eMedicine Specialties > Neurology > Movement and Neurodegenerative Diseases
Huntington Disease: Treatment & Medication
Updated: Sep 4, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
Treatment
Medical Care
Consider general safety measures and nonpharmacologic interventions first in the management of Huntington disease (HD).
- If chorea is severe enough to interfere with function, consider treatment with benzodiazepines, such as clonazepam or diazepam; valproic acid; dopamine-depleting agents, such as reserpine or tetrabenazine (approved by the US Food and Drug Administration [FDA] in August 2008); and finally, neuroleptics.
- The drug tetrabenazine has shown some positive effects in the treatment of chorea, for patients with HD. It selectively depletes central monoamines by reversibly binding to the type-2 vesicular monoamine transporter.
- Results from a phase III clinical study showed that this investigational drug is an effective treatment for chorea associated with HD. The dosing range that proved effective was 12.5-100 mg/d.16 Its manufacturer has been granted fast track and orphan drug status by the FDA. It is the first treatment for chorea in patients with HD in the United States. Always weigh potential adverse effects against the benefits of each drug.
- Patients who have HD and predominant features of bradykinesia and rigidity may benefit from treatment with levodopa or dopamine agonists.17
- Depression in patients with HD is treatable and should be recognized promptly. Selective serotonin reuptake inhibitors (SSRIs) should be considered as first-line therapy. Other antidepressants, including bupropion, venlafaxine, nefazodone, and tricyclic antidepressants, also can be used. Electroconvulsive therapy (ECT) can be used in patients with refractory depression.
- Antipsychotic medications may be necessary in patients with hallucinations, delusions, or schizophrenia-like syndromes. Newer agents, such as quetiapine, clozapine, olanzapine, and risperidone, are preferred to older agents because of the lower incidence of extrapyramidal side effects and the decreased risk for tardive syndromes.
- Irritability may be treated with antidepressants, particularly the SSRIs; mood stabilizers, such as valproic acid or carbamazepine; and, if needed, atypical neuroleptics.
- Other less frequent aspects of HD that may require pharmacologic treatment are mania, obsessive-compulsive disorder, anxiety, sexual disorders, myoclonus, tics, dystonia, and epilepsy.
Surgical Care
Ablative surgical procedures and fetal cell transplantation have been attempted in patients with HD. Currently, enough data to support this type of treatment are not available. It is still experimental.
Consultations
- Physical therapist
- Occupational therapist
- Speech therapist
- Psychiatrist
- Genetic counselor
Medication
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
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.
Adult
12.5 mg PO qam initially; after 1 wk, increase to 12.5 mg bid; titrate slowly at weekly intervals in 12.5-mg increments to identify dose that reduces chorea and is well tolerated; if 37.5-50 mg/d required, administer as tid regimen; not to exceed 100 mg/d
CYP2D6 poor metabolizers: Titrate as described; not to exceed single dose of 25 mg or daily dose of 50 mg
Patients requiring >50 mg/d should be genotyped for CYP2D6
Pediatric
Not established
Active metabolites (alpha and beta dihydrotetrabenazine [HTBZ]) are principally metabolized by CYP2D6; poor metabolizers of CYP2D6 or strong CYP2D6 inhibitors (eg, paroxetine) increase exposure to these metabolites; caution if coadministered with weak CYP2D6 inhibitors (eg, duloxetine, sertraline, amiodarone)
Patients who are actively suicidal or are untreated or inadequately treated for depression; coadministration with MAOIs or reserpine (at least 20 d should elapse after stopping reserpine before starting tetrabenazine); hepatic impairment
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Serious adverse effects include depression and suicidal ideation; common adverse effects include insomnia, depression, drowsiness, restlessness, and nausea; may worsen mood, cognition, rigidity, and functional capacity; may cause QTc prolongation
Anticonvulsant
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.
Adult
250 mg/d PO initially; not to exceed 60 mg/kg/d
Pediatric
Not established
Cimetidine, salicylates, felbamate, and erythromycin may increase toxicity; rifampin may reduce levels significantly; in children, salicylates decrease protein binding and metabolism of valproate; may result in variable changes of carbamazepine concentrations with possible loss of seizure control; may increase diazepam and ethosuximide toxicity (monitor closely); may increase phenobarbital and phenytoin levels, while either one may decrease valproate levels; may displace warfarin from protein binding sites (monitor coagulation tests); may increase zidovudine levels in HIV-seropositive patients
Documented hypersensitivity; hepatic disease
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Thrombocytopenia and abnormal coagulation parameters have occurred; risk of thrombocytopenia increases significantly at total trough plasma concentrations >110 mcg/mL in females and >135 mcg/mL in males; before initiating therapy, at periodic intervals, and prior to surgery determine platelet counts and bleeding time; reduce dose or discontinue therapy if hemorrhage, bruising, or hemostasis/coagulation disorder occurs; hyperammonemia may occur, resulting in hepatotoxicity; monitor patients closely for appearance of malaise, weakness, facial edema, anorexia, jaundice, and vomiting; may cause drowsiness
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.
Adult
0.25-0.5 mg/d PO initially; increase dose very slowly to avoid sedation
Pediatric
Not established
Phenytoin and barbiturates may reduce effects; CNS depressants increase toxicity
Documented sensitivity; significant hepatic disease; acute narrow-angle glaucoma (may use in open-angle glaucoma if patient receiving appropriate therapy)
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Data from several sources raise concerns about use during pregnancy; withdrawal symptoms may occur after abrupt discontinuation; most common adverse effects include sedation, ataxia, and other cognitive adverse effects
Caution in chronic respiratory disease or impaired renal function; withdrawal symptoms can result from abrupt discontinuation of medication
Antipsychotic agents
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.
Adult
0.5-1 mg/d PO initially; increase dose until benefit achieved or adverse effects appear; not to exceed 6 mg/d divided bid
Pediatric
Not established
May enhance hypotensive effects of other therapeutic agents because of potential for inducing hypotension; may antagonize effects of levodopa and dopamine agonists; long-term administration of carbamazepine may increase clearance of risperidone; long-term administration of clozapine may decrease clearance; fluoxetine may increase plasma concentration of antipsychotic fraction (ie, risperidone and 9-hydroxyrisperidone) by raising concentration of risperidone but not active metabolite, 9-hydroxyrisperidone
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Adverse effects include extrapyramidal symptoms, dizziness, hyperkinesia, somnolence, and nausea; advise patients to notify their physicians if they become pregnant or intend to become pregnant during therapy; caution when taking in combination with other centrally acting drugs and alcohol
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.
Adult
0.5 mg/d PO initially; may increase cautiously to 6-8 mg/d; gradually reduce dose to lowest effective maintenance dose upon achieving satisfactory response
Pediatric
Not established
May increase tricyclic antidepressant serum concentrations and hypotensive action of antihypertensive agents; phenobarbital or carbamazepine may decrease effects; anticholinergics may increase intraocular pressure; lithium may cause encephalopathy-like syndrome
Documented hypersensitivity; narrow-angle glaucoma; bone-marrow suppression; severe cardiac or liver disease; severe hypotension; subcortical brain damage
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in severe cardiovascular disorders because of possibility of transient hypotension and/or precipitation of anginal pain; potentially serious adverse effects include tardive dyskinesia (and other tardive syndromes) and neuroleptic malignant syndrome; other common adverse effects include extrapyramidal symptoms (eg, parkinsonism, akathisia, dystonia), insomnia, restlessness, anxiety, agitation, drowsiness, depression, and confusion
Rauwolfia alkaloids
These agents may improve choreic movements in patients.
Reserpine
Dopamine-depleting agent. Used in past to treat hypertension.
Adult
0.05-0.1 mg/d PO initially; increase cautiously at weekly intervals until benefit achieved or adverse effects appear
Pediatric
Not established
Tricyclic antidepressants may decrease antihypertensive effects; digitalis or quinidine may cause cardiac arrhythmias
Documented hypersensitivity; hypotension; severe depression
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in patients with renal impairment or peptic ulcer disease; parkinsonism, sedation, and depression are adverse effects that may be deleterious particularly in patients with HD; restlessness, hypotension, and dizziness may occur
Antidepressants
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.
Adult
10-20 mg/d PO initially; not to exceed 40-60 mg/d
Pediatric
Not established
Phenobarbital and phenytoin decrease effects; alcohol, cimetidine, sertraline, phenothiazines, and warfarin increase toxicity
Documented hypersensitivity; concurrent MAOIs
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Possibility of suicide attempt has to be adequately assessed, and close supervision of high-risk patients should accompany initial drug therapy; hypomania or mania can occur after use of SSRIs; caution in history of seizures, mania, renal disease, or cardiac disease
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Further Reading
Keywords
Huntington's disease, HD, Huntington chorea, hereditary chorea, huntingtin, involuntary movements, dementia, Huntington disease, behavior changes, juvenile HD, juvenile Huntington disease, autosomal dominant disorder, movement disorder, cognitive disorder, behavior disorder, chorea, neuronal dysfunction, neuronal loss
