Huntington Disease Medication
- Author: Fredy J Revilla, MD; Chief Editor: Selim R Benbadis, MD more...
Medication Summary
Although no therapy is currently available to delay the onset of symptoms or prevent the progression of the disease, symptomatic treatment of patients with Huntington disease (HD) may improve the quality of life and prevent complications. As is the case with other neurological diseases, HD makes individuals more vulnerable to side effects from medications, particularly cognitive adverse effects. Avoid polypharmacy if possible. Symptomatic treatment for HD can be divided into drugs to treat the movement disorder and drugs to treat psychiatric or behavioral problems.
Experimental therapies for HD currently are being tested in animal models and human trials. Awareness of ongoing research to find an effective cure for HD must be a part of the care plan of an individual patient and the patient's family.
Therapeutic options include dopamine-depleting agents (eg, reserpine, tetrabenazine) and dopamine-receptor antagonists (eg, neuroleptics). Long-term use of these drugs may carry a high risk of adverse effects. Choreic movements in patients with HD should be treated pharmacologically only if they become disabling to the patient. Neuroleptics may worsen other features of the disease, such as bradykinesia and rigidity, leading to further functional decline.
Results of some studies have suggested that valproic acid and clonazepam may be effective in the treatment of chorea, while results of other studies have been less conclusive. In the authors' experience, using valproic acid and clonazepam first may be worthwhile because of their safer adverse-effect profiles.
Tetrabenazine is a dopamine-depleting agent was approved by the FDA in August 2008. It may be more effective than reserpine in the treatment of chorea and less likely to cause hypotension. The dose is titrated slowly and may be increased over several weeks to a maximum 75-100 mg/d in divided doses.
Monoamine inhibitor
Class Summary
Tetrabenazine is the first drug approved specifically to treat chorea associated with Huntington disease.
Tetrabenazine (Xenazine)
Depletes neurotransmitter stores of dopamine, serotonin, and noradrenaline within nerve cells in the brain, thereby altering transmission of electric signals from the brain that control movement by reversibly inhibiting vesicular monoamine transporter 2 (VMAT2).
Efficacy and safety established in a randomized, double-blind, placebo-controlled, multicenter study. Patients treated with tetrabenazine had significant improvement in chorea compared with those treated with placebo. Additional studies support this effect. Indicated for chorea associated with Huntington disease.
Anticonvulsant
Class Summary
These agents are used to manage muscle spasms in chorea.
Valproic acid (Depakote, Depakene, Depacon)
Carboxylic acid commonly used as antiepileptic drug, mood stabilizer in mania, and prophylactic agent for migraine. When combined with sodium valproate in 1:1 molar relationship, called divalproex sodium. Mechanism by which valproate exerts its antiepileptic effects has not been established; its activity may be related to increased brain levels of GABA. No large clinical trials exist to support its use for hyperkinetic movement disorders, but it may be effective, as suggested by a few small studies in patients with chorea of different etiologies.
Daily maximum dose of 2000 mg in divided doses (bid or tid) is enough to determine whether drug is going to be effective for individual patient.
Clonazepam (Klonopin)
Belongs to benzodiazepine class of drugs. Enhances activity of GABA, major inhibitory neurotransmitter in CNS. Used commonly as antiepileptic drug. May be useful in treatment of chorea, but no large clinical trials exist to support its use. Does not induce parkinsonism or carry risk of tardive syndromes, as neuroleptics do; therefore, an adequate trial with this medication is reasonable before using dopamine antagonists.
Maximum daily dose of 2-4 mg divided bid/tid usually is enough to determine effectiveness for individual patient.
Antipsychotic agents
Class Summary
These agents may improve choreic movements in patients.
Risperidone (Risperdal)
Antipsychotic agent that belongs to new chemical class, benzisoxazole derivatives.
Antagonist of type 2 dopamine and serotonin receptors.
Less likely than typical neuroleptics to cause parkinsonism.
Haloperidol (Haldol)
First of butyrophenone class of major tranquilizers. Typical neuroleptics, such as haloperidol, are potent dopamine-receptor antagonists and should be used only as last resort to treat chorea.
Rauwolfia alkaloids
Class Summary
These agents may improve choreic movements in patients.
Reserpine
Dopamine-depleting agent. Used in past to treat hypertension.
Antidepressants
Class Summary
Depression is relatively common in patients with HD and should be treated pharmacologically as soon as diagnosis of depression is made. Depression in patients with HD can be treated with the same agents used for treatment of depression of any other cause. SSRIs may be used as first-line therapy because of their low adverse-effect profile, convenient dosing, and safety in the event of overdose. Other antidepressants can be used, including bupropion, venlafaxine, nefazodone, and the tricyclic antidepressants. Electroconvulsive therapy can be effective if an immediate intervention is required and in patients who do not respond to several good trials of medication.
Paroxetine (Paxil)
SSRI that can be used once daily. Most patients should take it in morning because can be stimulating and may cause insomnia. If sedation occurs, drug should be taken at bedtime. A few patients develop sexual problems, such as decreased libido, anorgasmia, or ejaculatory delay.
Huntington G. On chorea. Med Surg Report. 1872;26:320.
Folstein SE. Huntington's Disease: A Disorder of Families. The Johns Hopkins University Press;1989.
Vonsattel JP, DiFiglia M. Huntington disease. J Neuropathol Exp Neurol. May 1998;57(5):369-84. [Medline].
Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP Jr. Neuropathological classification of Huntington's disease. J Neuropathol Exp Neurol. Nov 1985;44(6):559-77. [Medline].
A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell. Mar 26 1993;72(6):971-83. [Medline].
Cooper JK, Schilling G, Peters MF, et al. Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture. Hum Mol Genet. May 1998;7(5):783-90. [Medline].
Davies SW, Turmaine M, Cozens BA, et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell. Aug 8 1997;90(3):537-48. [Medline].
Klement IA, Skinner PJ, Kaytor MD, et al. Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell. Oct 2 1998;95(1):41-53. [Medline].
Saudou F, Finkbeiner S, Devys D, et al. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell. Oct 2 1998;95(1):55-66. [Medline].
Tabrizi SJ, Scahill RI, Durr A, Roos RA, Leavitt BR, Jones R, et al. Biological and clinical changes in premanifest and early stage Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis. Lancet Neurol. Jan 2011;10(1):31-42. [Medline].
Wexler NS, Lorimer J, Porter J, Gomez F, Moskowitz C, Shackell E, et al. Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset. Proc Natl Acad Sci U S A. Mar 9 2004;101(10):3498-503. [Medline].
Wexler NS, Young AB, Tanzi RE, Travers H, Starosta-Rubinstein S, Penney JB, et al. Homozygotes for Huntington's disease. Nature. Mar 12-18 1987;326(6109):194-7. [Medline].
Ho A, Hocaoglu M. Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective. Clin Genet. Sep 2011;80(3):235-239. [Medline].
Nucifora FC Jr, Sasaki M, Peters MF, et al. Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science. Mar 23 2001;291(5512):2423-8. [Medline].
Graham RK, Deng Y, Slow EJ, Haigh B, Bissada N, Lu G. Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell. Jun 16 2006;125(6):1179-91. [Medline].
Stober T, Wussow W, Schimrigk K. Bicaudate diameter--the most specific and simple CT parameter in the diagnosis of Huntington's disease. Neuroradiology. 1984;26(1):25-8. [Medline].
Quaid KA. Presymptomatic testing for Huntington disease in the United States. Am J Hum Genet. Sep 1993;53(3):785-7. [Medline].
Ondo WG, Tintner R, Thomas M, Jankovic J. Tetrabenazine treatment for Huntington's disease-associated chorea. Clin Neuropharmacol. Nov-Dec 2002;25(6):300-2. [Medline].
Racette BA, Perlmutter JS. Levodopa responsive parkinsonism in an adult with Huntington's disease. J Neurol Neurosurg Psychiatry. Oct 1998;65(4):577-9. [Medline].
Barbeau A, Duvoisin RC, Gerstenbrand F, et al. Classification of extrapyramidal disorders. Proposal for an international classification and glossary of terms. J Neurol Sci. Aug 1981;51(2):311-27. [Medline].
Bruyn G, Bots G, Dom R. Huntington's chorea. Current neuropathological status. Adv Neurol. 1979;1:83-93.
DiFiglia M, Sapp E, Chase K, et al. Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron. May 1995;14(5):1075-81. [Medline].
DiFiglia M, Sapp E, Chase KO, et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science. Sep 26 1997;277(5334):1990-3. [Medline].
Fahn S. Concept and classification of dystonia. Adv Neurol. 1988;50:1-8. [Medline].
Folstein SE, Chase GA, Wahl WE, et al. Huntington disease in Maryland: clinical aspects of racial variation. Am J Hum Genet. Aug 1987;41(2):168-79. [Medline].
Gutekunst CA, Li SH, Yi H, Mulroy JS, Kuemmerle S, Jones R, et al. Nuclear and neuropil aggregates in Huntington's disease: relationship to neuropathology. J Neurosci. Apr 1 1999;19(7):2522-34. [Medline].
Gutekunst CA, Norflus F, Hersch SM. Recent advances in Huntington's disease. Curr Opin Neurol. Aug 2000;13(4):445-50. [Medline].
Harper PS. Huntington's Disease. 2nd ed. Philadelphia: WB Saunders Company Ltd; 1996.
Hersch S, Ferrante R. Neuropathology and pathophysiology of Huntington's disease. In: Watts RL, Koller WC, eds. Movement Disorders: Neurologic Principles and Practice. New York: McGraw-Hill; 1997:503-526.
Jenkins JB, Conneally PM. The paradigm of Huntington disease. Am J Hum Genet. Jul 1989;45(1):169-75. [Medline].
Kim M, Lee HS, LaForet G, et al. Mutant huntingtin expression in clonal striatal cells: dissociation of inclusion formation and neuronal survival by caspase inhibition. J Neurosci. Feb 1 1999;19(3):964-73. [Medline].
Kuemmerle S, Gutekunst CA, Klein AM, Li XJ, Li SH, Beal MF, et al. Huntington aggregates may not predict neuronal death in Huntington's disease. Ann Neurol. Dec 1999;46(6):842-9. [Medline].
Lasker AG, Zee DS, Hain TC, Folstein SE, Singer HS. Saccades in Huntington's disease: initiation defects and distractibility. Neurology. Mar 1987;37(3):364-70. [Medline].
Marshall FJ, Shoulson I. Clinical features and treatment of Huntington's disease. In: Watts RL, Koller WC, eds. Movement Disorders: Neurologic Principles and Practice. New York: McGraw-Hill; 1997.
PEARSON JS, PETERSEN MC, LAZARTE JA, BLODGETT HE, KLEY IB. An educational approach to the social problem of Huntington's chorea. Proc Staff Meet Mayo Clin. Aug 10 1955;30(16):349-57. [Medline].
Penney JB, Young AB. Huntington's disease. In: Jankovic J, Tolosa E, eds. Parkinson's Disease and Movement Disorders. 3rd ed. Baltimore: Williams & Wilkins; 1998.
Petersén A, Mani K, Brundin P. Recent advances on the pathogenesis of Huntington's disease. Exp Neurol. May 1999;157(1):1-18. [Medline].
REED TE, CHANDLER JH. Huntington's chorea in Michigan. I. Demography and genetics. Am J Hum Genet. Jun 1958;10(2):201-25. [Medline].
Shokeir MH. Investigations on Huntington's disease in the Canadian Prairies. I. Prevalence. Clin Genet. Apr 1975;7(4):345-8. [Medline].
Sørensen SA, Fenger K. Causes of death in patients with Huntington's disease and in unaffected first degree relatives. J Med Genet. Dec 1992;29(12):911-4. [Medline].
Print
