VMAT2 inhibitors are a class of medications used to manage specific movement disorders. These drugs influence the activity of chemical messengers, known as neurotransmitters, within the brain. By adjusting the balance of these messengers, VMAT2 inhibitors aim to reduce involuntary body movements.
How VMAT2 Inhibitors Work
The VMAT2 (Vesicular Monoamine Transporter 2) protein plays a role in the brain by packaging neurotransmitters into small sacs called vesicles. These neurotransmitters, including dopamine, serotonin, and norepinephrine, are then stored within these vesicles until they are released into the synapse, the tiny gap between nerve cells. This packaging and release mechanism is how nerve cells communicate with each other.
VMAT2 inhibitors work by blocking or reducing the activity of this VMAT2 protein. When VMAT2 is inhibited, the transporter cannot effectively load neurotransmitters into vesicles. This leads to a decrease in the amount of neurotransmitters available for release into the synaptic cleft.
The reduction in neurotransmitter release, particularly dopamine, helps to lessen uncontrolled movements. This mechanism differs from directly blocking neurotransmitter receptors, instead focusing on the storage and release process. By diminishing the “go” signals and strengthening “stop” signals in motor pathways, VMAT2 inhibitors can reduce abnormal involuntary movements.
Conditions Treated by VMAT2 Inhibitors
VMAT2 inhibitors are prescribed for neurological and movement disorders characterized by excessive or uncontrolled movements. These conditions often involve an imbalance in neurotransmitter activity, particularly an excess of dopamine. By reducing the amount of dopamine released, VMAT2 inhibitors help alleviate these symptoms.
One condition treated is tardive dyskinesia (TD), which involves repetitive, involuntary body movements that can arise as a side effect of long-term use of certain medications, such as antipsychotics. Studies suggest that 50% to 60% of people with TD experience meaningful improvement with these medications.
Another condition addressed is chorea associated with Huntington’s disease. Huntington’s disease is a genetic neurodegenerative disorder characterized by uncontrolled movements, cognitive decline, and psychiatric symptoms. The excessive dopamine activity in specific brain regions is thought to contribute to the motor symptoms of Huntington’s disease.
VMAT2 inhibitors alleviate the motor symptoms of Huntington’s disease by reducing this dopaminergic hyperactivity. While these medications help manage the involuntary movements, they do not prevent the progression or alter the underlying course of Huntington’s disease.
Common VMAT2 Inhibitor Medications
Tetrabenazine, known by the brand name Xenazine, was the first VMAT2 inhibitor approved in the United States in 2008 for the treatment of chorea associated with Huntington’s disease. It can be used off-label for other movement disorders.
Deutetrabenazine, marketed as Austedo, received FDA approval in 2017 for both tardive dyskinesia and chorea associated with Huntington’s disease. This medication has a modified chemical structure that allows for less frequent dosing compared to tetrabenazine.
Valbenazine, sold under the brand name Ingrezza, was also approved by the FDA in 2017 specifically for the treatment of tardive dyskinesia. Both deutetrabenazine and valbenazine are preferred over tetrabenazine for tardive dyskinesia due to their pharmacokinetic profiles and lower risk of side effects.
Potential Side Effects and Considerations
VMAT2 inhibitors can cause side effects. Common ones include somnolence (sleepiness), fatigue, nausea, and dry mouth. Some people may also experience insomnia, anxiety, or constipation.
A potential side effect is the emergence of parkinsonism-like symptoms, such as slowed movement, tremor, or stiffness. This can occur because the medications reduce dopamine activity, similar to the effects seen in Parkinson’s disease. Other considerations include drug interactions, especially with medications that affect liver enzymes like CYP2D6 and CYP3A4, which are involved in the metabolism of VMAT2 inhibitors.
VMAT2 inhibitors are contraindicated with monoamine oxidase inhibitors (MAOIs) due to the risk of excessive monoamine buildup. It is important to discuss all current medications with a healthcare professional to avoid adverse interactions. These medications require careful medical supervision, including dose adjustments and monitoring for side effects, to ensure safe and effective treatment.