Treatment Of Tardive Dyskinesia Research Articles

A Bioequivalence Comparison Between the Once-Daily Extended-Release Tablet and the Twice-Daily Tablet Formulations of Deutetrabenazine at Steady State.

Deutetrabenazine is approved for the treatment of tardive dyskinesia and chorea associated with Huntington's disease. This study compared the exposure between the once-daily (test) and twice-daily (reference) formulations of deutetrabenazine under fed conditions. Using a randomized crossover design, healthy adults (n = 262) received the 24mg of the test formulation once daily and 12 mg of the reference formulation twice daily, each for 7days. Plasma concentrations were collected on Days 4-6 before dose intake, and frequently for pharmacokinetic evaluation on Days 6 and 7 for determination of deutetrabenazine and active metabolites, deuterated α-dihydrotetrabenazine (α-HTBZ) and β-dihydrotetrabenazine (β-HTBZ). Geometric mean ratios (GMRs, test/reference) were computed for all analytes, and bioequivalence was tested for area under the plasma concentration-time curve over 24 hours at steady state (AUC0-24h,ss ) and for maximum plasma concentrations at steady state (Cmax,ss ). The GMRs for AUC0-24h,ss were 115% for deutetrabenazine and 95% for deuterated total (α+β)-HTBZ; and the GMR for Cmax,ss for deutetrabenazine was 95%. Relative bioavailability was assessed for Cmax,ss of the active metabolites; the GMR was 78% for total (α+β)-HTBZ. At steady state, deutetrabenazine administered as the once-daily formulation was bioequivalent to the twice-daily formulation for both AUC and Cmax, and the active metabolites were bioequivalent with regard to AUC0-24h,ss .

Practical Synthesis of Valbenazine via 1,3‐Dipolar Cycloaddition†

Comprehensive SummaryValbenazine (Ingrezza), a potent and highly selective inhibitor of vesicular monoamine transporter type 2 (VMAT2) through the active metabolite hydrotetrabenazine (HTBZ), has been approved for the treatment of tardive dyskinesia and, very recently, for chorea, which is associated with Huntington's disease. Despite numerous synthetic efforts dedicated to the synthesis of HTBZ, the industrial preparation of valbenazine uses dihydroisoquinoline as a starting material and the chiral resolution of racemic HTBZ derived from ketone reduction. Herein, we present a practical synthesis of HTBZ and valbenazine featuring a highly stereoselective 1,3‐dipolar cycloaddition and enzymatic kinetic resolution. The cascade process includes cycloaddition, N—O bond cleavage, and lactamization, which proved to be operationally simple. The allure of the enzymatic resolution developed in this work offers a rapid access toward affording tetrahydroisoquinoline (THIQ)‐fused piperidine in the production of medically significant compounds, such as yohimbine and reserpine.

Exploring real-world symptom impact and improvement in well-being domains for tardive dyskinesia in VMAT2 inhibitor-treated patients via clinician survey and chart review.

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

Historical developments, hotspots, and trends in tardive dyskinesia research: a scientometric analysis of 54 years of publications.

Since being recognized as an important drug-induced clinical entity during the 1960s, tardive dyskinesia (TD) has generated an extensive body of research seeking to understand its clinical characteristics, epidemiology, pathophysiology and management. Modern scientometric approaches allow interactive visualization of large bodies of literature to identify trends and hotspots within knowledge domains. This study thus aimed to provide a comprehensive scientometric review of the TD literature. Web of Science was searched for articles, reviews, editorials and letters with the term "tardive dyskinesia" in the title, abstract, or keywords through 12/31/2021. A total of 5,228 publications and 182,052 citations were included. Annual research output, prominent research areas, authors, affiliations and countries were summarized. VOSViewer and CiteSpace were used for bibliometric mapping and co-citation analysis. Structural and temporal metrics were used to identify key publications in the network. TD-related publications peaked in the 1990s, gradually declined after 2004, and showed a further small increase after 2015. The most prolific authors were Kane JM, Lieberman JA, and Jeste DV overall (1968-2021), and Zhang XY, Correll CU and Remington G in the last decade (2012-2021). The most prolific journal was the Journal of Clinical Psychiatry overall, and the Journal of Psychopharmacology in the last decade. Knowledge clusters in the 1960-1970s dealt with clinical and pharmacological characterization of TD. In the 1980s, epidemiology, clinical TD assessment, cognitive dysfunction and animal models predominated. During the 1990s, research diverged into pathophysiological studies, especially oxidative stress, and clinical trials on atypical antipsychotics, with a focus on clozapine and bipolar disorder. In the 1990-2000s, pharmacogenetics emerged. More recent clusters include serotonergic receptors, dopamine-supersensitivity psychosis, primary motor abnormalities of schizophrenia, epidemiology/meta-analyses, and advances in TD treatment, particularly vesicular monoamine transporter-2 inhibitors since 2017. This scientometric review visualized the evolution of scientific knowledge on TD over more than five decades. These findings will be useful for researchers to find relevant literature when writing scientific articles, choosing appropriate journals, finding collaborators or mentors for research, and to understand the historical developments and emerging trends in TD research.

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

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

Safety and efficacy of valbenazine for the treatment of chorea associated with Huntington's disease (KINECT-HD): a phase 3, randomised, double-blind, placebo-controlled trial

Valbenazine is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for treatment of tardive dyskinesia. To address the ongoing need for improved symptomatic treatments for individuals with Huntington's disease, valbenazine was evaluated for the treatment of chorea associated with Huntington's disease. KINECT-HD (NCT04102579) was a phase 3, randomised, double-blind, placebo-controlled trial, performed in 46 Huntington Study Group sites in the USA and Canada. The study included adults with genetically confirmed Huntington's disease and chorea (Unified Huntington's Disease Rating Scale [UHDRS] Total Maximal Chorea [TMC] score of 8 or higher) who were randomly assigned (1:1) via an interactive web response system (with no stratification or minimisation) to oral placebo or valbenazine (≤80 mg, as tolerated) for 12 weeks of double-blinded treatment. The primary endpoint was a least-squares mean change in UHDRS TMC score from the screening and baseline period (based on the average of screening and baseline values for each participant) to the maintenance period (based on the average of week 10 and 12 values for each participant) in the full-analysis set using a mixed-effects model for repeated measures. Safety assessments included treatment-emergent adverse events, vital signs, electrocardiograms, laboratory tests, clinical tests for parkinsonism, and psychiatric assessments. The double-blind placebo-controlled period of KINECT-HD has been completed, and an open-label extension period is ongoing. KINECT-HD was performed from Nov 13, 2019, to Oct 26, 2021. Of 128 randomly assigned participants, 125 were included in the full-analysis set (64 assigned to valbenazine, 61 assigned to placebo) and 127 were included in the safety-analysis set (64 assigned to valbenazine, 63 assigned to placebo). The full-analysis set included 68 women and 57 men. Least-squares mean changes from the screening and baseline period to the maintenance period in the UHDRS TMC score were -4·6 for valbenazine and -1·4 for placebo (least-squares mean difference -3·2, 95% CI -4·4 to -2·0; p<0·0001). The most commonly reported treatment-emergent adverse event was somnolence (ten [16%] with valbenazine, two [3%] with placebo). Serious treatment-emergent adverse events were reported in two participants in the placebo group (colon cancer and psychosis) and one participant in the valbenazine group (angioedema because of allergic reaction to shellfish). No clinically important ch anges in vital signs, electrocardiograms, or laboratory tests were found. No suicidal behaviour or worsening of suicidal ideation was reported in participants treated with valbenazine. In individuals with Huntington's disease, valbenazine resulted in improvement in chorea compared with placebo and was well tolerated. Continued research is needed to confirm the long-term safety and effectiveness of this medication throughout the disease course in individuals with Huntington's disease-related chorea. Neurocrine Biosciences.

A Bioequivalence Comparison at Steady State between the Newly Developed Once-Daily Extended Release Tablet Formulation and the Approved Twice-Daily Tablet Formulation of Deutetrabenazine (P2-11.015)

<h3>Objective:</h3> To assess the bioequivalence (BE) and relative bioavailability (BA) between a once-daily (QD) extended release formulation of deutetrabenazine and the approved twice-daily (BID) formulation at steady state under fed conditions. <h3>Background:</h3> Deutetrabenazine (Austedo, Teva) in a BID formulation is an approved treatment for tardive dyskinesia and chorea associated with Huntington disease. A QD formulation has been developed. <h3>Design/Methods:</h3> In a phase 1 study (TV50717-BE-10179) using a randomized cross-over design, healthy adult males and females (n=262) received 24 mg QD formulation (test) as a once daily administration and 12 mg BID formulation (reference) as a twice daily administration, each for 7 days in fed state. Safety was assessed throughout the study and pharmacokinetic (PK) blood sampling occurred on days 4–7. Test-to-reference geometric mean ratios (GMRs) and 90%CIs for BE acceptance limits (80.00% to 125.00%) were computed for PK parameters (area under the plasma concentration curve over 24-hours at steady-state [AUC_0–24hr,ss] and maximum plasma concentration at steady-state [C_max,ss]) of deutetrabenazine, active metabolites, deuterated α-HTBZ and β-HTBZ, and total (α+β)-HTBZ. Relative BA was assessed for C_max,ss of the active metabolites (individually and as a total sum). <h3>Results:</h3> The GMRs (90%CIs) for AUC_0–24hr,ss were 115.15% (110.38–120.14%) for deutetrabenazine, 95.40% (94.13–96.69%) for α-HTBZ, 94.13% (92.35–95.94%) for β-HTBZ, and 95.05% (93.67–96.46%) for total (α+β)-HTBZ. GMRs of C_max,ss were 95.09% (90.60–99.80%) for deutetrabenazine, 79.56% (78.21–80.94%) for α-HTBZ, 74.85% (73.13–76.60%) for β-HTBZ and 77.71% (76.26–79.16%) for total (α+β)-HTBZ. No new safety findings emerged in this study. <h3>Conclusions:</h3> At steady state, deutetrabenazine administered as the QD formulation was bioequivalent to the approved BID formulation for both AUC and C_max. The active metabolites at steady state were bioequivalent with regard to AUC between the QD and BID formulation; C_max was slightly lower for the QD formulation compared to the BID formulation. <b>Disclosure:</b> Dr. Sunzel has received personal compensation for serving as an employee of Teva Pharmaceuticals. Dr. Sunzel has stock in Teva Pharmaceuticals. An immediate family member of Dr. Sunzel has stock in Incyte. Laura Rabinovich-Guilatt has received personal compensation for serving as an employee of Teva Pharmaceuticals. Laura Rabinovich-Guilatt has stock in Teva Pharmaceuticals. Ms. Iyengar has received personal compensation for serving as an employee of Teva. Ms. Iyengar has stock in Teva. Mrs. Ruffo has nothing to disclose. Dr. Gutierrez has stock in Teva. Dr. Gordon has received personal compensation for serving as an employee of Teva. Dr. Gordon has stock in Teva. Dr. Ghibellini has received personal compensation for serving as an employee of Teva Pharmaceutical. Dr. Ghibellini has stock in Teva Pharmaceuticals.

Global Improvements and Psychiatric Stability in Adults with Tardive Dyskinesia: Post Hoc Analyses of Two Long-Term Valbenazine Studies (P11-11.010)

Global Improvements and Psychiatric Stability in Adults with Tardive Dyskinesia: Post Hoc Analyses of Two Long-Term Valbenazine Studies (P11-11.010)

Sustained Treatment Response With Long-Term Valbenazine in Patients With Tardive Dyskinesia

AbstractBackgroundValbenazine is a once-daily VMAT2 inhibitor approved for the treatment of tardive dyskinesia (TD), a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotics, antiemetics, and other dopamine receptor blocking agents. The efficacy, safety, and tolerability of valbenazine has been established in several phase 3 trials, including a long-term study (KINECT 4 [NCT02405091]) in which participants received open-label valbenazine (40 or 80 mg) for 48 weeks. Post hoc analyses of KINECT 4 data were conducted to assess patterns of treatment response.MethodsData from KINECT 4 treatment completers (participants who reached the Week 48 visit and had the longest duration of treatment) were analyzed post hoc. TD was assessed using the Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1–7, as rated by the study investigator), the Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD), and the Patient Global Impression of Change (PGIC). Analyses were conducted at Week 8 (first study visit after the valbenazine dose-optimization period) and Week 48 using the following definitions of response: ≥50% and ≥70% improvement from baseline in AIMS total score; rating of “much improved” or “very much improved” (score ≤2) on the CGI-TD and PGIC.ResultsOf the 167 participants who entered KINECT 4, 103 (62%) were treatment completers and included for analysis. Of these 103 participants, 39% and 86% met the ≥50% AIMS response threshold at Weeks 8 and 48, respectively. The percentages of participants who met the highly rigorous AIMS ≥70% response threshold at Weeks 8 and 48 were 17% and 52%, respectively. Of the 40 participants with AIMS ≥50% total score improvement at Week 8, 95% also met this threshold at Week 48 (“sustained response”). Of the 63 participants with &lt;50% AIMS improvement at Week 8, 81% achieved the ≥50% response threshold by end of treatment at Week 48. The proportion of participants meeting the threshold for CGI-TD response also increased over time, from 50% at Week 8 to 92% at Week 48. PGIC results were similar, with response rates of 53% and 88% at Weeks 8 and 48, respectively.ConclusionsPost hoc analyses of data from a 48-week, open-label study of once-daily valbenazine showed that the proportion of participants meeting rigorous treatment response thresholds increased over time. By the end of treatment at Week 48, &gt;80% of participants demonstrated robust improvements in TD, as assessed using the AIMS (≥50% improvement), CGI-TD (score ≤2), and PGIC (score ≤2).FundingNeurocrine Biosciences, Inc.

Med Check: FDA Actions on Xylazine, Austedo XR, and Zuranolone

Back to table of contents Previous article Next article Med CheckFull AccessMed Check: FDA Actions on Xylazine, Austedo XR, and ZuranoloneTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:23 Mar 2023https://doi.org/10.1176/appi.pn.2023.05.4.1FDA Aims to Curtail Illegal Importation of XylazineThe U.S. Food and Drug Administration (FDA) has taken action to restrict the illegal entry of xylazine ingredients and drug products into the country, according to an announcement released in February. Xylazine is a veterinary medication used to sedate large animals such as horses and deer. However, it has increasingly been found in illicit drugs such as illicitly manufactured fentanyl, and xylazine-related overdose deaths have risen in recent years (Psychiatric News, “Xylazine Increasingly Found in Overdose Deaths”).The FDA’s actions include heightened scrutiny of imports of drugs containing xylazine into the country, and FDA staff may detain shipments if they appear to violate the law. When FDA staff conduct entry reviews of xylazine, they will consider specific evidence offered by importers that the incoming product is properly labeled, not adulterated, and for legitimate veterinary use.According to the announcement, the FDA and its Office of Criminal Investigations are collaborating with federal, state, and local partners to investigate xylazine-related activities that could be subject to criminal prosecution, including online and in-person conduct. The FDA said it is coordinating with stakeholders in animal health to ensure that drugs containing xylazine are available to veterinarians for legitimate use.SAMHSA Publishes Advisory About Cannabidiol ProductsIn February the Substance Abuse and Mental Health Services Administration (SAMHSA) published an advisory about the potential harms, side effects, and unknowns of cannabidiol (CBD).The advisory covers how CBD is derived and how it differs from delta-9-tetrahydrocannabinol (THC). The advisory also explains that CBD products that are not approved do not have to meet any standards for content or potency (Psychiatric News, “Most OTC Cannabinoid Products Mislabeled”). It notes that the FDA has not approved CBD products to be marketed as food additives or dietary supplements and that the FDA has concluded that a new regulatory pathway is needed for CBD products.The advisory provides tips and action steps for health professionals, parents, caregivers, and the general public to take regarding education and awareness of the risk of CBD products.Austedo XR Approved for Treating Tardive Dyskinesia and Huntington’s ChoreaThe FDA has approved Austedo XR (deutetrabenazine extended-release tablets) for the treatment of tardive dyskinesia and chorea associated with Huntington’s disease in adults, Teva Pharmaceuticals announced in February. Austedo XR is taken once per day, compared with Austedo, which is taken twice per day. It will be available in three strengths: 6 mg, 12 mg, and 24 mg, and can be taken with or without food. The same total daily dosage can be used when switching between Austedo tablets and Austedo XR tablets.Austedo XR comes with a boxed warning about depression and suicidality in patients with Huntington’s disease. The warning instructs health professionals who prescribe the medication to monitor patients who take Austedo for the emergence or worsening of depression, suicidality, or changes in behavior. It also instructs health professionals to inform patients, caregivers, and families of the risk of depression and suicidality.FDA Grants Zuranolone Priority Review for Major Depression and Postpartum DepressionThe FDA has granted zuranolone priority review for the treatment of major depressive disorder (MDD) and postpartum depression (PPD), Sage Therapeutics announced in February. Zuranolone is an investigational drug being evaluated as a 14-day, rapid-acting, once-daily, oral treatment in adults with MDD and PPD.In the WATERFALL trial, 543 adults aged 18 to 64 years with MDD received either 50 mg of zuranolone or placebo daily for 14 days. All patients in the study had a Hamilton Rating Scale for Depression (HAMD-17) total score of at least 24 when they enrolled in the study. By day 15 of the trial, patients who took zuranolone had experienced an average drop of 14.1 points on the HAMD-17, compared with an average drop of 12.3 points in those who took placebo.In the SKYLARK trial, 195 women with PPD were randomized to take either 50 mg of zuranolone or placebo once per night for 14 days. On Day 15, scores on the 17-item Hamilton Rating Scale for Depression dropped a mean of 15.6 points among women who took zuranolone compared with a mean decrease in score of 11.6 points among women who took placebo.The FDA’s decision on whether to approve zuranolone for major depressive disorder and postpartum depression is expected by August 5. ■ ISSUES NewArchived

Treatment of tardive dyskinesias with vitamin E: A case series

IntroductionTardive dyskinesia is usually persistent, irreversible involuntary movement of the tongue, lips, face, trunk and extremities in patients taking long-term dopaminergic antagonist drugs. Although it is mostly associated with the use of neuroleptics, cases of tardive dyskinesia existed before the discovery of these agents. Patients with schizophrenia and other neuropsychiatric disorders are particularly at risk for tardive dyskinesia because they are exposed to neuroleptics and anticholinergic agents for longer periods than healthy individuals. Free radicals are thought to be probably involved in the pathogenesis of tardive dyskinesia. Vitamin E is a fat-soluble antioxidant, and it is thought to be effective in the treatment of antipsychotic-associated tardive dyskinesia, as it has a cytotoxic free radical-binding effect.ObjectivesIn this poster presentation, it was aimed to evaluate the clinical results of the treatment of tardive dyskinesia with high-dose vitamin E in four inpatients with serious mental illness and long-term antipsychotic use. In addition, the treatment of tardive dyskinesia will be discussed in the light of current literature data.MethodsIn the case report, there are three patients with schizophrenia and one with mild mental retardation. They were treated with 1600 IU of vitamin E per day. The patients continued their vitamin E treatment for 90 days. The severity of tardive dyskinesia of the patients was measured by Abnormal Involuntary Movement Scale (AIMS).ResultsAt the end of the 90 day treatment, the AIMS measurements of the subjects decreased 72,7%, 73,3%, 72,2% and 80% respectively.Image:ConclusionsIn our clinic, we observed that patients using long-term typical antipsychotics were prescribed antipsychotics in unindicated situations or in high doses, patients with high risk for tardive dyskinesia were not taken into consideration when planning treatment, and we encountered cases of tardive dyskinesia despite the widespread use of atypical antipsychotic drugs in hospitalized patients. The use of benzodiazepines is restricted especially in elderly individuals due to their side effects and the risk of addiction in long-term use. Although the clinical importance of vitamin E is unknown, it is preferred because it can be used with a low risk of side effects, considering that it can prolong bleeding time. Although the results of a review of tardive dyskinesia treatment do not suggest that vitamin E reliably improves tardive dyskinesia symptoms, our experience shows that patients benefit from vitamin E treatment. In this regard, there is a need for studies that will be conducted with a large sample and compare the effectiveness of vitamin E with the treatments known to be effective in tardive dyskinesia.Disclosure of InterestNone Declared

Deep Brain Stimulation in the Treatment of Tardive Dyskinesia

Tardive dyskinesia (TD) is a phenomenon observed following the predominantly long-term use of dopamine receptor blockers (antipsychotics) widely used in psychiatry. TD is a group of involuntary, irregular hyperkinetic movements, mainly in the muscles of the face, eyelid, lips, tongue, and cheeks, and less frequently in the limbs, neck, pelvis, and trunk. In some patients, TD takes on an extremely severe form, massively disrupting functioning and, moreover, causing stigmatization and suffering. Deep brain stimulation (DBS), a method used, among others, in Parkinson's disease, is also an effective treatment for TD and often becomes a method of last resort, especially in severe, drug-resistant forms. The group of TD patients who have undergone DBS is still very limited. The procedure is relatively new in TD, so the available reliable clinical studies are few and consist mainly of case reports. Unilateral and bilateral stimulation of two sites has proven efficacy in TD treatment. Most authors describe stimulation of the globus pallidus internus (GPi); less frequent descriptions involve the subthalamic nucleus (STN). In the present paper, we provide up-to-date information on the stimulation of both mentioned brain areas. We also compare the efficacy of the two methods by comparing the two available studies that included the largest groups of patients. Although GPi stimulation is more frequently described in literature, our analysis indicates comparable results (reduction of involuntary movements) with STN DBS.

Enhancement of adenosine A2A signaling improves dopamine D2 receptor antagonist-induced dyskinesia via β-arrestin signaling.

Repeated administration of dopamine D2 receptor (D2R) antagonists, which is the treatment for psychosis, often causes tardive dyskinesia (TD). Despite notable clinical demand, effective treatment for TD has not been established yet. The neural mechanism involving the hyperinhibition of indirect pathway medium spiny neurons (iMSNs) in the striatum is considered one of the main causes of TD. In this study, we focused on adenosine A2A receptors (A2ARs) expressed in iMSNs and investigated whether pharmacological activation of A2ARs improves dyskinetic symptoms in a TD mouse model. A 21-day treatment with haloperidol increased the number of vacuous chewing movements (VCMs) and decreased the number of c-Fos+/ppENK+ iMSNs in the dorsal striatum. Haloperidol-induced VCMs were reduced by acute intraperitoneal administration of an A2AR agonist, CGS 21680A. Consistently, haloperidol-induced VCMs and decrease in the number of c-Fos+/ppENK+ iMSNs were also mitigated by intrastriatal injection of CGS 21680A. The effects of intrastriatal CGS 21680A were not observed when it was concomitantly administered with a β-arrestin inhibitor, barbadin. Finally, intrastriatal injection of an arrestin-biased D2R agonist, UNC9994, also inhibited haloperidol-induced VCMs. These results suggest that A2AR agonists mitigate TD symptoms by activating striatal iMSNs via β-arrestin signaling.

Pharmacokinetics, safety and tolerability of valbenazine in Korean CYP2D6 normal and intermediate metabolizers.

Valbenazine is a selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for tardive dyskinesia treatment by the US Food and Drug Administration; its major active metabolite (NBI-98782) is a 45-fold more potent inhibitor of VMAT2 than the parent drug. This study aimed to evaluate the pharmacokinetics (PKs), safety, and tolerability and the effect of cytochrome P450 2D6 (CYP2D6) genotypes to the PKs after the administration of valbenazine in Korean participants. A randomized, double-blind, placebo-controlled, single- and multiple-dose study was conducted in healthy Korean male participants. The single-dose study was conducted for both 40 and 80 mg valbenazine and the multiple dose study was conducted for 40 mg. After a 1-week washout, the 40 mg dose group participants received valbenazine 40 mg or placebo once daily for 8 days. Serial blood samples were collected up to 96 h postdose for PK analysis. The CYP2D6 genotypes of the participants were retrospectively analyzed. A total of 50 participants were randomized, and 43 and 20 participants completed the single- and multiple-dose phases of the study, respectively. After single doses, the PK characteristics of valbenazine and its metabolites were similar between the 40 and 80 mg dose groups. After multiple doses, the mean accumulation ratios of valbenazine and NBI-98782 were ~1.6 and 2.4, respectively. Plasma concentrations of valbenazine and NBI-98782 were similar between CYP2D6 normal and intermediate metabolizers. Valbenazine was well-tolerated in healthy Koreans, and its PK characteristics were similar to results previously reported in Americans.

HSD79 Physicians’ Experience and Perceptions of Tetrabenazine for the Treatment of Tardive Dyskinesia

HSD79 Physicians’ Experience and Perceptions of Tetrabenazine for the Treatment of Tardive Dyskinesia

Inhibition of VMAT2 by β2-adrenergic agonists, antagonists, and the atypical antipsychotic ziprasidone

Vesicular monoamine transporter 2 (VMAT2) is responsible for packing monoamine neurotransmitters into synaptic vesicles for storage and subsequent neurotransmission. VMAT2 inhibitors are approved for symptomatic treatment of tardive dyskinesia and Huntington’s chorea, but despite being much-studied inhibitors their exact binding site and mechanism behind binding and inhibition of monoamine transport are not known. Here we report the identification of several approved drugs, notably β2-adrenergic agonists salmeterol, vilanterol and formoterol, β2-adrenergic antagonist carvedilol and the atypical antipsychotic ziprasidone as inhibitors of rat VMAT2. Further, plausible binding modes of the established VMAT2 inhibitors reserpine and tetrabenazine and hit compounds salmeterol and ziprasidone were identified using molecular dynamics simulations and functional assays using VMAT2 wild-type and mutants. Our findings show VMAT2 as a potential off-target of treatments with several approved drugs in use today and can also provide important first steps in both drug repurposing and therapy development targeting VMAT2 function.

A new era in the diagnosis and treatment of tardive dyskinesia.

Tardive dyskinesia (TD) is a heterogeneous, hyperkinetic movement disorder induced by dopamine-receptor blocking agents that presents a unique challenge in the treatment of psychosis. Although acceptance of TD as a serious consequence of antipsychotic treatment was resisted initially, subsequent research by many investigators in psychopharmacology contributed to a rich store of knowledge on many aspects of the disorder. While basic neuroscience investigations continue to deepen our understanding of underlying motor circuitry, past trials of potential treatments of TD focusing on a range of theoretical targets were often inconclusive. Development of newer antipsychotics promised to reduce the risk of TD compared to older drugs, but their improved tolerability unexpectedly enabled an expanding market that paradoxically both increased the absolute number of patients at risk and diminished attention to TD which was relegated to legacy status. Fortunately, development and approval of novel vesicular monoamine transporter inhibitors offered evidence-based symptomatic treatment of TD for the first time and rekindled interest in the disorder. Despite recent progress, many questions remain for future research including the mechanisms underlying TD, genetic predisposition, phenomenological diversity, whether new cases are reversible, how to implement best practices to prevent and treat TD, and whether the development of novel antipsychotics free of the risk of TD is attainable. We owe our patients the aspirational goal of striving for zero prevalence of persistent symptoms of TD in anyone treated for psychosis.

Treatment of Tardive Dyskinesia with High Dose Vitamin B6 Associated with Depression

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

Clinical Diagnosis and Treatment of Tardive Dyskinesia

Clinical Diagnosis and Treatment of Tardive Dyskinesia

Prevalence of Tardive Dyskinesia in an Electronic Medical Record Study at a Large Community Mental Health Treatment Center.

Objective: To determine the prevalence of tardive dyskinesia (TD) identified by clinicians in naturalistic data in a real-world treatment setting.Methods: Electronic medical record data were analyzed from a single large community mental health treatment center for all psychiatric provider encounters of 120,431 unique adult and child patients during a 5-year period from January 2013 through December 2017, focusing on clinician-identified TD in patients prescribed antipsychotic medication.Results: Only half of the antipsychotic-prescribed patients had Abnormal Involuntary Movement Scale (AIMS) information recorded in their medical records, and only 1% of those with AIMS data had a positive AIMS identifying TD. AIMS testing represented the largest source of all identified TD in these patients, but only one-third of the patients with a positive AIMS in the record had a clinical diagnosis of TD recorded in the prescriber's diagnostic impression list from billing code data. The clinical identification of only 1% of antipsychotic-prescribed patients with TD in this study is far below generally established TD prevalence estimates of previous research. An important methodological contributor to this discrepancy is generation of the data by treating clinicians in this study who greatly under identified TD relative to systematic research methodology.Conclusions: Given the recent availability of US Food and Drug Administration-approved pharmaceutical agents for treatment of TD, it is now more important than ever to identify and intervene in TD. Agency-wide policies and procedures can be established to ensure that TD assessments are systematically conducted with regularity and accuracy among all antipsychotic-prescribed patients.