinesia (TD), and the prevalence of the disorder is higher than commonly realized. The involuntary movements of TD can decrease patients' quality of life, cause embarrassment, and lead to social withdrawal. Clinicians must evaluate patients taking DRBAs for TD risk factors and regularly screen them for TD using a rating scale. Familiarity with tools and diagnostic criteria will enable clinicians to conduct a differential diagnosis. Once a diagnosis is made, medications approved by the US Food and Drug Administration can be used to treat the condition. These medications are effective, but clinicians should be aware of key differences. A baseline assessment and regular follow-up evaluations will allow the clinician to monitor the patient's progress and make adjustments to meet treatment goals.​.

Topics: Adrenergic Uptake Inhibitors; Adult; Antipsychotic Agents; Diagnosis, Differential; Dopamine Antagonists; Female; Humans; Male; Middle Aged; Schizophrenia; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins

Valbenazine, a vesicular monoamine transporter 2 (VMAT2, SLC18A2) inhibitor, is a newly approved treatment for tardive dyskinesia. VMAT2 is present in the membrane of secretory vesicles and transports dopamine (DA), norepinephrine (NE), serotonin (5-HT), histamine, glutamate (Glu), and GABA into vesicles for presynaptic release. We utilized microdialysis in awake, freely moving mice to determine the effect of NBI-98782, the active metabolite of valbenazine, alone, or in combination with several antipsychotic drugs (APDs), to influence neurotransmitter efflux in the medial prefrontal cortex (mPFC), dorsal striatum (dSTR), hippocampus and nucleus accumbens (NAC); we also compared it with tetrabenazine, the prototypical VMAT2 inhibitor. Acute NBI-98782 and tetrabenazine decreased mPFC, dSTR, hippocampus, and NAC DA, 5-HT, and NE efflux, while increasing that of DOPAC, HVA, and 5-HIAA. Sub-chronic NBI-98782 (7 days) decreased baseline DA and 5-HT efflux in both mPFC and dSTR. NBI-98782 elicited similar effects on neurotransmitter efflux in sub-chronic NBI-98782-treated mice but also enhanced ACh and GABA; the decrease in DA efflux in mPFC and dSTR was not significant in the sc-treated animals. NBI-98782 suppressed clozapine-, olanzapine- and risperidone-induced DA efflux in both mPFC and dSTR, and ACh efflux in mPFC. NBI-98782 suppressed the haloperidol-induced DA efflux in dSTR, with minimal effect on GABA efflux. NBI-98782 attenuated PCP-induced DA, 5-HT, NE and Glu efflux, and AMPH-induced DA and NE efflux, in both mPFC and dSTR, as well as PCP- and AMPH-induced hyperlocomotion, suggesting possible beneficial antipsychotic effects.

Topics: Animals; Antipsychotic Agents; Dopamine; Hippocampus; Locomotion; Male; Mice; Mice, Inbred C57BL; Microdialysis; Nucleus Accumbens; Phencyclidine; Prefrontal Cortex; Serotonin; Synaptic Transmission; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins

​​ Tardive dyskinesia (TD) is a condition of potentially irreversible abnormal involuntary movements associated with dopamine receptor blocking agents, such as antipsychotics. While prevention is the best strategy, it is not always possible. This report outlines strategies to reduce TD symptoms, including the use of the FDA-approved treatment options (valbenazine and deutetrabenazine).

Topics: Adrenergic Uptake Inhibitors; Adult; Clozapine; Humans; Psychiatry; Serotonin Antagonists; Tardive Dyskinesia; Tetrabenazine; Valine

​​​​​​ Clinicians now have 2 effective and well-tolerated vesicular monoamine transporter 2 (VMAT2) inhibitors-valbenazine and deutetrabenazine-for the treatment of patients with tardive dyskinesia (TD), a severe and potentially irreversible side effect associated with dopamine receptor blocking agents. Clinicians should use measurement-based care, eg, the Abnormal Involuntary Movement Scale with activation maneuvers, to assess and document TD symptoms and treatment progress. Each follow-up visit should be personalized with questions related to patients' functioning and level of distress regarding their specific TD symptoms. Family members, if available, can provide information on symptom changes and assistance with medication adherence. With continued treatment and measurement-based care, patients can experience improvement in their TD symptoms.

Topics: Adrenergic Uptake Inhibitors; Adult; Humans; Outcome Assessment, Health Care; Psychiatry; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins

Copulatory or pelvic thrusting dyskinesia is a subtype of tardive dyskinesia (TD) which is caused by exposure to dopamine blocking agents.. A man exhibiting rhythmic, stereotypical pelvic thrusting movements.. Recognition of copulatory dyskinesia as a distinctive iatrogenic disorder helps prevent unnecessary investigations and guides the implementation of corrective strategies.

Topics: Adrenergic beta-Antagonists; Aged; Aripiprazole; Clonazepam; Deprescriptions; Depressive Disorder; Drug Substitution; GABA Modulators; Humans; Male; Parkinsonian Disorders; Pelvis; Propranolol; Quinolones; Serotonin Agents; Tardive Dyskinesia; Tetrabenazine; Thiophenes; Treatment Failure; Valine

Topics: Antipsychotic Agents; Dopamine; Humans; Psychotic Disorders; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins

Tardive dyskinesia (TD) is a bothersome and - at times, disabling - movement disorder associated with exposure to dopamine receptor antagonist medications. On 11 April 2017, valbenazine became the first US FDA-approved medication indicated for the treatment of TD. Valbenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor that decreases the abnormal movements of TD. The FDA considered valbenazine a breakthrough therapy in 2014 given its underlying mechanism and its importance in addressing an unmet need, as there were no available FDA-approved medications indicated for TD. The advantages of valbenazine include once-daily dosing and a rapid onset of effect within 2 weeks of treatment initiation.

Topics: Adrenergic Uptake Inhibitors; Dopamine Antagonists; Humans; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins

Tardive dyskinesia (TD), the choreoathetoid movements of fingers, arms, legs, and trunk and irregular stereotypical movements of the mouth, face, and tongue, has been the scourge of antipsychotic medications since the approval of chlorpromazine. TD tends to occur late in treatment and sometimes remains after discontinuation of the antipsychotic medication. With the recent approval of two medications, valbenazine (Ingrezza

Topics: Antipsychotic Agents; Chlorpromazine; Drug-Related Side Effects and Adverse Reactions; Humans; Psychiatric Nursing; Tardive Dyskinesia; Tetrabenazine; Valine

Valbenazine is a novel vesicular monoamine transporter 2 inhibitor approved for the treatment of tardive dyskinesia in adults.. Using data from double-blind, placebo-controlled trials, analyses were conducted to evaluate the cardiovascular effects of once-daily valbenazine in patients with a psychiatric disorder who developed tardive dyskinesia after exposure to a dopamine-blocking medication.. Data were pooled from three 6-week, double-blind, placebo-controlled trials: KINECT (NCT01688037), KINECT 2 (NCT01733121), and KINECT 3 (NCT02274558). Data from the 42-week valbenazine extension period of KINECT 3 were also analyzed. Outcomes of interest included cardiovascular-related treatment-emergent adverse events, vital sign measurements, and electrocardiogram parameters.. The pooled safety population included 400 participants (placebo, n = 178; valbenazine 40 mg/day, n = 110; valbenazine 80 mg/day, n = 112). A history of cardiac disorders was present in 11.8% of participants, and 74.3% were taking a concomitant medication with known potential for QT prolongation. Mean changes from baseline to week 6 in supine vital signs and QTcF (Fridericia correction) were as follows for placebo, valbenazine 40 mg/day, and valbenazine 80 mg/day, respectively: systolic blood pressure (0.2, - 2.1, - 1.8 mmHg), diastolic blood pressure (- 0.1, - 1.6, - 1.2 mmHg), heart rate (- 1.7, - 2.2, - 1.7 bpm), QTcF interval (1.2, 1.1, 2.1 ms); all p > 0.05 for valbenazine vs. placebo. No statistically significant differences were observed between placebo and valbenazine in cardiovascular-related, treatment-emergent adverse events. No notable additional effects on cardiovascular outcomes were found with up to 48 weeks of valbenazine treatment.. Results from double-blind, placebo-controlled trials showed no apparent difference between valbenazine and placebo on cardiovascular outcomes. No additional cardiovascular risk was detected during a longer extension study with valbenazine.

Topics: Aged; Blood Pressure; Cardiovascular Diseases; Cardiovascular System; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Heart Rate; Humans; Middle Aged; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Tardive Dyskinesia; Tetrabenazine; Valine

Ingrezza and Austedo were approved last year. ICER calculations raise questions about their price.

Topics: Antipsychotic Agents; Drug Approval; Humans; Managed Care Programs; Tardive Dyskinesia; Tetrabenazine; United States; United States Food and Drug Administration; Valine

Five new drugs marketed within the last year, which are used for medical problems often experienced by the elderly, have been selected for consideration in this review. The uses and most important properties of these agents are discussed, and a rating for each new drug is determined using the New Drug Comparison Rating system developed by the author (DAH). Advantages, disadvantages, and other important information regarding each new drug are identified and used as the basis for determining the rating. The drugs include an anticoagulant, an antiparkinson agent, an agent for tardive dyskinesia, an agent for psoriasis, and an agent for constipation. The drugs reviewed are betrixaban, safinamide mesylate, valbenazine tosylate, guselkumab, and plecanatide.

Topics: Aged; Alanine; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticoagulants; Antiparkinson Agents; Benzamides; Benzylamines; Constipation; Drug Approval; Humans; Natriuretic Peptides; Psoriasis; Pyridines; Tardive Dyskinesia; Tetrabenazine; Valine

Topics: Antipsychotic Agents; Clinical Trials, Phase III as Topic; Dopamine; Drug Approval; Humans; Synaptic Transmission; Tardive Dyskinesia; Tetrabenazine; United States; United States Food and Drug Administration; Valine; Vesicular Monoamine Transport Proteins

Topics: Antipsychotic Agents; Humans; Neurotransmitter Uptake Inhibitors; Tardive Dyskinesia; Tetrabenazine; Treatment Outcome; Valine; Vesicular Monoamine Transport Proteins

Tardive dyskinesia (TD) is a hyperkinetic movement disorder that may result from treatment with antipsychotics or other dopamine receptor blocking agents. Underlying pathophysiology is incompletely understood but since the 1970s dopamine depleting agents have been used to reduce involuntary movements. The search for safe, effective treatments for TD is ongoing. Valbenazine, a novel VMAT2 inhibitor, has recently been FDA approved for treatment of TD. Areas covered: An overview of TD, unmet medical needs and current treatment guidelines are presented. The background, chemistry and clinical development of valbenazine to treat TD is detailed. A competitive market is developing as the treatment gap is identified and potential therapies are discussed in context of a broader market overview. Expert opinion: Antipsychotic use is growing among adults and children in the U.S. Consequently, prevalence of TD is expected to rise. Cessation of antipsychotics is often not possible as the psychiatric condition may deteriorate. Increasing doses of an antipsychotic to suppress involuntary movements is not sustainable long term as underlying TD worsens and movements typically recur. There were no FDA approved treatments for TD. The approval of valbenazine to treat TD is a critical step in addressing this gap in neurologic care.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Humans; Mental Disorders; Tardive Dyskinesia; Tetrabenazine; Treatment Outcome; Valine; Vesicular Monoamine Transport Proteins

Tetrabenazine (TBZ) activity is thought to result from four isomeric dihydrotetrabenazine (HTBZ) metabolites ([+]-α-HTBZ, [-]-α-HTBZ, [+]-β-HTBZ, [-]-β-HTBZ). Each isomer has a unique profile of vesicular monoamine transporter 2 (VMAT2) inhibition and off-target binding. Previously published data only report total isomer (α) and (β) concentrations. We developed a method to quantify the individual HTBZ isomers in samples from patients with Huntington's disease receiving TBZ. For comparison, concentrations of [+]-α-HTBZ, the single active metabolite shared by valbenazine (VBZ) and TBZ, were determined in samples from patients with tardive dyskinesia receiving VBZ.. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for quantitation of the four individual HTBZ isomers. Concentrations were determined in serum from patients with Huntington's disease administered TBZ and plasma from patients with tardive dyskinesia administered VBZ once daily.. In patients administered TBZ, [-]-α-HTBZ and [+]-β-HTBZ were the most abundant HTBZ isomers while [-]-β-HTBZ and [+]-α-HTBZ were present as minor metabolites. Only [+]-α-HTBZ was observed in patients administered VBZ.. Based on relative abundance and potency, [+]-β-HTBZ appears to be the primary contributor to VMAT2 inhibition by TBZ, a finding in contrast with the generally held assertion that [+]-α-HTBZ is the major contributor. [-]-α-HTBZ, the other abundant TBZ metabolite, has much lower VMAT2 inhibitory potency than [+]-β-HTBZ, but increased affinity for other CNS targets, which may contribute to off-target effects of TBZ. In contrast, pharmacological activity for VBZ is derived primarily from [+]-α-HTBZ. Individual HTBZ isomer concentrations provide a more clinically relevant endpoint for assessing on- and off-target effects of TBZ than total isomer concentrations.

Topics: Adrenergic Uptake Inhibitors; Adult; Chromatography, Liquid; Female; Humans; Huntington Disease; Isomerism; Male; Middle Aged; Tandem Mass Spectrometry; Tardive Dyskinesia; Tetrabenazine; Valine

BACKGROUND Tardive dyskinesia (TD) is a chronic involuntary movement disorder frequently induced by dopamine receptor blockers, particularly first-generation antipsychotics. Until recently, management of TD was restricted to lowering the dose of the current medication, switching to another medication, or using off-label treatments with insufficient evidence of efficacy. Valbenazine, a vesicular monoamine transporter-2 (VMAT2) inhibitor, became the first drug to be approved by the FDA specifically for the treatment of TD. CASE REPORT We describe the case of a 49-year-old African-American woman who was diagnosed with bipolar disorder at the age of 34 and treated with lithium carbonate (900 mg daily) and citalopram (10 mg daily). She also received low doses of second-generation antipsychotics for weeks at a time, but these were always discontinued due to severe sedation. Over a decade later, at the age of 45, she experienced rapid onset of severe TD symptoms. She enrolled in a phase III double-blind clinical trial and received valbenazine 80 mg, with encouraging results. CONCLUSIONS Once-daily dosing of valbenazine (80 mg) was effective and safe over a long period, even in this atypical case of severe and rapid-onset TD.

Topics: Adrenergic Uptake Inhibitors; Antimanic Agents; Female; Humans; Middle Aged; Tardive Dyskinesia; Tetrabenazine; Valine