*VMAT2 inhibitor? What’s that?*

Valbenazine (Ingrezza) is a selective inhibitor of vesicular monoamine transporter 2 (VMAT 2). In April, 2017, it was approved by the FDA for the treatment of adults with tardive dyskinesia. It is the first medication ever to be FDA-approved for the treatment of tardive dyskinesia.

What is VMAT 2?

VMAT2 sounds like the name of a rocket, I know. But actually, the vesicular monoamine transporter 2 (VMAT2) is a protein in presynaptic neurons that release monoamine neurotransmitters like dopamine. In the presynaptic neuron, VMAT2 transports these monoamines from the cytoplasm into synaptic vesicles. Once in the synaptic vesicles, the monoamines are protected from being metabolized by monoamine oxidase.

When VMAT 2 is inhibited, as with valbenazine treatment, uptake of monoamines (like dopamine) into synaptic vesicles is reduced. Therefore, the monoamines are not protected within vesicles and get metabolized. The gradual depletion of dopamine is, presumably, what leads to improvement in the tardive dyskinesia.

The “2” does not mean it is an improved version of VMAT! 🙂 VMAT occurs in two forms: VMAT 1 that is found in the periphery and VMAT2 that is found in the central nervous system.

The term “selective” VMAT2 inhibitor means that the medication inhibits only VMAT2 and not VMAT1. And that it does not have any other pharmacological effects, e.g., on various postsynaptic receptors.

Valbenazine is not the first or only VMAT 2 inhibitor. Nor is it the first or only medication to be shown to be effective for tardive dyskinesia.

*Which VMAT2 inhibitor should we choose?*

Three medications that are VMAT2 inhibitors are available in the US. All three of these medications are “selective” VMAT2 inhibitors. Alphabetically, they are:

1. *Deutetrabenazine (Austedo)*

Deutetetrabenazine (Austedo) was developed by adding deuterium to tetrabenazine. This modifies the pharmacokinetic profile and leads to more uniform levels of the drug.

It has been shown to be efficacious for tardive dyskinesia (Anderson et al., 2017).

Deutetrabenazine (Austedo) was approved by the FDA in 2017 for the treatment of chorea associated with Huntington’s disease and later in 2017 for the treatment of tardive dyskinesia in adults.

2. *Tetrabenazine (Xenazine)*

Tetrabenazine has been around for a while and is FDA-approved for the treatment of Huntington’s disease. Even though it is now generic, it is still expensive–at least $1500 per month for thirty tablets of 25 mg (per goodrx.com).

3. *Valbenazine (Ingrezza)*

This was the first medication to be FDA-approved (in April 2017) for the treatment of tardive dyskinesia.

*Depression and suicidality*

Especially for use in patients with mental health problems, it is important to note that both tetrabenazine and deutetrabenazine carry boxed (“black box”) warnings that the medication “Increases the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease.” The boxed warning then makes recommendations for caution and monitoring and ends by stating that tetrabenazine/deutetrabenazine is “contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression.”

In the valbenazine studies, no increased risk of depression or suicidality was found. Therefore, valbenazine (Ingrezza) does not carry any warning about possible depression or suicidality. A major reason for this difference may be that the valbenazine studies are in tardive dyskinesia and the tetrabenazine and deutetrabenazine studies are in Huntington’s disease. Persons with Huntington’s disease are very prone to developing depression and suicidal ideation. So, even with valbenazine, it will be wise for us to still be cautious, especially if using it in persons at higher risk of depression or suicidality.

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