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ARTICLES: Huntington Study Group Tetrabenazine as antichorea therapy in Huntington disease: A randomized controlled trial Neurology 2006; 66: 366-372 [Abstract] [Full text] [PDF]

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Tetrabenazine as antichorea therapy in Huntington disease: A randomized controlled trial

Aman A. Savani, Ivan S. Login   (22 September 2006)

Reply from the Authors

Frederick J. Marshall, Stanley Fahn, New York, NY, Kathleen Clarence-Smith, Washington, DC   (22 September 2006)

Tetrabenazine as antichorea therapy in Huntington disease: A randomized controlled trial 22 September 2006
Aman A. Savani, University of Virginia School of Medicine Box 800394; Univ Virginia, Charlottesville, VA 22908, Ivan S. Login Send Correspondence to journal: Re: Tetrabenazine as antichorea therapy in Huntington disease: A randomized controlled trial aas5u{at}virginia.edu Aman A. Savani, et al.	The HSG described the important benefit of tetrabenazine (TBZ) in patients with Huntington Disease. [1] We would like to stress the mechanism of action of this valuable agent. The only action ascribed to TBZ in achieving the clinical benefit was inhibiting presynaptic vesicular monoamine transporters to block amine reuptake and secondarily decrease dopamine levels. Although this mechanism is clearly established, TBZ is also functionally effective as a dopamine receptor antagonist based on a large body of rigorous literature. This additional mechanism could well contribute to the clinical benefit observed and possibly explain some unexpected results. In support of an independent action as a dopaminergic antagonist, TBZ: blocks dopamine- [2] and apomorphine-mediated [3] inhibition of pituitary prolactin release in vivo [2,3] and in vitro [2]; reduces apomorphine-mediated turning in the Ungerstedt model [3]; binds directly to dopamine receptors in striatum [2,3] and pituitary [2]; increases dopamine turnover or synthesis in animals [3] and importantly, even in patients [4] and can induce clinical dystonia. [5] It is unclear why the HSG overlooked these observations; one member co-authored 2 relevant pivotal studies. [3,5] We think this matter has more than simply academic interest. Dopamine receptor blockade could certainly contribute significantly to the clinical benefit along with dopamine depletion. We speculate further, that the apparent "ceiling effect," with clinical benefit predominantly at or below TBZ 50 mg/day, could be partly explained by a limiting effect of TBZ directly at the dopamine receptor. We hope the readership and the HSG will reconsider these clinical results with regard to the underlying mechanisms, and as further clinical studies are planned and executed. References 1. Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: A randomized controlled trial. Neurology 2006; 66: 366 - 372. 2. Login IS, Cronin MJ, MacLeod RM. Tetrabenazine has properties of a dopamine receptor antagonist. Ann Neurol 1982; 12: 257-262. 3. Reches A, Burke RE, Kuhn CM, Hassan MN, Jackson VR, Fahn, S. Tetrabenazine, an amine-depleting drug, also blocks dopamine receptors in rat brain. J Pharmacol Exp Ther 1983; 225(3): 515-521. 4. McLellan DL, Chalmers RJ, Johnson RH. A double-blind trial of tetrabenazine, thiopropazate and placebo in patients with chorea. Lancet 1974; 1: 104-106. 5. Burke RE, Reches A, Traub MM, Ilson J, Swash M, Fahn S. Tetrabenazine induces acute dystonic reactions. Ann Neurol 1985; 17: 200 -202. Disclosure: The authors report no conflicts of interest.
Reply from the Authors 22 September 2006
Frederick J. Marshall, University of Rochester Dept of Neurology, Univ. of Rochester, 1359 Mt. Hope Ave, Rochester, NY 14620, Stanley Fahn, New York, NY, Kathleen Clarence-Smith, Washington, DC Send Correspondence to journal: Re: Reply from the Authors fred.marshall{at}ctcc.rochester.edu Frederick J. Marshall, et al.	We thank Drs. Savani and Login for pointing out that tetrabenazine, in addition to its dopamine-depleting effect, may also have some effect in inhibiting dopamine receptors. We do not believe, however, that this effect is relevant at the pharmacological dosages used in patients. The dopamine receptor binding activity of tetrabenazine was described to occur in vitro at micromolar concentrations in a era prior to the full characterization of the vesicular monoamine transporter type-2 (VMAT- 2). [2] Inhibition of VMAT2 by tetrabenazine or its active metabolite, alpha- dihydro-tetrabenazine, occurs at nanomolar concentrations (1,000 times more potent). [6] Extrapolation from studies in animals show that brain concentrations of tetrabenazine are generally in the 10 to 50 nanomolar range (concentrations that are not known to affect the dopamine receptor). [7] Moreover PET-scan studies show that binding of á-dihydro- tetrabenazine is not displaced by haloperidol or apomorphine, indicating that it does not bind to the dopamine receptor in vivo. [8] How much of a role tetrabenazine’s dopamine receptor blocking activity plays is uncertain because the rapid 90% depletion of dopamine concentration by tetrabenazine is sufficient to produce its clinical antichoreic effect. A search via PubMed failed to find any reports of tetrabenazine causing tardive dyskinesia. This might indicate that either tetrabenazine has only a minor dopamine receptor blocking role at therapeutic levels or that the concomitant depletion of dopamine allows a means to avoid tardive dyskinesia. References 6. Scherman D, Jaudon P, Henry JP. Characterization of the monoamine carrier of chromaffin granule membrane by binding of [2- 3H]dihydrotetrabenazine. Proc Natl Acad Sci USA 1983;80:584-588. 7. Mehvar R, Jamali F. Concentration-effect relationships of tetrabenazine and dihydrotetrabenazine in the rat. J Pharm Sci 1987;76(6):461-465. 8. MR Kilbourn, PS Sherman, K Kuszpit. In vivo measures of dopaminergic radioligands in the rat brain: equilibrium infusion studies. Synapse 43:188-194, 2002. Disclosure: This study was funded by a grant from Prestwick Pharmaceuticals, Inc., to the University of Rochester and in turn through subcontracts to the participating research sites. The Huntington Study Group (HSG) is a nonprofit consortium of Huntington’s disease investigators (http://www.huntington-study-group.org/). None of the HSG investigators or staff had equity interests with Prestwick Pharmaceuticals, Inc.. Dr. Fahn received consulting fees of less than $10,000. Dr. Marshall presented data at national and international meetings for which he received travel reimbursement from Prestwick Pharmaceuticals, Inc. Dr. Clarence-Smith is an employee of Prestwick Pharmaceuticals, Inc.