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Joseph Jankovic - One of the best experts on this subject based on the ideXlab platform.
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Articles Safety and Efficacy of Tetrabenazine and Use of Concomitant Medications During Long-Term, Open-Label Treatment of Chorea Associated with Huntington’s and Other Diseases
2016Co-Authors: Vivienne Shen, Christine Hunter, Kathleen Clarence-smith, Joseph JankovicAbstract:Background: 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. Methods: 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 5 marked chorea reduction, excellent improvement in function; 2 5 moderate chorea reduction, very good improvement in function; 35 fair chorea improvement, only mild improvement in function; 45 poor or no response for chorea and function; and 5 5 worsening chorea, some functional deterioration. Efficacy and safety were analyzed retrospectively. Results: 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. Discussion: Tetrabenazine treatment was associated with long-term improvement in chorea. Adverse event rates were comparable to those reported fro
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safety and efficacy of Tetrabenazine and use of concomitant medications during long term open label treatment of chorea associated with huntington s and other diseases
Tremor and other hyperkinetic movements (New York N.Y.), 2013Co-Authors: Vivienne Shen, Kathleen Clarencesmith, Christine Hunter, Joseph JankovicAbstract:Background: 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. Methods: 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. Results: 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. Discussion: 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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long term safety and efficacy of Tetrabenazine in the treatment of chorea associated with huntington s disease p06 034
Neurology, 2012Co-Authors: Vivienne Shen, Kathleen Clarencesmith, Christine Hunter, Joseph JankovicAbstract:Objective: To assess long-term safety and efficacy of Tetrabenazine for chorea associated with Huntington9s disease (HD). Background At study initiation (1979), Tetrabenazine had not yet been approved in the US (2008). Design/Methods: In an open-label, Phase IIIb study conducted through an IND by the investigator (JJ), patients with hyperkinetic movement disorders were evaluated at Baylor College of Medicine. Tetrabenazine was used “last resort,” when other medications failed to provide satisfactory control. For HD-chorea patients, all previous chorea treatments were discontinued before Tetrabenazine initiation. Patients were initially hospitalized, and Tetrabenazine was started at 12.5 mg/day (≤300 mg/day maximum). Dosage was increased every 3 days, until a dosage-limiting AE occurred, and then down-titrated to greatest tolerated dosage. Visits were 6 weeks after hospitalization, and every 3 months thereafter. Responses were rated on a scale of 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 and some functional deterioration. 1 Dosage, efficacy, and AEs were collected at each visit. Results: Results for 217 patients with movement disorders who were treated with Tetrabenazine have been reported. 1 By 2004, 98 HD-chorea patients were treated with Tetrabenazine for a mean 3.1±2.5 years (range: 2 years. The 5 most common AEs possibly/probably related to Tetrabenazine were somnolence (31%), insomnia (14%), depression (13%), akathisia (11%), and nervousness (10%). Of those with valid ratings, 75% had either marked or very good responses at their optimal dosages. Conclusions: Tetrabenazine provided sustained improvement in chorea and function, with AE rates comparable to what has been previously reported. 1 Jankovic J, et al. Neurology . 1988;38:391–4. Supported by: Lundbeck Inc. Disclosure: Dr. Shen has received personal compensation for activities with Lundbeck Inc as an employee. Dr. Clarence-Smith has received personal compensation for activities with Lundbeck Research USA, Inc. Dr. Hunter has received personal compensation for activities with Lundbeck Research USA, Inc. as a consultant. Dr. Jankovic has received personal compensation for activities with Allergan, Inc., Chelsea Therapeutics, Serono Inc., Merz Pharma, Lundbeck Research USA, Inc, Teva Neuroscience as a consultant. Dr. Jankovic has received personal compensation in an editorial capacity for Medlink: Neurology in Clinical Practice. Dr. Jankovic has received research support from Allergan, Inc, Allon Therapeutics, Ceregene, Inc., Chelsea Therapeutics; Diana Helis Henry Medical Research Foundation, Serono Inc., Huntington9s Disease Society of America, Huntington Study Group, Impax Pharmaceuticals, Ipsen Limited, Lundbeck Research USA, Inc.
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Tetrabenazine for moderate vs severe disabling chorea associated with huntington s disease hd p06 032
Neurology, 2012Co-Authors: Vivienne Shen, Kathleen Clarencesmith, Christine Hunter, Joseph JankovicAbstract:Objective: To assess dosing, efficacy, and safety of Tetrabenazine for patients with moderate vs. severe/disabling HD-chorea. Background At study initiation (1979), Tetrabenazine had not yet been approved in the US (2008). Design/Methods: In an open-label study, patients with hyperkinetic movement disorders were evaluated at Baylor College of Medicine. Tetrabenazine was used “last resort,” when other medications failed to provide satisfactory control. For HD-chorea patients, all previous chorea treatments were discontinued before Tetrabenazine initiation. Patients were initially hospitalized, and Tetrabenazine was started at 12.5 mg/day (≤300 mg/day maximum). Dosage was increased every 3 days, until a dosage-limiting AE occurred, and then down-titrated to greatest tolerated dosage. Visits were 6 weeks after hospitalization, and every 3 months thereafter. Responses were rated on a scale of 1–5 (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/no response for chorea/function; 5 = worsening chorea/some functional deterioration). 1 Results: By 2004, 98 HD-chorea patients had participated. At baseline, 44 had moderate and 54 had severe/disabling chorea. 45% with moderate vs. 61% with severe/disabling chorea received Tetrabenazine >2 years. Average daily dosages (SD; range of mean dosages) were 60.5 mg (25.9; 16.9–138.1) and 74.8 mg (45.0; 21.4–225.5) for moderate and severe/disabling chorea, respectively. On optimal dosages, 71% of moderate chorea patients achieved a marked or very good rating (any time point) vs. 78% for severe/disabling. Five most common AEs (moderate, severe/disabling) were somnolence (43%, 22%), insomnia (16%, 15%), depression (23%, 11%), akathisia (7%, 15%), and nervousness (7%, 13%). Conclusions: Tetrabenazine dosing is highly individualized, independent of chorea severity. Responses to Tetrabenazine and AE rates were similar for patients grouped by chorea severity. 1 Jankovic J, et al. Neurology . 1988;38:391–4. Supported by: Lundbeck Inc. Disclosure: Dr. Shen has received personal compensation for activities with Lundbeck Inc as an employee. Dr. Clarence-Smith has received personal compensation for activities with Lundbeck Research USA, Inc. Dr. Hunter has received personal compensation for activities with Lundbeck Research USA, Inc. as a consultant. Dr. Jankovic has received personal compensation for activities with Allergan, Inc., Chelsea Therapeutics, Serono Inc., Merz Pharma, Lundbeck Research USA, Inc, Teva Neuroscience as a consultant. Dr. Jankovic has received personal compensation in an editorial capacity for Medlink: Neurology in Clinical Practice. Dr. Jankovic has received research support from Allergan, Inc, Allon Therapeutics, Ceregene, Inc., Chelsea Therapeutics; Diana Helis Henry Medical Research Foundation, Serono Inc., Huntington9s Disease Society of America, Huntington Study Group, Impax Pharmaceuticals, Ipsen Limited, Lundbeck Research USA, Inc.
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Concomitant Use of Antidepressants and Neuroleptics with Tetrabenazine during Treatment of Huntington's Disease (HD) (P06.039)
Neurology, 2012Co-Authors: Kathleen Clarence-smith, Vivienne Shen, Christine Hunter, Joseph JankovicAbstract:Objective: To assess antidepressant/neuroleptic use by HD-chorea patients receiving Tetrabenazine. Background At study initiation (1979), Tetrabenazine had not yet been approved in the US (2008). Design/Methods: Patients with hyperkinetic movement disorders were evaluated at Baylor College of Medicine. Tetrabenazine was used “last resort.” All previous chorea treatments were discontinued before Tetrabenazine initiation. Patients were initially hospitalized, and Tetrabenazine was started at 12.5 mg/day. Dosage was increased every 3 days, until a dosage-limiting AE occurred, and then down-titrated to greatest tolerated dosage. Visits were 6 weeks after hospitalization, and every 3 months thereafter. Responses were rated on a 1–5 scale (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/no response for chorea/function; 5 = worsening chorea/some functional deterioration). 1 Results: By 2004, 98 HD-chorea patients had participated. At baseline, 31 were on antidepressants (tricyclics or SSRIs). Later, 25 additional patients received an antidepressant (tricyclics or SSRIs). Percentages ever reporting marked/very good responses were 73% vs. 82% for those receiving vs. not receiving antidepressants. Five most common AEs for the two groups were somnolence (30%, 37%), insomnia (20%, 4%), depression (20%, 7%), akathisia (14%, 4%), nervousness (13%, 4%). Twelve patients received neuroleptics before Tetrabenazine initiation, and most discontinued them after initiation. Later, 25 had a neuroleptic added. Percentages ever reporting marked/very good responses were 65% for those on neuroleptics (any time) vs. 88% for those not on neuroleptics. Five most common AEs were somnolence (36%, 27%), insomnia (15%, 16%), depression (17%, 16%), akathisia (8%, 16%), nervousness (15%, 4%). Conclusions: Most Tetrabenazine-treated patients received a concomitant antidepressant, neuroleptic, or both. Tetrabenazine responses and Tetrabenazine-related AEs did not differ substantially between patients with or without these concomitant medications. 1 Jankovic J, et al. Neurology . 1988;38:391–4. Supported by: Lundbeck Inc. Disclosure: Dr. Clarence-Smith has received personal compensation for activities with Lundbeck Research USA, Inc. Dr. Shen has received personal compensation for activities with Lundbeck Inc as an employee. Dr. Hunter has received personal compensation for activities with Lundbeck Research USA, Inc. as a consultant. Dr. Jankovic has received personal compensation for activities with Allergan, Inc., Chelsea Therapeutics, Serono Inc., Merz Pharma, Lundbeck Research USA, Inc, Teva Neuroscience as a consultant. Dr. Jankovic has received personal compensation in an editorial capacity for Medlink: Neurology in Clinical Practice. Dr. Jankovic has received research support from Allergan, Inc, Allon Therapeutics, Ceregene, Inc., Chelsea Therapeutics; Diana Helis Henry Medical Research Foundation, Serono Inc., Huntington9s Disease Society of America, Huntington Study Group, Impax Pharmaceuticals, Ipsen Limited, Lundbeck Research USA, Inc.
John D. Salamone - One of the best experts on this subject based on the ideXlab platform.
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partial reversal of the effort related motivational effects of Tetrabenazine with the mao b inhibitor deprenyl selegiline implications for treating motivational dysfunctions
Pharmacology Biochemistry and Behavior, 2018Co-Authors: Hector M Contrerasmora, Samantha E. Yohn, Mercè Correa, Margaret Rowland, John D. SalamoneAbstract:People with depression and Parkinsonism frequently show effort-related motivational symptoms, such as anergia, psychomotor retardation, and fatigue. Tasks that assess effort-related choice are being used as animal models of these motivational symptoms. The present studies characterized the ability of monoamine oxidase (MAO) inhibitors with varying selectivity profiles to reverse the low effort bias induced by the monoamine storage inhibitor Tetrabenazine. Tetrabenazine produces depressive symptoms in humans, and because of its selective inhibition of VMAT-2, it preferentially depletes DA at low doses. Effort-based decision making is studied with tasks offering choices between high effort options leading to highly valued reinforcers vs. low effort/low reward options. Tetrabenazine shifted choice behavior, reducing selection of fixed ratio 5 lever pressing, but increasing intake of the concurrently available but less preferred lab chow. These effects of 0.75mg/kg Tetrabenazine were attenuated by co-administration of the MAO-B inhibitor deprenyl (selegiline). The ability of deprenyl to reverse the effects of Tetrabenazine was marked by an inverted-U shaped dose response curve, with the middle dose (2.5mg/kg) being effective. In contrast, neither the MAO-A selective antagonist moclobemide nor the nonselective drug pargyline reversed the effects of Tetrabenazine, and moclobemide decreased lever pressing when administered alone. Deprenyl was originally developed as an antiparkinsonian drug, but it also has been shown to have antidepressant effects in humans and induce antidepressant-like effects in classical rodent models of depression. These studies have implications for the potential use of MAO-B inhibitors as treatments for the motivational symptoms of depression and Parkinsonism.
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Oral Ingestion and Intraventricular Injection of Curcumin Attenuates the Effort-Related Effects of the VMAT-2 Inhibitor Tetrabenazine: Implications for Motivational Symptoms of Depression.
Journal of natural products, 2017Co-Authors: Samantha E. Yohn, Mercè Correa, Dea Gorka, Anisha Mistry, Samantha L Collins, Emily Qian, Arushi Manchanda, Robin H. Bogner, John D. SalamoneAbstract:Effort-related choice tasks are used for studying depressive motivational symptoms such as anergia/fatigue. These studies investigated the ability of the dietary supplement curcumin to reverse the low-effort bias induced by the monoamine storage blocker Tetrabenazine. Tetrabenazine shifted effort-related choice in rats, decreasing high-effort lever pressing but increasing chow intake. The effects of Tetrabenazine were reversed by oral ingestion of curcumin (80.0–160.0 mg/kg) and infusions of curcumin into the cerebral ventricles (2.0–8.0 μg). Curcumin attenuates the effort-related effects of Tetrabenazine in this model via actions on the brain, suggesting that curcumin may be useful for treating human motivational symptoms.
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The VMAT-2 inhibitor Tetrabenazine alters effort-related decision making as measured by the T-maze barrier choice task: reversal with the adenosine A_2A antagonist MSX-3 and the catecholamine uptake blocker bupropion
Psychopharmacology, 2015Co-Authors: Samantha E. Yohn, Christian Thompson, Patrick A. Randall, Christie A. Lee, Christa E. Müller, Younis Baqi, Mercè Correa, John D. SalamoneAbstract:Rationale Depressed people show effort-related motivational symptoms, such as anergia, retardation, lassitude, and fatigue. Animal tests can model these motivational symptoms, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor Tetrabenazine. Tetrabenazine produces depressive symptoms in humans and, at low doses, preferentially depletes dopamine. Objectives The current studies investigated the effects of Tetrabenazine on effort-based decision making using the T-maze barrier task. Methods Rats were tested in a T-maze in which the choice arms of the maze contain different reinforcement densities, and under some conditions, a vertical barrier was placed in the high-density arm to provide an effort-related challenge. The first experiment assessed the effects of Tetrabenazine under different maze conditions: a barrier in the arm with 4 food pellets and 2 pellets in the no barrier arm (4–2 barrier), 4 pellets in one arm and 2 pellets in the other with no barrier in either arm (no barrier), and 4 pellets in the barrier arm with no pellets in the other (4–0 barrier). Results Tetrabenazine (0.25–0.75 mg/kg IP) decreased selection of the high cost/high reward arm when the barrier was present, but had no effect on choice under the no barrier and 4–0 barrier conditions. The effects of Tetrabenazine on barrier climbing in the 4–2 condition were reversed by the adenosine A_2A antagonist MSX-3 and the catecholamine uptake inhibitor and antidepressant bupropion. Conclusions These studies have implications for the development of animal models of the motivational symptoms of depression and other disorders.
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The VMAT-2 inhibitor Tetrabenazine alters effort-related decision making as measured by the T-maze barrier choice task: reversal with the adenosine A2A antagonist MSX-3 and the catecholamine uptake blocker bupropion.
Psychopharmacology, 2014Co-Authors: Samantha E. Yohn, Christian Thompson, Patrick A. Randall, Christie A. Lee, Christa E. Müller, Younis Baqi, Mercè Correa, John D. SalamoneAbstract:Rationale Depressed people show effort-related motivational symptoms, such as anergia, retardation, lassitude, and fatigue. Animal tests can model these motivational symptoms, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor Tetrabenazine. Tetrabenazine produces depressive symptoms in humans and, at low doses, preferentially depletes dopamine.
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Effort-related motivational effects of the VMAT-2 inhibitor Tetrabenazine: Implications for animal models of the motivational symptoms of depression
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013Co-Authors: Eric J. Nunes, Samantha E. Yohn, Patrick A. Randall, Christa E. Müller, Younis Baqi, Mercè Correa, Evan E. Hart, Charlotte Freeland, Laura López-cruz, John D. SalamoneAbstract:Motivated behaviors are often characterized by a high degree of behavioral activation, and work output and organisms frequently make effort-related decisions based upon cost/benefit analyses. Moreover, people with major depression and other disorders often show effort-related motivational symptoms such as anergia, psychomotor retardation, and fatigue. It has been suggested that tasks measuring effort-related choice behavior could be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT) inhibitor Tetrabenazine. Tetrabenazine produces depressive symptoms in humans and, because of its selective inhibition of VMAT-2, it preferentially depletes dopamine (DA). Rats were assessed using a concurrent fixed-ratio 5/chow feeding choice task that is known to be sensitive to dopaminergic manipulations. Tetrabenazine shifted response choice in rats, producing a dose-related decrease in lever pressing and a concomitant increase in chow intake. However, it did not alter food intake or preference in parallel free-feeding choice studies. The effects of Tetrabenazine on effort-related choice were reversed by the adenosine A2A antagonist MSX-3 and the antidepressant bupropion. A behaviorally active dose of Tetrabenazine decreased extracellular DA in nucleus accumbens and increased expression of DARPP-32 in accumbens medium spiny neurons in a pattern indicative of reduced transmission at both D1 and D2 DA receptors. These experiments demonstrate that Tetrabenazine, which is used in animal models to produce depression-like effects, can alter effort-related choice behavior. These studies have implications for the development of animal models of the motivational symptoms of depression and related disorders.
Vivienne Shen - One of the best experts on this subject based on the ideXlab platform.
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Articles Safety and Efficacy of Tetrabenazine and Use of Concomitant Medications During Long-Term, Open-Label Treatment of Chorea Associated with Huntington’s and Other Diseases
2016Co-Authors: Vivienne Shen, Christine Hunter, Kathleen Clarence-smith, Joseph JankovicAbstract:Background: 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. Methods: 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 5 marked chorea reduction, excellent improvement in function; 2 5 moderate chorea reduction, very good improvement in function; 35 fair chorea improvement, only mild improvement in function; 45 poor or no response for chorea and function; and 5 5 worsening chorea, some functional deterioration. Efficacy and safety were analyzed retrospectively. Results: 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. Discussion: Tetrabenazine treatment was associated with long-term improvement in chorea. Adverse event rates were comparable to those reported fro
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safety and efficacy of Tetrabenazine and use of concomitant medications during long term open label treatment of chorea associated with huntington s and other diseases
Tremor and other hyperkinetic movements (New York N.Y.), 2013Co-Authors: Vivienne Shen, Kathleen Clarencesmith, Christine Hunter, Joseph JankovicAbstract:Background: 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. Methods: 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. Results: 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. Discussion: 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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long term safety and efficacy of Tetrabenazine in the treatment of chorea associated with huntington s disease p06 034
Neurology, 2012Co-Authors: Vivienne Shen, Kathleen Clarencesmith, Christine Hunter, Joseph JankovicAbstract:Objective: To assess long-term safety and efficacy of Tetrabenazine for chorea associated with Huntington9s disease (HD). Background At study initiation (1979), Tetrabenazine had not yet been approved in the US (2008). Design/Methods: In an open-label, Phase IIIb study conducted through an IND by the investigator (JJ), patients with hyperkinetic movement disorders were evaluated at Baylor College of Medicine. Tetrabenazine was used “last resort,” when other medications failed to provide satisfactory control. For HD-chorea patients, all previous chorea treatments were discontinued before Tetrabenazine initiation. Patients were initially hospitalized, and Tetrabenazine was started at 12.5 mg/day (≤300 mg/day maximum). Dosage was increased every 3 days, until a dosage-limiting AE occurred, and then down-titrated to greatest tolerated dosage. Visits were 6 weeks after hospitalization, and every 3 months thereafter. Responses were rated on a scale of 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 and some functional deterioration. 1 Dosage, efficacy, and AEs were collected at each visit. Results: Results for 217 patients with movement disorders who were treated with Tetrabenazine have been reported. 1 By 2004, 98 HD-chorea patients were treated with Tetrabenazine for a mean 3.1±2.5 years (range: 2 years. The 5 most common AEs possibly/probably related to Tetrabenazine were somnolence (31%), insomnia (14%), depression (13%), akathisia (11%), and nervousness (10%). Of those with valid ratings, 75% had either marked or very good responses at their optimal dosages. Conclusions: Tetrabenazine provided sustained improvement in chorea and function, with AE rates comparable to what has been previously reported. 1 Jankovic J, et al. Neurology . 1988;38:391–4. Supported by: Lundbeck Inc. Disclosure: Dr. Shen has received personal compensation for activities with Lundbeck Inc as an employee. Dr. Clarence-Smith has received personal compensation for activities with Lundbeck Research USA, Inc. Dr. Hunter has received personal compensation for activities with Lundbeck Research USA, Inc. as a consultant. Dr. Jankovic has received personal compensation for activities with Allergan, Inc., Chelsea Therapeutics, Serono Inc., Merz Pharma, Lundbeck Research USA, Inc, Teva Neuroscience as a consultant. Dr. Jankovic has received personal compensation in an editorial capacity for Medlink: Neurology in Clinical Practice. Dr. Jankovic has received research support from Allergan, Inc, Allon Therapeutics, Ceregene, Inc., Chelsea Therapeutics; Diana Helis Henry Medical Research Foundation, Serono Inc., Huntington9s Disease Society of America, Huntington Study Group, Impax Pharmaceuticals, Ipsen Limited, Lundbeck Research USA, Inc.
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Tetrabenazine for moderate vs severe disabling chorea associated with huntington s disease hd p06 032
Neurology, 2012Co-Authors: Vivienne Shen, Kathleen Clarencesmith, Christine Hunter, Joseph JankovicAbstract:Objective: To assess dosing, efficacy, and safety of Tetrabenazine for patients with moderate vs. severe/disabling HD-chorea. Background At study initiation (1979), Tetrabenazine had not yet been approved in the US (2008). Design/Methods: In an open-label study, patients with hyperkinetic movement disorders were evaluated at Baylor College of Medicine. Tetrabenazine was used “last resort,” when other medications failed to provide satisfactory control. For HD-chorea patients, all previous chorea treatments were discontinued before Tetrabenazine initiation. Patients were initially hospitalized, and Tetrabenazine was started at 12.5 mg/day (≤300 mg/day maximum). Dosage was increased every 3 days, until a dosage-limiting AE occurred, and then down-titrated to greatest tolerated dosage. Visits were 6 weeks after hospitalization, and every 3 months thereafter. Responses were rated on a scale of 1–5 (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/no response for chorea/function; 5 = worsening chorea/some functional deterioration). 1 Results: By 2004, 98 HD-chorea patients had participated. At baseline, 44 had moderate and 54 had severe/disabling chorea. 45% with moderate vs. 61% with severe/disabling chorea received Tetrabenazine >2 years. Average daily dosages (SD; range of mean dosages) were 60.5 mg (25.9; 16.9–138.1) and 74.8 mg (45.0; 21.4–225.5) for moderate and severe/disabling chorea, respectively. On optimal dosages, 71% of moderate chorea patients achieved a marked or very good rating (any time point) vs. 78% for severe/disabling. Five most common AEs (moderate, severe/disabling) were somnolence (43%, 22%), insomnia (16%, 15%), depression (23%, 11%), akathisia (7%, 15%), and nervousness (7%, 13%). Conclusions: Tetrabenazine dosing is highly individualized, independent of chorea severity. Responses to Tetrabenazine and AE rates were similar for patients grouped by chorea severity. 1 Jankovic J, et al. Neurology . 1988;38:391–4. Supported by: Lundbeck Inc. Disclosure: Dr. Shen has received personal compensation for activities with Lundbeck Inc as an employee. Dr. Clarence-Smith has received personal compensation for activities with Lundbeck Research USA, Inc. Dr. Hunter has received personal compensation for activities with Lundbeck Research USA, Inc. as a consultant. Dr. Jankovic has received personal compensation for activities with Allergan, Inc., Chelsea Therapeutics, Serono Inc., Merz Pharma, Lundbeck Research USA, Inc, Teva Neuroscience as a consultant. Dr. Jankovic has received personal compensation in an editorial capacity for Medlink: Neurology in Clinical Practice. Dr. Jankovic has received research support from Allergan, Inc, Allon Therapeutics, Ceregene, Inc., Chelsea Therapeutics; Diana Helis Henry Medical Research Foundation, Serono Inc., Huntington9s Disease Society of America, Huntington Study Group, Impax Pharmaceuticals, Ipsen Limited, Lundbeck Research USA, Inc.
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Concomitant Use of Antidepressants and Neuroleptics with Tetrabenazine during Treatment of Huntington's Disease (HD) (P06.039)
Neurology, 2012Co-Authors: Kathleen Clarence-smith, Vivienne Shen, Christine Hunter, Joseph JankovicAbstract:Objective: To assess antidepressant/neuroleptic use by HD-chorea patients receiving Tetrabenazine. Background At study initiation (1979), Tetrabenazine had not yet been approved in the US (2008). Design/Methods: Patients with hyperkinetic movement disorders were evaluated at Baylor College of Medicine. Tetrabenazine was used “last resort.” All previous chorea treatments were discontinued before Tetrabenazine initiation. Patients were initially hospitalized, and Tetrabenazine was started at 12.5 mg/day. Dosage was increased every 3 days, until a dosage-limiting AE occurred, and then down-titrated to greatest tolerated dosage. Visits were 6 weeks after hospitalization, and every 3 months thereafter. Responses were rated on a 1–5 scale (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/no response for chorea/function; 5 = worsening chorea/some functional deterioration). 1 Results: By 2004, 98 HD-chorea patients had participated. At baseline, 31 were on antidepressants (tricyclics or SSRIs). Later, 25 additional patients received an antidepressant (tricyclics or SSRIs). Percentages ever reporting marked/very good responses were 73% vs. 82% for those receiving vs. not receiving antidepressants. Five most common AEs for the two groups were somnolence (30%, 37%), insomnia (20%, 4%), depression (20%, 7%), akathisia (14%, 4%), nervousness (13%, 4%). Twelve patients received neuroleptics before Tetrabenazine initiation, and most discontinued them after initiation. Later, 25 had a neuroleptic added. Percentages ever reporting marked/very good responses were 65% for those on neuroleptics (any time) vs. 88% for those not on neuroleptics. Five most common AEs were somnolence (36%, 27%), insomnia (15%, 16%), depression (17%, 16%), akathisia (8%, 16%), nervousness (15%, 4%). Conclusions: Most Tetrabenazine-treated patients received a concomitant antidepressant, neuroleptic, or both. Tetrabenazine responses and Tetrabenazine-related AEs did not differ substantially between patients with or without these concomitant medications. 1 Jankovic J, et al. Neurology . 1988;38:391–4. Supported by: Lundbeck Inc. Disclosure: Dr. Clarence-Smith has received personal compensation for activities with Lundbeck Research USA, Inc. Dr. Shen has received personal compensation for activities with Lundbeck Inc as an employee. Dr. Hunter has received personal compensation for activities with Lundbeck Research USA, Inc. as a consultant. Dr. Jankovic has received personal compensation for activities with Allergan, Inc., Chelsea Therapeutics, Serono Inc., Merz Pharma, Lundbeck Research USA, Inc, Teva Neuroscience as a consultant. Dr. Jankovic has received personal compensation in an editorial capacity for Medlink: Neurology in Clinical Practice. Dr. Jankovic has received research support from Allergan, Inc, Allon Therapeutics, Ceregene, Inc., Chelsea Therapeutics; Diana Helis Henry Medical Research Foundation, Serono Inc., Huntington9s Disease Society of America, Huntington Study Group, Impax Pharmaceuticals, Ipsen Limited, Lundbeck Research USA, Inc.
Christine Hunter - One of the best experts on this subject based on the ideXlab platform.
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Articles Safety and Efficacy of Tetrabenazine and Use of Concomitant Medications During Long-Term, Open-Label Treatment of Chorea Associated with Huntington’s and Other Diseases
2016Co-Authors: Vivienne Shen, Christine Hunter, Kathleen Clarence-smith, Joseph JankovicAbstract:Background: 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. Methods: 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 5 marked chorea reduction, excellent improvement in function; 2 5 moderate chorea reduction, very good improvement in function; 35 fair chorea improvement, only mild improvement in function; 45 poor or no response for chorea and function; and 5 5 worsening chorea, some functional deterioration. Efficacy and safety were analyzed retrospectively. Results: 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. Discussion: Tetrabenazine treatment was associated with long-term improvement in chorea. Adverse event rates were comparable to those reported fro
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safety and efficacy of Tetrabenazine and use of concomitant medications during long term open label treatment of chorea associated with huntington s and other diseases
Tremor and other hyperkinetic movements (New York N.Y.), 2013Co-Authors: Vivienne Shen, Kathleen Clarencesmith, Christine Hunter, Joseph JankovicAbstract:Background: 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. Methods: 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. Results: 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. Discussion: 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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long term safety and efficacy of Tetrabenazine in the treatment of chorea associated with huntington s disease p06 034
Neurology, 2012Co-Authors: Vivienne Shen, Kathleen Clarencesmith, Christine Hunter, Joseph JankovicAbstract:Objective: To assess long-term safety and efficacy of Tetrabenazine for chorea associated with Huntington9s disease (HD). Background At study initiation (1979), Tetrabenazine had not yet been approved in the US (2008). Design/Methods: In an open-label, Phase IIIb study conducted through an IND by the investigator (JJ), patients with hyperkinetic movement disorders were evaluated at Baylor College of Medicine. Tetrabenazine was used “last resort,” when other medications failed to provide satisfactory control. For HD-chorea patients, all previous chorea treatments were discontinued before Tetrabenazine initiation. Patients were initially hospitalized, and Tetrabenazine was started at 12.5 mg/day (≤300 mg/day maximum). Dosage was increased every 3 days, until a dosage-limiting AE occurred, and then down-titrated to greatest tolerated dosage. Visits were 6 weeks after hospitalization, and every 3 months thereafter. Responses were rated on a scale of 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 and some functional deterioration. 1 Dosage, efficacy, and AEs were collected at each visit. Results: Results for 217 patients with movement disorders who were treated with Tetrabenazine have been reported. 1 By 2004, 98 HD-chorea patients were treated with Tetrabenazine for a mean 3.1±2.5 years (range: 2 years. The 5 most common AEs possibly/probably related to Tetrabenazine were somnolence (31%), insomnia (14%), depression (13%), akathisia (11%), and nervousness (10%). Of those with valid ratings, 75% had either marked or very good responses at their optimal dosages. Conclusions: Tetrabenazine provided sustained improvement in chorea and function, with AE rates comparable to what has been previously reported. 1 Jankovic J, et al. Neurology . 1988;38:391–4. Supported by: Lundbeck Inc. Disclosure: Dr. Shen has received personal compensation for activities with Lundbeck Inc as an employee. Dr. Clarence-Smith has received personal compensation for activities with Lundbeck Research USA, Inc. Dr. Hunter has received personal compensation for activities with Lundbeck Research USA, Inc. as a consultant. Dr. Jankovic has received personal compensation for activities with Allergan, Inc., Chelsea Therapeutics, Serono Inc., Merz Pharma, Lundbeck Research USA, Inc, Teva Neuroscience as a consultant. Dr. Jankovic has received personal compensation in an editorial capacity for Medlink: Neurology in Clinical Practice. Dr. Jankovic has received research support from Allergan, Inc, Allon Therapeutics, Ceregene, Inc., Chelsea Therapeutics; Diana Helis Henry Medical Research Foundation, Serono Inc., Huntington9s Disease Society of America, Huntington Study Group, Impax Pharmaceuticals, Ipsen Limited, Lundbeck Research USA, Inc.
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Tetrabenazine for moderate vs severe disabling chorea associated with huntington s disease hd p06 032
Neurology, 2012Co-Authors: Vivienne Shen, Kathleen Clarencesmith, Christine Hunter, Joseph JankovicAbstract:Objective: To assess dosing, efficacy, and safety of Tetrabenazine for patients with moderate vs. severe/disabling HD-chorea. Background At study initiation (1979), Tetrabenazine had not yet been approved in the US (2008). Design/Methods: In an open-label study, patients with hyperkinetic movement disorders were evaluated at Baylor College of Medicine. Tetrabenazine was used “last resort,” when other medications failed to provide satisfactory control. For HD-chorea patients, all previous chorea treatments were discontinued before Tetrabenazine initiation. Patients were initially hospitalized, and Tetrabenazine was started at 12.5 mg/day (≤300 mg/day maximum). Dosage was increased every 3 days, until a dosage-limiting AE occurred, and then down-titrated to greatest tolerated dosage. Visits were 6 weeks after hospitalization, and every 3 months thereafter. Responses were rated on a scale of 1–5 (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/no response for chorea/function; 5 = worsening chorea/some functional deterioration). 1 Results: By 2004, 98 HD-chorea patients had participated. At baseline, 44 had moderate and 54 had severe/disabling chorea. 45% with moderate vs. 61% with severe/disabling chorea received Tetrabenazine >2 years. Average daily dosages (SD; range of mean dosages) were 60.5 mg (25.9; 16.9–138.1) and 74.8 mg (45.0; 21.4–225.5) for moderate and severe/disabling chorea, respectively. On optimal dosages, 71% of moderate chorea patients achieved a marked or very good rating (any time point) vs. 78% for severe/disabling. Five most common AEs (moderate, severe/disabling) were somnolence (43%, 22%), insomnia (16%, 15%), depression (23%, 11%), akathisia (7%, 15%), and nervousness (7%, 13%). Conclusions: Tetrabenazine dosing is highly individualized, independent of chorea severity. Responses to Tetrabenazine and AE rates were similar for patients grouped by chorea severity. 1 Jankovic J, et al. Neurology . 1988;38:391–4. Supported by: Lundbeck Inc. Disclosure: Dr. Shen has received personal compensation for activities with Lundbeck Inc as an employee. Dr. Clarence-Smith has received personal compensation for activities with Lundbeck Research USA, Inc. Dr. Hunter has received personal compensation for activities with Lundbeck Research USA, Inc. as a consultant. Dr. Jankovic has received personal compensation for activities with Allergan, Inc., Chelsea Therapeutics, Serono Inc., Merz Pharma, Lundbeck Research USA, Inc, Teva Neuroscience as a consultant. Dr. Jankovic has received personal compensation in an editorial capacity for Medlink: Neurology in Clinical Practice. Dr. Jankovic has received research support from Allergan, Inc, Allon Therapeutics, Ceregene, Inc., Chelsea Therapeutics; Diana Helis Henry Medical Research Foundation, Serono Inc., Huntington9s Disease Society of America, Huntington Study Group, Impax Pharmaceuticals, Ipsen Limited, Lundbeck Research USA, Inc.
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Concomitant Use of Antidepressants and Neuroleptics with Tetrabenazine during Treatment of Huntington's Disease (HD) (P06.039)
Neurology, 2012Co-Authors: Kathleen Clarence-smith, Vivienne Shen, Christine Hunter, Joseph JankovicAbstract:Objective: To assess antidepressant/neuroleptic use by HD-chorea patients receiving Tetrabenazine. Background At study initiation (1979), Tetrabenazine had not yet been approved in the US (2008). Design/Methods: Patients with hyperkinetic movement disorders were evaluated at Baylor College of Medicine. Tetrabenazine was used “last resort.” All previous chorea treatments were discontinued before Tetrabenazine initiation. Patients were initially hospitalized, and Tetrabenazine was started at 12.5 mg/day. Dosage was increased every 3 days, until a dosage-limiting AE occurred, and then down-titrated to greatest tolerated dosage. Visits were 6 weeks after hospitalization, and every 3 months thereafter. Responses were rated on a 1–5 scale (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/no response for chorea/function; 5 = worsening chorea/some functional deterioration). 1 Results: By 2004, 98 HD-chorea patients had participated. At baseline, 31 were on antidepressants (tricyclics or SSRIs). Later, 25 additional patients received an antidepressant (tricyclics or SSRIs). Percentages ever reporting marked/very good responses were 73% vs. 82% for those receiving vs. not receiving antidepressants. Five most common AEs for the two groups were somnolence (30%, 37%), insomnia (20%, 4%), depression (20%, 7%), akathisia (14%, 4%), nervousness (13%, 4%). Twelve patients received neuroleptics before Tetrabenazine initiation, and most discontinued them after initiation. Later, 25 had a neuroleptic added. Percentages ever reporting marked/very good responses were 65% for those on neuroleptics (any time) vs. 88% for those not on neuroleptics. Five most common AEs were somnolence (36%, 27%), insomnia (15%, 16%), depression (17%, 16%), akathisia (8%, 16%), nervousness (15%, 4%). Conclusions: Most Tetrabenazine-treated patients received a concomitant antidepressant, neuroleptic, or both. Tetrabenazine responses and Tetrabenazine-related AEs did not differ substantially between patients with or without these concomitant medications. 1 Jankovic J, et al. Neurology . 1988;38:391–4. Supported by: Lundbeck Inc. Disclosure: Dr. Clarence-Smith has received personal compensation for activities with Lundbeck Research USA, Inc. Dr. Shen has received personal compensation for activities with Lundbeck Inc as an employee. Dr. Hunter has received personal compensation for activities with Lundbeck Research USA, Inc. as a consultant. Dr. Jankovic has received personal compensation for activities with Allergan, Inc., Chelsea Therapeutics, Serono Inc., Merz Pharma, Lundbeck Research USA, Inc, Teva Neuroscience as a consultant. Dr. Jankovic has received personal compensation in an editorial capacity for Medlink: Neurology in Clinical Practice. Dr. Jankovic has received research support from Allergan, Inc, Allon Therapeutics, Ceregene, Inc., Chelsea Therapeutics; Diana Helis Henry Medical Research Foundation, Serono Inc., Huntington9s Disease Society of America, Huntington Study Group, Impax Pharmaceuticals, Ipsen Limited, Lundbeck Research USA, Inc.
Samantha E. Yohn - One of the best experts on this subject based on the ideXlab platform.
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partial reversal of the effort related motivational effects of Tetrabenazine with the mao b inhibitor deprenyl selegiline implications for treating motivational dysfunctions
Pharmacology Biochemistry and Behavior, 2018Co-Authors: Hector M Contrerasmora, Samantha E. Yohn, Mercè Correa, Margaret Rowland, John D. SalamoneAbstract:People with depression and Parkinsonism frequently show effort-related motivational symptoms, such as anergia, psychomotor retardation, and fatigue. Tasks that assess effort-related choice are being used as animal models of these motivational symptoms. The present studies characterized the ability of monoamine oxidase (MAO) inhibitors with varying selectivity profiles to reverse the low effort bias induced by the monoamine storage inhibitor Tetrabenazine. Tetrabenazine produces depressive symptoms in humans, and because of its selective inhibition of VMAT-2, it preferentially depletes DA at low doses. Effort-based decision making is studied with tasks offering choices between high effort options leading to highly valued reinforcers vs. low effort/low reward options. Tetrabenazine shifted choice behavior, reducing selection of fixed ratio 5 lever pressing, but increasing intake of the concurrently available but less preferred lab chow. These effects of 0.75mg/kg Tetrabenazine were attenuated by co-administration of the MAO-B inhibitor deprenyl (selegiline). The ability of deprenyl to reverse the effects of Tetrabenazine was marked by an inverted-U shaped dose response curve, with the middle dose (2.5mg/kg) being effective. In contrast, neither the MAO-A selective antagonist moclobemide nor the nonselective drug pargyline reversed the effects of Tetrabenazine, and moclobemide decreased lever pressing when administered alone. Deprenyl was originally developed as an antiparkinsonian drug, but it also has been shown to have antidepressant effects in humans and induce antidepressant-like effects in classical rodent models of depression. These studies have implications for the potential use of MAO-B inhibitors as treatments for the motivational symptoms of depression and Parkinsonism.
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Oral Ingestion and Intraventricular Injection of Curcumin Attenuates the Effort-Related Effects of the VMAT-2 Inhibitor Tetrabenazine: Implications for Motivational Symptoms of Depression.
Journal of natural products, 2017Co-Authors: Samantha E. Yohn, Mercè Correa, Dea Gorka, Anisha Mistry, Samantha L Collins, Emily Qian, Arushi Manchanda, Robin H. Bogner, John D. SalamoneAbstract:Effort-related choice tasks are used for studying depressive motivational symptoms such as anergia/fatigue. These studies investigated the ability of the dietary supplement curcumin to reverse the low-effort bias induced by the monoamine storage blocker Tetrabenazine. Tetrabenazine shifted effort-related choice in rats, decreasing high-effort lever pressing but increasing chow intake. The effects of Tetrabenazine were reversed by oral ingestion of curcumin (80.0–160.0 mg/kg) and infusions of curcumin into the cerebral ventricles (2.0–8.0 μg). Curcumin attenuates the effort-related effects of Tetrabenazine in this model via actions on the brain, suggesting that curcumin may be useful for treating human motivational symptoms.
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The VMAT-2 inhibitor Tetrabenazine alters effort-related decision making as measured by the T-maze barrier choice task: reversal with the adenosine A_2A antagonist MSX-3 and the catecholamine uptake blocker bupropion
Psychopharmacology, 2015Co-Authors: Samantha E. Yohn, Christian Thompson, Patrick A. Randall, Christie A. Lee, Christa E. Müller, Younis Baqi, Mercè Correa, John D. SalamoneAbstract:Rationale Depressed people show effort-related motivational symptoms, such as anergia, retardation, lassitude, and fatigue. Animal tests can model these motivational symptoms, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor Tetrabenazine. Tetrabenazine produces depressive symptoms in humans and, at low doses, preferentially depletes dopamine. Objectives The current studies investigated the effects of Tetrabenazine on effort-based decision making using the T-maze barrier task. Methods Rats were tested in a T-maze in which the choice arms of the maze contain different reinforcement densities, and under some conditions, a vertical barrier was placed in the high-density arm to provide an effort-related challenge. The first experiment assessed the effects of Tetrabenazine under different maze conditions: a barrier in the arm with 4 food pellets and 2 pellets in the no barrier arm (4–2 barrier), 4 pellets in one arm and 2 pellets in the other with no barrier in either arm (no barrier), and 4 pellets in the barrier arm with no pellets in the other (4–0 barrier). Results Tetrabenazine (0.25–0.75 mg/kg IP) decreased selection of the high cost/high reward arm when the barrier was present, but had no effect on choice under the no barrier and 4–0 barrier conditions. The effects of Tetrabenazine on barrier climbing in the 4–2 condition were reversed by the adenosine A_2A antagonist MSX-3 and the catecholamine uptake inhibitor and antidepressant bupropion. Conclusions These studies have implications for the development of animal models of the motivational symptoms of depression and other disorders.
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The VMAT-2 inhibitor Tetrabenazine alters effort-related decision making as measured by the T-maze barrier choice task: reversal with the adenosine A2A antagonist MSX-3 and the catecholamine uptake blocker bupropion.
Psychopharmacology, 2014Co-Authors: Samantha E. Yohn, Christian Thompson, Patrick A. Randall, Christie A. Lee, Christa E. Müller, Younis Baqi, Mercè Correa, John D. SalamoneAbstract:Rationale Depressed people show effort-related motivational symptoms, such as anergia, retardation, lassitude, and fatigue. Animal tests can model these motivational symptoms, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor Tetrabenazine. Tetrabenazine produces depressive symptoms in humans and, at low doses, preferentially depletes dopamine.
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Effort-related motivational effects of the VMAT-2 inhibitor Tetrabenazine: Implications for animal models of the motivational symptoms of depression
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013Co-Authors: Eric J. Nunes, Samantha E. Yohn, Patrick A. Randall, Christa E. Müller, Younis Baqi, Mercè Correa, Evan E. Hart, Charlotte Freeland, Laura López-cruz, John D. SalamoneAbstract:Motivated behaviors are often characterized by a high degree of behavioral activation, and work output and organisms frequently make effort-related decisions based upon cost/benefit analyses. Moreover, people with major depression and other disorders often show effort-related motivational symptoms such as anergia, psychomotor retardation, and fatigue. It has been suggested that tasks measuring effort-related choice behavior could be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT) inhibitor Tetrabenazine. Tetrabenazine produces depressive symptoms in humans and, because of its selective inhibition of VMAT-2, it preferentially depletes dopamine (DA). Rats were assessed using a concurrent fixed-ratio 5/chow feeding choice task that is known to be sensitive to dopaminergic manipulations. Tetrabenazine shifted response choice in rats, producing a dose-related decrease in lever pressing and a concomitant increase in chow intake. However, it did not alter food intake or preference in parallel free-feeding choice studies. The effects of Tetrabenazine on effort-related choice were reversed by the adenosine A2A antagonist MSX-3 and the antidepressant bupropion. A behaviorally active dose of Tetrabenazine decreased extracellular DA in nucleus accumbens and increased expression of DARPP-32 in accumbens medium spiny neurons in a pattern indicative of reduced transmission at both D1 and D2 DA receptors. These experiments demonstrate that Tetrabenazine, which is used in animal models to produce depression-like effects, can alter effort-related choice behavior. These studies have implications for the development of animal models of the motivational symptoms of depression and related disorders.
