From the Guidelines
Deutetrabenazine works by inhibiting vesicular monoamine transporter 2 (VMAT2) in the central nervous system. This mechanism reduces the uptake of monoamines like dopamine, serotonin, and norepinephrine into synaptic vesicles, thereby decreasing their release into the synapse. By specifically targeting dopamine storage and release in the brain, deutetrabenazine helps regulate excessive dopaminergic activity that contributes to movement disorders. The medication is a deuterated form of tetrabenazine, which means hydrogen atoms have been replaced with deuterium atoms, allowing for slower metabolism, longer half-life, and more consistent blood levels throughout the day. This pharmacokinetic advantage enables twice-daily dosing rather than three times daily as with tetrabenazine, potentially improving adherence and reducing peak-dose side effects. Deutetrabenazine is primarily used to treat chorea associated with Huntington's disease and tardive dyskinesia, with typical starting doses of 6 mg twice daily, gradually titrated based on response and tolerability up to a maximum of 48 mg daily (24 mg twice daily). Common side effects include sedation, depression, akathisia, and parkinsonism, which should be monitored during treatment, as noted in studies related to VMAT2 and its role in neuroendocrine applications 1. Key points about deutetrabenazine's mechanism of action include:
- Inhibition of VMAT2
- Reduction of monoamine uptake into synaptic vesicles
- Decrease in monoamine release into the synapse
- Regulation of excessive dopaminergic activity
- Treatment of chorea associated with Huntington's disease and tardive dyskinesia.
From the FDA Drug Label
The precise mechanism by which deutetrabenazine exerts its effects in the treatment of tardive dyskinesia and chorea in patients with Huntington’s disease is unknown but is believed to be related to its effect as a reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals The major circulating metabolites (α-dihydrotetrabenazine [HTBZ] and β-HTBZ) of deutetrabenazine, are reversible inhibitors of VMAT2, resulting in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores.
The mechanism of action of deutetrabenazine is believed to be related to its effect as a reversible depletor of monoamines from nerve terminals. The major circulating metabolites of deutetrabenazine, α-dihydrotetrabenazine (HTBZ) and β-HTBZ, are reversible inhibitors of VMAT2, resulting in:
- Decreased uptake of monoamines into synaptic vesicles
- Depletion of monoamine stores Key points about the mechanism of action of deutetrabenazine include:
- Reversible depletion of monoamines: deutetrabenazine is believed to deplete monoamines such as dopamine, serotonin, norepinephrine, and histamine from nerve terminals.
- Inhibition of VMAT2: the major circulating metabolites of deutetrabenazine, α-HTBZ and β-HTBZ, are reversible inhibitors of VMAT2. 2
From the Research
Mechanism of Action of Deutetrabenazine
- Deutetrabenazine is a reversible inhibitor of vesicular monoamine transporter type 2 (VMAT2) 3, 4, 5
- It works by depleting presynaptic dopamine by blocking VMAT2, which seems to be safer and has little or no risk of tardive dyskinesia 5
- Deutetrabenazine is metabolized to four deuterated dihydrotetrabenazine (deuHTBZ) metabolites: [+]-α-deuHTBZ, [+]-β-deuHTBZ, [-]-α-deuHTBZ, and [-]-β-deuHTBZ 6
- The deuHTBZ metabolites have different pharmacokinetic profiles and varying degrees of VMAT2 inhibition and off-target interactions 6
- [-]-α-deuHTBZ is the most abundant deuHTBZ metabolite, but it is a relatively weak VMAT2 inhibitor with appreciable affinity for dopamine and serotonin receptors 6
- [+]-β-deuHTBZ is the most potent VMAT2 inhibitor among the deuHTBZ metabolites, but it represents only 29% of total circulating deuHTBZ metabolites 6
Comparison with Other VMAT2 Inhibitors
- Deutetrabenazine has a similar mechanism of action to other VMAT2 inhibitors, such as valbenazine and tetrabenazine 3, 4, 5
- However, deutetrabenazine has a different pharmacokinetic profile and metabolite composition compared to valbenazine 6, 7
- The choice of VMAT2 inhibitor may depend on individual patient factors and the specific clinical context 7