VMAT2 Inhibitors in Movement Disorders: Pharmacogenetics Shapes Personalised Dosing
This Lancet review covers the therapeutic role of VMAT2 inhibitors (tetrabenazine, deutetrabenazine, valbenazine) in hyperkinetic movement disorders including Huntington's disease and tardive dyskinesia. Cytochrome P450 genetic variation significantly affects drug metabolism and necessitates personalised dosing. The review highlights structural insights into VMAT2 inhibition that may guide next-generation drug design, with direct relevance for laboratories offering CYP2D6 testing to optimise these therapies.
The original study
Vesicular monoamine transport inhibitors: current uses and future directions.
- Authors
- Rosenthal LS, Farag M, Aziz NA, Bang J
- Journal
- Lancet (London, England)
- Type
- Journal Article, Review
- PMID
- 40783291
Original abstract
Advancements over the past decade in understanding vesicular monoamine transporter 2 (VMAT2) inhibitors highlight their key role in the treatment of movement and neuropsychiatric disorders. VMAT2 is crucial for packaging neurotransmitters such as serotonin, dopamine, and norepinephrine into synaptic vesicles, facilitating their release and reuptake in synaptic transmission. VMAT2 inhibitors, such as tetrabenazine, deutetrabenazine, and valbenazine, show therapeutic efficacy in managing hyperkinetic movement disorders, including Huntington's disease, tardive dyskinesia, and Tourette's syndrome. These inhibitors modulate excessive synaptic activity by reducing neurotransmitter storage and release. Genetic variations, particularly in the cytochrome P450 enzyme family, influence VMAT2 inhibitor metabolism, necessitating personalised dosing to optimise efficacy and minimise adverse events. Recent studies have provided further structural insights into VMAT2 inhibition mechanisms, paving the way for the development of inhibitors with enhanced potency and selectivity. Leveraging pharmacogenetics for precision medicine and exploring VMAT2 inhibition in broader therapeutic contexts could revolutionise treatment frameworks for neurological and psychiatric conditions.