Advances in Tardive Dyskinesia: Valbenazine, VMAT2 Inhibition, and the Future of Care

A guest expert discusses his decades of schizophrenia research and highlights how valbenazine has transformed the treatment of tardive dyskinesia with rapid, dramatic, and well-tolerated results.

Read the full transcript:

Jean-Pierre Lindenmayer, MD: I am Dr Jean-Pierre Lindenmayer, and I’m the director of the Psychopharmacology Schizophrenia Program here at Manhattan Psychiatric Center, which is associated with the Nathan Klein Institute of Psychiatric Research. I’m also a clinical professor of psychiatry at the New York University Grossman School of Medicine.

I am a clinical researcher who has been working in the field of schizophrenia for the past 30 years. My interests have certainly included tardive dyskinesia and, more broadly, side effects of antipsychotic medications. I’ve also been involved in the development of all currently available second-generation antipsychotics.

We are particularly interested in subsyndromal aspects of schizophrenia not well addressed by current psychopharmacology—namely, negative symptoms and cognitive symptoms. We have instituted research programs for these syndromes, and we’ve had some very interesting results. For instance, in cognition, we have actually looked not at pharmacological interventions, but at cognitive remediation in a computerized environment, which actually works very well. Unfortunately, some of these results haven’t yet translated into day-to-day clinical care, which I think would be important to do.

The other area of negative symptoms—we are particularly interested in how to measure negative symptoms in an appropriate and objective way, because it’s kind of left to the rater to decide how much of negative symptoms patients have, and we know that that is not easy to assess because we rely essentially on the patient’s behavior, on the patient’s communication. What we are looking at is how we can digitally capture negative symptoms, both on facial movements and on voice analysis. And we sense that these measures may be much more informative than the clinical ratings of negative symptoms. This is something we are currently examining very intensively.

What were the key findings in your research exploring the treatment of tardive dyskinesia with valbenazine?

Dr Lindenmayer: Let me first give some historical background on this. When we started to look at tardive dyskinesia, these newer drugs, like valbenazine, were not available. And also at that time, we had a tardive dyskinesia clinic, which was meeting once a week, and we had at least 30 to 40 patients waiting to be seen. Today, that would be impossible to do because you wouldn’t find the patients with tardive dyskinesia.

In other words, tardive dyskinesia has significantly decreased. And I don’t think that people are fully aware of that. While certainly it was an issue, I would say 15 to 20 years ago—because we were dealing essentially with the first-generation antipsychotics, which were the primary suspects in creating tardive dyskinesia—these days, we see many fewer cases of tardive dyskinesia, and the cases are much, much milder than what we used to see.

And if you’re asking why has tardive dyskinesia decreased so significantly, is it due to the introduction of these drugs? Probably not. It has much more to do with the use of the second-generation antipsychotics, such as risperidone, olanzapine, paliperidone, etc. These drugs have much better—I would say—profiles in terms of being much less at risk to create tardive dyskinesia.

It goes so far that current clinicians who haven’t seen these tardive dyskinesia cases in the past have difficulty actually diagnosing tardive dyskinesia. Often, they confuse it with Parkinsonian symptoms, such as some tremor of the tongue or tremor of the mouth, which they mistake and think is tardive dyskinesia, when in fact it is acute extrapyramidal side effects from medications.

I think tardive dyskinesia these days is no longer the kind of burning and certainly unfavorable side effect which we used to have. Now, valbenazine is one of the two VMAT2 inhibitors which were introduced and are approved currently for tardive dyskinesia. They did introduce a newer mechanism of action, which many people may not fully appreciate. It’s an interesting mechanism—it’s called VMAT2 inhibition.

In other words, presynaptically we have dopamine being formed, and it is saved in granules, and it then gets excreted into the postsynaptic space, and then it binds with a dopamine receptor on the other side. Now, what the VMAT2 inhibitors do—they inhibit presynaptically the storage of the dopamine molecules so that these molecules swim around in the presynaptic space and get destroyed essentially and are no longer available to stimulate the postsynaptic dopamine receptor.

It sounds a little bit complicated, but I hope I made it clear. This is a presynaptic destruction of dopamine, which then is no longer available to stimulate the postsynaptic dopamine receptor, which we think is hypersensitive in tardive dyskinesia, and therefore will be effective in reducing tardive dyskinesia.

And I must say, looking back and comparing how effective are these drugs, I would say they are dramatically effective. I have done many, many drug trials with many different drugs, where you might see a little bit of an effect. But here, this was unmistakably one of the most dramatic effects: the tardive dyskinesias in our research patients decreased markedly.

That was part of the good news. The other part was that it was pretty well tolerated, so side effects were really minimal, at least certainly in our hands. We felt this was an excellent introduction of a new drug, and it was eventually approved and is currently in use at 40 and 80 milligrams per day. I would say we do have a treatment now for tardive dyskinesia, and it is an effective treatment and well tolerated.

How should clinicians interpret the similar efficacy outcomes seen at both 40 mg and 80 mg, particularly considering dose escalation guided by response and tolerability?

Dr Lindenmayer: That’s a good question. It touches on 2 issues: how quickly valbenazine responds, and the dose. The response is fairly rapid. Within about 2 to 3 weeks, you can clearly see whether or not tardive dyskinesia has improved.

In general, what we recommend is to start with 40 milligrams and to see how is the response. If the response is not sufficient, if it’s not discernible, you move up to 80 milligrams, which is the maximum dose, and you hold the dose at that point. You may eventually be able to go back down to 40 milligrams if there’s a good response and there are tolerability issues. But generally, both 40 and 80 milligrams respond well and have good tolerability.

The next issue clinicians consider is how long to keep the treatment. Should they stop, will the TD come back? We do have some answers. First, you do need to keep the treatment on. You can certainly consider reducing and discontinuing the treatment and see what happens. What we have seen is that TD returns. However, it is usually not as intense as what you saw at baseline before starting treatment.

Is there a curative effect of this mechanism, some way it resets receptor dynamics? Possibly, but we can’t say TD disappears once you stop. Most of the time, you are obliged to continue the treatment.

Another question clinicians ask is whether you should change the antipsychotic causing the TD. My answer is absolutely. If the drug is a high-potency dopamine blocker, you may want to consider switching to a lower-potency agent—for example, moving from risperidone to quetiapine. Or reducing the antipsychotic dose before you add valbenazine.

Older treatments we used before VMAT2 inhibitors are now largely obsolete. Vitamin E had mixed evidence. GABAergic compounds like topiramate were tried but caused sedation. Clozapine could work, but required switching antipsychotics. Now we don’t need to invoke these because VMAT2 inhibitors are so effective.

Based on your experience with CONNECT-TD and the current landscape, what do you see as the most important directions or unanswered questions for the future of TD research?

Dr Lindenmayer: Well, let me give you the short answer. I think we have an effective drug, we have a fairly good understanding of the mechanism, and also of the underlying mechanism of tardive dyskinesia. I’m not sure this is really an area ripe for more research. If I had the money, I’d probably invest in other areas, because here we have a good treatment that is well tolerated.

That said, questions remain. One is whether VMAT2 inhibition is the only mechanism. Recently, there’s been interest in neuromelanin—a downstream product of dopamine, potentially toxic, that can now be imaged. It might be useful as a biomarker for TD. That would be desirable.

Another issue is why VMAT2 inhibition doesn’t also help psychosis. If reducing dopamine presynaptically helps TD, shouldn’t it also reduce positive psychotic symptoms? A study recently tested valbenazine added to antipsychotics in patients with an incomplete response. The design was to continue the current antipsychotic and add valbenazine or placebo. Unfortunately, the results were negative, the valbenazine group did no better. That was disappointing, and it raises questions about whether VMAT2 inhibition is the sole mechanism in TD.

In terms of therapy, though, TD is well addressed now. What would be important is for younger clinicians to gain exposure to how TD looks so they can recognize it. Many have never seen classic TD and may misdiagnose it.

Also, special attention is needed for long-term care populations, like nursing homes, where antipsychotics may be used by non-psychiatrists for sedation or agitation. Those patients are especially sensitive to side effects, and TD can impair eating, speaking, and swallowing. If providers don’t recognize TD, it may go untreated. Educational efforts there are very important.