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How VMAT2 Inhibitors Make Life-Changing Improvements for People With TD

Stephen R. Saklad, PharmD, BCPP

Clinical Professor
Division of Pharmacotherapy
College of Pharmacy
The University of Texas
Clinical Pharmacologist
San Antonio State Hospital
San Antonio, Texas


Stephen R. Saklad, PharmD, BCPP: consultant/advisor/speaker: Neurocrine, Teva.


View ClinicalThoughts from this Author

Released: November 28, 2022

Key Takeaways

  • Tardive dyskinesia (TD) is more common in people who are receiving first-generation antipsychotics due to the high level of dopamine receptor blockade, but it also is seen in people who are receiving second-generation antipsychotics.
  • VMAT2 inhibitors reduce TD symptoms by causing a decrease in the amount of dopamine released in the central nervous system.
  • Improvements in TD symptoms can be seen within a few weeks to a couple of months following initiation of a VMAT inhibitor.

What Causes Tardive Dyskinesia?
Tardive dyskinesia (TD) is a drug-induced abnormal involuntary movement disorder associated with the use of dopamine-receptor blocking agents (DRBAs). Among the DRBAs, TD is most associated with the use of antipsychotics. The prevalence of TD is approximately 30% in people treated with first-generation antipsychotics (FGAs); these rates decrease to 23% in people currently treated with a second-generation antipsychotic (SGA) who have a history of treatment with an FGA. Rates of TD are as low as 7% in people currently receiving an SGA with no previous exposure to an FGA.

What is the reason for the difference in risk between FGAs and SGAs? It comes down to their mechanisms of action. One of the major differences between newer atypical antipsychotics, or SGAs, and typical antipsychotics, or FGAs, is their receptor binding activity. FGAs primarily block the dopamine 2 receptors, whereas SGAs block serotonin 2A receptors and dopamine 2 receptors. Because the major risk factor for developing TD is related to the amount of dopamine receptor blockade, the typically “stronger” antipsychotic agents with higher amounts of dopamine receptor blockade hold a higher risk for TD development, whereas the serotonin and dopamine binding of the SGAs appears to be responsible for the decreased risk of drug‑induced parkinsonism and TD.

Higher antipsychotic doses and antipsychotic use for mood disorders also put people at risk for TD. Other risk factors include older age, female gender, and menopause. These factors may increase a person’s exposure to an antipsychotic medication. However, numerous factors lead to an increased risk for developing TD, so it is very difficult to determine the exact cause in an individual with multiple risk factors. 

First Steps to TD Prevention and Management
Many people who have TD experience disfiguring movements, a decrease in their ability to maintain social interactions, and an overall decreased quality of life. Unfortunately, this is usually a permanent disorder—thus, we need to prevent it. Best practice for preventing TD is to use antipsychotics, especially FGAs, only when there is a clear indication for them and to use them at the optimal minimal effective dose for the patient. Not everyone can avoid antipsychotic therapy, so the next step in preventing TD is carefully monitoring for it at each appointment—at least every 6 months. If someone develops what appears to be TD while receiving an antipsychotic for a few months, the ideal strategy is to gradually taper off the antipsychotic medication—if appropriate to their individual situation. Occasionally, the antipsychotic‑induced movement disorder turns out to be a drug withdrawal dyskinesia that will fade away during a period of months. However, most of the cases will be TD, which does not resolve even if the antipsychotic medication is stopped. When the DRBA dose is reduced in someone who has been receiving an antipsychotic medication for at least a few months, this may lead to a reemergence of their psychiatric problem and result in an apparently paradoxical increase, not a decrease, in their TD symptoms due to the reduced dopamine blockade. Switching therapy also may be an option, but it is typically done because of intolerances other than TD. 

VMAT2 Inhibitors
The VMAT2 inhibitors valbenazine and deutetrabenazine have revolutionized our understanding of how TD can be treated. These agents block the pump that moves dopamine from cell cytosol into the presynaptic vesicle. The VMAT2 inhibitors decrease the amount of dopamine released with each action potential. This decreased amount of dopamine release reduces the outflow of the basal ganglia, the area of the brain associated with smooth movement coordination. This reduction in dopamine outflow compensates for the increased number of dopamine receptors that have likely developed in response to DRBA use.

Although the VMAT2 inhibitors have not been specifically tested as antipsychotics, we know there are similarities between them. The good news is that the extent of this similarity means VMAT2 inhibitors can be used concomitantly with antipsychotics and actually may enhance their effect—some post hoc analyses have shown improvement in psychiatric rating scales in the presence of the VMAT2 inhibitors. Unfortunately, VMAT2 inhibitors also have been shown to be similar to antipsychotics in that they may cause drug‑induced parkinsonism symptoms, although this can usually be easily treated. The large benefits in people with TD outweigh the risks in almost all cases.

The VMAT2 inhibitors are very effective drugs. Initial improvements in irregular movements can be expected within a few weeks of starting treatment. After a couple of months, most people or their caregivers report significant improvement—often described as a life‑changing amount of improvement. One consideration, however, is that these medications are very expensive. It is, therefore, important for prescribers to know that all companies that make VMAT2 inhibitors offer patient assistance programs to help with cost if insurance doesn’t cover the medication.

There are other options if cost or intolerance/allergy precludes a patient from using a VMAT2 inhibitor. These alternative therapies for TD have been available for years and include melatonin, vitamin E, vitamin B6, and ginkgo biloba. All of these alternatives are much less effective than the VMAT2 inhibitors when comparing effect size and amount of clinical improvement, but some people may have some benefit.

Your Thoughts?
The VMAT2 inhibitors have not only revolutionized our treatment options, but also have resulted in life-changing improvements for people with TD. In your clinical practice, do you treat people who suffer from TD? Do you feel comfortable with using a VMAT2 inhibitor to manage their disease? Answer the polling question and join the discussion by posting a comment. 

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