What is the mechanism of action of Ingrezza? A pharmacological deep dive

October 8, 2025 •

2 min read

Ingrezza (valbenazine) was the first medication specifically approved by the FDA for the treatment of tardive dyskinesia (TD), a challenging involuntary movement disorder. The answer to what is the mechanism of action of Ingrezza lies in its selective inhibition of a crucial protein in the brain's dopamine pathway. This targeted approach helps to normalize nerve signaling that has gone awry.

Quick Summary

This article explains how Ingrezza works by selectively inhibiting the VMAT2 protein to regulate dopamine levels in the brain. The reduced dopamine signaling helps control involuntary movements associated with tardive dyskinesia and Huntington's chorea.

Key Points

Selective VMAT2 Inhibitor: Ingrezza works by blocking the vesicular monoamine transporter 2 (VMAT2), a protein crucial for regulating neurotransmitter levels in the brain.
Reduced Dopamine Release: By inhibiting VMAT2, Ingrezza decreases the amount of dopamine packaged into vesicles and released into the synaptic cleft.
Targets Hypersensitivity: This reduction in dopamine signaling helps counteract the hypersensitivity of dopamine D2 receptors, which is a key factor in tardive dyskinesia.
Controls Involuntary Movements: The overall effect is a modulation of the motor control pathways, which leads to a decrease in the uncontrolled, involuntary movements of tardive dyskinesia and Huntington's disease chorea.
Pharmacological Specificity: Unlike some older treatments, Ingrezza is highly selective for VMAT2, with minimal affinity for other dopaminergic or serotonergic receptors, which contributes to a more focused therapeutic effect.
Once-Daily Dosing: Ingrezza is a once-daily medication, simplifying treatment adherence for patients with chronic movement disorders.

Ingrezza's Primary Target: The VMAT2 Protein

Ingrezza's mechanism of action centers on the vesicular monoamine transporter 2, or VMAT2. VMAT2 is found on synaptic vesicles within neurons and is responsible for transporting monoamine neurotransmitters like dopamine into these vesicles for storage and eventual release.

Ingrezza (valbenazine) is a selective inhibitor of VMAT2, meaning it binds to and blocks this specific transporter without significantly affecting others. This selective action prevents dopamine from being effectively packaged into synaptic vesicles.

The Effect on Dopamine Signaling

By blocking VMAT2, Ingrezza causes monoamines not stored in vesicles to be broken down, reducing the amount available for release. This leads to a decrease in dopamine released into the synapse, which is beneficial in movement disorders linked to excessive dopamine signaling. In tardive dyskinesia, this helps counteract the hypersensitivity of dopamine D2 receptors caused by other medications.

Pathophysiology of Movement Disorders and Ingrezza's Role

Tardive Dyskinesia (TD)

TD, characterized by involuntary movements, often results from long-term use of dopamine-blocking drugs. This leads to increased sensitivity of D2 receptors. Ingrezza reduces dopamine flux, mitigating the exaggerated response of these hypersensitive receptors and thus reducing involuntary movements.

Chorea Associated with Huntington's Disease (HD)

Chorea in HD is linked to neuronal loss and excess dopaminergic activity. Ingrezza helps restore balance by reducing synaptic dopamine. Studies show it can significantly improve chorea symptoms.

Ingrezza vs. Other VMAT2 Inhibitors

Ingrezza is a VMAT2 inhibitor, but differs from others. Below is a comparison of key VMAT2 inhibitors.


Feature	Ingrezza (Valbenazine)	Deutetrabenazine (Austedo)	Tetrabenazine (Xenazine)
Mechanism	Highly selective VMAT2 inhibitor	VMAT2 inhibitor	VMAT2 inhibitor
Metabolism	Prodrug, metabolized by CYP3A4 and CYP2D6 to its active form	Deuterated tetrabenazine, less susceptible to CYP2D6 metabolism	Metabolized by CYP2D6
Dosing	Once-daily	Twice-daily	Three times daily
Titration	No required titration for TD, gradual titration for HD chorea	Gradual titration	Gradual titration
Side Effects	Somnolence, fatigue, rash, insomnia, dry mouth	Somnolence, fatigue, depression, akathisia	Depression, sedation, insomnia, restlessness
Indications	TD and HD chorea	TD and HD chorea	HD chorea (off-label for TD)

Pharmacokinetics and Efficacy

Valbenazine is a prodrug converted to its active form, alpha-dihydrotetrabenazine. Its once-daily dosing may improve compliance. Clinical trials demonstrate its effectiveness, with studies showing remission in a significant portion of TD patients and improvement in HD chorea within weeks.

Conclusion

In summary, Ingrezza's mechanism involves selective, reversible VMAT2 inhibition. This blocks dopamine packaging and release, moderating dopaminergic signaling to reduce involuntary movements in tardive dyskinesia and Huntington's disease chorea. Its VMAT2 specificity and once-daily dosing make it an effective and manageable treatment option.

For more detailed information on tardive dyskinesia and its management, consult the National Institute of Neurological Disorders and Stroke.

Frequently Asked Questions

The vesicular monoamine transporter 2 (VMAT2) is a protein responsible for moving monoamine neurotransmitters, including dopamine, from the cytoplasm into synaptic vesicles for future release.

By blocking VMAT2, Ingrezza prevents dopamine from being properly stored in synaptic vesicles. The free-floating dopamine in the cell's cytoplasm is then broken down by enzymes, leading to reduced overall dopamine availability for release.

Prolonged use of certain psychiatric medications that block dopamine receptors can lead to an upregulation and hypersensitivity of these receptors. This results in an overactive response to dopamine signaling, which causes the involuntary movements of tardive dyskinesia.

No, Ingrezza does not cure these conditions. It is a symptomatic treatment that helps control the involuntary movements but does not address the underlying pathology of the diseases.

Yes, Ingrezza (valbenazine) is a once-daily, highly selective VMAT2 inhibitor. Its selectivity and once-daily dosing distinguish it from other VMAT2 inhibitors like tetrabenazine, which is often dosed three times per day.

While some improvements in symptoms may be noticed within a few weeks, it can take several months for Ingrezza's full therapeutic effect to become apparent. For tardive dyskinesia, maximal effects can take up to 32 weeks.

Yes. The reduction in dopaminergic activity can lead to side effects like sleepiness, fatigue, dry mouth, and, in some cases, symptoms resembling parkinsonism or restlessness.