clinical topic updates

Clinical Trials, Long-term Follow-up, and Experience With VMAT2 Inhibitors

by Andrew J. Cutler, MD

Overview

The emergence of vesicular monoamine transporter 2 (VMAT2) inhibitors has ushered in a new era in the management of tardive dyskinesia (TD). In clinical trials, both valbenazine and deutetrabenazine were well tolerated and led to clinically meaningful improvements in TD symptoms.

Expert Commentary

Andrew J. Cutler, MD

Clinical Associate Professor of Psychiatry
SUNY Upstate Medical University
Lakewood Ranch, FL
Chief Medical Officer
Neuroscience Education Institute
Carlsbad, CA

“It is important to realize that VMAT2 inhibitors can be added to the patient’s psychiatric regimen without the risk of destabilizing their psychiatric condition.” 

Andrew J. Cutler, MD

The story of the development of VMAT inhibitors is interesting from a historical perspective. Reserpine, an early VMAT inhibitor that was originally developed to be an antipsychotic, is nonselective. It blocks not only VMAT2, which is primarily found in the brain, but also VMAT1 in the periphery, causing a significant antihypertensive effect for which the agent was ultimately used.

VMATs essentially package intracellular dopamine into vesicles. With selective VMAT2 inhibition in the brain, you get less dopamine packaged into those vesicles in the brain and less dopamine released into the synapse. The rationale behind VMAT2 inhibition for TD is that decreasing the amount of presynaptic dopamine release may help to balance out, or reregulate, the supersensitized dopamine system of TD.

Tetrabenazine is an effective, selective, reversible VMAT2 inhibitor that was originally developed to treat schizophrenia; it is also used in Huntington’s disease; however, its short half-life, requiring 3 or 4 doses a day, is a problem, and there are some related tolerability issues.

Valbenazine and deutetrabenazine are derivatives of tetrabenazine. Each agent circumvented the issue of a short half-life in a different way. Both are extremely effective and are much better tolerated than tetrabenazine. The US Food and Drug Administration approved valbenazine and deutetrabenazine for TD in 2017, giving us the first truly effective treatments for this disorder.

In 12-week trials, valbenazine 40 to 80 mg per day and deutetrabenazine 12 to 48 mg per day both decreased Abnormal Involuntary Movement Scale scores, resulting in clinically meaningful improvements. Additionally, both agents had a number needed to treat of approximately 5 and a number needed to harm of approximately 100, which is a very good risk-benefit ratio. And both valbenazine and deutetrabenazine have been studied in longer-term extension studies and were found to be efficacious and tolerable in older and younger populations.

While there are no head-to-head comparisons, there are some differences between these agents. They have different active metabolites, raising the possibility that patients who do not do well with 1 VMAT2 inhibitor might do better with the other. Valbenazine is given once daily with or without food, whereas deutetrabenazine is given twice daily with food. Further, titration is more complicated with deutetrabenazine, as valbenazine has only 3 doses (ie, 40-, 60-, and 80-mg capsules) and therefore fewer dosing options. Both agents are metabolized by cytochrome P450 2D6, but valbenazine is also metabolized by cytochrome P450 3A4 and therefore has more drug-drug interaction potential.

It is important to realize that VMAT2 inhibitors can be added to the patient’s psychiatric regimen without the risk of destabilizing their psychiatric condition. Reserpine and tetrabenazine, the 2 early VMAT inhibitors, carry boxed warnings for depression and suicidality, which can occur if dopamine is significantly depleted. However, in clinical trials, the underlying psychiatric symptoms remained stable with valbenazine and deutetrabenazine. There were no changes in psychotic symptoms or increases in depression, suicidality, or manic symptoms. In fact, there is an ongoing study to ascertain whether adding a VMAT2 inhibitor to an antipsychotic regimen may provide additional improvement in psychotic symptoms.

References

Anderson KE, Stamler D, Davis MD, et al. Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Psychiatry. 2017;4(8):595-604. doi:10.1016/S2215-0366(17)30236-5

Citrome L. Clinical management of tardive dyskinesia: five steps to success. J Neurol Sci. 2017;383:199-204. doi:10.1016/j.jns.2017.11.019

ClinicalTrials.gov. Journey study: evaluate the efficacy, safety, and tolerability of valbenazine as adjunctive treatment for schizophrenia. Updated May 24, 2022. Accessed June 16, 2022. https://clinicaltrials.gov/ct2/show/NCT05110157

Factor SA, Remington G, Comella CL, et al. The effects of valbenazine in participants with tardive dyskinesia: results of the 1-year KINECT 3 extension study. J Clin Psychiatry. 2017;78(9):1344-1350. doi:10.4088/JCP.17m11777

Marder SR, Singer C, Lindenmayer J-P, et al. A phase 3, 1-year, open-label trial of valbenazine in adults with tardive dyskinesia. J Clin Psychopharmacol. 2019;39(6):620-627. doi:10.1097/JCP.0000000000001111

Sajatovic M, Alexopoulos G, Burke J, Farahmand K, Siegert S. The effects of valbenazine on tardive dyskinesia in older and younger patients. Int J Geriatr Psychiatry. 2020;35:69-79. doi:10.1002/gps.5218

Sajatovic M, Wilhelm A, Finkbeiner S, et al. Long-term safety and efficacy of deutetrabenazine in younger and older patients with tardive dyskinesia. CNS Spectr. 2021;26(2):157-158. doi:10.1017/S1092852920002527

Solmi M, Pigato G, Kane JM, Correll CU. Treatment of tardive dyskinesia with VMAT-2 inhibitors: a systematic review and meta-analysis of randomized controlled trials. Drug Des Devel Ther. 2018;12:1215-1238. doi:10.2147/DDDT.S133205

Stahl SM. Comparing pharmacologic mechanism of action for the vesicular monoamine transporter 2 (VMAT2) inhibitors valbenazine and deutetrabenazine in treating tardive dyskinesia: does one have advantages over the other? CNS Spectr. 2018;23(4):239-247. doi:10.1017/S1092852918001219

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