<p>VMAT2 inhibitors have transformed the treatment landscape for tardive dyskinesia (TD), decreasing dopamine release presynaptically to reduce involuntary movements. Nonetheless, challenges remain that can complicate the treatment of TD and drive the need for individualized therapy and multidisciplinary approaches.</p>

There are 2 US Food and Drug Administration (FDA)–approved treatments available for TD. This is quite revolutionary because there were no treatments for TD when I started my psychiatric training. Over time, we tried to research different avenues of treatment. Then we had 2 approvals from the FDA for the reversible VMAT2 inhibitors valbenazine and deutetrabenazine, and this represents a huge advance in our management of TD.

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By using these medications, one presupposes that the mechanism of TD is excessive dopamine and dysregulation of the dopamine receptors in the motor striatum, and we need to decrease the amount of dopamine that is released presynaptically. VMAT2 inhibitors do the job in the motor striatum, reducing the frequency of dyskinetic movements.

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From a psychiatric viewpoint, it would be great if we could predict who will ultimately develop TD. We know that this involves complex genetics, with some genes identified as increasing the propensity for TD. If we could know a patient’s genetic predisposition for developing TD in advance, then maybe we could select treatments accordingly. Another issue can be adherence to the treatments that we currently have available for TD. It would also be great to have a long-acting injectable VMAT2 inhibitor to simplify treatment.

The mechanism of VMAT2 inhibitors is still antidopaminergic, similar to that of the dopamine receptor–blocking medications used to treat schizophrenia. The key difference is that VMAT2 inhibitors act presynaptically to reduce dopamine release, so there is less dopamine available to act postsynaptically. For this reason, even though these medications interfere with the dopaminergic system, they do not actually potentiate TD like a dopamine receptor blocker might.

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VMAT2 inhibitors are the class of medications that I would reach for first for patients with TD. If somebody has a difficult time with one VMAT2 inhibitor, I might try them on the other to find out whether they could still get a response with good tolerability.

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We have a fair understanding of the pathways involved in TD and what needs to be done within those pathways. To that end, VMAT2 inhibitors are fairly potent. Sometimes, the issues with these medications are related to tolerability, and perhaps even access. I think that this is where there could potentially be some more work done. Otherwise, I agree with Dr Citrome. Understanding how to mitigate the risk of TD by knowing something more about the population who might develop it could be very informative. That type of research holds a lot of promise.

When it comes down to treatment, I think that it is important to highlight the challenges we sometimes face when trying to decide who will need ongoing psychiatric treatment and how to coordinate treatment if the patient still requires it. Traditionally, the management of TD relied on a reduction of the medications that were causing TD or a potential switch to a different agent that has a lower risk of inducing or exacerbating TD symptoms. However, this method carries the risk of increasing psychiatric symptoms, so adjusting the medications or deciding to discontinue them requires close coordination with other providers who are treating the patient.

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Discovering new ways to treat TD has been challenging because we may only have a partial understanding of its pathophysiology. We know that dopamine receptor hypersensitivity plays a key role; however, a variety of other agents have been tested in the past to look at other mechanisms of action, with fairly limited benefit. We have explored targeting glutamatergic and serotonergic transmission, but with very limited results. Until we increase our understanding of what causes TD and who gets it, I think that developing novel drugs that more effectively target and modulate VMAT2 will be key going forward.