Is tetrabenazine (vesicular monoamine transporter 2 (VMAT2) inhibitor) a suitable treatment option for a patient with Chorea-Ballismus spectrum, particularly those with a history of depression or suicidal ideation?

Tetrabenazine for Chorea-Ballismus Spectrum

Direct Recommendation

Tetrabenazine is an effective treatment for chorea-ballismus spectrum disorders, but it is absolutely contraindicated in patients with active suicidal ideation, untreated or inadequately treated depression, or a history of suicidal behavior. 1

Critical Safety Considerations for Depression and Suicidality

The FDA black box warning explicitly contraindicates tetrabenazine in patients who are actively suicidal or have untreated/inadequately treated depression. 1 This is based on compelling clinical trial data:

• In a 12-week controlled trial, 19% (10/54) of patients treated with tetrabenazine developed depression or worsening depression versus 0% on placebo 1
• In open-label extension studies, the rate of depression/worsening depression reached 35% 1
• Among all HD chorea studies (n=187), one patient committed suicide, one attempted suicide, and six had suicidal ideation 1

Before initiating tetrabenazine, you must:

• Screen for current depression, suicidal ideation, and history of suicide attempts 1
• Ensure any existing depression is adequately treated and stable 1
• Inform patients, caregivers, and families about the risks of depression and suicidality 1
• Establish a monitoring plan for new or worsening depression 1

If depression or suicidality emerges during treatment, consider discontinuing tetrabenazine immediately. 1

Efficacy for Chorea-Ballismus Spectrum

Tetrabenazine demonstrates robust efficacy across the chorea-ballismus spectrum:

• For choreiform movements: Six of seven patients with Huntington's chorea showed striking improvement with tetrabenazine 50 mg three times daily in controlled assessment 2
• For ballismus: One patient with hemiballismus was judged improved in a 17-patient trial of various hyperkinetic movement disorders 2
• Long-term efficacy: Mean reduction in Total Maximal Chorea score of 4.6 units maintained at 80 weeks, with mean dosage of 63.4 mg/day 3

The mechanism—reversible inhibition of vesicular monoamine transporter type 2 (VMAT2)—depletes central dopamine, norepinephrine, and serotonin, effectively suppressing hyperkinetic movements. 4, 5

Dosing Algorithm

Initial titration (for patients WITHOUT depression/suicidal history):

• Start at 12.5 mg once daily in the morning 1
• Increase by 12.5 mg weekly, allowing at least 3-5 days between dose adjustments 1
• Titrate to optimal chorea control or maximum tolerated dose 1

Dosing limits based on CYP2D6 status:

• For extensive/intermediate metabolizers: Maximum 100 mg/day (50 mg per single dose) 1
• For poor metabolizers or unknown status: Maximum 50 mg/day (25 mg per single dose) 1
• CYP2D6 genotyping is mandatory before exceeding 50 mg/day 1

Real-world dosing patterns: Most patients (66.5%) receive ≤50 mg/day, with common reasons for stopping titration being optimal chorea control (55.5%), intolerability (31.2%), or reaching maximum dose despite suboptimal control (11.4%). 6

Monitoring Requirements

Psychiatric monitoring (highest priority):

• Assess for depression and suicidality at every visit 1
• Patients expressing suicidal ideation require immediate evaluation 1

Motor and cognitive monitoring:

• Parkinsonism and dysarthria scores significantly increased at 80 weeks compared to baseline 3
• Monitor for akathisia (reported in 9 patients in 80-week study), sedation/somnolence (18 patients), and dysphagia 1, 3
• Periodically reassess whether chorea improvement justifies continued treatment given adverse effects 1

Common adverse effects requiring monitoring:

• Sedation/somnolence, depressed mood, anxiety, insomnia, akathisia, parkinsonism 3
• Neuroleptic malignant syndrome (rare but potentially fatal) 1

Absolute Contraindications

Do not use tetrabenazine in patients with:

• Active suicidal ideation or untreated/inadequately treated depression 1
• Hepatic impairment 1
• Concurrent MAOI use (requires 14-day washout) 1
• Recent reserpine use (requires 20-day washout) 1
• Concurrent deutetrabenazine or valbenazine use 1

Alternative VMAT2 Inhibitors for High-Risk Patients

For patients with depression history or suicidal ideation, consider alternative VMAT2 inhibitors:

• Valbenazine may have less off-target effects including behavioral changes and akathisia due to VMAT2 selectivity, though head-to-head trials are lacking 7
• Deutetrabenazine is another FDA-approved option for HD chorea 4, 6

However, all VMAT2 inhibitors carry psychiatric risks and require careful monitoring. 7

Clinical Pitfalls to Avoid

• Never initiate tetrabenazine without screening for depression and suicidal ideation—the 19% incidence of depression in controlled trials versus 0% on placebo makes this non-negotiable 1
• Do not exceed 50 mg/day without CYP2D6 genotyping—poor metabolizers have 3-fold higher α-HTBZ and 9-fold higher β-HTBZ levels 1
• Distinguish adverse effects from disease progression—decreasing dose or stopping the drug temporarily can help differentiate 1
• Monitor for akathisia specifically—it is commonly misinterpreted as anxiety or psychotic agitation, potentially leading to inappropriate dose increases 8