COMMENTARY

Explaining the Renewed Interest in Tardive Dyskinesia

Jeffrey A. Lieberman, MD

Disclosures

February 25, 2019

This transcript has been edited for clarity.

Hello. This is Dr Jeffrey Lieberman of Columbia University in New York City, speaking to you today for Medscape.

You may have noticed in the past year or so the increasing frequency of publications and educational and promotional materials concerning tardive dyskinesia (TD). You can find them in journals, your emails, and on websites such as Medscape.

Going 'Back to the Future' With TD

TD is a neurologic, drug-induced side effect that produces involuntary movements and can be irreversible if measures are not taken to either reduce the dose of antipsychotic drugs or institute treatment.

TD is something that may not even be known to many of the younger psychiatrists or mental health professionals, but it certainly is known to me. Earlier in my career, I actually began my research activities focusing on TD and publishing the results. However, I drifted away from TD intentionally to focus on schizophrenia. The reason for that is that although I appreciated that this research was interesting and very much needed, I also realized that it had a limited future, given the introduction of what were called atypical, or second-generation, antipsychotic drugs, beginning with clozapine in 1989 and then many others to follow.

By virtue of these drugs' different pharmacologic profiles, their lower affinity for the dopamine 2 receptor, and their ability to reduce the prevalence of neurologic side effects of tremor, bradykinesia, rigidity, and TD itself, it seemed that this condition would probably diminish over time and therefore be less consequential.

In fact, that is what happened. The emphasis on TD declined, as did the frequency of its side effects and the number of publications about it. Correspondingly, there was an increase in research publications reporting on the other side effects that emerged with the second-generation drugs: weight gain and metabolic disturbances in glucose and lipid metabolism.

Why the Reemerging Focus on TD?

All of that seemed to change on April 11, 2017, when valbenazine (Ingrezza) was approved by the US Food and Drug Administration (FDA), making it the first such drug to have a specific indication for TD. Valbenazine works by inhibiting the vesicular monoamine transporter 2 (VMAT2), which reabsorbs dopamine in the presynaptic neuron into vesicles and keeps it from being released.

In August of the same year, deutetrabenazine (Austedo) also received FDA approval for TD. Deutetrabenazine is also a VMAT2 inhibitor, which was initially approved for Huntington disease.

With the introduction of these two FDA-approved drugs, their marketing in the United States naturally increased, which coincidentally corresponded to the increased publications and frequency of information in the form of advertisements and medical education that you now see. This has occurred even though the magnitude of the clinical problem continues to diminish.

The Road to New TD Treatments

Some people still will be and currently are affected by TD. The advent of new treatments is therefore all to the good and something to be welcomed and used when appropriate. However, one cannot help but notice the resurgent interest in TD in the form of a striking increase in information, publications, and research that has coincided with the marketing of these new patented medications, and whatever their price point is.

These medications follow similar mechanisms of action as previous ones used for TD, probably the most widely employed of which was tetrabenazine. This was a drug that was used sometimes for TD but also for Huntington disease and various types of idiopathic dystonias. Tetrabenazine also acted at the presynaptic membrane of dopamine neurons and reversibly inhibited the VMAT2 transporter. It was not quite as fancy as the newer drugs in terms of its pharmacodynamic activities, but it had fundamentally the same or similar mechanisms of action and was reasonably effective, albeit with various side effects.

Tetrabenazine followed on resperine, the original compound that acted in this way and could be used in such movement disorders. Reserpine is actually an ancient drug derived from the root of the Rauwolfia serpentina plant. Although it acted in a similar way to the other drugs I mentioned, it went beyond them by being, let us say, heavy handed in its effects. It acted at the presynaptic membrane by depleting dopamine and irreversibly inhibiting VMAT2 and VMAT1. The fact that the VMAT1 transporters were mainly distributed in the periphery outside the central nervous system meant that this could cause more peripheral side effects than did the others, which were active more at the VMAT2 located within the brain.

These two new drugs—valbenazine and deutetrabenazine—have breathed new life into this area, but it is disproportionate to the magnitude of the clinical problem.

A Marketing Push Brings TD Back Into the Spotlight

I do not want to throw cold water on progress. We need all we can get, especially when pharma has deemphasized its research in psychotropic drug development. However, the point I would make is that the occurrence of this increased interest and reporting is clearly driven by marketing. We get a flavor for the extent of this by looking at the number of TD publications in the scientific literature that have occurred over the past few years. There were 27 publications on TD in 2014, 22 in 2015, 31 in 2016, 54 in 2017, and so far there have been 61 in 2018 at the time of this recording.

Clearly, there has been renewed interest in TD, mainly prompted by the introduction of new drugs, which have marketing budgets associated with them. It is not all bad, but it just shows you what I think is obvious to people: Money talks.

This is in no way a criticism of the pharmaceutical industry, researchers, or continuing medical education organizations such as Medscape. Over recent decades, the pharmaceutical industry has been increasingly criticized, even vilified, for its excessive marketing and increased pricing for various medications. We shouldn't believe that there is any similarity between pharma and the tobacco industry and try to similarly drive pharma out of existence. If we did so, we'd find ourselves "up a creek," and it would be disastrous. What we need to do is to work with pharma in a constructive, appropriate, and professionally and ethically rigorous manner.

I am sure that most of us are not naive. We realize that a lot of what drives research and continuing medical education has to do with funds that come from private entities, not from universities, the National Institutes of Health, or foundations. As a result, we see these ebbs and flows of interest in different clinical areas. TD and the new drugs that are available or are being developed to treat it are just a current example.

I appreciate your attention and thank you for listening. This is Dr Jeffrey Lieberman of Columbia University, speaking to you today for Medscape.

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