So our first presentation today is going to be clinical: Critical Screening and Timely Diagnoses of Tardive Dyskinesia in Older Adults: Evidence-Based Strategies for Clinical Practice.

I'm Jeremy Schreiber, so I will be the one presenting the kickoff lecture for this series today.

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Disclosures

You can see my disclosures here.

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Learning Objectives

Let's talk about the learning objectives for this particular presentation. And they are going to be to identify risk factors for tardive dyskinesia that increase susceptibility in our older individuals. We will talk about implementing best practices for using screening tools and assessment tools with patients who may be at risk for developing tardive dyskinesia. We will also talk about how to interpret those tools and to identify tardive dyskinesia considering the patient and the caregiver reports. And then we will also talk about kind of developing an individualized treatment plan for these diverse populations with tardive dyskinesia. In other words, what are we going to do when we do recognize tardive dyskinesia?

So we will start with a poll question or 2 here. And then we will get into some questions and we will get right into the meat of this.

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Let’s Vote!

Thank you all so much for joining me. Let's start with some votes.

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Poll 7

And we have poll number 7. How knowledgeable do you feel regarding the safety profile of VMAT2 inhibitors in older patients? Is it:

1. Very unknowledgeable;
2. Unknowledgeable;
3. I'm in the middle, neutral;
4. Knowledgeable; or
5. Very knowledgeable.

And there is no right or wrong answer here.

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Poll 8

All right. Let's move on to our last polling question. How many people at risk for developing TD, in essence treated with antipsychotics, do you provide care for in a typical week? Is it:

1. 1-4 patients;
2. 5-10;
3. 11-15;
4. 16-20;
5. More than 20 patients; or
6. Not applicable. This doesn't apply to me.

All right. We are going to move forward into the pretest question.

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Pretest 1

So this is where we kind of evaluate how I do as a presenter or any of the presenters do. Hopefully we get some improvement in knowledge. So if you don't know the answer to these that is completely fine. Hopefully we can improve your knowledge as we go through this presentation today. This is pretest question number 1. Which of the following factors do not contribute to the increased risk of TD in older patients compared to younger patients? Is it:

1. Decreased number of dopaminergic neurons in the motor circuitry;
2. Diminished immune functioning;
3. More likely to have been treated with first-generation or what we call typical antipsychotics; or
4. Statistically longer duration of mental illness.

All right. We see some answers coming in here. Very nice, very nice.

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Pretest 2

All right. Let's move on to our next pretest question. So let's say you are treating a 68-year-old patient with fluoxetine and olanzapine for depression. She wears dentures and notes she sometimes has trouble keeping them in her mouth. Over a period of a month when you are performing the AIMS examination without wearing her dentures, she shows movements involving her lips, her tongue, and her jaw. No involuntary movements are seen in other parts of her body. Would you diagnose this patient with TD and offer treatment? Is the answer:

1. Yes;
2. No, because TD requires moderate or severe movements;
3. No, because TD diagnosis requires movements in both facial and non-facial areas; or
4. No, because she was not aware of the movements.

I know this one's a little tougher than the last one. All right, let's move on to our last pretest question. And then I get to talk about tardive dyskinesia and what we do about it.

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Pretest 3

So our third pretest question here. A 70-year-old patient with schizophrenia who's currently treated with olanzapine and fluoxetine would like to initiate a VMAT2 inhibitor for symptoms of tardive dyskinesia. He also has mild renal impairment. What are his FDA-approved treatment options considering the label recommendations? Is that going to be:

1. Either deutetrabenazine or valbenazine with no adjustments needed to the starting dose;
2. Either deutetrabenazine or valbenazine at a lower starting dose due to the 2D6 inhibition from fluoxetine;
3. Either deutetrabenazine or valbenazine at a lower starting dose due to the renal impairment; or
4. Valbenazine at a lower starting dose due to 2D6 inhibition from fluoxetine. And in parentheses here says deutetrabenazine is contraindicated by renal impairment.

I know this question here is tricky. You got people on inhibitors of 2D6. You have a patient with renal impairment. What do we do? What do we do? Do we have to adjust the starting dose? Why? Hopefully we will find out. Let's get into this.

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What Is Tardive Dyskinesia (TD)?

So we will start with what is tardive dyskinesia. Well, tardive dyskinesia is a clinically distinct movement disorder. And that means that it’s not dystonia or akathisia or drug-induced parkinsonism. This is a movement disorder in and of itself. And it’s associated with exposure to dopaminergic-blocking agents.

And I practice in psychiatry. So commonly we are going to look at these agents being the first-generation agents, the first-generation antipsychotics or the second-generation antipsychotics, what we commonly call typical and atypical antipsychotics, or it can be associated with other central dopamine antagonists.

And from the DSM, what they say is the features of TD are abnormal, involuntary movements that develop in association with the use of medication that blocks postsynaptic dopamine receptors. So it is occurring from the medications that we are using.

And these patients are going to exhibit these symptoms. And these movements have to be present for at least 1 month. So we will call this at least 4 weeks. And they can be choreiform or athetoid; that means that these movements are semirhythmic or they’re writhing movements. They're nonrepetitive.

And take in mind, though, that these movements are not rhythmic. So if you see rhythmic movements, that is not going to be TD. If you can dance to it, it is not TD. If there is a tremor, tremor is not TD.

Now some patients might tap but you can see like a pause. It might be tap, tap, tap, pause. And then they can tap again. But there is with drug-induced parkinsonism and some other disorders, the tremor is unrelenting. It just continues. There is a meter, there is a cadence. It is perpetual. And you can distinguish what the next movement is going to be.

With tardive dyskinesia, those movements can repeat. But oftentimes they are not rhythmic. So someone might make a jaw movement that kind of goes over, and they might make another jaw movement, but they might not make that movement again for a few more seconds or a few minutes before they make that movement. In other words, there is a lack of rhythmicity with the movements of tardive dyskinesia.

And the other thing I'll tell you about the movements of tardive dyskinesia is they're oftentimes multiplanar. In other words, you may see them move anterior to posterior, laterally to transverse. These movements can be out and over this sort of stuff. You know, their fingers can go down and then out these sorts of things. So the movements oftentimes take up more than 1 plane.

When you finally see a patient with this and you recognize it and you are going to treat it, that’s not really called tardive dyskinesia in the DSM. The ICD-10 code here is G24.01 which is drug-induced subacute dyskinesia, which is what you will need to have your patients diagnosed with when you are looking at utilizing the FDA-approved treatments for this.

All right. That being said, how do patients present? What do they look like?

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Clinical Presentation

Well, most commonly we are going to see TD here on our face. We see a lot of chewing - chewing movement, jaw movements. They can kind of move it anterior posteriorly, laterally. They might clench it. You might see tongue movements both outside the mouth and potentially inside the mouth. You might see a patient exhibit bonbon sign, which is when they take their tongue and they put it into their cheek like this. That may just go into their cheek or it may move. So you might see patients kind of do this or they'll do this.

Some patients will talk to you about sores they develop in their mouths from chewing movements, these sorts of things. Patients might bulge their cheeks out. So you might see patients kind of go like that.

And the thing to note here is that we don't really have any muscles that allow us to kind of pop our cheeks out. So patients’ diaphragm can be involved when their lips are closed, if it tries to force that air out when their lips are closed, their cheeks will puff out.

You can also see lip movements. They might pucker or smack or kind of pull over to the side. They might frown or grimace or blink excessively. We see that a lot as well. Patients can—in terms of the truncal area, they might twist or, you know, kind of rock or shrug their shoulders or thrust their hips. I'm not Patrick Swayze, so I'm not thrusting my hips for this audience. You know, that is not going to happen.

And really, the hardest one for me to diagnose in terms of clinical presentation is when I have patients rock. Because sometimes rocking can be self-soothing. And the patients are doing that for that. And it is not necessarily tardive dyskinesia. But if you have patients that rock this way and then they start rocking this way, you know, you are looking at that much more likely to be tardive dyskinesia. You are looking at kind of 2 planes there as well.

And then you can see things in the limbs too. You can see arm movements, but you can see their fingers move what we call piano fingers. You turn that over, it is guitar fingers. You can see their toes or their fingers kind of splay out or hyperextend. You might see some foot tapping as well. And we have a lot of patients that are actually going to develop this condition.

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Prevalence

Now, the data that I have here is that almost half a million people in the United States probably have tardive dyskinesia. I've seen other statistics that around 800,000 patients may actually have tardive dyskinesia. We do see a higher prevalence of that with our patients that are treated with the first-generation agents. And the prevalence rate there is about 30%. So nearly 1 in 3 patients that are treated with these first-generation agents, these are agents like haloperidol, thioridazine, these sorts of agents, these first-generation agents.

Conversely, the way we practice now in the United States is oftentimes we are using the second-generation antipsychotics. And if you look all the way at the right-hand side, you can see the prevalence rate here being 7.2%. And that equates to about 1 in every 14 patients has really the potential and a strong degree of likelihood with continued utilization of these medications that they'll develop tardive dyskinesia. So we really need to be kind of watching for this.

And then conversely, if people are on second-generation agents, but they've ever had exposure to the first-generation agents, it is about 1 in 5 patients that will develop tardive dyskinesia. And some of our patients are more at risk.

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Is the Older Population at Risk?

One of those groups is the older population. So tardive dyskinesia is about 500% to 600% more likely to occur in patients that are over age 55 compared to younger patients. And why is that?

Well, it is due to several factors that we think when you research the literature, first of which is oxidative stress. We just have neuronal degradation, and we have an age-related decrease in the dopaminergic neurons in the substantia nigra. So think about that movement pathway. Or we have our patients having this decrease in these dopamine neurons.

The other thing to note is that older patients are also more susceptible to kind of extrapyramidal signs more early in treatment. And if you think about tardive dyskinesia, one of the risk factors is that patients who have developed any movement disorder in the past are going to be more likely to develop tardive dyskinesia in the future. And the theory here is that really there is something going on in that movement pathway where certain patients are just more at risk to develop movement disorders compared to other patients.

And we also know that, you know, patients that are in skilled nursing facilities get prescribed antipsychotics much more commonly than their community-dwelling counterparts. These patients may be having behavioral disturbances. And so these patients also, these 55-year-old and higher patients have oftentimes spent a longer duration with their illness compared to younger patients.

If you think about depression, you know, depression doesn't usually have its first manifestation when people are 60. If you look at schizophrenia in males, it starts in the late teens to early 20s. Females, it is just a hair later than that. So these patients develop their illnesses younger and they continue to live, which is good. But they've spent more time being ill, so they have a greater potential to be recipients of treatment with antipsychotic medications.

And the other thing to note is that older patients are also more susceptible to tardive dyskinesia with lower dosages of the second-generation agents.

Now, when you look at the DSM, what it says is that patients need to be treated with second-generation agents for a period of 3 months in order to eventually develop tardive dyskinesia. But they have a call out and they say except for older patients. Older patients only need to be on atypical antipsychotics or treated with antipsychotics at large for 1 month before they can develop tardive dyskinesia.

So we have a group of patients that’s more susceptible to develop tardive dyskinesia with low dosages of our agents, and not only low dosages, but treatment for a shorter period of time. And if you think about the way we treat depression in this country, oftentimes we adjunct with the atypical antipsychotics, and we tend to use lower dosages of these medications.

So these elderly patients really are at a very high risk of developing tardive dyskinesia.

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Risk Factors

But there is other risk factors as well. So patients if they have a history of mood disorder, think about mood disorder being bipolar, being depression, not necessarily that of a thought disorder if females are postmenopausal, if patients have a history of substance use. In clinical practice, I've seen much more tardive dyskinesia in patients that have used crack cocaine, methamphetamine, these types of dopaminergic type medications.

However, when you look at the literature, it talks about, you know, utilization of alcohol. So I think as we look at substance use, this is kind of a broad category. And I'm not really aware that one particular substance vs another substance is going to increase the risk. But there is treatment risk factors. And this is based on the way we practice. So the more exposure that patients have to antipsychotics, the more potent that antipsychotic is, the more likely our patients will develop TD.

Treatment with anticholinergics, which is not really the way to go. That can worsen tardive dyskinesia, can worsen those symptoms. And any history of a drug-induced movement disorder is going to exacerbate the risk for these patients.

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Dopamine Receptor Antagonists

So what I've done is I've included a list of dopamine receptor antagonists for you. On the left-hand side, it is the typical antipsychotics. In the middle, it’s the atypical antipsychotics. But there are certainly other dopaminergic antagonists. So I added those on the right-hand side of this chart for you, just so you are aware of the agents that block dopamine.

And if these agents are blocking dopamine, they have the ability to cause tardive dyskinesia. But I talked about the potency of the dopamine receptor as well.

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Antipsychotic Receptor Binding Properties

So I added a chart here. And this comes to you from the 2020 Practice Guidelines for the Treatment of Patients With Schizophrenia that was released by the American Psychiatric Association. And this is showing you the relative potency at the dopamine receptor, among the other kind of binding profiles of these agents.

One thing to note here is that you do not see the kind of newest agent on the market that we used for the treatment of patients with schizophrenia - with schizophrenia, which is a combination of xanomeline and trospium. Because it is not technically an antipsychotic, it has an entirely different mechanism for these patients, and therefore it doesn't really have the warnings for tardive dyskinesia and other movement disorders.

But it is not a dopaminergic blocking agent, which is why it is not on this list. It is also not an antipsychotic medication. It is a muscarinic medication. But that is a whole different lecture.

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Suggested Assessments for Patients With Schizophrenia: Antipsychotic-Induced Movement Disorders

But what does the APA say we do? Well, if you look at that 2020 practice guideline for the treatment of patients with schizophrenia, what it says for us is that we should be doing at baseline or the initial assessment is we should be at least doing a clinical assessment. So that’s at least a once over. And you are looking for not just tardive dyskinesia but other movement disorders as well, such as akathisia, dystonia, parkinsonism, etc, that is at the initial visit a once over.

But they also say, you know, I mean, if we are going to be prescribing these medications, we should probably be using a structured tool such as the AIMS or the DISCUS. In clinical practice, I most commonly use the AIMS. I think that it has a lot of utility in clinical practice because it is pretty rapid. It’s pretty quick and it fits well. You can document it easy and chart, and it keeps you adherence with the guidelines.

Now they also have other recommendations. If we’re treating patients with antipsychotic medications, they say that we should be doing kind of that clinical assessment. That’s your once over. At least look at your patients. I know it might sound silly, but they want us to look at our patients at least every visit, do an assessment.

And a lot of times, like in my notes, I'll document things like in my kind of my neurological section, I'll put, you know, no hyperkinetic movements noted or no abnormal movements noted. And that way it’s documented that I've done this.

But people that are at high risk. So these are going to be the patients that we talked about a couple slides ago. Maybe they're more advanced in their years or postmenopausal females. They have a history of substance use or they've been on these agents for a prolonged period of time. The APA wants us using a structured assessment at least every 6 months in patients that are low risk. Let's call these patients possibly your patients with major depressive disorder, that you are adjuncting with a low dose of an atypical antipsychotic and they haven't been taking these agents very long.

Then they say, “Hey, these low-risk patients, we want that to be done at least annually with the structured assessment.”

But the other thing I want to say here and that I think is very important. So this is what the APA guidelines come from for these patients with schizophrenia. Now you might be thinking, “Well, I might use atypical antipsychotics for people with depression.”

I think the point here is that if you have patients where you are utilizing atypical antipsychotics, regardless of the underlying condition, we should be doing our monitoring of those medications appropriately, just like we should be doing our laboratories regardless of the underlying disorder or disease that our patient may be suffering with.

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Assessment and Screening Tools

And so let's talk about some of these screening tools. I'm going to spend the most time probably talking about the AIMS. And I'm going to do that because when I first started practice, no one taught me how to do the AIMS. They kind of gave me a piece of paper with the AIMS on it, and they were like, go to it.

But here's your screening tools. The AIMS stands for the Abnormal Involuntary Movement Scale. The DISCUS is the Dyskinesia Identification System. The Impact-TD, which is also a very important scale. But I look at this scale as one of those things that helps us uncover how our patients are actually experiencing living with tardive dyskinesia and what impact it may have on them, you know, and how they are perceived in society or their vocation and so forth.

You can also look at the ESRS, which just looks at Extrapyramidal Symptom Rating Scale, and it is not exclusive to tardive dyskinesia.

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AIMS Scoring and Interpretation

So let's talk about the AIMS here. First thing to note is that the AIMS is broken up into 7 body regions. You can see those. Kind of the first 4 are facial and oral movements. The next 2 are extremity movements. Then you have trunk movements to wrap that up with number 7. It is scored zero to 4. And how is it scored?

Zero is your patient isn't making any abnormal movements. One, it is minimal. It might be extreme normal. This is where you, as a clinician, are looking at your patient. And maybe your patient made a movement, but maybe they didn't. It is kind of hard for you to tell it might be, you know, really considered to be normal. And if that’s the case, that’s going to be a 1.

If you notice a movement and it’s there, that’s at least going to be a 2 for mild, 3 is moderate, 4 is severe. Mild, moderate and severe are looking at amplitude and frequency. So how big are the movements. And take in mind my torso movements are going to be way bigger than potentially my forehead movements. You know, my muscles in my forehead aren't going to move as far as the muscles in my torsos can move.

So I look at this at kind of the range, you know, what is the range of the patient's muscular involvement there? And then is it happening very frequently?

So if the movements have a big range, if they have a big amplitude or they have near constant frequency, I'm going to grade this as severe. If it is low in terms of their amplitude and low in terms of the frequency, it’s going to be mild. And in between those 2, it is going to be moderate. But one thing I will caution you on is, please don't just think if your patient has mild movements it doesn't bother them either.

The reason that I even do talks on tardive dyskinesias because in 2017 I had a patient with some lip quivering. Yeah, her lip moves. I looked at, I thought it was, you know, like insignificant almost, you know, and I thought, well, that’s not bad, but I really wanted to try these VMAT2 inhibitors that have recently become FDA approved.

You know, we haven't had any treatments for tardive dyskinesia, which was first described in the literature before mankind walked on the moon. So we had no treatments until 2017 when these medicines are coming to market. So here this patient’s in my office, mid 40-year-old female, history of substance use mood disorder. She tells me that her lip movements don't really bother her. I don't really think they're that bad.

And I was like, “Hey, you know, like, you know, let's just try one of these medicines.” And so my patient was agreeable. She left the office. She came back in the next month. And before I could ask her, you know, kind of the standard things that we ask patients, like, “How you been doing since last visit or what's been going on?” Before I can even do that, she's closing the door to my office and she's like, “I got a date.” And I was like, “So what?” “You should have seen me in college.”

“All right. No, no, no, I didn't say that.” What I said was I said, “Okay, you got a date.” And she said, “No, no, Jeremy, you don't understand. Like I haven't had a date in 10 years.” And I said, “What do you mean you haven't had a date in 10 years?” And she said, “Do you know how hard it is to have a date when you are chewing your face off?”

And I tell you this story because this patient taught me something. This patient taught me that I can't judge the severity of the movements or the impact of the movements based on my perception of the severity.

The other thing that it taught me, and probably most importantly here, is that it also taught me that my patients underreport the severity of impact that this condition has on them. So we have a condition with our patients that, A, as healthcare providers, we are undergrading and severity. Our patients are underreporting at severity. And these people have been betrayed by their bodies. They're oftentimes ostracized by society, ostracized by their family. So this is truly a devastating condition.

So I'll bring it back to, as you’re scoring this and you are like, “Well, it is mild.” I don't think that that doesn't mean anything. That’s not the case.

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Muscles of Facial Expression

So the way we score this and kind of where these body areas are is the muscles of facial expression are here around the eyes.

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Lips and Perioral Area

Your lips and perioral area are right here.

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Jaw

The jaw obviously is kind of just here.

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Tongue

And then you have the tongue again inside, outside the mouth.

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Upper (Arms, Wrists, Hands, Fingers)

You have the upper limbs, which are going to kind of be bicep and down, wrist, hand fingers.

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Lower (Legs, Knees, Ankles, Toes)

The lower limbs which are going to be your legs, knees, ankles, toes.

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Neck, Shoulders, Hips

And then in terms of the trunk movements, you are looking at your neck, your shoulders and your hips there.

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AIMS Scoring and Interpretation

So when you score this and you take a look at a patient, let's say that somebody, you know, it is not really blinking at all, but their lips are, you know, kind of doing some stuff and they get a 3. It is not quite severe, but it is more than mild. So you score that as a 3. Their jaw moved around a little bit. Their tongue moved around a little bit. So you tally 1 through 7.

And if you add 3 plus 2 plus 1, what you get there is a total score of 6 on the AIMS. But what's the severity? The severity isn't like my patient told me, it doesn't bug them. It’s not - you know, well, I think it’s not that bad. The severity is you take the highest individual item score and you carry that down. So the highest individual item score in this particular case would be a 3 for the lips and perioral area. So you run that right down the severity becomes a 3. That’s all great.

So that’s kind of like what we look at and we call the movements. One thing to note is that if someone has tremor that is not scored on the AIMS, you are not scoring AIMS as the upper extremity movement. Tremor doesn't count. You pull that out when you score the AIMS by the way, because tremor is not tardive dyskinesia.

And this is all well and good, but what's the impact of it?

[00:33:45]

DOMAINS Impacted

There are a lot of domains in which our patients are impacted. Social domain, physical domain, you know, psychological domain, vocational domain. And so this scale that you see on the right-hand side is the Impact-TD scale. And I'm telling you tardive dyskinesia bothers patients. You know, they've done studies where they've taken the actors and they said, “Go apply for a job, and then we’ll have you go apply for another job and act like you have some TD movements.”

And so they did that. And then they assessed the people that interviewed them. And they said, “What do you think about this person, you know, evaluate them. You know, would you hire this person? Are they suitable for a front office job?”

And when they ask the interviewers about the people they interviewed—and again, sometimes they were, you know, kind of not exhibiting movements of TD and sometimes they were exhibiting movements of TD. When they exhibited movements of TD, the people that interviewed them would be like, “Well, they're not suitable for a front office job. We are going to put them in the back office, right? I probably don't want to get to know them as much as I would want to get to know someone that didn't have the symptoms of tardive dyskinesia.”

So these patients that have tardive dyskinesia, their vocational capacity doesn't continue to go up. It gets limited by having this particular condition. So this is something that affects the capacity of our patients because these people have to interact in society. You know, and I don't know if any of you out there in the audience have ever raised chickens, but if you've ever raised chickens if one of the chickens is born malformed, you know what the other chickens do? Well, the other chickens peck it to death.

You know, this is a condition that patients are going to have, and they're going to present these physical symptoms, these movements that are going to be occurring that other people can see. I was at Dairy Queen with my son about a year ago, maybe a year and a half at this point. And, you know, it is just the 2 of us in there having some ice cream. And he starts whispering aggressively to me.

What's an aggressive whisper? Well, I'm glad you asked. An aggressive whisper is when he goes, “Dad.” I was like, “What?” He's like, “We got to go.” I was like, “What do you mean we have to go? Like, we don't have to go.” He's like, “There’s a guy over there.” And sure enough, I look and there is a guy over there. He's just a hair disheveled, but he's making all these wonky movements, and it’s wigging my kid out so bad that he wants to leave the restaurant.

And so you see these patients that have this condition, they start to get ostracized from society. And this is definitely not what we want. The nice thing about this Impact-TD scale is that it can help us understand what truly these patients are experiencing.

I'll tell you one more story and then we will kind of move on. I don't know if you can see behind me here, but I have a lot of Legos, right? I have a ton of Legos behind me. I build Legos all the time with my 6-year-old. And this gentleman comes into my office and has some finger movements. And he tells me, like a lot of patients, “Well, it doesn't really bug me.” He's retired. He doesn't have to button his shirt every day. He's not having any problem with silverware. And the more we talk, he eventually says to me, “You know what I can't do? I can't build Legos with my grandchildren—can't build Legos with my grandchildren.”

Well, you know what? If I couldn't build Legos with my son? Like - I'm sorry, I'm almost going to cry. That would be devastating to me. But not only would it impact me, it would impact my progeny. It would impact, you know, my lineage. So this isn't a condition that people just get and they have no impact.

[00:37:29]

TD Negatively Impacts Life No Matter the Underlying Diagnosis (Schizophrenia, MDD, BD)

The problem is, is that the impact from this is oftentimes unrecognized by us as healthcare providers. And we really do need to look at it, because when you look at the impact, regardless of the underlying diagnoses, what you are seeing here in red are patients with TD and blue without TD. You can see that there’s more social withdrawal. There’s decreased mental and physical functioning. Their quality of life gets worse.

And on top of that, when patients develop tardive dyskinesia, on the right-hand side, you’re seeing the results of a survey that were published by Dr. Rakesh Jain. You know, about 50% of patients almost start skipping doses of their antipsychotic. Almost 40% of patients stop taking their antipsychotic altogether. These people stop going to their healthcare provider.

And what's really, really scary is that 1 out of 5, 20% of these patients told other people not to take their medicine. So you have a condition that when people develop it, it starts to erode the treatment of the other conditions they have. And believe me, word of mouth is important. I mean, I don't know about you all, but have you ever had patients where you've tried to prescribe something to them and, you know, like you think that they're on board with this, they understand that it’s going to benefit them and they leave and they come back and they're like, yeah, I never took that.

But have you ever had patients where you prescribe something to them? They didn't take it. And then, you know, they come back in to see you at the next visit and they're like, oh yeah, I didn't take that medicine, but I was talking to the guy at the AA meeting and he was like, “Oh, yeah, I got put on that medicine too and it really worked well for me.” And the next thing you know, they're taking their medicine because the guy at AA told them it was a good idea.

So word of mouth is really profoundly important. And if we have a condition that really starts to cause 1 out of every 5 patients to advise people to stop taking their medicines, that can be problematic. So we want to make sure we’re diligent about treating it.

[00:39:30]

Current Treatment Paradigm for TD: 2021+

And then how do we treat it? What's the paradigm? Well, the paradigm is to use the level A products. So things get a level A recommendation when there is enough literature and enough safety data and enough—not only literature and safety data, but efficacy to support their utilization. The things that get a level A recommendation and are FDA-approved are the VMAT2 inhibitors. And you can see that on the right-hand side of your screen here.

Level B, kind of your next level recommendation are going to be things like clonazepam or ginkgo biloba. Level C is going to be amantadine. And then what we call like a Level C-plus is going to be deep brain stimulation.

If you look at the left-hand side of your screen in the rounded blue rectangle, you can see that it says tetrabenazine should be considered only if both, deutetrabenazine and valbenazine are not available. So deutetrabenazine and valbenazine are the 2 FDA-approved treatments for the patients with tardive dyskinesia.

But you know what you don't see on this list anywhere for tardive dyskinesia are anticholinergics.

[00:40:38]

Anticholinergics: Not Recommended to Treat TD

And why? Because they're not recommended to treat TD. So the American Academy of Neurology doesn't recommend these agents. The American Psychiatric Association doesn't recommend these agents for TD. Matter of fact, if you look at the benztropine package insert, it even says it works for all forms of EPS except TD. And the problem is, is that the anticholinergics can even worsen it.

But for the longest time we didn't have any medications to treat TD. So tardive dyskinesia kind of got lumped into the whole what we just generically call EPS, because we’re not movement disorder neurologists. I mean, some of you might be, but we are not all movement disorder neurologists. And we don't always know if it is drug-induced parkinsonism or tardive dyskinesia or akathisia or dystonia or any of the other kind of movement disorders.

And so some of those have responded to benztropine in the past. So it might work for all of them. And it is not the case. It is not the case at all. And on top of that, the anticholinergic agents can also increase confusion, increase fall risk. And we have a group of patients. If you think back to when I was talking about these patients who might be a little bit more advanced in their years, who are receiving antipsychotic medications for depression as adjunct. Start giving people anticholinergics, their fall risk is going to go up. You know their GI motility is going to go down. It is also possibly going to increase confusion.

And more than 50% of patients with major depressive disorder report cognitive problems. So, you know, like anticholinergics are really not going to be what we should be looking for.

But Dr. Chepke did a survey, and Dr. Chepke’s survey went out and he said, “Hey, you know like what do we think?” Can we use benztropine to treat TD?” And you see that data on the left. “And how about can we use benztropine to prevent TD?” Right. And you see that data on the right. And what you are looking at here in psychiatry are the 2 lefts of those graphs.

So in psychiatry, we’re doing a little bit better than primary care. But 40% to 46% of us think that we can either use benztropine to treat or prevent TD. And in primary care, it’s even as high as 65% to 80% of us think that we could use benztropine to treat it. And it does get a little bit better in terms of preventing it.

But there’s a great deal of misinformation out there about benztropine, and it’s really not optimal.

But if you understand what's going on with tardive dyskinesia and with the VMAT2 inhibitors and what the role of vesicular monoamine transmission is on dopamine signaling, we can appreciate why the VMAT2 inhibitors may be what we should be using and why they work.

[00:43:17]

The Role of VMAT2 on Dopamine Signaling

So what I've shown you here in these kind of these 2 cartoons. On the left-hand side, let's call this, you know, kind of a normal neuron. I'll orient you to the graph here. You can see that kind of that peach circle there is your synaptic vesicle. The green hot doggy thing is the VMAT2. Across the bottom, the purple butterfly-looking thing is the dopamine receptor. And the red butterfly thing is the dopamine transporter. So what normally happens?

Well, what normally happens is dopamine gets packaged into the vesicles, the vesicles move over to the edge of the synaptic cleft. They kind of burst or rupture or whatever, and they allow the dopamine to flow out into the synaptic cleft. It acts on those postsynaptic dopamine receptors. It does its job, and then it goes back up across the dopamine transporter, goes across the vesicular monoamine transporter once it is in the presynaptic neuron into that vesicle for repackaging and rerelease.

But when we prescribe antipsychotic drugs, that’s the green trapezoid on the right-hand side. Those are the dopamine receptor blocking agents. What they do is they block dopamine postsynaptically.

Well, we believe in neuroplasticity and that the brain changes. So we think what happens is, is that we have an upregulation or hypersensitivity of those postsynaptic D2 receptors. And so upregulation is make more hypersensitivity is when kind of more conductivity occurs when those receptors are activated. And when this occurs in that nigrostriatal pathway, our patients start to rock and roll, right? So we block those receptors. The receptors upregulate.

Take in mind tardive dyskinesia is related to hyperdopaminergic signaling or increased dopamine signaling. So we’re using these dopamine receptor blocking agents. But there is more signaling happening because of the upregulation or hypersensitivity of those dopamine receptors. With patients with like drug-induced parkinsonism or something like that, it is oftentimes more acute. So we block those receptors. And then we have a decreased amount of dopamine signaling.

So drug-induced parkinsonism and tardive dyskinesia are in essence opposite conditions. And you know kind of coming from completely opposite pathophysiology. And that’s why if you use anticholinergic medications that are going to kind of increase dopaminergic signaling, it can make TD worse. That’s why they might help a little bit with drug-induced parkinsonism.

[00:45:38]

Rationale for VMAT2 Inhibitors

And the VMAT2 inhibitors are in essence looking at turning the faucet down, because what VMAT2 inhibitors are doing is they are working presynaptically. That’s your purple trapezoid here, your purply pink trapezoid. It’s blocking that vesicular monoamine transporter so less dopamine can get packaged into vesicle. Less dopamine can be released. We turn that dopamine faucet down.

And when we turn that dopamine faucet down, we have less activity postsynaptically. And then our patients stop rocking and rolling. But if we turn it down too much, our patients can develop drug-induced parkinsonism. By the way, that can be occurring from the VMAT2 inhibitor or from the dopamine receptor blocking agent that they're on.

The APA's recommendation in the case of drug-induced parkinsonism is to reduce the offending agent. Sometimes that could be VMAT2 inhibitor, sometimes it could be an antipsychotic or dopamine receptor blocking agents.

[00:46:32]

VMAT2 Inhibitors: Similar Yet Dissimilar

Now, I told you that there are 2 VMAT2 inhibitors on the market. So these agents are similar but they're also dissimilar. So I'm going to talk about these. And I would like to—before I get too far into this, I deliver a lot of lectures surrounding TD, and oftentimes people ask me, “Well, if I've tried a VMAT2 inhibitor and it doesn't work, like VMAT2 inhibitors don't work.”

That is not the case at all. If you have a patient with tardive dyskinesia and you've tried a VMAT2 inhibitor and it doesn't work, look, consider the other VMAT2 inhibitor. These drugs are efficacious drugs. They very similar, yet they're also dissimilar as well. So let's talk about that.

[00:47:13]

Deutetrabenazine vs Valbenazine Metabolism

So if you remember, I talked about tetrabenazine saying that it is not recommended unless deutetrabenazine or valbenazine aren't available. Tetrabenazine comes down and has 4 metabolites. It has a plus alpha, plus beta, minus alpha, minus beta. These are the isomers. Deuterated tetrabenazine is a deuterated form of tetrabenazine, so they replace a hydrogen with deuterium.

I'll talk a little bit more about this in a moment, but the point here is, is that deutetrabenazine, you know, it metabolizes into the 4 isomers of tetrabenazine, just a deuterated formulation of those. And valbenazine undergoes hydrolysis and it becomes just that plus alpha metabolite of tetrabenazine. Valbenazine becomes that. So they share a little bit of commonality with - with tetrabenazine.

[00:48:03]

Deutetrabenazine

So here's deutetrabenazine. This is where you can see those Ds. That’s the deuteration. That’s deuterium. They've just basically replaced the hydrogen ions there. And so now you have deuterium instead.

[00:48:14]

Deuteration Slows the Breakdown of Active Metabolites

And what does that do? Well, deuteration slows the breakdown of the active metabolites. It slows down the breakdown of this product. Because one of the problems with tetrabenazine when trying to use it to treat tardive dyskinesia is you'd have to use it like 4 or more times a day, and the patients don't tolerate those serum spikes. And so it is really intolerable for the patients.

So they solve this by deuteration. And when they do that, it slows it down. You can allow the serum concentrations to come up without having to give this product 4 times a day, like tetrabenazine that was really intolerable.

[00:48:50]

Deutetrabenazine

That being said, deutetrabenazine has indications in chorea associated with Huntington's disease and tardive dyskinesia. This whole presentation today has been on tardive dyskinesia. But in patients with Huntington's, we know that that’s a neurodegenerative condition. We know that there’s suicide is very common in these patients. There is a warning for suicidality or untreated inadequately treated depression in patients with Huntington's disease.

It’s also contraindicated in patients with hepatic impairment and concomitant use of reserpine MAOIs or tetrabenazine or valbenazine.

And take in mind, we don't want to be using the MAOIs, because if we are not allowing the monoamines to get packaged into vesicle and they're hanging out in that presynaptic neuron, you know, they kind of need to be broken down.

In terms of dose adjustments, it wasn't really studied in renal impairment, but you don't have to do dose adjustments there. And if you remember my questions at the beginning, they were about you have a patient on fluoxetine and olanzapine who also has renal impairment. What do we do? I'm not telling you that you have to do anything different in renal impairment with this product. You start this product just like you normally would.

But what about that fluoxetine component of this product? You know, there are 3 primary 2D6 inhibitors that we use in psychiatry. These are going to be paroxetine, fluoxetine, and bupropion.

And one of the patients and one of the questions earlier was on fluoxetine. So do we have to adjust the dose? Well, in people who are CYP2D6 poor metabolizers or if they're on those CYP2D6 inhibitors, the maximum top-line dose with deutetrabenazine is 36 milligrams a day. Notice I'm not telling you to start any lower. I'm not telling you to start differently. I'm just saying that as you go up, don't go up beyond 36. You’re going to stop there in patients that are on agents like fluoxetine.

So how do we give it? If you are using the BID formulation, start at 6 milligrams twice a day with food increased by 6 weekly as tolerated. The maximum is 24 milligrams twice a day, which would be 48 milligrams of a total daily dose. There’s also an extended release formulation of this product, which is really nice because it is once a day, start at 12 milligrams and go up by 6 milligrams weekly as tolerated. You are going to top out there at 48 milligrams once a day.

And QTc prolongation wasn't clinically significant within the recommended dosing range.

[00:51:24]

ARM-TD: Deutetrabenazine Flexible-Dose Trial

Where does the data come from, from this product? Well, it comes from the ARM-TD trial. This is flexibly dosed. You have significant AIMS reductions. The point here that I want to get to is when you are looking at kind of a flexible dose trial, flexible dose trials, the investigators look and they say, “Okay, well, we are going to titrate this patient up to efficacy and where it is tolerable.” And when you look at this the mean dose that titration was 38.8. So it tells me that we probably need to be kind of at this upper dosage range when we are treating patients with tardive dyskinesia with deutetrabenazine.

[00:51:58]

AIM-TD: Deutetrabenazine Fixed-Dose Trial

When you look at the fixed dose trial, which is AIM-TD, you’re looking at the greatest reductions occurring at 24 and 36 milligrams. So again, another suggestion to kind of be a little bit more. This isn't always the case of kind of start low and go slow. As a matter of fact, when you look at this product, if you were to look at the data, increases in serum concentration of this medication are associated with increased benefits and efficacy, but it is not associated with increased adverse events.

So I'm kind of encouraging you when you prescribe this to make sure you get to doses that we consider to be therapeutic.

[00:52:36]

Long-term Data: Open-Label Extension Study of ARM-TD and AIM-TD Participants

They studied this in the 3-year trial as well, kind of this open-label extension study—sorry, not a trial—an open-label extension. They're looking at the safety. And these patients were either an arm or a prior. And as you look at this, the AIMS scores continue to go down over those 3 years.

But the other thing to note here is the average daily dose is 38 to 39 milligrams. So it’s really telling us where most of our patients are going to be.

[00:53:02]

Deutetrabenazine: Safety in Placebo-Controlled Trials

In terms of its safety, there are only 5 adverse events that are greater than that of placebo. It’s nasopharyngitis, insomnia, depression, akathisia, arthralgia.

The discontinuations in the clinical trials were similar to that of placebo, and not a whole lot more patients needed dose reductions in the active treatment group vs that of placebo.

[00:53:24]

Deutetrabenazine: Subgroup Efficacy (Open Label)

But what about some subgroups? What if people are psychotic or people have mood disorders. You’re seeing reductions in both of those patient groups over that 3-year time period on the left. What about patients that were receiving dopamine receptor blocking agents vs those that weren't reductions in both of those groups as well.

[00:53:45]

Valbenazine

We’ll talk about valbenazine here.

[00:53:44]

Valbenazine

Valbenazine, again, kind of it is right there at that plus alpha. It’s indicated for TD and chorea associated with Huntington's. The only contraindication is hypersensitivity. You start at 40, after a week go to 80. But you can think about 40 or 60 based on if your patients, you know, respond to it and they tolerate it.

You know, if I put someone on 40 milligrams and they tolerate this medication and they, you know, it causes an amelioration of their symptoms, I don't titrate up. I just stay there. Something else that’s really nice about this particular medicine is it comes in a sprinkle formulation. So you can sprinkle that right on soft foods.

Now they don't recommend that you put that in water or milk. And they don't recommend you put it into tubes. But applesauce putting those sorts of things.

This also has dose adjustments for these patients that are on these strong CYP2D6 inhibitors. They recommend a top-line dose of 40. But again you are starting right there at 40. You are not adjusting your starting dose. You are just adjusting your top-line dose.

In terms of 3A4 inhibitors, they also recommend 40 milligrams is kind of your maximum dose there as well. And in terms of hepatic impairment, we talked about the contraindication for hepatic impairment a few slides back with the other product. With this product with mild hepatic impairment, you don't have to make any adjustments. But with severe or moderate hepatic impairment, just top line out there at 40 milligrams.

[00:55:03]

KINECT 3: Valbenazine Fixed-Dose Trial

Where does the data come from? It comes from the KINECT 3, which is a fixed-dose trial. Nice reductions in the AIMS scores. Both the 40 and 80 milligrams had - had phenomenal reductions, effect sizes of like a 0.6 and a 0.9, which are very high.

[00:55:21]

Long-term Data for Valbenazine

Long-term data for this product is also very good. I'd love to tell you that these things are treatments, but really, what you are seeing here is that if people kind of are taking this product over time, you can see the reductions occur over those 48 weeks. But if you take the people off of this, symptoms tend to come back. So nice reductions there.

[00:55:38]

Valbenazine: Safety in Placebo-Controlled Trials

Here's its safety profile. Well-tolerated agent. You know, the only one of these adverse events that’s, you know, greater than 5% and twice the rate of placebo somnolence. But that’s actually a combination of somnolence, sedation, and fatigue to even get to that metric there.

[00:55:54]

Valbenazine: Change in AIMS Score (Open Label)

When you look at change in the AIMS scores, you know, if you look at the 48-week data, we will call this the year data. Most of these patients are actually getting down to having individual item scores of a 2 or less or a 1 or less in 80% to 99% of patients.

And if you just look at the minimal clinically important difference, most of the patients in the valbenazine arm got there. I mean 97% of patients achieved at least that minimal clinically important difference.

[00:56:26]

Individualized Treatments

I'll talk about just these. Just a couple more points. We’ll wrap this up. We’ll move over to the questions.

[00:56:32]

In Vitro Pharmacology

This is just kind of the in vitro pharmacology. And I realized that as I'm looking at this, I really probably need to make a coloration change. So when we are trying to inhibit VMAT2, which is what we are doing when we are trying to treat our patients with tardive dyskinesia, that occurs through the plus alpha metabolite or the plus beta metabolite.

And valbenazine on the right-hand side, the only thing it does is that plus alpha. Deutetrabenazine, you can see that it does about 29% of that plus beta 2% with that plus alpha. And the other aspects of that really aren't on target for VMAT2. So they can kind of hit some ancillary receptors, although the degree of, you know, kind of outcome, if these things even really make a difference is, you know, kind of really in question.

[00:57:19]

Prescribing Considerations

Things to note, because people ask me what's the difference between the 2. So patients over age 65, you know, no dosage adjustment required for valbenazine. You know, for deuterated tetrabenazine, you know, they didn't really study a vast number of these patients, but there is not really any kind of dosing response that we would expect to be different in terms of hepatic impairment. I covered that already contraindicated for deutetrabenazine reduce in moderate or severe to 40 milligrams of valbenazine. You don't have to do anything with mild hepatic impairment.

In terms of renal impairment, no dosage adjustments required for valbenazine. You also don't have to do any dosage adjustments for deutetrabenazine as well. If people were on anticholinergics in the valbenazine trials, you could feel comfortable there. I'm personally comfortable prescribing deuterated tetrabenazine when I have people that are also on anticholinergics because, you know, it can take a little while to get these patients off the anticholinergics.

And if they have TD, probably want to look at starting a VMAT2 inhibitor and then slowly reducing your anticholinergics.

There are some other things here to note. But again, you know, really it comes down to you are not adjusting the starting dosages of these things. You are just adjusting the top-line dose in some of these other categories.

[00:58:33]

Summary

So in summary, older patients are at an increased risk. We should be screening our patients. We should be monitoring. It is not just the patients with schizophrenia. Anticholinergics really aren't our friend. And we should individualize our treatment.

[00:58:45]

Let’s Vote Again!

Let's get to the questions here.

[00:58:48]

Posttest 1

All right. In terms of our posttest 1, which of the following factors do not contribute to the increased risk of TD in older patients compared to younger patients? Is it:

1. A decreased number of dopaminergic neurons in the motor circuitry;
2. Diminished immune functioning;
3. These patients are more likely to have been treated with the first-generation or the typical antipsychotics; or
4. These people have had a statistically longer duration of mental illness.

So which of the following factors do not contribute to the increased risk of TD?

All right. Let's take a look at our polls here. See if I can see my results here. So in terms of the posttest, I think I messed you all up. No, I did good.

[00:59:46]

Posttest 1: Rationale

So we went from the pretest at 48% of you guessing B to almost all of you getting this correct in the posttest. It’s diminished immune functioning. You know, these patients obviously have issues with the dopaminergic neurons. They're more likely to be treated with the typicals. And they've had a longer duration of mental illness.

[01:00:05]

Posttest 2

So let's move on to our second posttest. You are treating a 60-year-old patient with fluoxetine and olanzapine for depression. She wears dentures and notes she sometimes has trouble keeping them in her mouth. Over a period of a month, when the AIMS is performed without wearing her dentures, she shows movements involving her lips, tongue, and jaw. No involuntary movements are seen in other parts of her body. Would you diagnose this patient with TD and offer treatment? Do you choose:

1. Yes;
2. No, because TD diagnosis requires moderate or severe movements;
3. No, because TD diagnosis requires movements in both facial and non-facial areas; or
4. No, because she was not aware of the movements.

All right. Let's take a look at these results here. Can we show the polls? All right. So in terms of our pretest, we did a really good job. 80% of you said yes.

[01:01:11]

Posttest 2: Rationale

We moved that number up for the posttest because certainly the answer is yes. An AIMS score reflecting at least mild movements in any areas indicative of TD. And by the way, the American Psychiatric Association recommends the treatment of tardive dyskinesia with a VMAT2 inhibitor if there is an impact on our patients.

So this patient is, you know, having a bit of an impact. So we should be treating this. And it’s been going on for a month. So let's take a look at our last posttest question here.

[01:01:37]

Posttest 3

A 70-year-old patient with schizophrenia currently treated with olanzapine and fluoxetine, would like to initiate a VMAT2 inhibitor for symptoms of TD. He also has mild renal impairment. What are his FDA-approved treatment options considering the label recommendations? Is it:

1. Either deutetrabenazine or valbenazine with no adjustments needed to the starting dose. We will see if y’all listen to me, I hope so. You guys have been doing great so far;
2. Either deutetrabenazine or valbenazine at lower starting dose due to the 2D6 inhibition from fluoxetine;
3. Either deutetrabenazine or valbenazine at a lower starting dose due to renal impairment; or
4. Valbenazine at a lower starting dose due to 2D6 inhibition from fluoxetine and deutetrabenazine being contraindicated in these patients.

All right. Let's take a look at the results of the polls.

[01:02:46]

Posttests 3: Rationale

Alright. In the pretest, 7% of you were number A or letter A, I guess I would say. And we moved that way up. Almost half of you got it right. So a lot of learning occurred. But I think I need to do a little bit better job if I deliver this presentation in the future.

I'm going to, you know, also say thank you and take some questions at this time. I think that I showed you the rationale here. I'll leave it up just for another moment, but I do want to say thank you and see if I can answer some questions here.

[01:03:17]

Q&A

So Shamika asks, does mild TD clear up on its own? No. Once patients have TD, they have TD. The symptoms of the presentation can wax and wane depending on the stress level that our patients are experiencing. So that is not going to clear up on its own.

So Emily says how far progressed does TD have to be before it is irreversible. So Emily, thank you for the question. TD by nature is going to be a condition that’s chronic. What we do right now is we have treatments for this where we can kind of diminish the presentation of it. But once patients develop TD, they tend to have this through the course of their illness.

There’s very small amounts in the literature that talk about some patients having kind of remission from TD. Let's see here.

Oh. Claire says, does the patient fill out the AIMS, or do providers fill it out based on observation? Well, providers fill that out, Claire. So we have patients do stuff like this. They tap their fingers so they concentrate on that. We look for movements in other body areas. We have them open their mouth, stick out their tongue. And if we see people that are making movements, then we are going to be scoring that.

Some of the manufacturers of the VMAT2 inhibitors do have some questionnaires that the patients can fill out. That way, they kind of alert us that they are making movements, and that can give us a better ability to treat them.

We have another question here, which is my question is what is the incidence of patients with depression receiving an antipsychotic medication in addition to an SSRI, or switching to an atypical antipsychotic medication with nonschizophrenic diagnoses?

You know, I think that the question really here is, do we see a lot of patients that are being treated with antipsychotic medications for depression compared to, are we just using them in patients with schizophrenia? And we are using antipsychotics significantly more now than we used to. As a matter of fact, over the past decade, our utilization of antipsychotics in the United States has gone up by 400%. And I apologize for being a little bit wordy during my presentation. We did have some other questions in here, and I thank you all so very much for those.