What is the optimal pharmacologic treatment plan for Huntington's chorea, including first‑line VMAT2 inhibitors, dosing, and second‑line options?

Management of Huntington's Chorea

First-Line Pharmacological Treatment

VMAT2 inhibitors are the FDA-approved first-line treatment for chorea in Huntington's disease, with deutetrabenazine (Austedo) and valbenazine (Ingrezza) preferred over tetrabenazine due to superior tolerability profiles. 1, 2, 3

VMAT2 Inhibitor Selection and Dosing

Deutetrabenazine (Austedo/Austedo XR):

• Start at 6 mg twice daily (12 mg/day total) for immediate-release or 12 mg once daily for extended-release formulation 3
• Titrate weekly by 6 mg/day increments based on chorea reduction and tolerability 3
• Maximum dose: 48 mg/day for extensive CYP2D6 metabolizers; 36 mg/day for poor CYP2D6 metabolizers 3
• Administer immediate-release with food; extended-release can be taken with or without food 3
• Swallow tablets whole—do not crush, chew, or break 3

Valbenazine (Ingrezza):

• Start at 40 mg once daily for one week 2
• Increase to 80 mg once daily after the first week 2
• For chorea specifically, may titrate in 20 mg increments every two weeks; 40-60 mg daily may be considered based on response 2
• Can be taken with or without food 2
• Maximum dose: 40 mg/day for poor CYP2D6 metabolizers or patients with moderate-to-severe hepatic impairment 2

Tetrabenazine (older option):

• Start at 12.5 mg daily in week 1, then 12.5 mg twice daily in week 2 1
• Titrate weekly by 12.5 mg to tolerated dose that reduces chorea 1
• Doses ≥37.5 mg/day require three divided doses; maximum single dose 25 mg 1
• Patients requiring >50 mg/day must undergo CYP2D6 genotyping 1
• Maximum: 50 mg/day for poor metabolizers; 100 mg/day for extensive metabolizers 1

Evidence Hierarchy for VMAT2 Inhibitor Selection

Deutetrabenazine demonstrates significantly lower risk of moderate-to-severe adverse events compared to tetrabenazine, including reduced neuropsychiatric effects (agitation, akathisia, depression, drowsiness, insomnia, parkinsonism) and lower rates of dose reduction. 4 The deuterated formulation extends active metabolite half-lives and minimizes drug concentration fluctuations, which likely accounts for improved tolerability. 5, 6, 7

Tetrabenazine showed 75% of patients achieving marked or very good chorea reduction during long-term treatment (mean 3.1 years), but was associated with somnolence (39%), insomnia (33%), and depression (31%). 8

Critical Contraindications and Warnings

All VMAT2 inhibitors carry a boxed warning for depression and suicidality in Huntington's disease patients. 1, 2, 3

Absolute contraindications:

• Active suicidal ideation or untreated/inadequately treated depression 1, 2, 3
• Hepatic impairment 1, 3
• Concurrent use with MAOIs, reserpine, or other VMAT2 inhibitors 1, 2, 3

Monitor closely for:

• Emergence or worsening of depression, suicidality, or unusual behavioral changes 1, 2, 3
• QT prolongation—avoid in patients with congenital long QT syndrome or arrhythmias 2, 3
• Neuroleptic malignant syndrome—discontinue immediately if suspected 1, 2, 3
• Parkinsonism and akathisia—reduce dose or discontinue if clinically significant 1, 2, 3
• Sedation/somnolence—may impair driving ability 1, 2, 3

Drug Interactions Requiring Dose Adjustment

Strong CYP2D6 inhibitors (fluoxetine, paroxetine):

• Limit deutetrabenazine to maximum 36 mg/day 3
• Limit valbenazine to 40 mg/day 2
• Limit tetrabenazine to 50 mg/day with maximum single dose of 25 mg 1

Strong CYP3A4 inhibitors:

• Limit valbenazine to 40 mg/day 2

Strong CYP3A4 inducers:

• Concomitant use with valbenazine not recommended 2

Second-Line Pharmacological Options

When VMAT2 inhibitors are contraindicated, poorly tolerated, or inadequately effective, antipsychotics can be used to manage both chorea and psychiatric symptoms. 9, 10

Antipsychotic options:

• Haloperidol—typical antipsychotic with dopamine antagonism 9, 10
• Sulpiride—selective D2/D3 antagonist 9, 10
• Quetiapine—atypical antipsychotic with lower extrapyramidal side effect risk 9, 10

These agents address chorea through dopamine receptor blockade but carry risks of extrapyramidal symptoms, tardive dyskinesia, and metabolic effects that must be weighed against benefits. 9

Non-Pharmacological Management

Establish predictable daily routines with consistent timing for meals, activities, and sleep to reduce confusion and anxiety. 10

Create a safe environment by removing fall hazards and reducing environmental stimuli that may trigger agitation. 10

Physical therapy, occupational therapy, and speech therapy should be integrated to address motor dysfunction, activities of daily living, and dysphagia as the disease progresses. 9

Common Pitfalls to Avoid

Do not initiate VMAT2 inhibitors without screening for depression and suicidality—this is the most critical safety concern with boxed warnings across all three agents. 1, 2, 3

Do not exceed recommended maximum doses without CYP2D6 genotyping—poor metabolizers have significantly increased drug exposure and adverse event risk. 1, 3

Do not combine VMAT2 inhibitors with each other or with reserpine—this is absolutely contraindicated due to excessive monoamine depletion. 1, 2, 3

Do not overlook drug interactions with CYP2D6 and CYP3A4 inhibitors—failure to adjust doses appropriately increases risk of adverse events including QT prolongation. 1, 2, 3

Do not continue treatment without periodic reassessment—regularly evaluate whether chorea reduction justifies potential adverse effects on mood, cognition, rigidity, and functional capacity. 1

Emerging Therapies

Antisense oligonucleotide therapy (tominersen) showed initial promise by reducing mutant huntingtin protein in cerebrospinal fluid, but the phase III GENERATION HD1 trial was halted in 2021 due to faster neurologic decline in high-dose groups. 9, 10 A new phase II trial (GENERATION HD2) is evaluating lower doses (60 mg and 100 mg every 16 weeks) in younger patients with lower disease burden, with completion expected in 2027. 9, 10

Gene editing approaches using CRISPR-Cas9 and CRISPR-Cas13d systems are in preclinical development, targeting CAG repeat expansion at the DNA or RNA level. 9, 10 These strategies face challenges including off-target effects, delivery to target brain regions, and limited benefit in late-stage patients with extensive neuronal loss. 9