Exploring What are the new VMAT2 inhibitors: Advancements in Movement Disorder Treatment

October 10, 2025 •

3 min read

Since the U.S. Food and Drug Administration (FDA) approved two novel VMAT2 inhibitors in 2017, the treatment paradigm for movement disorders like tardive dyskinesia and Huntington's chorea has been significantly modernized. These newer agents address long-standing challenges associated with earlier treatments, answering the critical question: what are the new VMAT2 inhibitors that offer improved efficacy and tolerability?

Quick Summary

Valbenazine (Ingrezza) and deutetrabenazine (Austedo) are new VMAT2 inhibitors approved to treat tardive dyskinesia and Huntington's chorea. They offer significant improvements over older therapies, including enhanced pharmacokinetic profiles and better tolerability, leading to more effective symptom management.

Key Points

Newer Agents: Valbenazine (Ingrezza) and deutetrabenazine (Austedo, Austedo XR) are the most recent VMAT2 inhibitors approved by the FDA, representing a major improvement over older options like tetrabenazine.
Improved Tolerability: These second-generation inhibitors have a more favorable side effect profile, with a lower incidence of somnolence and depression compared to the first-generation tetrabenazine.
Convenient Dosing: Valbenazine and deutetrabenazine feature longer half-lives, allowing for less frequent dosing—once daily for valbenazine and Austedo XR, and twice daily for Austedo tablets.
Targeted Action: The improved agents are more selective in their VMAT2 inhibition, minimizing off-target effects and providing a more focused therapeutic action.
Expanded Indications: Both newer VMAT2 inhibitors are approved for treating tardive dyskinesia and chorea associated with Huntington's disease, expanding treatment options for both conditions.
Future Development: Ongoing research includes the development of even newer, third-generation VMAT2 inhibitors aimed at further enhancing efficacy and safety.

Understanding the Role of VMAT2

The vesicular monoamine transporter 2 (VMAT2) is a protein essential for regulating neurotransmitter levels, particularly dopamine, in the brain. It packages monoamines into synaptic vesicles for release. Excessive dopamine activity is linked to involuntary movements in certain neurological conditions. VMAT2 inhibitors block this transporter, reducing synaptic dopamine and helping to control these movements.

The First Generation: Tetrabenazine

Tetrabenazine (Xenazine) was the first VMAT2 inhibitor approved by the FDA in 2008 for Huntington's disease chorea. Its limitations included frequent dosing and significant side effects such as sedation, depression, and a risk of suicidality. These issues led to the development of newer inhibitors.

What are the new VMAT2 inhibitors: The Second Generation

Introduced in 2017, valbenazine and deutetrabenazine are second-generation VMAT2 inhibitors with improved pharmacokinetic profiles and tolerability.

Valbenazine (Ingrezza): A Highly Selective Inhibitor

Valbenazine (Ingrezza) was approved in 2017 for tardive dyskinesia (TD) and in 2023 for Huntington's disease chorea. Its high selectivity for VMAT2 is believed to contribute to better tolerability. It is administered once daily due to its extended half-life. Its metabolism is less dependent on the CYP2D6 enzyme, simplifying its use. Clinical trials have shown significant TD symptom improvement with low discontinuation rates.

Deutetrabenazine (Austedo): The Deuterated Alternative

Deutetrabenazine (Austedo, Austedo XR) was approved in 2017 for both HD chorea and TD. Deuteration gives it a longer half-life and more stable plasma concentrations. It is dosed twice daily (tablet) or once daily (XR). Its smoother concentration curve results in fewer peak-related side effects compared to tetrabenazine.

How the New VMAT2 Inhibitors Work

Valbenazine and deutetrabenazine block the VMAT2 protein in presynaptic neurons, preventing dopamine from being packaged into vesicles. This reduces dopamine levels in the synapse and controls involuntary movements in TD and HD chorea. Key aspects include reversible inhibition, selective targeting (especially valbenazine), and metabolic advantages leading to improved dosing and reduced side effects.

Comparison of Modern VMAT2 Inhibitors


Feature	Valbenazine (Ingrezza)	Deutetrabenazine (Austedo)	Tetrabenazine (Xenazine)
Mechanism	Highly selective, reversible VMAT2 inhibition.	Deuterated, reversible VMAT2 inhibition.	Reversible VMAT2 inhibition (not selective).
Indications	Tardive dyskinesia, Huntington's chorea.	Tardive dyskinesia, Huntington's chorea.	Huntington's chorea (off-label for TD).
Dosing	Once-daily capsule.	Twice-daily tablet or once-daily extended-release.	Multiple daily doses (typically 3).
Half-life	Extended (15–22 hours).	Extended due to deuteration.	Short.
Tolerability	Favorable, lower risk of depression.	Favorable, lower risk of depression.	Less favorable, higher risk of depression.
Key Innovation	High selectivity for VMAT2.	Deuteration for improved pharmacokinetics.	First-ever VMAT2 inhibitor approved.

Safety and Side Effects of New VMAT2 Inhibitors

While better tolerated, the new VMAT2 inhibitors have safety considerations. Both valbenazine and deutetrabenazine have boxed warnings for increased risk of depression and suicidality in HD patients. They also carry a risk of neuroleptic malignant syndrome (NMS) and parkinsonism. Common side effects include somnolence, fatigue, diarrhea, dry mouth, headache, and insomnia. Serious risks include QT prolongation and akathisia. Drug interactions with strong CYP2D6 or CYP3A4 inhibitors require monitoring.

Looking Ahead: The Future of VMAT2 Pharmacology

Research continues to develop improved VMAT2 inhibitors. Neurocrine Biosciences is working on NBI-1140675, a second-generation compound in Phase 1 studies. Future efforts will focus on increased selectivity, novel delivery methods, and expanding indications to other neurological conditions.

Conclusion

The advent of valbenazine and deutetrabenazine has significantly advanced the treatment of movement disorders. These modern VMAT2 inhibitors offer improved efficacy and tolerability compared to tetrabenazine, providing better options for managing tardive dyskinesia and Huntington's chorea. Ongoing research aims to deliver even more refined therapeutic solutions for these conditions.

For more detailed information on specific medications, consult authoritative resources such as the U.S. National Library of Medicine. https://medlineplus.gov/druginfo/

Frequently Asked Questions

The main differences are in dosing frequency and side effects. Newer agents like valbenazine and deutetrabenazine have longer half-lives, allowing for once- or twice-daily dosing compared to the multiple daily doses required for older tetrabenazine. They also offer improved tolerability and a better side effect profile.

VMAT2 inhibitors work by blocking a protein called vesicular monoamine transporter 2, which helps regulate neurotransmitter levels, particularly dopamine, in the brain. By inhibiting this transporter, they reduce the amount of dopamine released into the synapse, which helps to control involuntary movements like tardive dyskinesia and Huntington's chorea.

The new VMAT2 inhibitors, valbenazine (Ingrezza) and deutetrabenazine (Austedo, Austedo XR), are used to treat adults with tardive dyskinesia and chorea associated with Huntington's disease.

Common side effects for valbenazine include sleepiness and fatigue. For deutetrabenazine, common side effects include sleepiness, diarrhea, dry mouth, and fatigue. Both are generally well-tolerated.

Both valbenazine and deutetrabenazine carry a boxed warning for increased risk of depression and suicidality in patients with Huntington's disease. Other serious risks include neuroleptic malignant syndrome (NMS), parkinsonism, akathisia, and QT prolongation.

No head-to-head clinical trials comparing valbenazine and deutetrabenazine have been conducted, so there is no definitive evidence that one is superior to the other. The best choice depends on individual patient factors, tolerability, dosing frequency preference, and physician discretion.

Yes, research is ongoing for further improvements in VMAT2 pharmacology. A second-generation compound, NBI-1140675, is in Phase 1 clinical studies as of March 2025, suggesting a continued focus on advancing these treatments.