What is the recommended first‑line pharmacologic therapy for chorea in a patient with Huntington’s disease, including dosing and monitoring?

First-Line Pharmacologic Therapy for Chorea in Huntington's Disease

Tetrabenazine is the recommended first-line pharmacologic agent for chorea in Huntington's disease, starting at 12.5 mg once daily in the morning and titrating slowly by 12.5 mg weekly to a target dose of 37.5-50 mg/day divided three times daily, with a maximum of 100 mg/day for extensive CYP2D6 metabolizers. 1

Initial Dosing Strategy

• Start tetrabenazine at 12.5 mg once daily in the morning for the first week 1
• Increase to 25 mg/day (12.5 mg twice daily) after week one 1
• Continue weekly titration by 12.5 mg increments to identify the lowest dose that controls chorea while remaining tolerable 1
• Doses of 37.5-50 mg/day should be divided into three times daily administration, with maximum single dose of 25 mg 1

Dosing Above 50 mg/Day

• CYP2D6 genotyping is mandatory before exceeding 50 mg/day to identify poor metabolizers versus extensive metabolizers 1
• Extensive and intermediate metabolizers can be titrated up to 100 mg/day maximum (37.5 mg maximum single dose) using the same weekly 12.5 mg increment strategy 1
• Poor metabolizers should not exceed 50 mg/day total and 25 mg per single dose due to impaired drug clearance 1

Alternative First-Line Agents

• Deutetrabenazine and valbenazine are FDA-approved alternative VMAT2 inhibitors with potentially improved tolerability profiles compared to tetrabenazine 2
• Deutetrabenazine offers pharmacokinetic advantages through deuterium modification, resulting in more stable plasma levels and potentially fewer peak-dose adverse effects 3, 4
• Among HD experts, tetrabenazine, tiapride (in Europe), olanzapine, and risperidone are the preferred first-choice agents 5

Critical Monitoring Requirements

Depression and Suicidality Screening

• Tetrabenazine carries a black box warning for increased risk of depression and suicidal ideation in HD patients 1
• The drug is absolutely contraindicated in actively suicidal patients and those with untreated or inadequately treated depression 1
• Close observation for emergence or worsening of depression, suicidality, or unusual behavioral changes must accompany therapy 1
• Patients with prior suicide attempts, suicidal ideation, or history of depression require particular caution, as these are already increased in HD 1

Motor and Psychiatric Adverse Effects

• If akathisia, restlessness, parkinsonism, insomnia, anxiety, or sedation develop during titration, immediately halt dose escalation and reduce the dose 1
• If adverse reactions persist despite dose reduction, consider withdrawing tetrabenazine or initiating specific treatment such as antidepressants 1
• Real-world data show 41.8% of patients experience treatment gaps ≥60 days, with median time to discontinuation of 293.5 days, highlighting tolerability challenges 6

When to Initiate Treatment

• Pharmacologic treatment for chorea should be initiated when involuntary movements interfere with daily functioning, cause social isolation, gait instability, falls, or physical injury 5
• Not all HD patients with chorea require pharmacotherapy; only 36.1% of patients with manifest chorea in the Enroll-HD cohort received chorea-specific medication 7

Adjunctive Non-Pharmacologic Management

• Speech therapy is beneficial for orofacial chorea affecting speech and swallowing 8, 9
• Occupational therapy assists with activities of daily living impacted by choreiform movements 8, 9

Treatment Pattern Considerations

• Among treated patients receiving first-line therapy, 49.9% receive VMAT2 inhibitor monotherapy and 27.7% receive antipsychotic monotherapy 7
• Of patients started on VMAT2 inhibitors or antipsychotics as first-line, 92% and 84% respectively remain on these drug classes (alone or in combination) throughout follow-up 7
• Combination therapy is the most common second-line approach when monotherapy proves insufficient 7

Critical Pitfall to Avoid

• Do not prescribe tetrabenazine without first screening for active suicidal ideation, untreated depression, and prior psychiatric history—this is a contraindication, not merely a precaution 1
• Do not exceed 50 mg/day without CYP2D6 genotyping, as poor metabolizers will accumulate toxic drug levels 1
• Tetrabenazine can be administered without regard to food, simplifying the dosing regimen 1