Tetrabenazine Treatment for Chorea Associated with Huntington's Disease
Tetrabenazine is the recommended first-line pharmacological treatment for chorea associated with Huntington's disease, with an individualized dosing regimen starting at 12.5 mg daily and gradually titrating up to a maximum of 100 mg daily for extensive metabolizers or 50 mg daily for poor metabolizers. 1
Dosing Recommendations
- Initial dosing should start at 12.5 mg daily for the first week, increasing to 25 mg (12.5 mg twice daily) in the second week, with subsequent weekly increases of 12.5 mg until reaching an effective dose that adequately reduces chorea 1
- Doses of 37.5 mg and up to 50 mg per day should be administered in three divided doses, with a maximum single dose not exceeding 25 mg 1
- For patients requiring doses above 50 mg daily, CYP2D6 genotyping is necessary to determine metabolizer status 1:
- Poor metabolizers (PMs): Maximum daily dose of 50 mg with maximum single dose of 25 mg
- Extensive metabolizers (EMs) and intermediate metabolizers (IMs): Maximum daily dose of 100 mg with maximum single dose of 37.5 mg
Efficacy
- Clinical trials demonstrate that tetrabenazine significantly reduces chorea severity compared to placebo, with a reduction of 5.0 units in chorea severity on the Unified Huntington's Disease Rating Scale (UHDRS) versus 1.5 units with placebo (p < 0.0001) 2
- Long-term studies show that 75% of patients achieve marked or very good responses at their optimal dosages, with sustained improvement in chorea for up to 80 weeks 3, 4
- The mean effective dosage in long-term treatment is approximately 63.4 mg daily (range 12.5-175 mg) 4
Safety Considerations and Monitoring
- WARNING: Tetrabenazine increases the risk of depression and suicidal thoughts/behavior in patients with Huntington's disease 1
- Contraindicated in patients who are actively suicidal or have untreated/inadequately treated depression 1
- Contraindicated in patients with hepatic impairment 1
- Contraindicated in patients taking MAOIs, reserpine, deutetrabenazine, or valbenazine 1
- Most common adverse events (occurring in >10% of patients and at least 5% greater than placebo) include 1:
- Sedation/somnolence
- Fatigue
- Insomnia
- Depression
- Akathisia
- Anxiety
- Nausea
Monitoring Requirements
- Regular assessment for emergence or worsening of depression, suicidality, or unusual behavior changes 1
- Periodic reevaluation of benefit versus adverse effects, particularly regarding mood, cognition, rigidity, and functional capacity 1
- Monitor for development of parkinsonism, which may increase with long-term use 4
- Dose reduction should be considered if serious adverse reactions occur; if these do not resolve, withdrawal of tetrabenazine should be considered 1
Special Considerations
- Maximum dose should not exceed 50 mg/day with a maximum single dose of 25 mg when administered with strong CYP2D6 inhibitors (e.g., fluoxetine, paroxetine) 1
- QTc prolongation: Not recommended in combination with other drugs that prolong QTc 1
- Real-world data shows that many patients receive lower doses than in clinical trials (average 45.5 mg/day), likely due to tolerability concerns 5
- Treatment discontinuation is common in real-world settings, with approximately 42% of patients experiencing a ≥60-day gap in therapy 5
Alternative Options
- Other medications for chorea management include deutetrabenazine and valbenazine, which may offer improved tolerability profiles 6
- Antipsychotics such as haloperidol, sulpiride, and quetiapine may also be used to improve chorea and psychiatric abnormalities 6
Tetrabenazine remains an effective treatment for HD-related chorea, but careful monitoring for psychiatric adverse effects and movement disorders is essential for optimizing outcomes and quality of life.