Vesicular Monoamine Transporter 2 (VMAT2) inhibitors are a class of medications that influence the activity of chemical messengers in the brain. These drugs primarily manage movement disorders characterized by involuntary movements. They modulate the balance of specific neurotransmitters, which are chemicals that transmit signals between nerve cells. This targeted action helps to reduce unwanted body movements associated with these conditions.
Understanding Tardive Dyskinesia
Tardive dyskinesia (TD) is a neurological condition characterized by involuntary, repetitive body movements. The term “tardive” indicates a delayed onset, with symptoms often appearing after months or years of medication use, while “dyskinesia” refers to abnormal, uncontrolled movements. This condition affects over 500,000 people in the United States.
Common symptoms of TD include uncontrollable movements of the face, such as grimacing, lip smacking, tongue protrusion, or rapid eye blinking. Movements can also affect the limbs and trunk, manifesting as swaying, rocking the pelvis, or foot tapping. TD is caused by the long-term use of dopamine receptor blocking agents, such as antipsychotics, which are medications used to treat various psychiatric conditions. Some antidepressants and medications for gastrointestinal or neurological problems can also lead to TD.
How VMAT Inhibitors Work
VMAT inhibitors target the Vesicular Monoamine Transporter 2 (VMAT2) protein, which regulates neurotransmitter levels in the brain. VMAT2 is located on synaptic vesicles within neurons and packages monoamines, including dopamine, norepinephrine, and serotonin, from the cytoplasm into these vesicles. This packaging is essential for the regulated release of these neurotransmitters into the synaptic cleft, the space between neurons where signals are transmitted.
By inhibiting VMAT2, these medications reduce the amount of monoamines, particularly dopamine, stored in synaptic vesicles. When less dopamine is stored, less is available for release into the synaptic cleft when a nerve signal occurs. This reduction in dopamine release helps decrease the overstimulation of dopamine receptors, which is believed to contribute to the involuntary movements seen in tardive dyskinesia. Unbound dopamine in the cytoplasm is then degraded by enzymes like monoamine oxidase (MAO), further reducing its availability.
Approved VMAT Inhibitors
Several VMAT inhibitors have received regulatory approval for treating tardive dyskinesia, offering important treatment options. Valbenazine (Ingrezza) and deutetrabenazine (Austedo) are two such medications approved by the U.S. Food and Drug Administration (FDA) in 2017. These drugs represent a significant advance in managing TD symptoms.
Both valbenazine and deutetrabenazine are taken orally, once daily. Tetrabenazine, an older VMAT2 inhibitor approved in 2008 for Huntington’s chorea, is also used off-label for TD. However, valbenazine and deutetrabenazine were specifically developed and approved for TD. Their development involved chemical modifications to improve their bioavailability and duration of action compared to tetrabenazine.
Important Considerations for Treatment
Treatment with VMAT inhibitors requires careful supervision by a physician due to potential side effects and drug interactions. Common side effects include somnolence (drowsiness), fatigue, and mild parkinsonism symptoms, such as slowed movements or changes in gait. Nausea, insomnia, dry mouth, and constipation have also been observed.
Patients should be monitored for QTc prolongation, a change in the heart’s electrical activity, especially if they have a history of heart conditions or are taking other medications that can affect the QTc interval. VMAT inhibitors are contraindicated with monoamine oxidase inhibitors (MAOIs) because preventing monoamine storage can lead to their buildup, potentially causing serotonin syndrome. These medications are metabolized by specific liver enzymes, meaning other drugs affecting these enzymes could alter VMAT inhibitor levels in the body. Adjustments to dosing may be necessary for individuals who are poor metabolizers of certain enzymes or who are taking strong inhibitors of these enzymes.