What are the management options for Huntington's disease?

Management of Huntington's Disease

Pharmacological Management of Chorea

Tetrabenazine is the only FDA-approved medication with Class 1 evidence for treating chorea in Huntington's disease and should be the first-line pharmacological agent when chorea requires treatment. 1, 2, 3

Tetrabenazine Dosing Protocol

• Start at 12.5 mg once daily in the morning, then increase to 12.5 mg twice daily after one week 1
• Titrate upward by 12.5 mg weekly intervals to identify the lowest dose that controls chorea while remaining tolerable 1
• For doses up to 50 mg/day, no genetic testing is required 1
• For doses above 50 mg/day, mandatory CYP2D6 genotyping is required before further titration 1
  • Extensive/intermediate metabolizers: maximum 100 mg/day (37.5 mg per dose, three times daily) 1
  • Poor metabolizers: maximum 50 mg/day (25 mg per dose, twice daily) 1
• Tetrabenazine reduced chorea scores by 3.5 units more than placebo (5.0 vs 1.5 units) in controlled trials 1

Critical Safety Considerations for Tetrabenazine

Tetrabenazine carries a black box warning for depression and suicidality and is absolutely contraindicated in actively suicidal patients or those with untreated/inadequately treated depression. 1

• Screen all patients for depression, suicidal ideation, and prior suicide attempts before initiating therapy 1
• Patients, caregivers, and families must be explicitly warned about suicide risk and instructed to report concerning behaviors immediately 1
• Close monitoring for emergence or worsening of depression, suicidality, akathisia, parkinsonism, insomnia, anxiety, or sedation is mandatory during titration 1

Alternative Pharmacological Agents for Chorea

When tetrabenazine is contraindicated or not tolerated:

• Deutetrabenazine (Austedo) and valbenazine (Ingrezza) are FDA-approved alternatives for chorea management 4
• Antipsychotics (haloperidol, sulpiride, quetiapine) can manage both chorea and comorbid psychiatric symptoms simultaneously 4, 5
• Use the "start low, go slow" principle with all antipsychotics to minimize extrapyramidal side effects 5

Management of Psychiatric Symptoms

Psychiatric manifestations often cause more disability than motor symptoms and must be treated aggressively as they typically respond well to appropriate therapy. 6, 7

Specific Psychiatric Interventions

• Antipsychotics address psychosis, severe behavioral disturbances, and chorea concurrently 5
• Antidepressants for depression (common in HD population) 6
• Mood stabilizers for irritability and emotional lability 6
• Anxiolytics for anxiety symptoms 6
• Consider multipurpose medications to simplify regimens and improve compliance (e.g., haloperidol for chorea, agitation, and anorexia together) 6

Non-Pharmacological Management

Non-pharmacological interventions should be implemented before or alongside medications, as overlooking these approaches leads to suboptimal outcomes. 4, 5

Environmental and Behavioral Strategies

• Establish predictable daily routines with consistent timing for meals, activities, and sleep to reduce confusion and anxiety 4, 5
• Create a safe environment by removing hazards, installing safety locks, and reducing environmental stimuli that trigger agitation 4, 5
• Use the "three R's" approach: repeat, reassure, and redirect when managing behavioral disturbances 5
• Break complex tasks into simple steps with clear, simple instructions for each step 5
• Implement visual cues, calendars, and labels to assist with orientation 5

Multidisciplinary Support

• Physical therapy for motor function and fall prevention 6, 7
• Occupational therapy for activities of daily living 6, 7
• Speech therapy for dysarthria and dysphagia 6, 7
• Nutritionist consultation for weight loss management 6
• Social work for coordination of services and caregiver support 6, 7

Emerging Disease-Modifying Therapies

While no curative treatments currently exist, promising gene and cell therapy approaches are in clinical trials and represent the future of HD treatment. 8, 4

Investigational Approaches

• Antisense oligonucleotide (ASO) therapy (Tominersen) targets mutant huntingtin protein at the RNA level and has demonstrated significant mHTT reduction in cerebrospinal fluid 4
• Gene editing techniques aim to correct or delete the mutated HTT gene at the DNA level 4
• RNA interference (RNAi) strategies suppress mutant HTT expression 4
• Cell therapy strategies aim to replace lost neurons or provide trophic support to damaged brain regions 4

Critical Management Pitfalls to Avoid

• Never initiate pharmacological treatment without first implementing non-pharmacological strategies 4, 5
• Do not use one-size-fits-all dosing; medication tolerance varies significantly between patients due to genetic factors (especially CYP2D6 status) 1
• Avoid polypharmacy when possible; select agents that address multiple symptoms simultaneously 6
• Do not overlook medication side effects, which can be difficult to distinguish from disease progression 6
• Never prescribe tetrabenazine without screening for depression and suicidality first 1
• Conduct periodic medication reviews as the disease progresses, as treatment needs change over time 3

Cognitive Impairment Management

Cognitive decline remains a largely unmet therapeutic need with few effective treatment options currently available. 6

• Acetylcholinesterase inhibitors have been studied but lack consistent evidence of benefit 9
• Focus on environmental modifications and caregiver education to compensate for cognitive deficits 5