VMAT2 Inhibitors in Neuropsychiatric Disorders

The basal ganglia and dopaminergic pathways play a central role in hyperkinetic movement disorders. Vesicular monoamine transporter 2 (VMAT2) inhibitors, which deplete dopamine at presynaptic striatal nerve terminals, are a class of drugs that have long been used to treat hyperkinetic movement disorders, but have recently gained more attention following their development for specific indications in the United States. At present, there are three commercially available VMAT2 inhibitors: tetrabenazine, deutetrabenazine, and valbenazine. Pharmacokinetics, metabolism, and dosing vary significantly between the three drugs, and likely underlie the more favorable side effect profile of the newer agents (deutetrabenazine and valbenazine). Tetrabenazine and deutetrabenazine have demonstrated safety and efficacy in the treatment of chorea associated with Huntington's disease, including in randomized controlled trials, although direct comparison studies are limited. Both deutetrabenazine and valbenazine have demonstrated safety and efficacy in the treatment of tardive dyskinesia, with multiple double-blind, placebo-controlled trials, whereas tetrabenazine has been studied less rigorously. There have been no blinded, prospective trials with tetrabenazine in Tourette's syndrome (TS); however, double-blind, placebo-controlled trials in TS are ongoing for both deutetrabenazine and valbenazine. Given the favored side effect profile of newer VMAT2 inhibitors, clinicians should be aware of the distinctions between agents and become familiar with differences in their use, especially as there is potential for their utilization to increase across the range of hyperkinetic movement disorders.