Mastering VMAT-2 Inhibitors: Optimizing Treatment Strategies for TD

Welcome dear colleagues and welcome to this conversation on mastering VMAT2 inhibitors, the goal being optimizing treatment strategies for tardive dyskinesia. Welcome. And I'm so glad we're having this conversation this year because had we tried to do this 10 years ago or 20 years ago, it would have been a very short conversation. Of course, all I would have said to you is, we have no treatments, but isn't it amazing?

In 2025, I'm able to be here with you and be able to tell you we have made great progress in the treatment of tardive dyskinesia, but it comes with obligations. We not only have two FDA approved VMAT2 inhibitors for the treatment of tardive dyskinesia in our adult patients with tardive dyskinesia, but we have an obligation to master them. We do really need to know these medications quite well so that we can optimize our treatment strategies for tardive dyskinesia.

So I will offer you a few tips, a few suggestions, and hopefully whet your appetite so significantly and strongly that you will continue pursuing an even deeper dive into understanding your VMAT2 inhibitors.

So here we go, folks. First of all, we have two. The first one is called valbenazine. The second one is called dutetrabenazine. Okay? So that's the generic names of these medications. We are very lucky in some ways that both have been approved by the FDA to be used alongside an antipsychotic of any kind or by themselves because some patients, even after they stop their antipsychotics, still have tardive dyskinesia and the FDA has approved them in both sets of issues. Additionally, the label for both the medications does not restrict us to only use it in schizophrenia or bipolar disorder or whatever the case might be, as long as they have tardive dyskinesia, as long as they have it and if it's moderate and if it's severe, we are invited by the guidelines from APA to use one or the other VMAT2. And if the condition is mild, then we're also invited to use it as long as impairment is present. Okay, so let's get that out of the way.

Now let's focus on valbenazine just for a moment. We will dive into both medications in not profound depth because of lack of time, but enough to get things rolling. So that medication is obviously available as capsules, but now it is also available in a formulation that can be used for patients who have trouble swallowing. Okay, so that's the good news.

Second thing, on dutetrabenazine, we have two formulations available. The twice a day use of the medication, which is just the deutetrabenazine, but there's also a deutetrabenazine extended release, which can be used just once a day. So it's not just that the FDA has approved these two medications, even in the relatively short time they have been out, there have been formulation advancements that I think are just terrific.

Both of them are available in multiple doses and I can quickly tell you a little bit about the therapeutic dosing as well. So valbenazine is approved—they had a 40 milligram dose, a 60 milligram dose, 80 milligram dose. You will of course be referring to the package insert for both of these two medications for much greater detail than I can provide you in this relatively short time.

And deutetrabenazine, including the extended release version, let's focus on that, is available in seven different strengths. Okay, they can be used any time of the day, and there are no food restrictions with valbenazine, and there's no food restriction with deutetrabenazine extended release.

What are the areas of commonalities? Well, first of all, they both have been studied, and I mean rigorously studied, in a wide variety of patients in high quality, double-blind, placebo control, multi-center, randomized trials, and both of them have convinced the FDA and us that this is a valid treatment option for the treatment of tardive dyskinesia. Now both of them have their own individual set of side effects. They are not overlapping, which is a good thing, we'll come back to talk, to a deeper talk on that in just a second or two.

But what they do share in common is that they're both VMAT2 inhibitors, vesicular monomane transporter type two inhibitors. Now, what is a VMAT2? So VMAT2 in fact is a transporter. It's a transporter that lives presynaptically in neurons and its main job is to these monoamines into these vesicles in the presynaptic neuron. And if you have a VMAT2 inhibitor present, you can see, right, that the vesicles simply would not contain that much neurotransmitter. And as a result, the release of the neurotransmitter into the synaptic cleft is diminished. So there we go. That's the mechanism of action.

Because the mechanism of action is what it is, it can be safely and appropriately combined with any of the typical or atypical antipsychotics that a patient might need. I'm going to quickly cover perhaps three or four topics on this issue of mastering VMAT to inhibitors, but just please note this is a beginning conversation and I'm going to encourage you to remain deeply interested in this topic in order for you to not just master it, but in some ways, super master this topic.

So the first question is, when do we initiate treatment and how to adjust antipsychotic regimens in this particular scenario? So when to initiate treatment, I have very direct, useful and practical information for you. So we initiate if our patient's tardive dyskinesia is impairing, no matter what is going on, if it's mild, moderate or severe. Point number two, and these are all words of advice from the American Psychiatric Association guidelines. They say if the patient has moderate or severe tardive dyskinesia, the odds that the patient is impacted and impaired by the disorder is so high, please initiate one of the two VMAT2 inhibitors. So that's the first thing. Doesn't that make it easier? If it's mild, look for the presence of impairment, please proceed. If it's moderate or severe, automatically the assumption is it is in the patient's best interest to receive a VMAT2 inhibitor. Now, how do we adjust antipsychotic medications that are being concurrently used?

And I have lots and lots of good news for you here. First of all, neither one of the two medications automatically require us to decrease, increase or change the underlying antipsychotic just because the patient is on a VMAT2 inhibitor. Now, there might be many other reasons that you want to change the medication. It's ineffective, it's causing side effects. The patient needs less of it by all means, feel free to change the antipsychotic regimen, but not because the patient is on a VMAT2 inhibitor. All right.

The second thing we should talk about is in terms of VMAT2 inhibition, the mechanism of action for both of them appears to be quite similar. There are, however, differences. There are differences and the differences are enough that there is good clinical lore and rationale that if for efficacy reasons or for tolerability reasons, if one or the other medication is not optimum for a patient, feel free to shift to the other VMAT2 inhibitor. This is such an important point. I hope you'll allow me to say it one more time.

Because there are enough differences pharmacodynamically and pharmacokinetically, it is perfectly legitimate if a patient has suboptimum response or suboptimum side effect burden or both. Shifting to the other VMAT2 inhibitor that's approved by the FDA is a very legitimate next step to take. So, I guess what I'm saying is you can go from valbenazine to dutetrabenazine, you can go from dutetrabenazine to valbenazine. I had alluded just a moment ago about differences in metabolics. And there are differences. There are differences.

Both of the medications are of course metabolized in the liver, but there are differences. And because of the length of this podcast, I won't be diving into great details, but please remember, the 2D6 pathway and the 304 pathway in the cytochrome P450 system in the human liver are two of the very important highways, highways of removal of a variety of medications. And that of course includes VMAT2 inhibitors. There are differences between these two entities, valbenazine and dutetrabenazine. And it behooves us clinicians when we encounter individual patients to get a sense of what is the profile of a patient's needs and what can't they tolerate, what's not appropriate, what might even be contraindicated. So I would urge you to keep in mind drug-drug interactions and metabolism considerations must be kept front and center of our minds as we decide on a medication.

Now, finally, I would like to touch base on overcoming patient resistance and managing side effects because both of these are real issues for us experts to deal with. Well, no patient really runs to us and embraces the diagnosis or tardive dyskinesia and says, thank you, thank you. I've been waiting for this diagnosis. my gosh, this is the answer to all my problems. No, that doesn't happen.

Developing tardive dyskinesia is never a fortunate side effect. It's always an unfortunate side effect. And you and I should use maximum empathy and humility and motivational interviewing skills to very gently move our patients into understanding and then finally acceptance of their diagnosis. And they really should know that you and I will be excellent team members in the path towards recovery.

And we must roll with resistance because often, particularly in patients with schizophrenia, there is a lack of awareness. And we must find in us tools that would work for an individual patient to help them overcome the resistance. Many patients resist the idea of taking one more medication. We have to find in us a rationale, an appropriate scientific, ethical, and really humanistic explanation.

Why even though taking one more medication is an added burden to you, it ultimately is a net positive for you, dear patient. We have to take our time explaining it to patients. And then finally, managing side effects is a crucial issue. While the side effect burden of both of these two medications is remarkably clean, considering all the medications you and I use, we must appreciate that individual patients can have side effects like sedation or dry mouth, or they might have akathisia. They might have a number of potential side effects, though, as I've said before, generally speaking, the medications, both of them are quite well tolerated.

We should be familiar that dose optimization means not just getting to the right dose, but getting to the right dose at the right time for that patient. And that may require a slower titration. It may require not going up to the highest dose. It may require some great thoughtfulness. Because if you have decided to offer a patient a VMAT2 inhibitor, wouldn't it be a grand tragedy if the patient prematurely discontinues such an important treatment option for them?

As a result, focusing on issues of patient resistance and appropriate management of side effects is so important. Okay, dear colleagues, I so appreciate you being with me as we discussed components of mastering VMAT to inhibitors and how one can go about optimizing treatment strategies for our patients with tardive dyskinesia. I'm wishing you and your patients the very best and I look forward to talking with you more on this important topic. Goodbye for now