What are the treatment options for chorea in Huntington's disease?

Treatment Options for Chorea in Huntington's Disease

Tetrabenazine, deutetrabenazine (Austedo), and valbenazine (Ingrezza) are the most effective medications for treating chorea in Huntington's disease, with tetrabenazine being FDA-approved specifically for this purpose. 1

First-Line Pharmacological Options

Tetrabenazine

• FDA-approved indication: Treatment of chorea associated with Huntington's disease 2
• Mechanism: Acts as a reversible inhibitor of vesicular monoamine transporter type 2 (VMAT2), depleting dopamine 3
• Dosing protocol:
  • Starting dose: 12.5 mg once daily in the morning
  • Titration: Increase by 12.5 mg weekly to identify tolerated dose
  • Typical effective dose range: 25-75 mg/day
  • Maximum recommended daily dose: 100 mg (for extensive metabolizers)
  • Maximum single dose: 37.5 mg 2
• Efficacy: Significantly reduces chorea scores compared to placebo (5.0 unit reduction vs 1.5 unit reduction) 2
• Key considerations:
  • CYP2D6 genotyping required for doses above 50 mg/day
  • Doses above 50 mg should be given in three divided doses 2

Deutetrabenazine (Austedo)

• Advantage: Better tolerability profile compared to tetrabenazine 1
• Mechanism: Similar to tetrabenazine but with deuterium substitution for improved pharmacokinetics
• Clinical significance: May be preferred for patients who experience side effects with tetrabenazine 4

Valbenazine (Ingrezza)

• Benefit: Improved side effect profile 1
• Consideration: Alternative option for patients who cannot tolerate tetrabenazine or deutetrabenazine

Antipsychotics for Dual Symptom Control

For patients with both chorea and psychiatric symptoms:

• Options: Haloperidol, sulpiride, quetiapine 1
• Advantage: Dual benefit for both motor and psychiatric symptoms
• When to consider: First-line for patients with prominent psychiatric symptoms alongside chorea

Monitoring and Safety Considerations

Critical Safety Warning

• Depression and suicidality risk: Tetrabenazine can increase risk of depression and suicidal thoughts 2
• Contraindications: Active suicidality or untreated/inadequately treated depression 2
• Monitoring requirements:
  • Close observation for emergence or worsening of depression
  • Regular assessment of suicidality
  • Screening for depression before and during treatment 1

Dose Adjustment Considerations

• Side effect management: If akathisia, parkinsonism, depression, insomnia, anxiety, or sedation occur:
  1. Stop titration
  2. Reduce dose
  3. If symptoms persist, consider discontinuation or specific treatment (e.g., antidepressants) 2

Common Pitfalls

• Underdosing: Many patients receive suboptimal doses (≤50 mg) despite inadequate symptom control 4
• Poor persistence: Non-persistence to tetrabenazine is associated with increased emergency room visits and hospitalizations 4
• Inadequate monitoring: Failure to monitor for psychiatric symptoms can lead to serious adverse outcomes

Emerging Therapies

While symptomatic treatment remains the mainstay, several disease-modifying approaches are in development:

• Antisense Oligonucleotide (ASO) therapy: Targets reduction of mutant huntingtin protein levels 1
• Gene therapy approaches: Aim to correct or delete the mutated HTT gene 5
• Small molecule splice modulators: Branaplam (LMI070) showed initial promise but development was halted due to peripheral neuropathy 5
• Cell-based therapies: Neural stem cell transplantation shows potential in preclinical models 5

Treatment Algorithm

1. Initial assessment:

   • Determine severity of chorea and impact on daily functioning
   • Screen for depression, suicidality, and psychiatric symptoms
   • Consider CYP2D6 metabolizer status

2. First-line treatment:

   • For chorea without significant psychiatric symptoms: Begin tetrabenazine
   • For chorea with psychiatric symptoms: Consider antipsychotics (haloperidol, sulpiride, quetiapine)

3. If inadequate response or intolerance to tetrabenazine:

   • Switch to deutetrabenazine (better tolerability)
   • Consider valbenazine as an alternative

4. For persistent symptoms despite optimal medication:

   • Consider combination therapy
   • Evaluate for clinical trial eligibility for emerging therapies

5. Regular monitoring:

   • Motor symptoms
   • Psychiatric symptoms
   • Cognitive function
   • Swallowing function
   • Sleep patterns
   • Medication side effects

While current treatments focus on symptom management, ongoing research into disease-modifying therapies offers hope for future interventions that may alter the course of this progressive neurodegenerative disorder.