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Review
. 2025 Aug 9;406(10503):650-664.
doi: 10.1016/S0140-6736(25)01072-4.

Vesicular monoamine transport inhibitors: current uses and future directions

Liana S Rosenthal  1 , Mena Farag  2 , N Ahmad Aziz  3 , Jee Bang  4
Affiliations
Review

Vesicular monoamine transport inhibitors: current uses and future directions

Liana S Rosenthal et al. Lancet. .

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.

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Conflict of interest statement

Declaration of interests LSR has no relevant financial or non-financial interests to disclose related to the present manuscript. She receives research funding support from the National Institute of Neurological Disorders and Stroke, the Daniel B and Florence E Green Family Foundation, and the Macks Family Foundation. She receives additional programmatic support from the Gordon and Marilyn Macklin Foundation. She receives salary support for her role as the site Principal Investigator for research studies with Biohaven Pharmaceuticals, Pfizer, and EIP Pharma and for serving on the Clinical Events Committee for a research study with Functional Neuromodulation. She also serves on the steering committees for the Parkinson Study Group's research study with both UCB and Bial Pharmaceuticals. She also served on advisory boards for Reata Pharmaceuticals, Biogen Pharmaceuticals, and Biohaven Pharmaceuticals, as a consultant for Biohaven Pharmaceuticals and Merck Healthcare KGaA, and as a one-time consultant for UCB Pharmaceuticals. She receives support for meeting attendance from the Parkinson's Study Group, Biohaven Pharmaceuticals, and the National Ataxia Foundation. She is one of the inventors on a patent owned by Johns Hopkins related to identifying Poly-ADP-ribose in the cerebrospinal fluid and a patent application related to alpha-synuclein strain properties. Neither patent is related to vesicular monoamine transporter inhibitors and she has received no income from these patents. NAA has no relevant financial or non-financial interests to disclose related to the present manuscript. He served as the Chair of the Scientific and Bio-advisory Committee of the European Huntington Disease Network (2022–24) and is currently on the Executive Committee of the European Huntington Disease Network. His work is supported by institutional funds, a European Research Council Starting Grant (number 101041677), an Alzheimer's Association Research Grant (AARG-19-616534), and the project “InVirtuo 4.0” by the Ministry of Culture and Science of the State of North Rhine-Westphalia, Germany. JB has no relevant financial or non-financial interests to disclose related to the present manuscript. She has received consulting fees from Gerson Lehrman Group and Adept Field solutions, honoraria from the American Association of Neurology, and support for attending the Huntington Study Group annual meeting in 2022 from Prilenia. She participated in the Wave Life Scientific Advisory Board, and uniQure Scientific Advisory Board. In addition, she is a member of the Executive Membership Committee of the Huntington Study Group, which is an unpaid position. MF declares no competing interests.

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