Tetrabenazine for Huntington's Disease: How VMAT2 Inhibition Reduces Chorea
Mechanism of Action
Tetrabenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor. VMAT2 packages monoamines (dopamine, serotonin, norepinephrine, histamine) into presynaptic vesicles for release.
Effect on Neurotransmission
- Blocks VMAT2 → monoamines remain in cytoplasm → degraded by MAO.
- Depletes presynaptic monoamine stores → reduced release into synaptic cleft.
- Primarily reduces dopamine availability in striatum.
Clinical Use
- Indication: Chorea associated with Huntington's disease (FDA-approved 2008; also approved in Canada, EU).
- Dosing: Titrated slowly (start 12.5 mg/day; max 100–150 mg/day in divided doses) to balance chorea control vs. side effects.
- Efficacy: Reduces chorea severity (UHDRS chorea score) but does not alter disease progression.
Key Side Effects
- Sedation, fatigue
- Parkinsonism (bradykinesia, rigidity)
- Depression, suicidality (black box warning)
- Akathisia, insomnia
- QT prolongation (caution with other QT drugs)
Monitoring
Regular assessment for depression, suicidality, parkinsonism, ECG if risk factors.
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