VMAT2 inhibitors are a class of medications designed to manage certain neurological conditions characterized by involuntary movements. These drugs specifically target a protein within the brain, influencing the way chemical messengers are stored and released.
The Role of VMAT2 in the Body
VMAT2, or Vesicular Monoamine Transporter 2, is a protein found primarily in the membranes of synaptic vesicles within neurons in the brain and nervous system. Its main function involves packaging monoamine neurotransmitters, such as dopamine, serotonin, norepinephrine, and histamine, from the cell’s internal fluid into these small, bubble-like storage units called synaptic vesicles.
Once these neurotransmitters are safely stored within vesicles, they are ready for release into the synaptic cleft when a nerve signal arrives. VMAT2 ensures that an appropriate amount of these chemical messengers is available for precise communication between nerve cells. This regulated release is crucial for a wide array of bodily functions, including the control of mood, movement, attention, and motivation.
How VMAT2 Inhibitors Function
VMAT2 inhibitors work by binding to the VMAT2 protein, which then prevents it from properly packaging monoamine neurotransmitters into synaptic vesicles. This reduces the uptake of these neurotransmitters, particularly dopamine, into the vesicles. As a result, less neurotransmitter is available for release into the synaptic cleft.
The reduction in neurotransmitter storage leads to a decrease in their overall release and subsequent activity in the brain. This mechanism helps to diminish the overstimulation of certain receptors, such as dopamine D2 receptors, which are implicated in various movement disorders. By controlling the amount of neurotransmitters available, VMAT2 inhibitors effectively reduce uncontrolled movements.
Conditions Treated by VMAT2 Inhibitors
VMAT2 inhibitors are prescribed for specific medical conditions marked by involuntary, hyperkinetic movements. These conditions include tardive dyskinesia and chorea associated with Huntington’s disease. Tardive dyskinesia is a neurological disorder characterized by repetitive, uncontrolled muscle movements, often affecting the face with actions like lip-smacking or blinking, and can arise from long-term use of certain psychiatric medications.
Huntington’s disease is an inherited neurodegenerative disorder that causes progressive chorea, which are sudden, involuntary movements of the extremities, trunk, face, and neck. In these conditions, VMAT2 inhibitors help alleviate symptoms by reducing excessive dopaminergic activity in the brain.
Common examples of VMAT2 inhibitors used in clinical practice include tetrabenazine (Xenazine), deutetrabenazine (Austedo), and valbenazine (Ingrezza). Tetrabenazine was approved in 2008 for Huntington’s chorea, and is used off-label for tardive dyskinesia. Deutetrabenazine and valbenazine received FDA approval in 2017 for tardive dyskinesia, with deutetrabenazine also approved for Huntington’s disease chorea and valbenazine subsequently approved for chorea associated with Huntington’s disease in 2023.
Important Considerations and Side Effects
VMAT2 inhibitors can cause a range of side effects. Common side effects include sleepiness, fatigue, dry mouth, and insomnia. Some individuals may also experience gastrointestinal issues such as diarrhea or constipation.
More serious considerations include the potential for depression and suicidal ideation, particularly in patients with Huntington’s disease who may already experience mood disorders. There is also a risk of parkinsonism, characterized by symptoms like tremor or rigidity, due to the reduction in dopamine levels. Contraindications include concomitant use with monoamine oxidase inhibitors (MAOIs), as this combination can lead to an unsafe buildup of monoamine neurotransmitters. Physicians carefully monitor patients for these and other potential adverse effects, adjusting dosages as needed to manage symptoms effectively while minimizing risks.