VMAT2inhibitors

VMAT2 inhibitors are a class of medications that block vesicular monoamine transporter 2 (VMAT2), reducing the transport of monoamines such as dopamine, norepinephrine, and serotonin into synaptic vesicles. By depleting presynaptic monoamine stores, these drugs decrease neurotransmitter release and dampen dopaminergic signaling in the central nervous system. This mechanism can lessen involuntary movements associated with certain movement disorders.

Clinical use of VMAT2 inhibitors centers on hyperkinetic conditions related to long-term antipsychotic use and other motor disorders. They are most notably employed for tardive dyskinesia, a tardive movement disorder that can follow chronic antipsychotic treatment. They are also used to treat chorea in Huntington’s disease. The most widely recognized agents in this class are tetrabenazine, valbenazine, and deutetrabenazine. Tetrabenazine is the oldest VMAT2 inhibitor and has been used for Huntington’s disease and, off-label, for tardive dyskinesia. Valbenazine and deutetrabenazine are newer agents approved specifically for tardive dyskinesia and are often preferred for their dosing schedules and tolerability profiles.

Common agents and notes:

- Tetrabenazine: effective for chorea but associated with depressive symptoms and other neurological side effects.

- Valbenazine: approved for tardive dyskinesia; may cause somnolence, akathisia, and mood changes.

- Deutetrabenazine: approved for tardive dyskinesia; designed to have a more favorable pharmacokinetic profile but can still cause depression, somnolence, and extrapyramidal symptoms.

Adverse effects and safety considerations include sedation, mood changes, and extrapyramidal symptoms; there is a need for monitoring mood and suicidality. Drug interactions, particularly with CYP2D6 inhibitors or inducers, can affect exposure and dosing. Reserpine, an older VMAT inhibitor, is rarely used today due to broader adverse effects.