Use of Tetrabenazine in Huntington Disease Patients on Antidepressants or with Advanced Disease: Results from the TETRA-HD Study
Neurologist, Johns Hopkins University PLoS Currents
11/2011; 3:RRN1283. DOI: 10.1371/currents.RRN1283
Background: The safety and effectiveness of tetrabenazine in different sub-populations of Huntington disease (HD) is not known. We evaluated its safety in individuals on an antidepressant and its effectiveness in advanced HD.
Methods: The TETRA-HD study was a randomized, placebo-controlled, double-blind study of 84 individuals with HD who were randomized 2:1 to receive tetrabenazine (54 participants) or placebo (30 participants). We used data from the 12-week randomized controlled study of tetrabenazine to evaluate the incidence of depressed mood either as an adverse event or as a two points or greater worsening on the “depressed mood” item of the Unified Huntington Disease Rating Scale. We also evaluated the effectiveness of tetrabenazine in reducing chorea in advanced HD. Advanced HD was defined as a baseline maximum total chorea score of 19 or greater or as a total functional capacity score of seven or less. Only individuals who were randomized to tetrabenazine (n=54) were included in these analyses.
Results:At baseline, 27 (56%) of the 48 participants randomized to tetrabenazine who completed the trial were taking an antidepressant. The incidence of depressed mood did not differ between those taking (15%) and not taking (5%) an antidepressant (p=0.37), and the proportion of individuals experiencing a substantial worsening in their mood scores also did not differ (7% v. 10%; p=1.00).
Based on chorea, 14 of the 54 (26%) tetrabenazine participants enrolled had advanced HD, and based on function, 22 (41%) had advanced HD. Chorea declined by 8.1 units among those with baseline scores 19 or greater compared to 4.3 units for those with scores under 19 (p<0.01), but the relative rates of decline did not differ (p=0.62). The decline in chorea did not differ by HD severity as measured by function (p=0.20).
Conclusion: In this post hoc analysis, tetrabenazine was not associated with an increased incidence of depressed mood among those taking antidepressants and was effective at reducing chorea in those with advanced HD. Larger, prospective studies are needed to confirm these findings.
Available from: Jack Chen
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ABSTRACT: Tetrabenazine (TBZ) is a monoamine storage inhibitor that was first introduced in the 1970s for the management of hyperkinetic movement disorders. Despite acceptance and usage worldwide, TBZ was only recently approved in the United States for the treatment of Huntington chorea. This review focuses on the use of TBZ in various hyperkinetic movement disorders, which are considered "rare" or "orphan" diseases, to help practitioners better understand its clinical role and use.
This review describes the clinical efficacy and tolerability of TBZ in the management of dystonia, Huntington chorea, tardive dyskinesia (TDk), and tic disorders.
A Cochrane Library, EMBASE, MedlinePlus, PubMed, and clinical trials database search (up to May 2012) was conducted to identify articles and studies using the subject terms tetrabenazine, Huntington disease, dystonia, tardive dyskinesia, Tourette, tics, and hyperkinetic movement. Only English-language articles were reviewed.
TBZ variably undergoes extensive first-pass metabolism to active metabolites, some of which are metabolized by the cytochrome P450 2D6 isozyme. Pharmacology studies demonstrate that TBZ reversibly inhibits the activity of vesicular monoamine transporter 2, resulting in depletion of central dopamine. For management of dystonias, 1 of 3 small prospective blinded studies and 4 of 5 retrospective studies reported clinical benefit with TBZ use in pediatrics and adults. For Huntington chorea, 2 randomized, double-blind, placebo-controlled studies along with open-label studies demonstrate the effectiveness of TBZ in adults. For TDk, 9 of 11 studies (prospective controlled and retrospective) reported positive benefit. For Gilles de la Tourette syndrome, 9 of 11 studies (prospective controlled and retrospective) reported positive benefit on motor and phonic tics in pediatric and adult patients. Overall, adverse effects are dose and age related and include depression, fatigue, parkinsonism, and somnolence.
TBZ is an effective oral therapy for chorea of Huntington disease and may be considered as an alternative agent for the management of dystonia, TDk, and tic disorders (these latter 3 conditions are off-label uses in the United States). The drug possesses an acceptable tolerability profile and has been used in pediatric and adult populations.
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ABSTRACT: This review highlights the recent advances in Huntington's disease, with particular focus on clinical characterization of prodromal Huntington's disease, as well as the growing literature regarding pathophysiological mechanisms and their relevance to potential therapeutic targets.
Clinical and neuroradiological abnormalities can be demonstrated in gene-positive individuals prior to the onset of manifest Huntington's disease, even as far as 15 years before the disease onset. Although some measures show promise as potential markers of disease progression, further longitudinal studies are required. Several molecular pathways have been implicated in the process of neurodegeneration involved in Huntington's disease and provide potential therapeutic targets.
With predictive testing allowing the identification of gene-positive individuals prior to disease onset, the prodromal stage of Huntington's disease provides an ideal period for the use of disease-modifying therapy. A quantifiable and reliable biomarker for monitoring disease progression is crucial for clinical studies of neuroprotection, and this remains an area of active research. Understanding of the underlying pathophysiological mechanisms continues to grow, based mainly on cellular and animal models of Huntington's disease.
Available from: Joseph Jankovic
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ABSTRACT: Although tetrabenazine, a drug that depletes presynaptic dopamine by inhibiting vesicular monoamine transporter 2 (VMAT2), was approved by the U.S. Food and Drug Administration in 2008 for the treatment of chorea associated with Huntington's disease (HD), there is a paucity of data on its long-term efficacy and safety.
Approximately 2,000 patients with a variety of hyperkinetic movement disorders had been treated with open-label tetrabenazine at the Movement Disorders Clinic, Baylor College of Medicine, since 1979. Tetrabenazine was usually started at 12.5 mg/day, and the dosage was gradually increased (up to 300 mg/day). Responses were rated by the investigator 1-5, with 1 = marked chorea reduction, excellent improvement in function; 2 = moderate chorea reduction, very good improvement in function; 3 = fair chorea improvement, only mild improvement in function; 4 = poor or no response for chorea and function; and 5 = worsening chorea, some functional deterioration. Efficacy and safety were analyzed retrospectively.
By 2004, 98 HD chorea patients had received tetrabenazine for a mean of 3.1 years (range ≤1-11.4 years). Of those with valid ratings, 75% had either marked or very good responses (rating 1 or 2) at their optimal dosages. The most common adverse events occurring in ≥5% of the patients were somnolence (39%), insomnia (33%), depression (31%), accidental injury (26%), and dysphagia (19%). Efficacy and safety were comparable to results for non-HD chorea patients.
Tetrabenazine treatment was associated with long-term improvement in chorea. Adverse event rates were comparable to those reported from controlled trials.
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