What are the treatment options for Huntington's disease (HD) chorea?

From the Guidelines

Treatment for Huntington's disease chorea should focus on managing symptoms with medications such as tetrabenazine, deutetrabenazine, antipsychotics, amantadine, or riluzole, alongside a multidisciplinary approach to maintain function and improve quality of life. When considering treatment options, it's essential to prioritize managing the involuntary movements that characterize this genetic neurodegenerative disorder. According to the American College of Medical Genetics and Genomics standards and guidelines for clinical genetics laboratories, 2014 edition 1, Huntington disease is a neurodegenerative disease of mid-life onset that produces choreic movements and cognitive decline.

Key Treatment Options

• Tetrabenazine (12.5-100 mg daily in divided doses) is a first-line medication that depletes dopamine by inhibiting vesicular monoamine transporter type 2.
• Deutetrabenazine (6-48 mg daily in divided doses) offers similar efficacy with potentially fewer side effects due to its longer half-life.
• Antipsychotics like risperidone (0.5-2 mg daily), olanzapine (2.5-10 mg daily), or haloperidol (0.5-5 mg daily) may also be effective by blocking dopamine receptors.
• Amantadine (100-300 mg daily) or riluzole (50 mg twice daily) might provide modest benefit in some patients.

Treatment Approach

Treatment should start at low doses with gradual titration to minimize side effects such as sedation, depression, or parkinsonism. Regular monitoring for adverse effects is essential, particularly for depression and suicidal ideation with tetrabenazine. A multidisciplinary approach including physical therapy, occupational therapy, and speech therapy is crucial to maintain function. While these medications can reduce chorea, they do not alter disease progression, and treatment goals should focus on improving quality of life and daily functioning rather than complete symptom elimination.

From the FDA Drug Label

Tetrabenazine tablets are indicated for the treatment of chorea associated with Huntington’s disease. The treatment options for Huntington's disease (HD) chorea include tetrabenazine.

• The dose of tetrabenazine should be individualized for each patient.
• The starting dose is 12.5 mg per day, and it can be increased to 25 mg per day after one week.
• The maximum recommended daily dose is 100 mg, and the maximum recommended single dose is 37.5 mg.
• Patients should be closely monitored for the emergence or worsening of depression, suicidality, or unusual changes in behavior.
• Particular caution should be exercised in treating patients with a history of depression or prior suicide attempts or ideation 2.
• The efficacy of tetrabenazine in treating HD chorea was established in a randomized, double-blind, placebo-controlled multi-center trial 2.

From the Research

Treatment Options for Huntington's Disease (HD) Chorea

• Tetrabenazine is a US Food and Drug Administration (FDA)-approved treatment for chorea associated with HD, which works by reversible depletion of monoamines, particularly dopamine, from presynaptic terminals via inhibition of human vesicular monoamine transporter type 2 3.
• Deutetrabenazine is another FDA-approved treatment for HD-associated chorea, which is a deuterated form of tetrabenazine and has a longer drug half-life and less frequent daily dosing 4, 5.
• Clinical trials have shown that both tetrabenazine and deutetrabenazine are effective in improving chorea symptoms in HD patients, with deutetrabenazine having a more favorable tolerability profile compared to tetrabenazine 4, 5, 6.
• The most common reasons for stopping upward titration of tetrabenazine were optimal chorea control, intolerability of higher doses, and reaching the maximum recommended dosage despite suboptimal chorea control 7.
• Deutetrabenazine has been shown to have a lower risk of moderate to severe adverse events, neuropsychiatric adverse events, and dose reduction or dose reduction/suspension compared to tetrabenazine 6.

Comparison of Tetrabenazine and Deutetrabenazine

• Both tetrabenazine and deutetrabenazine are vesicular monoamine transporter 2 (VMAT2) inhibitors, but deutetrabenazine has a longer half-life and less frequent daily dosing due to its deuterium modifications 4, 5.
• Clinical trials have shown that deutetrabenazine has a similar efficacy to tetrabenazine in improving chorea symptoms, but with a more favorable tolerability profile 4, 5, 6.
• Indirect treatment comparison has demonstrated that deutetrabenazine has a lower risk of adverse events, including moderate to severe adverse events, neuropsychiatric adverse events, and dose reduction or dose reduction/suspension, compared to tetrabenazine 6.

Clinical Trials and Studies

• The First-HD trial showed that deutetrabenazine was efficacious in treating chorea and was generally well tolerated 4, 5.
• The TETRA-HD trial showed that tetrabenazine was efficacious in treating chorea, but had tolerability concerns possibly due to its pharmacokinetic properties 6.
• The ARC-HD study showed that subjects who converted from tetrabenazine to deutetrabenazine had a similar efficacy for chorea, but with a more favorable adverse effect profile 5.