Search

BackgroundIndividuals 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.MethodsParticipants 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).ResultsAt 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).ConclusionsValbenazine was well-tolerated and persistent improvements in TD were found in adults who received once-daily treatment for >1 year.

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.

PurposeThe purpose of this review is to summarize the current evidence for valbenazine and deutetrabenazine use for the treatment of tardive dyskinesia (TD).SummaryA 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.ConclusionsValbenazine 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.

Tardive dyskinesia (TD) is a condition where we have a limited understanding of the cause and of management. The delayed-onset movements can occur due to prolonged exposure to dopamine receptor-blocking agents (DRBAs). They can be physically disabling and lead to ridicule and stigmatization. TD also interferes with treatment adherence. The increased trend of prescriptions for off-label use of various DRBAs, especially antipsychotics, has increased the risk of TD. No currently available antipsychotic is free of the risk of TD, though the atypicals have a lower risk. The Abnormal Involuntary Movements Scale is the most widely used and recommended tool for the assessment and monitoring of TD. Varied treatment strategies have been tried including cessation of the DRBA, switch to a lower potency antipsychotic, and concomitant use of other medications such as clonazepam and Vitamin E. Most of these strategies have minimal evidence. The recent US Food and Drug Administration approval of two VMAT2 inhibitors, deutetrabenazine and valbenazine, for the treatment of TD has brought some relief to these patients. Cost may be a limiting factor in their use. Nonpharmacological treatment such as deep-brain stimulation, botulinum toxin, and electroconvulsive therapy is to be used only in intractable/incapacitating movements. Despite these newer options, the best strategy in the management of TD continues to be prevention. Judicious use of antipsychotics, regular monitoring of patients on DRBAs, and early diagnosis and intervention are strategies that significantly reduce the development of TD and improve the quality of life of patients.

Tardive dyskinesia (TD) consists of involuntary movements of the tongue, lips, face, trunk, and extremities that occur in patients treated long-term with dopamine antagonist medications. TD can be associated with significant functional impairment and be socially stigmatizing. TD, once established, has proved to be often irreversible and remains a significant treatment issue. An accurate and early diagnosis of TD is crucial because the risk of permanence increases over time. Clinicians should be educated on which patients are most at risk for TD and conduct assessments through clinical examination or through the use of a structured evaluative tool such as the Abnormal Involuntary Movement Scale (AIMS). Patients and caregivers need to be educated about the risks of and alternatives to antipsychotic medication and early signs of TD. New treatment approaches to persistent TD are available and approved by the US Food and Drug Administration: the vesicular monoamine transporter-2 (VMAT2) inhibitors, deutetrabenazine and valbenazine. When treatment is initiated, a baseline assessment should be obtained by clinicians using the AIMS and follow-up assessments should be done on a regular basis. In this educational activity, Drs Correll and Citrome offer a review of the diagnostic and treatment fundamentals for TD.

Tardive dyskinesia (TD) is an involuntary movement disorder associated with agents that block dopamine receptors, particularly antipsychotics. TD commonly involves the orofacial muscles and extremities, and, because these movements are out of the patient's control, they can have serious physical and psychological effects. An accurate and early diagnosis of TD is crucial because the risk of permanence increases over time. To minimize the risk of TD development, clinicians should use the lowest necessary doses of dopamine receptor blocking agents, and, if allowed by the treated condition, the dopamine receptor blocking agents should be stopped after the shortest necessary time. Clinicians should try to avoid parkinsonian adverse effects and akathisia and prefer second-generation antipsychotics over first-generation antipsychotics. Moreover, clinicians should differentiate between TD and other drug-induced movement disorders, particularly drug-induced parkinsonism, as anticholinergic treatment can worsen TD. To facilitate measurement-based care, clinicians should use the Abnormal Involuntary Movement Scale examination to screen for and routinely monitor TD, especially when providing treatments intended to decrease the symptoms and impact of TD. Two vesicular monoamine transporter-2 (VMAT2) inhibitors, deutetrabenazine and valbenazine, are approved by the US Food and Drug Administration to treat TD. For patients who have moderate to severe or disabling TD, the American Psychiatric Association recommends treatment with the VMAT2 inhibitors. Clinicians should communicate with patients and care partners about risk factors for and signs of TD, as well as available treatment options for TD and what they can expect in terms of short- and long-term results.

Objective To evaluate the effects of once‐daily valbenazine (40 or 80 mg/d) in older and younger adults with tardive dyskinesia (TD). Methods 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). Results 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 .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 .05]; placebo, 19.4%); younger than 55 years (80 mg/d, 39.5% [P

Aim: Utilize the Bucher indirect treatment comparison (ITC) method to compare valbenazine and deutetrabenazine efficacy using clinical trial data. Methods: Outcomes included mean change from baseline in Abnormal Involuntary Movement Scale (AIMS) total score, AIMS response (≥50% improvement), clinical global impression of change response (score ≤2) and safety outcomes. Data were pooled by trial and dose; outcomes were analyzed at multiple time points. Results: ITC of AIMS score improvement significantly favored valbenazine 80 mg/day at 6 weeks versus deutetrabenazine 36 mg/day at 8 weeks, while valbenazine 40 mg/day was statistically similar to all doses of deutetrabenazine at all time points. No significant differences between drugs were found in AIMS and clinical global impression of change responses and safety outcomes. Conclusion: In this ITC of pooled trial data, valbenazine was generally favorable over deutetrabenazine, although dose titration and equivalency should be considered when interpreting results.

Background 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). Objectives To estimate an minimal clinically important difference for the Abnormal Involuntary Movement Scale using valbenazine trial data and an anchor‐based method. Methods 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). Results 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

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.

Tardive dyskinesia (TD) is a heterogeneous syndrome of involuntary hyperkinetic movements that is often persistent and occurs belatedly during treatment with antipsychotics. Recent approval of two dopamine-depleting analogs of tetrabenazine based on randomized controlled trials offers an evidence-based therapeutic approach to TD for the first time. These agents are optimally used within the context of a comprehensive approach to patient management that includes a practical screening and monitoring program, sensitive and specific criteria for the diagnosis of TD, awareness of the severity and impact of the disorder, informed discussions with patients and caregivers, and a rational basis for prescribing decisions about continued antipsychotic and adjunctive agents. Areas of limited or inconclusive data, bias and misunderstandings about key aspects, and neglect of training about TD in recent years contribute to barriers in providing effective care and promoting patient safety.

Objectives The aim of this study was to review our "real-world" experience with the vesicular monoamine transporter 2 (VMAT2) inhibitors tetrabenazine (TBZ), deutetrabenazine (DTBZ), and valbenazine (VBZ) for treatment of hyperkinetic movement disorders. Access and adherence to VMAT2 inhibitors may be limited by insurance and regulatory issues, inexperience with their use by the prescribing physician, lack of efficacy, or side effects. Methods We performed a retrospective chart review, supplemented with a questionnaire, of all our patients treated with a VMAT2 inhibitor between January 1, 2017, and August 30, 2018. Results We identified 135 patients (57.8% male) and 178 prescriptions for VMAT2 inhibitors (TBZ, n = 45 [25.3%]; DTBZ, n = 104 [58.4%]; VBZ, n = 29 [16.3%]). Tourette syndrome/tics was the most common diagnosis (n = 67 [49.6%]) for which VMAT2 inhibitors were prescribed. The VMAT2 inhibitor mean treatment durations (range; SD) and daily dosages (range; SD) were as follows: TBZ (n = 31), 5.1 months (1-19; 3.9) at 48.8 mg (12.5-112.5; 29.6); DTBZ (n = 51), 8.0 months (0.25-16.5; 4.4) at 34.4 mg (6-96; 20.7); and VBZ (n = 20), 6.0 months (0.1-16; 5.6) at 64 mg (40-160; 35.3). The VMAT2 inhibitors effectively controlled hyperkinetic movement disorders as measured by a 1- to 4-point Likert scale (1 = normal or mildly ill, 4 = severely ill) comparing illness severity before starting and while on treatment (score of 1 in 13.0%-26.7% vs 60.9%-71.9% of patients). Side effects were mild and improved or resolved following dose reduction, drug cessation, or addition of adjunctive medications. Conclusions The VMAT2 inhibitors are effective and safe in a range of hyperkinetic movement disorders but are not readily accessible by patients in the United States for indications not approved by the Food and Drug Administration.

Tardive dyskinesia (TD) is a common, iatrogenic movement disorder affecting many individuals treated with dopamine-receptor blocking agents (DRBAs). Studying treatment of TD can be complex, as the symptoms can be affected by changes in either dosage or type of DRBA, as well as by the variable natural course of the disease. Historically many pharmacological therapies have been studied in TD, finding varying degrees of treatment success. Most recently, the VMAT2 inhibitors valbenazine and deutetrabenazine were rigorously studied in TD in large, phase III clinical trials, and were shown to be beneficial in this population. In this article, we will review various treatments of TD, including manipulation of the offending agent, VMAT2 inhibitors, other non-VMAT2-inhibiting medications, and non-pharmacological approaches.

Purpose of review This a comprehensive review of the literature regarding the use of Valbenazine in treating tardive dyskinesia. A primarily oral movement disorder induced by chronic exposure to certain classes of medications, tardive dyskinesia is often resistant to many therapeutic approaches. This review presents the background, evidence, and indications for the use of Valbenazine as a treatment option for this condition. Recent Findings Tardive dyskinesia is a disorder arising from long-term exposure to medications that blocked dopamine receptors, primarily antipsychotics. It is characterized by abnormal movements of the oral-buccal-lingual structures as well as associated pain and hypertrophy. Simply stopping the use of the dopamine blocking agents effectively alleviates the symptoms but is not always reliable hence the need for another therapeutic approach. Valbenazine is thought to function as a highly selective inhibitor of the VMAT2 vesicular monoamine transporter resulting in decreased availability of dopamine in the presynaptic cleft. This leads to decreased dopaminergic activation of the striatal motor pathway. The FDA approved Valbenazine in 2017 to treat tardive dyskinesia in adults and needs to be evaluated with existing therapeutic approaches. Summary The chronic use of dopamine receptor blocking agents, most commonly antipsychotics, can lead to a movement disorder called tardive dyskinesia. Once symptom onset has occurred, these movement abnormalities can persist for years to permanently, depending on the speed and effectiveness of treatment. Valbenazine is a relatively newer option for the treatment of tardive dyskinesia in adults. Compared to other pharmaceutical agents, it is more selective and has limited toxicities making it an effective treatment regimen. However, further research, including additional direct comparison studies, should be conducted to fully evaluate this drug’s usefulness.

ObjectiveTardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotics and other dopamine receptor blocking agents. Long-term safety of the approved TD medication, valbenazine, was demonstrated in 2 clinical trials (KINECT 3 [NCT02274558], KINECT 4 [NCT02405091]). Data from these trials were analyzed post hoc to evaluate the onset and resolution of adverse events (AEs).MethodsParticipants in KINECT 3 and KINECT 4 received up to 48 weeks of once-daily valbenazine (40 or 80 mg). Data from these studies were pooled and analyzed to assess the incidence, time to first occurrence, and resolution for the following AEs of potential clinical interest: akathisia, balance disorder, dizziness, parkinsonism, somnolence/sedation, suicidal behavior/ideation, and tremor.ResultsIn the pooled population (N=314), all AEs of potential clinical interest occurred in 85% (somnolence/sedation, dizziness); >70% (akathisia, balance disorder, tremor).ConclusionsIn long-term clinical trials, the incidence of AEs of potential clinical interest was low (70–100%). All patients taking valbenazine should be routinely monitored for AEs, particularly those that may exacerbate the motor symptoms associated with TD.FundingNeurocrine Biosciences, Inc.

Introduction: Significant need exists for effective, well-tolerated pharmacologic treatments for Tourette syndrome (TS). Medications that inhibit vesicular monoamine transporters (i.e. VMAT2 inhibitors) downregulate presynaptic packaging and release of dopamine into the neuronal synapse and are effective in treating hyperkinetic movement disorders such as Huntington’s chorea and tardive dyskinesia (TD); thus, they may be useful in treating TS. Areas covered: This review describes the clinical program evaluating the safety and efficacy of valbenazine in the treatment of involuntary tics associated with TS in adult and pediatric subjects. While there was a trend in the 6 completed trials toward greater improvement in valbenazine-treated versus placebo subjects on the primary efficacy endpoint (Yale Global Tic Severity Scale Total Tic Score), this difference did not reach statistical significance. Valbenazine was generally well-tolerated in the studies, and treatment-emergent adverse events were consistent with valbenazine studies in TD. Expert opinion: Due to the failure to meet the primary endpoint in these trials, further investigation of valbenazine for TS is unlikely. Given the need for safe and effective TS therapies and the key role of VMAT2 in modulating dopaminergic activity, it is reasonable for future studies to investigate other VMAT2 inhibitors as potential treatments for TS.

In this chapter, we review available treatment options for tardive dyskinesia and their pharmacologic mechanisms.

Hyperkinetic movement disorders are a common group of movement abnormalities in children, characterized with repetitive unintended involuntary movements. Major hyperkinetic movements include tremor, tic, dystonia, myoclonus, and chorea. Although a number of drugs have been proven to be beneficial for these abnormalities, some patients may become resistant to conventional treatments. Vesicular monoamine transporter2 (VMAT2) inhibitors (Tetrabenazine, Deutetrabenazine, and Valbenazine) are new agents introduced in the last decade for treating some of movement disorders, in particular tardive dyskinesia, Huntington chorea, and Tourette syndrome. In this brief review, we discussed the role of these drugs in managing hyperkinetic movement disorders.

Individuals with intellectual disability (ID) commonly suffer from comorbid psychiatric and behavioral disorders that are frequently treated by antipsychotic medications. All individuals exposed to first- and second/third- generation antipsychotics are at risk for developing tardive dyskinesia (TD), characterized by abnormal, involuntary movements of the mouth/tongue/jaw, trunk, and extremities. TD can be highly disruptive for affected individuals and their caregivers, causing embarrassment, isolation, behavioral disturbances, and reduced functioning and quality of life. Information on TD incidence in individuals with ID is limited, but 2 small US studies reported TD prevalence rates of 42-45% in inpatients with ID. The safety and efficacy of vesicular monoamine transporter type 2 (VMAT2) inhibitors approved for treatment of TD in adults have been demonstrated in multiple clinical trials, but they excluded individuals with ID. Clinical characteristics and treatment outcomes of 5 adults (aged 28–63 years) with mild-to-severe ID and TD are presented, illustrating TD symptoms before/after treatment. All individuals had multiple comorbid psychiatric, behavioral, and other medical conditions, history of antipsychotic exposure, and abnormal movements affecting the tongue/mouth/jaw ( n = 5 ), upper extremities ( n = 5 ), lower extremities ( n = 3 ), and trunk ( n = 2 ), resulting in diminished ability to speak ( n = 2 ), ambulate ( n = 3 ), and perform activities of daily living ( n = 3 ). Treatment with valbenazine resulted in meaningful improvements in TD symptoms and improved daily functioning, demeanor, and social/caregiver interactions. Given the high likelihood of antipsychotic exposure in the ID population, it is appropriate to screen for TD at every clinical visit through careful monitoring for abnormal movements and questioning the individual/caregiver regarding abnormal movements or TD-related functional impairments (i.e., speaking, swallowing, eating, ambulating, and social functioning). In this study, 5 individuals with ID and TD received once-daily valbenazine and experienced marked improvement in TD symptoms and daily functioning, resulting in increased quality of life for affected individuals and caregivers.

​​ 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).

A critical appraisal and clinical application of Hauser RA, Factor SA, Marder SR, et al. KINECT 3: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial of Valbenazine for Tardive Dyskinesia. Am J Psychiatry. 2017;174(5):476-484. https://doi.org/10.1176/appi.ajp.2017.16091037 and Factor SA, Remington G, Comella CL, et al. The Effects of Valbenazine in Participants with Tardive Dyskinesia: Results of the 1-Year KINECT 3 Extension Study. J Clin Psychiatry. 2017;78(9):1344-1350. https://doi.org/10.4088/JCP.17m11777 exploring the efficacy of a newer therapy for tardive dyskinesia, and describing recommendations for a patient with acute medical problems and longstanding tardive dyskinesia.

Highlights • Drug induced parkinsonism caused by valbenazine and deutetrabenazine. • Possible side effects of VMAT-2 inhibitors. • Valbenazine and deutetrabenazine can unmask underlying Parkinson’s Disease.

Tetrabenazine is a US Food and Drug Administration (FDA)-approved drug that exhibits a dopamine depleting effect and is used for the treatment of chorea in Huntington’s disease. Mechanistically, tetrabenazine binds and inhibits vesicular monoamine transporter type 2, which is responsible for importing neurotransmitters from the cytosol to the vesicles in neuronal cells. This transportation contributes to the release of neurotransmitters inside the cell to the synaptic cleft, resulting in dopaminergic signal transmission. The highly potent inhibitory activity of tetrabenazine has led to its advanced applications and in-depth investigation of prodrug design and metabolite drug discovery. In addition, the synthesis of enantiomerically pure tetrabenazine has been pursued. After a series of research studies, tetrabenazine derivatives such as valbenazine and deutetrabenazine have been approved by the US FDA. In addition, radioisotopically labeled tetrabenazine permits the early diagnosis of Parkinson’s disease, which is difficult to treat during the later stages of this disease. These applications were made possible by the synthetic efforts aimed toward the efficient and asymmetric synthesis of tetrabenazine. In this review, various syntheses of tetrabenazine and its derivatives have been summarized.

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.

Tardive dyskinesia (TD) is a serious and often irreversible involuntary muscle movement that involves the face, lips, tongue, trunk, and extremities. TD is a risk in the use of antipsychotic medications, whether it is typical or first generation or atypical or second-generation antipsychotic. The risk is highest in patients receiving long-term antipsychotic treatment. Before the availability of valbenazine, clozapine was used to reverse or at least ameliorate TD. We report a case of a patient on long-term antipsychotic treatment whose TD was initially reversed by clozapine but was completely reversed by valbenazine.

SUMMARYThe development of rational treatments for tardive dyskinesia has been held back by limitations to our understanding of its aetiology, which even now does not extend far beyond its association with centrally acting dopamine-blocking drugs. This article reviews briefly the major aetiological theories and addresses general management and specific treatment options. Primary prevention and early recognition remain the crucial management issues because, once the condition is established, there are no satisfactory treatments. The article considers two newly developed drugs, valbenazine and deutetrabenazine, in some detail as, although they are not yet licensed in Europe, they have largely been responsible for an upsurge in interest in tardive dyskinesia in the North American literature and are likely to be widely promoted in the future. Although possessed of undoubted benefits, the evidence suggests that these represent small steps rather than large leaps forward in treatment.LEARNING OBJECTIVES•Be able to discuss the major aetiological theories on the causation of a common, and sometimes serious, adverse action of antidopaminergic drugs•Understand general management and specific treatment options•Understand the pharmacology and efficacy of two drugs recently approved by the FDA for the treatment of tardive dyskinesiaDECLARATION OF INTERESTD.C.O. is psychiatric commissioner on the Commission on Human Medicines, the UK drug regulator, and chair of its expert advisory group on CNS drugs. He is also a member of the psychiatry Scientific Advisory Group of the European Medicines Agency.

Introduction Drug-induced parkinsonism (DIP) and tardive dyskinesia (TD) are stigmatizing movement disorders associated with exposure to dopamine receptor blocking agents such as antipsychotics, but they differ in their pathophysiology and clinical management. Treatment for one may worsen the other, and there are important diagnostic clues that assist in making an accurate assessment and instituting a rational treatment plan. Methods A literature review was executed to identify articles relating to the presentation, pathophysiology, epidemiology, and management of DIP and TD. Results DIP and TD prevalence estimates range from approximately 20 to 35% among antipsychotic users, but may be higher in select populations. DIP often presents as bradykinesia and rigidity, as well as rhythmic tremor, and the majority of cases appear within hours to weeks of initiation of therapy with an antipsychotic, or if dosage of the antipsychotic is increased. TD onset is delayed, typically appearing after at least 3 months or longer of treatment, and patients will commonly present with involuntary, abnormal facial movements such as lip smacking, puckering, chewing, or tongue protrusion. DIP often resolves with discontinuation of the causative agent, but TD may be permanent. Broadly, proposed mechanisms underlying these adverse events include decreased dopamine concentrations in the nigrostriatal pathway of the striatum and dopamine hypersensitivity, for DIP and TD, respectively. Pharmacologic treatment approaches for DIP have commonly included anticholinergic agents such as benztropine; however, anticholinergic medications can make TD worse. Switching the antipsychotic medication to one with lower propensity for DIP is an option for some patients. Amantadine, a non-anticholinergic agent used for the treatment of DIP, may be preferred in patients with comorbid DIP and TD. In TD, treatment options include the new reversible vesicular monoamine 2 transporter inhibitors, valbenazine and deutetrabenazine. Conclusions It is important for clinicians to be able to recognize DIP and TD in patients using antipsychotics so that they can minimize the impact of these adverse events on their patients’ quality of life. Accurate diagnosis will drive the selection of the correct treatment. Plain Language Summary Plain language summary available for this article.

Background Management of tardive syndromes (TS) is challenging, with only a few evidence-based therapeutic algorithms reported in the American Academy of Neurology (AAN) guideline in 2013. Objective To update the evidence-based recommendations and provide a practical treatment algorithm for management of TS by addressing 5 questions: 1) Is withdrawal of dopamine receptor blocking agents (DRBAs) an effective TS treatment? 2) Does switching from typical to atypical DRBAs reduce TS symptoms? 3) What is the efficacy of pharmacologic agents in treating TS? 4) Do patients with TS benefit from chemodenervation with botulinum toxin? 5) Do patients with TS benefit from surgical therapy? Methods Systematic reviews were conducted by searching PsycINFO, Ovid MEDLINE, PubMed, EMBASE, Web of Science and Cochrane for articles published between 2012 and 2017 to identify new evidence published after the 2013 AAN guidelines. Articles were classified according to an AAN 4-tiered evidence-rating scheme. To the extent possible, for each study we attempted to categorize results based on the description of the population enrolled (tardive dyskinesia [TD], tardive dystonia, tardive tremor, etc.). Recommendations were based on the evidence. Results and recommendations New evidence was combined with the existing guideline evidence to inform our recommendations. Deutetrabenazine and valbenazine are established as effective treatments of TD (Level A) and must be recommended as treatment. Clonazepam and Ginkgo biloba probably improve TD (Level B) and should be considered as treatment. Amantadine and tetrabenazine might be considered as TD treatment (Level C). Pallidal deep brain stimulation possibly improves TD and might be considered as a treatment for intractable TD (Level C). There is insufficient evidence to support or refute TS treatment by withdrawing causative agents or switching from typical to atypical DRBA (Level U).

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.

Valbenazine (Ingrezza®) is an orally bioavailable, selective and reversible vesicular monoamine transporter 2 (VMAT2) inhibitor that is indicated for the once-daily treatment of adults with tardive dyskinesia (TD) in the USA. By inhibiting VMAT2, thereby interfering with the presynaptic uptake and storage of dopamine and other monoamines, valbenazine is thought to counteract the heightened postsynaptic dopaminergic activity that is believed to cause TD. In adults with dopamine-receptor blocking agent-induced TD and underlying schizophrenia, schizoaffective disorder or mood disorder, valbenazine was associated with rapid, significant and sustained on-treatment improvements in TD severity relative to placebo. Somnolence is the most common treatment-emergent adverse event associated with valbenazine and, importantly, depression and extrapyramidal symptoms have not been associated with its use.

Tourette syndrome (TS) is a neurodevelopmental disorder of unknown etiology characterized by spontaneous, involuntary movements and vocalizations called tics. Once thought to be rare, TS affects 0.3–1% of the population. Tics can cause physical discomfort, emotional distress, social difficulties, and can interfere with education and desired activities. The pharmacologic treatment of TS is particularly challenging, as currently the genetics, neurophysiology, and neuropathology of this disorder are still largely unknown. However, clinical experience gained from treating TS has helped us better understand its pathogenesis and, as a result, derive treatment options. The strongest data exist for the antipsychotic agents, both typical and atypical, although their use is often limited in children and adolescents due to their side-effect profiles. There are agents in a variety of other pharmacologic categories that have evidence for the treatment of TS and whose side-effect profiles are more tolerable than the antipsychotics; these include clonidine, guanfacine, baclofen, topiramate, botulinum toxin A, tetrabenazine, and deutetrabenazine. A number of new agents are being developed and tested as potential treatments for TS. These include valbenazine, delta-9-tetrahydrocannabidiol, and ecopipam. Additionally, there are agents with insufficient data for efficacy, as well as agents that have been shown to be ineffective. Those without sufficient data for efficacy include clonazepam, ningdong granule, 5-ling granule, omega-3 fatty acids, and n-acetylcysteine. The agents that have been shown to be ineffective include pramipexole and metoclopramide. We will review all of the established pharmacologic treatments, and discuss those presently in development.

Tardive dyskinesia remains a significant, potentially stigmatizing or crippling adverse effect for any patient treated with an antipsychotic medication. While second- and third-generation antipsychotics have exhibited lower annual incidence rates for tardive dyskinesia than classic or first-generation agents, 3.9% versus 5.5%, the estimated incidence rate is only modestly lower. When coupled with the fact that second- and third-generation antipsychotic medications have come to be employed in treating a wider range of disorders (e.g., autism spectrum disorders, mood disorders, personality disorders, etc.), it is clear that the population of patients exposed to the risk of tardive dyskinesia has expanded. On April 3, 2017, the U.S. Food and Drug Administration (FDA) approved a deuterated version of tetrabenazine (Xenozine®) for the treatment of the involuntary choreic movements associated with Huntington's disease. More recent data, however, have indicated that deuterium tetrabenazine or deutetrabenazine (Austedo®) is effective in treating tardive dyskinesia. Moreover, like the other derivative of tetrabenazine, valbenazine (Ingrezza®), deutetrabenazine offers less frequent dosing and a better short-term adverse effect profile than that of tetrabenazine. Longer use in a broader range of patients, however, will be required to identify risks and benefits not found in short-term trials, as well as optimal use parameters for treatment of tardive dyskinesia.

AimsTardive dyskinesia (TD) is a disabling extra-pyramidal side effect (EPSE) associated with long-term antipsychotic medication, with an incidence rate of 5% per year of typical antipsychotic exposure. The Abnormal Involuntary Movement Scale (AIMS) is a validated tool for screening for TD and its use is recommended every 3–6 months in those taking antipsychotics. Atypical antipsychotics present a lower risk and have contributed to complacency in monitoring and treatment. The primary aim of this audit was to establish whether AIMS was completed for all patients taking regular antipsychotic medication for three months or more. Secondary aims were to investigate whether patients were informed about EPSEs on initiation, titration and change of antipsychotics, and whether they were assessed for the emergence of side effects during subsequent clinical reviews.MethodThis single-site audit examined the care of inpatients on Ward 4 of the Becklin Centre, a male working-age acute psychiatric ward, between 1st November 2020 and 31st January 2021. Patients aged 18–65 years who were prescribed regular antipsychotics were eligible for inclusion. Exclusion criteria included the presence of other neurological movement disorders. 50 patients were included. Data collection took place between 8th February and 6th March 2021; this involved reviewing patient records throughout their inpatient stay on Care Director, an electronic patient record system. Results were compiled using a pre-determined data collection tool and analysed using Microsoft Excel.ResultFor 14 (28.0%) patients there was documented evidence of the provision of verbal information surrounding EPSEs during initiation or change of antipsychotics, and 12 (24.0%) received written or verbal information about wider side effects. For 19 (38.0%) there was a documented assessment of side effects during clinical review following the initiation or change of antipsychotic medication. Of the 33 patients who took antipsychotics for over three months, 3 (9.1%) received an AIMS assessment.ConclusionAn inadequate proportion of inpatients prescribed long-term antipsychotics were assessed for TD, likely due to a lack of awareness of the relevant guidance. A substantial number of patients were not informed about side effects, suggesting an element of medical paternalism. This study provides opportunity to improve practice by educating the medical workforce and raising awareness of TD symptoms amongst the wider team. Valbenazine is a new FDA-approved treatment for adults with tardive dyskinesia, representing a further avenue for management. Greater focus on patient involvement, and communication surrounding anticipated side effects, is likely to benefit compliance with treatment and improve the doctor-patient relationship.

Dear Editor,We appreciate the interest from Xue et al. in our cost-effectiveness analysis of valbenazine versus deutetrabenazine for the treatment of tardive dyskinesia (TD)1, and are gratified tha...

Dear Editor,We read with great interest the study by Ganz et al.1, a cost-effectiveness analysis (CEA) of valbenazine versus deutetrabenazine for the treatment of tardive dyskinesia (TD) from a thi...

Tourette syndrome (TS) causes academic, social, emotional, physical, and functional problems. Most TS patients also have comorbid neuropsychological conditions. The purpose of this review is to provide updated information to the clinician about phenomenology, epidemiology, comorbidities, pathophysiology and management strategies for tics (a hallmark of TS) and TS. Recent findings suggest that TS is likely due to a combination of several different genes and environmental factors, with possible involvement of the cortical-basal ganglia-thalamocortical circuit and related multiple neurotransmitters. First-line management includes psychoeducation for families, patients, and school personnel, as well as behavioral therapy. Non-medicine treatment for tics is advancing to include younger children and increase access via remote service applications. Pharmacotherapy is used if appropriate and several new medicines are under investigation (e.g., Tetrabenazine, valbenazine, deutetrabenazine, ecopipam, cannabinoids). Deep brain stimulation and Mouthguard therapy can be used for children with intractable illness.

Tardive dyskinesia (TD) has long been thought to be a generally irreversible consequence of the use of dopamine receptor blocking agents. There is now an opportunity to successfully manage this condition with agents approved by the US Food and Drug Administration. This is important because TD has not been eliminated with the use of second-generation antipsychotics, and the expansion of antipsychotics to treat conditions other than schizophrenia has resulted in millions of additional individuals at risk for developing TD. Recognition of TD requires careful observation; a structured approach using the Abnormal Involuntary Movement Scale is encouraged. Harm reduction can be achieved by using antipsychotics judiciously when possible and by paying attention to other modifiable risk factors such as drug-induced parkinsonian symptoms and the use of anticholinergic medication. Once TD has emerged and is associated with dysfunction or distress, treatment with a VMAT2 inhibitor such as deutetrabenazine or valbenazine is well supported by several controlled clinical trials.

Introduction Valbenazine is a novel vesicular monoamine transporter 2 inhibitor approved for the treatment of tardive dyskinesia in adults. Objective 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. Methods 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. Results 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. Conclusions 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.

​​ Tardive dyskinesia (TD) is a disorder characterized by involuntary movements, typically of the orofacial muscles and also of the extremities and other muscle groups. The condition is associated with exposure to dopamine receptor blocking agents, including antipsychotics. Because the indications and off-label uses for these agents have expanded over the last 2 decades, a larger number of patients are receiving antipsychotic medications than in the past. While evidence suggests that patients being treated with second-generation antipsychotics have less risk for developing TD than those treated with first-generation antipsychotics, the decreased risk is not as great as was originally expected. In addition, patients with chronic psychiatric conditions often require long-term use of antipsychotics, putting them at risk for TD. This article addresses the prevalence, risk factors, and prevention of TD; assessment strategies including diagnostic criteria and rating scales; and evidence for TD treatments, including 2 newly approved medications: deutetrabenazine and valbenazine. ​​​.

Objective To provide information on the most important properties of new therapeutic agents marketed in 2017. Data sources Product labeling supplemented selectively with published studies and drug information reference sources. Data synthesis Seven new therapeutic agents marketed in the United States in early 2017 are considered in this first part of a series: ocrelizumab, safinamide mesylate, edaravone, valbenazine tosylate, deutetrabenazine, crisaborole, and dupilumab. Indications, mechanisms of action, and information on dosage and administration for these new agents are reviewed, as are the most important pharmacokinetic properties, adverse events, and other risks and precautions. The new drugs are compared with older drugs marketed for the same indications, and advantages and disadvantages are identified. Summary Ocrelizumab is the first drug shown to be effective in the treatment of primary progressive multiple sclerosis and is more effective than interferon beta-1a in the treatment of relapsing multiple sclerosis. Safinamide is the third monoamine oxidase type B inhibitor for the treatment of patients with Parkinson disease, joining rasagiline and selegilene. Edaravone is only the second drug to be approved for the treatment of amyotrophic lateral sclerosis (ALS), joining riluzole, and has been reported to slow the worsening of ALS symptoms. Valbenazine is the first drug demonstrated to be effective for the treatment of tardive dyskinesia, a neurological disorder that is most often experienced by patients treated for long periods with antipsychotic medications. Deutetrabenazine is the deuterated form of tetrabenazine in which deuterium, the "heavy hydrogen" isotope of regular hydrogen, is used instead of hydrogen in two of the substituent groups. Both agents are used to treat chorea associated with Huntington disease, but deutetrabenazine has a longer duration of action, may be administered less frequently, and may be better tolerated. Crisaborole joins the topical corticosteroids and topical calcineurin inhibitors as options for the topical treatment of mild to moderate atopic dermatitis. Dupilumab, which inhibits interleukins 4 and 13, is administered subcutaneously for the treatment of adults with moderate to severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

Background 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. Methods 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. Results 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. Conclusions 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.

Summary Background Tardive dyskinesia results from exposure to dopamine receptor antagonists, such as typical and atypical antipsychotics. If clinically appropriate, clinicians often manage this disorder by lowering the dose of, or discontinuing, the causative drug. There is a significant unmet need for a treatment option that does not disrupt treatment regimens for underlying psychiatric illnesses. We aimed to assess the efficacy, safety, and tolerability of fixed doses of deutetrabenazine—a novel vesicular monoamine transporter-2 inhibitor—in patients with tardive dyskinesia. Methods We did this double-blind, randomised, placebo-controlled, phase 3 trial at 75 centres in the USA and Europe. Patients aged 18–80 years with tardive dyskinesia (≥3 months before screening) were randomly assigned centrally (1:1:1:1), via interactive response technology, to receive one of three fixed doses of deutetrabenazine (12 mg/day, 24 mg/day, or 36 mg/day) or matching placebo. Randomisation was stratified by baseline use of dopamine receptor antagonists. Patients were started on oral deutetrabenazine 12 mg/day, and this dose was increased through week 4 until the randomised dose was achieved, then maintained over 8 weeks. During the treatment period, patients, investigators, their site personnel, and sponsor were masked to group assignment. The primary efficacy endpoint was change in Abnormal Involuntary Movement Scale (AIMS) score from baseline to week 12 in patients with at least one post-baseline rating. The primary efficacy analysis was done in the modified intention-to-treat population (baseline AIMS score ≥6 and at least one post-baseline rating). The safety analysis was done in patients who received any study drug. This trial is registered with ClinicalTrials.gov, number NCT02291861. Findings Between Oct 29, 2014, and Aug 19, 2016, we randomly assigned 298 patients to receive at least one dose of placebo (n=74), deutetrabenazine 12 mg/day (n=75), 24 mg/day (n=74), or 36 mg/day (n=75); 222 patients comprised the modified intention-to-treat population and 293 patients comprised the safety population. From baseline to week 12, the least-squares mean AIMS score improved by −3·3 points (SE 0·42) in the deutetrabenazine 36 mg/day group, −3·2 points (0·45) in the 24 mg/day group, and −2·1 points (0·42) in the 12 mg/day group, with a treatment difference of −1·9 points (SE 0·58, 95% CI −3·09 to −0·79; p=0·001), −1·8 points (0·60, −3·00 to −0·63; p=0·003), and −0·7 points (0·57, −1·84 to 0·42; p=0·217), respectively, versus −1·4 points (0·41) in the placebo group. The rate of adverse events was similar between patients in the deutetrabenazine 36 mg/day group (n=38/74 [51%]), 24 mg/day group (n=32/73 [44%]), and 12 mg/day group (n=36/74 [49%]), and those in the placebo group (n=34/72 [47%]). Serious adverse events were reported in four (5%) patients given deutetrabenazine 36 mg/day, six (8%) patients given 24 mg/day, and two (3%) patients given 12 mg/day, compared with four (6%) patients given placebo. Two (1%) patients in the safety population died, one each in the deutetrabenazine 24 mg/day and 36 mg/day groups; neither death was deemed related to study drug by the investigator or sponsor. Interpretation Deutetrabenazine 24 mg/day and 36 mg/day provided a significant reduction in tardive dyskinesia, with favourable safety and tolerability. These findings suggest that dosing regimens could be individualised and tailored for patients on the basis of dyskinesia control and tolerability. Funding Teva Pharmaceutical Industries.