VMAT2 Inhibitors in Geriatric and Complex Populations: Mechanistic Insights, Formulation Advances, and Age-Appropriate Dosing Strategies

Introduction

Dr Jonathan Meyer (University of California, San Diego): Hello, everyone, out there in TV Land and those who are here in person. Time for our next session. And we're going to hear about use of VMAT2 Inhibitors in Geriatric and Complex Populations: Mechanistic Insights, Formulation Advances, and Age-Appropriate Dosing Strategies, presented by Dr Sanjay Gupta. No, not that Dr Sanjay Gupta.

So he is from the - CMO at the BryLin Hospital; Volunteer Professor of Psychiatry at Jacob’s School of Medicine, SUNY Upstate Medical Center; Chief of the Division of Psychiatry at the Roswell Park Cancer Center; Medical Director from Endeavour Health Services, Buffalo, New York. Did I forget anything?

Dr Sanjay Gupta (Roswell Park Cancer Center): I think that was plenty.

[00:00:48]

Disclosures

Dr Meyer: Okay. You can see his disclosures here on the second slide.

[00:00:52]

Learning Objectives

And with the putting up of his learning objectives, I'll turn it over to Dr Gupta. Thank you so much.

Dr Gupta: Thank you, Dr Myers. Welcome, everybody. And I'd like to welcome our people in the back 9, the guys at home who are watching us virtually.

So our learning objectives: identify risk factors for TD that increase the susceptibility in older adults; implement best practices for using screening and assessment tools; interpret screening tools results to identify TD, considering patient and caregiver reports; evaluate the safety and effectiveness of VMAT2 inhibitors in older adults and special populations; and then make an individualized treatment plan.

[00:01:44]

Let’s Vote!

I was just wondering if - the questions. We should start the questions? Dr Meyer, you moved along a little fast.

[00:01:54]

          Poll 1

Okay. So we have this poll, though. How knowledgeable do you feel regarding the screening and diagnosis of tardive dyskinesia in older adults? I might use the word TD in future.

1. Very knowledgeable;
2. Unknowledgeable;
3. Neutral;
4. Knowledgeable;
5. Very knowledgeable.

So pick anyone.

Okay. All right. It's good. Good start.

[00:02:44]

          Poll 2

So poll 2. How knowledgeable do you feel regarding the safety profile of VMAT2 inhibitors in older adults?

1. Very unknowledgeable;
2. Unknowledgeable;
3. Neutral;
4. Knowledgeable; and
5. Very knowledgeable.

Pick 1.

Okay. All right. Here's a neutral response.

[00:03:37]

          Pretest 1

So this could be a trick question, so you got to pay attention. Which item in the DSM-5-TR diagnostic criteria for TD differs for older adults, meaning greater than 60 years vs younger patients?

1. Symptoms must be present for greater than or equal to 4 weeks;
2. Must follow greater than or equal to 3 months of treatment with dopamine receptor-blocking agent or antipsychotic;
3. Movements must be choreiform or semirhythmic rather than rhythmic;
4. Must involve orofacial movements.

Pick 1. Remember, the key word is older adults.

Okay. All right. Okay. Good spread.

[00:04:56]

          Pretest 2

All right. This could be another trick question. I think Nicola put in some trick ones here. Which is most typically indicative of TD?

1. Symptoms worsen after increasing the dose of antipsychotic medication and worsen with anticholinergic medication such as benztropine or trihexyphenidyl;
2. Symptoms worsen after increasing the dose of antipsychotic medication and improve with anticholinergic medication.
3. Symptoms worsen after decreasing the dose of antipsychotic med and worsen with anticholinergic med; and
4. Symptoms worsen after increasing the dose of antipsychotic medication and improve with anticholinergic medication.

Pick 1. Okay. Very good. Next.

[00:06:30]

          Pretest 3

So this is a 50-year-old woman with bipolar II who has been stable for several years on quetiapine 300 mg and lithium 1200. Serum lithium level 0.9, therapeutic. She also has rheumatoid arthritis and a history of cirrhosis. Her liver disease is currently Child-Pugh class B, considered moderate impairment, with stable labs and no history of encephalopathy.

Joan is employed as a sales consultant. She enjoys work, but says that the involuntary lip smacking and tongue movements have become extremely problematic. They are more noticeable, and colleagues have asked her if she's anxious. She has also started avoiding some social gatherings with friends, families and coworkers. Her healthcare professional diagnosed TD 6 months ago.

Prior attempt to taper quetiapine led to recurrence of hypomania, with decreased need for sleep and pressured speech. Joan is now psychiatrically stable, but the TD symptoms are distressing and interfere with quality of life. So what are our options?

1. Start benztropine 1 mg TID to reduce abnormal movements;
2. Start deutetrabenazine immediate-release 6 mg BID with food and titrating upwards;
3. Start valbenazine 40 mg daily; and
4. Start tetrabenazine 12.5 mg TID.

There is more than 1 appropriate treatment choice in the options given.

Okay. All right. Very good. So I'm going to just start my talk with a quick patient vignette. And then at the end we'll discuss what the outcome was.

[00:09:08]

What Is TD?

So there was a 68-year-old older adult male in my practice who is a grandfather of 4  grandchildren. He's married, and he has bipolar disorder that I treated for probably 12, 13 years. He came to me from his primary care practice, you know, given Prozac 20, then 40, then Dr Goldberg suggested 2 mg of aripiprazole and so forth. But he was very manic, like he started a blueberry farm. So he was that manic. Okay.

So he's been stable for all this time on divalproex and lurasidone. I see him every 4 months. And not uncommon now, the family came to me and said he has tongue movements and people on a vacation asked him about it. Okay, so I want you to just think about that and then we can discuss that at the end.

Now, a number of you may not have prescribed the drug, thioridazine. Right? And famously, TD then used to be called the Mellaril shuffle. Right, Dr Meyer?

[00:10:23]

Informed Consent

Okay. So let's get started off. With tardive dyskinesia, 1 of the most important things in older adults. And we use the term older adults now because it's touchy. Nobody wants to be elderly. Okay. So the term is older adults. Informed consent is a key piece, and informed consent regarding the use of a dopamine receptor-blocking agent with the healthcare proxy who is usually a daughter, is very important. It's always good to have a daughter. Why? Because when I do informed consent with a daughter, it's half an hour. Okay.

If I do informed consent with a son, it's like 2 minutes. Okay. You guys understand that? They ask you all kinds of questions, the ladies. And then after that, they say, I'm going to do my own research. So anyway, so the point is, informed consent is a key piece because the patient may have some cognitive impairment, which you may or may not detect. But it's always good to have another family member. But even with the patient, informed consent and documentation is key.

[00:11:29]

Antipsychotics Are Widely Used

All right. So let's move on to the next slide. If we look here, antipsychotics are commonly prescribed nowadays. Look at schizophrenia, only 9—9.6%, maybe 10%. But the rest is all mood disorders, anxiety disorders, depression, bipolar personality and so forth. And the antipsychotic prescription has grown 4-fold. Huge increase in the non–long term care population.

Okay. Think about your 2 mg of aripiprazole, how often you write that or something like that. In the long-term care population, psychotropics, 80% of the time. And then you've got anticonvulsants and actually antipsychotics are going down because there is a very aggressive management from the federal government and auditing that has to be less than 10% and so forth. So it's going down dramatically.

And they have this term called GDR, gradual dose reduction, with antipsychotic medications. But often when I get called in a long-term care setting where I also practice, the person is on 3 or 4 psychotropic medications. But they really do need an antipsychotic because they may have psychosis related to dementia. And then you use 1 and the other 3 can be tapered off. So I just wanted to say I had all those titles, but I'm a clinician like all of you. I see patients every day most of the day. Okay.

[00:13:12]

TD: It’s Not Just Schizophrenia Anymore!!

Now, look, it's not just schizophrenia, but this is showing a high rate of prescription, whether it's dementia, personality disorder, mood disorders. This was a large study done by Laughlin. They had, I think, 164,000 patients, a large epidemiological study. And they came up with some reasonable results. So I think this is very important for us to know. And a lot of us are prescribing habits have changed because the safety of antipsychotics has also improved.

[00:13:43]

Tardive Dyskinesia

So what is TD? I think a lot of you know it is involuntary. Affects specific parts of the body that occurs in those treated with long-term dopamine receptor-blocking agents, such as my patient was probably on lurasidone for 12 years or something to that effect.

Mostly you will see it around the face and head, but it's also on the neck, trunk, upper extremities, lower extremities. In rare cases, buccal oropharyngeal muscles are involved, so there might be swallowing difficulties. There might be the diaphragm may be involved and there might be breathing difficulties. And I had 1 very rare case which I published and the pectoral muscles were involved.

I was working with a very flamboyant neurologist who wanted to call it exotic dancer syndrome, and the journal editor said, “No, let's make it an atypical presentation of TD.” So that's what happened. But it can involve - involve other muscles.

Now we have to always differentiate between withdrawal-emergent dyskinesia and TD. Withdrawal-emergent is when you lower the dose or you stop the antipsychotics, TD-like movements occur but they're gone within 4-8 weeks. If they persist then we call it TD. And of course these symptoms fluctuate and they're gone during sleep. If the patient is anxious, they're greater.

And sometimes patients can control them to some extent, like the patient I was telling you when he was out playing golf with his friends, he would try to control it. But he also had a significant habit of drinking, meaning at 12:00, he would start drinking with golf going on. So - so you can see how substance abuse comes in.

Be cautious of masking symptoms with increasing the dose. So you may feel the patient is anxious or agitated, and you may raise the dose, which might mean we are chasing our tail.

[00:15:52]

Diagnostic Criteria Caveats for TD

All right. The diagnostic criteria from the DSM-TR, the movements are involuntary. They're choreoathetoid, lasting at least 4 weeks and developing in association with the use of antipsychotic, DRBA or neuroleptic medicine. These are different terms for the same medicines. At least 3 months minimum, okay?

Movements of this type occur after stopping the medicine, changes in dosage or reduction, or they can occur at any time.

Third point is key. Symptoms of TD develop after a shorter period of time in older adults, like 1 month. In older adults, 1 month is enough, exposure.

[00:16:40]

Where Do TD Movements Occur?

Now in my clinic, I have shown videos to the front office staff of TD. Why did I do that? Because often the patient is sitting there unobserved and they can tip me off on some patients, but most of the time you see it in the upper, head, face, blinking, that area, then the upper limbs. You know, typically people say take off the shoes to do an exam. But, you know, a lot of times with chronically ill patients, you take off the shoes. Then you smell toe jam, you know.

So personally, I don't take off the shoes a lot of the time. Because I deal with severe and persistently mentally ill people. Okay.

[00:17:27]

TD: Symptom-Based Differential Diagnosis

Now these are certain other aspects in the differential. Remember, TD can occur alone. But always consider the point that it can occur with mannerisms which are semi-purposeful movements.

Stereotypies. Stereotypies usually occur early on in life before age 3. They're kind of complex movements. And then tics. Tics are simple tics, complex tics. Just shrugging could be a tic, or that - you know, you heard that tic.

And then myoclonus, which is a jerky movement. It can occur in narcolepsy and then other disorders also.

Dystonia. Those who have done inpatient work may see dystonia. The person just tightens up like that. It's very frightening. We have to give an injectable such as benztropine or chlorpheniramine to relieve that. And so often we use the anticholinergics with medicines like haloperidol to avoid that.

Now we rarely find dystonia with the atypicals. Tremor is rhythmic. You see the tremor. And then akathisia is a feeling of restlessness, like something is crawling under the skin, like the person wants to stand. Then they want to sit. And it's a very uncomfortable feeling, but it can hoodwink the clinician that you might think that they're anxious or they’re agitated and raise the dose of the medicine, hence chasing the tail. So we have to be careful of that.

And then, of course, parkinsonism is a side effect of a lot of the antipsychotics. Okay. Though we are moving in a different direction now.

[00:19:12]

Is It TD or Drug-Induced Parkinsonism?

All right. So just to look at this onset with TD is delayed, right? We said months to years after initiation of antipsychotic. And the patient I mentioned, he’s - he's been on for 10 or 12 years. The movements are arrhythmic, generally affecting the face and trunk. And if you raise the dose, TD gets better. And reduction of the dose, TD gets worse. And anticholinergic medicines worsen TD.

Drug-induced parkinsonism, just the opposite, rhythmic tremor. You raise the dose, the movements get worse. You lower the dose, they get better. Anticholinergics help. Okay. So there's a difference.

And of course in our options to treat TD, VMAT2 inhibitors, we've got 2. They are FDA-approved. So I have come to the conclusion after many years of practice that I like to do FDA-approved practice. First, use those meds.

[00:20:20]

Tremors: Tips and Tricks (Assessment)

All right. Some tips and tricks for assessment of tremors. Other movements, rhythmic and regular in frequency. If the answer is yes, it may be due to blockade of the D2 receptor. It may be due to mood stabilizers like divalproex. It may be due to lithium. Antidepressants, stimulants. I know stimulants are commonly used. They can coexist with TD. So tremors can co-exist with TD.

Is the patient restless? Okay, if the patient is restless, it's a different scenario. Is the inner sense of restlessness? If yes, consider akathisia. Okay? Akathisia can also exist with TD. If the answer is no, then it's likely to be TD.

And I think some of these are more complicated than meets the eye. You get a neurological consultation.

[00:21:19]

An Additional Consequence of Having TD: A Negative Impact on Medication Adherence

So here we're looking at patients with TD reported. So what are the problems that happen when patients have TD?

Number 1, they skip doses of medicines. Okay. And ask me about this patient, I'll tell you later at the end what he did. They stopped taking the medicine all together. Then they influenced other people to stop their medicines, too. And of course, some of them stop going to the doctor. So the outcome is not good in general.

[00:21:52]

RE-KINECT: TD Severity and Functional Impact

Now this is the RE-KINECT trial. It was done by Dr Caroff. He's right here in the audience. He's a kind of a stalwart in the field, if I may acknowledge that. And if we look, TD affects people in multiple ways. So we have to dispel the old myth that patients are not aware of TD. It affects how they talk, how they eat, walk, in multiple ways, breathing and being productive. It impairs socialization. Just like this patient of mine went to some islands in the Mediterranean and other friends asked him, “What's going on with your tongue?” You know, like that.

[00:22:38]

Risk Factors for TD

Okay. So let's look at risk factors for TD.

[00:22:43]

TD Prevalence: Meta-analysis

The mean prevalence is 25%, the global mean prevalence of TD. This is based on a meta-analysis done by Carbon.

Now, overall that was 25% review of 41 studies. If we look at patients who are only on first-generation antipsychotics such as haloperidol, it's about 30%. Those who were in the past on first-generation and now you have switched them to a second-generation, then the TD prevalence goes down to 20%.

And those who are naive to first-generation, they only had a second-generation agent, it is 7.2%. So another myth needs to be dispelled is the fact that people think, well, I will not see TD because I'm using atypical antipsychotics. I have an office practice. I do not see patients with schizophrenia. A lot of the slides that I showed suggest that if you only use atypicals, out of 100 patients you have, 7 could have TD. So screening is important.

[00:23:58]

Risk Factors for TD

All right. Some of the risk factors. Several studies have shown that diabetes could be a risk factor associated. Mukherjee did 1 study way back, followed by Linda Ganzini and also then Margaret Werner published in the American Journal regarding that.

Smoking, alcohol and substance use. I already talked to you about my patient. He—before golf, he's got to drink. Right? So there you go.

Higher cumulative and current antipsychotic dose or plasma levels, meaning high-dose antipsychotics. Now, you know, when we talk about substance use, you guys remember that ad? It shows fried eggs. This is your brain on drugs. So it is just neurodegeneration from - from drugs. Again, the nervous system gets damaged.

Early Parkinsonian adverse events can also be a tipoff. And then treatment-emergent akathisia, and of course anticholinergic cotreatment.

So if I may mention a couple of points about anticholinergic co-treatment. In the striatum there's a balance between cholinergic, acetylcholine and dopamine. Anticholinergics, in summary they upset that balance. It's not so simple, but I'm just make - making it simple and making the case why we should not use anticholinergics or use them briefly and taper off, especially with the atypicals.

Now non-modifiable risk factors, longer duration of illness. As Dr Goldberg mentioned many times, depression. If they've had it for the fifth time or sixth time and you've added aripiprazole 2 mg, or brexpiprazole, they're going to continue for a long time on that medicine. So intellectual disability and brain damage, negative symptoms in schizophrenia. Mood disorders are specifically a risk factor. And then cognitive symptoms associated with mood disorders, and some gene polymorphisms. We don't know that very well, but it's listed.

[00:26:11]

TD in Older Adults

Okay. In older adults now. In this, older adults were defined as age 55 and above. Okay. Treated with risperidone or olanzapine. The diagnosis was dementia in about 58% and mood disorder in 30% or 31%. The TD risk was higher in females in Black patients, patients treated with first-generation antipsychotics, current or historical, and patients with past antidepressant treatment.

Cumulative TD risk was 6.7 and then - after 1 year, but after 2 years, it increased to 11%, 11.1%. And again, I will stress this fact as little as 1 month exposure.

[00:27:02]

Benztropine/Trihexyphenidyl

Now, I've already talked about why not to use this. I explained all that. But in older adults, there's another issue that it worsens cognition. These medicines worsen cognition. They cause dry mouth, blurry vision, urine retention, constipation.

Okay. Another aspect in older - older adults is they’re on digoxin, there could be on furosemide, there could be on prednisone. And those medicines also have an inherent anticholinergic activity. So the total anticholinergic load may go up. So that's why we want to try to avoid benztropine/trihexyphenidyl.

[00:27:48]

Screening Tools for TD

Okay. Let's look at screening tools.

[00:27:50]

Structured Screening Is Standard of Care

So I guess high-risk patients, every 3 months. Any patients taking first-generation antipsychotics or high-risk but second-generation every 6 months. And any taking SGAs every 12 months. But again, that may be when you do the AIMS scale.

Actually, there was a modified Delphi method published I think in 2000 - it was recently published in 1 of the journals. And a bunch of experts there agreed on the fact that every visit should - they should - patients should be screened for TD. Doesn't mean you do the AIMS scale, but you do some quick exam to just look for it, see if it's there. If you need - and also if there are antipsychotic, is that dose the right dose, should you lower the dose and so forth.

Okay. Now 3% to 5% higher risk in older adults. We mentioned that. Okay? And then of course parkinsonism, dystonia raises the risk. Substance use, same things here in this. Let's move past this.

[00:29:00]

Abnormal Involuntary Movement Scale

So this is the AIMS scale. It's a gold standard. It's in many EMRs. And - and - and people use paper and scan it in the EMR. That's fine too. But it has 7 items. And it'll look 4 of the 7 items on the face. So how important that is. And that's why I say observation of the face, and that's why my staff have watched videos to tip - tip off. Okay.

I'll also tell you this, now I have had patients, some ladies who come and say, “Do I have TD because they have been, you know, putting on makeup, watching themselves in the mirror and they see some tongue movements.” And there are ads going around, right? I mean, you know, direct to consumer advertising that raises the awareness.

So neck, shoulders, lower legs, knees. And of course we do the total AIMS score as items 1 through 7. In some of the literature, you had to have 2 milds to be diagnosed with TD or 1 moderate. The Delphi changed that to 1 mild in 1 section in other words.

[00:30:16]

Activation Maneuvers

Okay. Here are some other activation maneuvers. Okay. Visual observation is very important. Many times what happens is, in a practice, we are busy typing into the EMR and the patient is sitting there and eye contact really needs to be made. So examination begins when the patient enters your office.

Visual observation intake staff. One way is you ask them to open your mouth and touch each finger with the thumb, okay, and then with the other side. And some of the patients with chronic schizophrenia can't even do that. But the idea is to distract them and you watch them out.

The other is you - to have them drop the hands and say name, words, with the letter T or letter N, whatever letter, and they're focused on that. You watch the face and mouth, and then have them walk. Okay. So different.

[00:31:11]

Schooler-Kane Criteria for Tardive Dyskinesia

There's the research criteria by Dr Kane and Nina Schooler. At least 3 months of cumulative neuroleptic drug treatment. Mild movements greater than 2 body parts. See, there's the criteria. Greater than 2 body parts or a moderate in 1 body part. Persistence greater than 3 months, and the absence of other conditions which could cause TD.

[00:31:39]

Differential Diagnosis

So in the differential diagnosis, there are several. Tourette's comes in, orof - other spontaneous orofacial dyskinesias. And 1 of the things, in older adults, you always want to ask in a way that you don't offend them, “Are you wearing dentures?” Okay, without the dentures. You know, so that we want to ask.

And then, of course, we've got other comorbid conditions like dystonia, akathisia and then Huntington's disease, Wilson's disease. Wilson's is rare. Sydenham's chorea is rare, but Huntington's can. I've had a couple of patients of Huntington's lately.

[00:32:20]

Tips for Brief Screening

Okay. Now, tips for brief screening. You can get this at mind-td.com. Okay, mind-td.com. But this is a good way to remember, M for moments. Do you have any extra unwanted movements? I, impact. Do you feel embarrassed or self-conscious? Has - N, notice. Has anybody else noticed these movements? Do you go to the grocery store and somebody in the lane asks you, “Hey, what's going on with your mouth?” You know.

So I tell my patients, you just - if somebody asks you that, just say I'm chewing gum. Okay? And if somebody asks, you're blinking too much. Just say I have some trouble with my contacts. Simple. That's what I tell them.

Daily activities. Do movements interfere with your daily activities? If the fingers are effective, typing may be difficult. Some patients may not be able to drive, so some activities may be impacted.

[00:33:18]

IMPACT-TD Scale

All right. So this leads us to an IMPACT-TD scale. Okay. And this IMPACT-TD scale does something different. It looks at various domains and assesses how tardive dyskinesia affected this patient. In what way? Was it social? It caused psychiatric issues, psychological issues, functional issues?

And I think it's a nice scale. But I think in how we see patients every 15, 20 minutes, it would be hard to do. So it's more in the research area I'd say.

[00:33:52]

Can Patients Screen for TD?

All right. Can patients screen for TD? Yeah, of course. Can they - and this was a study done by Dr Caroff. Here, patients and clinicians came fairly close together. If you look at head and face, facial muscles, lips and tongue and jaw. You know, the clinicians report 65% and the patients were 69%. About the same. So patients do pretty good.

So it's important to validate what they feel and see, especially patients with mood disorders. Maybe they might be a little problem with patients who are really very, very sick with schizophrenia. But don't underestimate anybody I would say. Okay?

[00:34:36]

Monitoring for Tardive Dyskinesia in the Real World

Monitoring for TD in the real world. So this is a lot of what I do. I do AIMS not every time but periodically. New York State has some guidelines. We follow those, okay? But you ask them to hold the hand straight, open the mouth and touch the fingers. Okay.

And the nice thing about that is, once I had to go in front of the judge about a patient to be retained for treatment, and the judge asked, “What the - what does the doc do?” And so the patient said, “He talks to me for a little while, and then he asked me to open my mouth and do this.” I said, “Good.” That's a good thing that patient remembers that. Okay. So remember—the patient remembers they were being screened for TD.

All right. Activation methods. I think we've talked about that. This is redundant. All right.

[00:35:27]

Reducing Risk for Tardive Dyskinesia

Importantly, we want to reduce the risk of getting TB. That's the number 1 thing. So - well, you know, avoid using antipsychotics. I'm just changing the word DRBA to antipsychotics. If you can. Now of course there are studies. Dr Goldberg showed you this nice data with lumateperone, aripiprazole, cariprazine, you know - and - but again, do it judiciously. Use the lowest dose possible and then see if they can be discontinued or not. Those are important things.

I think sometimes in my treatment algorithm, I might use esketamine before antipsychotics. It depends on how the patient - how the patient can - can they commit to coming twice a week for 2 hours each time? Those things make a difference. And then watch for coarse, tremors. And then, of course, if you haven't heard me before, anticholinergic agents should be avoided.

[00:36:33]

Treatments for TD

All right, so treatments. Let's get on to the treatments.

[00:36:37]

Summary of Treatments for TD

Now, if you review the literature on TD, everything in the kitchen sink has been tried. Okay? Now there was a time we were very bullish on vitamin E, but then some larger trials and Cochrane analysis revealed that it's not that effective. But then people think 1200 to 1600 IU can reduce the TD from getting worse. So - so that's where that stands.

But I think the strong data is about clozapine. Okay. Strong data for clozapine. There are a bunch of studies that show - the rest is all low, except for the VMAT2 inhibitors.

[00:37:21]

TD Evidence-Based Treatment Options

What are the APA guidelines say that actually these days, however, there's a legal situation, everybody goes to the treatment guidelines. APA guidelines recommend considering starting a VMAT2 inhibitor to address TD-associated impairments and impact on psychosocial functioning. Similarly, the American Academy of Neurology recommends a similar thing. Okay.

And of course, the VMAT2 inhibitors include tetrabenazine, which is not FDA-approved for TD. It is the first 1; deutetrabenazine and valbenazine. So I'll just say this 1 time. Valbenazine was approved by the FDA in April of 2017 and deutetrabenazine in August of 2017. So essentially, we have 2 drugs that are FDA-approved for the treatment of tardive dyskinesia.

[00:38:17]

The Dopamine Hypothesis of Psychosis

I have had this also happen. You call an insurance company to get authorized, whether it is valbenazine or deutetrabenazine. And they say, “Did you try benztropine?” You know, that has happened.

[00:38:34]

Dopaminergic Pathways of the Brain

Okay. So now just let's get back briefly to the dopamine hypothesis. And what we know is there's a showering of dopamine in the ventral tegmental area leading to psychosis. Okay. And then we block that dopamine with our dopamine blockers, the antipsychotics that results in EPS long-term blockade results in TD. It affects the tuberoinfundibular pathway. There could be galactorrhea, but at the same time, dopamine in the frontal cortex is good to prevent—is good for cognitive functioning. And it is intertwined with multiple neurotransmitters. Not that simple as what I said.

[00:39:14]

VMAT2 Inhibitor Mechanism of Action

Now, how do VMAT2 inhibitors work? What usually happens is when we give dopamine receptor-blocking agents like antipsychotics, they block the D2 receptors postsynaptically. There's also some hypersensitivity and an increase in number of these D2 receptors. So when dopamine comes there, they get tickled. And then you get the hyperkinetic movement disorder which is TD. So there's actually a protein, vesicular monoamine transporter protein, VMAT2—type 2, that is on the membrane in the presynaptic.

And that takes the dopamine in, it packages it and then it releases it in the cleft. So it protects the monoamines from dissolution from the other enzymes. So what our drugs do, which is valbenazine and deutetrabenazine, the 2 FDA-approved agents. They block that action. So as a result, less dopamine is released in the cleft. The receptors are less tickled. And then you see the hyperkinetic movements go down.

But as a collateral damage of that could be there's some rare cases of Parkinson's that happen.

[00:40:40]

VMAT2 Inhibitors

All right. So here's a comparative slide. I don't think I would recommend anybody using tetrabenazine. Okay. It's not FDA-approved. It's got to be done 3 times a day because of a small half-life. It's also contraindicated in hepatic impairment. So let's focus between deutetrabenazine. It is in 2 forms, immediate-release and extended-release and valbenazine.

Deutetrabenazine and valbenazine are both approved for Huntington's chorea and TD. Both have that. Both are reversible VMAT2 inhibitors. That means when you stop it, the changes can come back. The TD can come back. Okay.

Then maximum dose for deutetrabenazine is 48 mg and for valbenazine is 80 mg. There's immediate release and extended release for that, so immediate release, deutetrabenazine is twice a day with meals. Extended-release is once a day. It can be given with or without food. And then qDay dosing for valbenazine.

All right. Now, when it comes to hepatic impairment, 2 of these medicines are contraindicated: tetrabenazine, deutetrabenazine. These are contraindicated. And I presume all of us clinicians see a lot of patients, a lot of them have hepatic problems. Or you screen, you know, who has hepatic problems or not.

So if somebody has hepatic problems, these 2 are contraindicated. Only valbenazine is approved in that sense. That too the dose has to be 40 mg, not 80. So moderate. Mild hepatic impairment, no issues with valbenazine going up to 80. But the moment is moderate, it's 40 mg. Okay? Pay attention to that one.

Okay. The cytochrome P450 system genotypes, maximum dose is not 48 but 36 for deutetrabenazine, and for valbenazine it is 40 mg. So the doses are lower, means they have been studied in that mode.

When it comes to renal, there's no adjustment required for valbenazine. The other 2 have not been studied.

[00:43:11]

Treatment of TD With Tetrabenazine Not FDA Approved

All right. So - well, I mean, this is - I - I don't think we use tetrabenazine, but this is a slide just to tell you it's not approved. There are some studies that show it works. I've tried it before, before valbenazine came out. I think it's probably history now.

[00:43:28]

Deutetrabenazine vs Valbenazine Metabolism

Okay. So what about deutetrabenazine? Deutetrabenazine is deuterium is added to the hydrogen and tetrabenazine is converted to deutetrabenazine, and we have valbenazine. Now the interesting thing is valbenazine has only 1 metabolite, as you see here, hydro tetrabenazine alpha positive one. Okay.

Deutetrabenazine has 4 metabolites. Now when we look at these metabolites, the alpha-plus, which valbenazine has, has effect on the VMAT2 and the beta-plus that deutetrabenazine has, has an effect along with the alpha - alpha-plus. So 100% of the valbenazine - at least this is what the - all those bench studies reveal. 100% of valbenazine goes to that receptor to - to do its job, but with deutetrabenazine, it is only 31%.

[00:44:33]

In Vitro Pharmacology

This is just showing you the same thing what I just said.

[00:44:36]

Deutetrabenazine

Okay. Deutetrabenazine, VMAT2 inhibitor. It's a novel molecule, structurally similar to TBZ, tetrabenazine. I already mentioned about the deuterium. So the reason for adding deuterium was then tetrabenazine instead of giving 3 times a day, deutetrabenazine can be given twice and then they have an XR preparation. Extended-release can be given once a day. Okay.

It's FDA approved in both Huntington's and TD, and it started at a dose of 12 mg a day. And then every week you increase it by 6 mg to get to 48 mg.

Okay. Now I think the XR formulation is helpful because it's once a day.

[00:45:31]

Deutetrabenazine AIM-TD: Change in AIMS Total Score From Baseline

Now, this is the AIM trial done for deutetrabenazine. There was placebo and they tested 3 fixed doses, 12 mg, 24 and 36, double-blind 12-week trial.

What it shows that the 12-mg dose did not do any better than placebo. The 2 did. There was probably a 3-point reduction in the AIMS score. So the other 2, 24 and 36, work vs placebo.

[00:46:04]

Valbenazine

Valbenazine, also a novel agent. It had breakthrough status from the FDA because TD, for a long time there was no treatment and we threw everything at these patients. After a while, we began to - well, we can't do anything. So when they came out with this, they had to do less studies. So it had - it got fast tracked. And I already talked about the fact that alpha-positive dihydrotetrabenazine is the only metabolite and that's effective to 100%.

The half-life is 20 hours. That means you can give it once a day, which is helpful. You know, our patients, correct? How often - how many times a day they take medicines. Then it's approved for TD in 2017. We mentioned that. The new thing is there is a 60 mg dose, okay. And initially, the guidance was start at 40, go to 80.

A new trial was done which will get up to that. They say now start at 40, see how they do. If they're doing really well, leave it at 40. If not, go up. Okay. If people have side effects, you have the option to go down to 60.

Also, valbenazine has this granule or sprinkle option for older adults. So it can be used in food.

[00:47:30]

Valbenazine KINECT 4: AIMS Score

So this is that KINECT 4 trial in which—this is open-label. There was no placebo. Patients had TD. There were medically stable in open-label fashion. They were started on 40 mg of valbenazine. After 4 weeks, there was a assessment done. And then based on how the patient was doing, they went up to 80 or remained at that and they were kept at - they were kept that way for 48 weeks with assessments.

And then there was a 4-week time frame where the medicine was stopped. Of course, you see, the TD comes back in a lot of those patients. But what they found was a good, I think, 35%, 40% of the patients did very well at 40 mg. So this study was based on input from clinicians. So I think that was kind of nice.

And also some people had remission with that. So this - that was also nice.

[00:48:27]

Valbenazine KINECT 4: Patient-Reported Outcomes

All right. So this is another KINECT 4 reported outcomes. So this is the Tardive Dyskinesia Impact Scale. So this - this was developed by Neurocrine Biosciences who makes valbenazine. And the idea is that what we, as clinicians see, we track AIMS scores. But the patient doesn't care about the AIMS score that much. They're caring about how it impacts their day to day life. Social. Can they go to the mall? Can they work on their computer? And that also kind of improves with - with the medicine being given on an ongoing basis.

So the impact of TD is more important to our patients than what the AIMS score is. The AIMS score is good for us. It's good to give it to the insurance company and say, “Hey, this is the AIMS score and the diagnosis is G24. But for us - I mean for the patients, impact is important.

[00:49:25]

Deutetrabenazine and Valbenazine: Dosing Details

So dosing details. I think we already talked about, XR, deutetrabenazine 12 mg once a day and every week you raise it. Okay. In CYP2D6 inhibitors, the maximum is 36 mg. And of course it's contraindicated with liver problems.

Deutetrabenazine has BID dosing, the 1 which is immediate release. You do 6, 9, and 12, okay. Available tablets, you start at 6 BID and then every week you go up. So a fair amount of titration is what I'm saying.

Valbenazine, most straightforward, start at 40. See how it goes. Go to 80. If you're having side effects, go back to 60. With CYP3A4 inhibitors and CYP2D6 inhibitors, you go down to 40. If they've got moderate liver issues, 40. Deutetrabenazine is contraindicated with liver issues. Both drugs are contraindicated with monoamine oxidase inhibitors.

[00:50:29]

When to Consider Clozapine

All right. When to consider clozapine? Okay. Treatment resistance and response in psychosis group was pooled. And they found actually that clozapine, there were 13 trials and 35 case reports. So there's a fair amount of data. But those of us who have used clozapine know it is a fairly involved drug. Even though REMS is gone, it's still fairly involved. Okay.

And it - but for those patients where clozapine works, it does wonders. So it is still underutilized in my opinion.

[00:51:07]

VMAT2 Inhibitors in Older Adults

Older adults.

[00:51:09]

Deutetrabenazine in Older and Younger Patients

So studies were done in older adults. And in essence in this study they're looking at data from the ARM-TD and the AIM-TD which was done for deutetrabenazine. And they found there was not that difference between under 55 and over 55. I'm just summarizing all that. It worked for both groups.

Okay. Same thing with valbenazine. Greater than 50, AIMS reduction. They look at AIMS - not remission. They look at 50% improvement in the AIMS. Once again in the trials, they found that it was whether they were under 55 or 55, worked pretty well. They tolerated pretty well.

In the trials, the maximum dose - maximum age, I think was 85, in the valbenazine trials.

[00:52:07]

Valbenazine: Specific to Older Adults

Okay. And my patient was 68. So all right. This is just to show you in a graphic form that age did not discriminate how these medicines worked.

[00:52:23]

In Vitro Studies Crushing Valbenazine Capsules for Mixing With Soft Foods/Liquids or Administration via G-Tube

Okay. Now this slide is to show you that actually valbenazine underwent studies with regard to their sprinkle or granule formation. They did 3 types of studies. One was dissolving the whole capsule and then crushed capsule and contents were measured for 1 hour. And they found there was no difference. Everything worked as planned.

Similarly, study 2, it was mixed with soft foods, such as happens in long-term care, or some older adults who are at home and can't swallow pills and so forth. Similar findings they found that the adequate levels were achieved, the dissolution was good.

And of course the third one was valbenazine recovery evaluated after crushed contents dispersed in water or delivered by g-tube because that also happens. I have 1 or 2 patients who get it by g-tube and that also works. So in other words, having this formulation of sprinkles is helpful. But if sprinkles cannot be obtained, you can dissolve the capsules.

[00:53:31]

Xanomeline and Trospium Chloride

All right. So in this whole point of tardive dyskinesia, dopamine receptor blockers, antipsychotics, I wanted to introduce the concept of xanomeline and trospium. Everybody familiar with that?

Okay, so I guess this is a M1 and M4 receptor agonist. Maybe something to think about in the future. But all those patients right now who get on this treatment for T - for schizophrenia, it's only approved in schizophrenia. Right now, their central nervous system is exposed to second-generation antipsychotics.

The real answer will be when people who have not had that exposure yet. But TD is not a warning in the package insert. And it's something as an option when we talked about the preventive strategy to think about that. So we'll know in the future how that goes.

[00:54:31]

Key Summary Points

So here are some summary points. Number 1, we do want to prevent TD. We don't want to have to treat it. We want to prevent TD. And it is not a nice thing. You don't feel good when you find you stabilize somebody for 10, 12 years and then they have TD. You don't feel good about it.

Okay. It's permanent, it’s debilitating, and it's a neurological condition by long-term exposure. Now remember, in older adults, 1 month is good to get TD.

Screening of course is the key. You don't have to do - I don't do the AIMS every time. I do it every 3 months. Some people every 6 months. But every visit I do look at the face, arms quick, like I explained to you.

And of course, we need to modify screening on a case by case basis. People who work in long-term care, you see people on a wheelchair. How are you going to get a look at their feet? They are covered with a blanket. You know, I mean, it's not easy. Okay. So train the staff to watch the patients. Your staff are your best eyes and ears.

And of course, informed consent is key in older adults. Okay, you may or may not do the Montreal Cognitive Assessment or the Mini-Mental Status Exam, but in older adults, it's a good idea to have it and then know if they can make that decision or not. So I routine - routinely call the son or daughter or next of kin and have a word with them, even if the patient is in good shape. And - and they never really mind you calling their family.

Of course, screen for hepatic impairment. We talked about the fact deutetrabenazine is contraindicated. And then treat with FDA-approved agents. The VMAT2 inhibitors are FDA-approved. I would not use an agent that's not FDA-approved, like, you know, Ginkgo. It has not been studied.

The idea of FDA-approved is efficacy has been studied and also side effects have been documented, so we know a lot about that.

[00:56:46]

Let’s Vote Again!

So I think that is it. So we'll vote again.

[00:56:50]

          Posttest 1

Question one. Okay. Which item in the DSM-5-TR diagnostic criteria for TD for older vs younger patients, greater than 60 years.

1. Symptoms must be present for greater than 4 weeks;
2. Must follow greater than or equal to 3 months treatment with dopamine-receptor blocking agent;
3. Movements must be choreiform or semirhythmic rather than rhythmic;
4. Must involve the orofacial muscles.

Pick 1. Do they play the same music every time? No, definitely.

Okay. All right. Well, maybe they won't let me go home. All right. So - so the answer really is 3 movements - sorry. That 1 must follow greater than 3 months. It's less than 1 month. One month or less, that's the answer.

[00:58:20]

          Posttest 1: Rationale

Okay, so here it is. For patients aged 60 or older, TD may be diagnosed after as little as 1 month of antipsychotic treatment. For patients of any age, symptoms must be present for at least 4 weeks, must be choreiform and semirhythmic and so forth. So the idea is older adults like us saying 4 weeks is enough.

[00:58:44]

          Posttest 2

Okay, next. All right. Which is most typically indicative of TD?

1. Symptoms worsen after increasing the dose of antipsychotic medication and worsen with anticholinergic medication;
2. Symptoms worsen after increasing the dose of antipsychotic and improve with anticholinergic medicine;
3. Symptoms worsen after decreasing the dose of antipsychotic medication and worsen with anticholinergic medication; and
4. Symptoms worsen after increasing the dose of antipsychotic and improve with anticholinergic.

So there's 1 correct answer. Come on guys. Okay. All right.

[00:59:58]

          Posttest 2: Rationale

So symptoms worsen after decreasing the dose of antipsychotic. That's when you can unmask TD. And of course, I've harped on the fact that anticholinergics upset that balance in the striatum. And so they are not used to treat TD.

Next.

[01:00:13]

          Posttest 3

Okay. The patient case. Joan, a 50-year-old woman with bipolar II, has been stable for several years on quetiapine 300 and lithium 1200. Good lithium level. She also has rheumatoid arthritis, history of cirrhosis. Her liver disease is currently Child-Pugh class B means moderate liver disease, with stable labs and no history of encephalopathy.

She has TD lip smacking and so forth, had become increasingly noticeable and colleagues have asked her, “Are you anxious?” And she's avoiding social gatherings. Her healthcare professional diagnosed TD 6 months ago. A prior attempt to reduce or taper quetiapine failed, and she's back on and stable. But she's frustrated and distressed that TD is interfering with her quality of life. So which is the correct?

1. Benztropine 1 mg TID to reduce abnormal movements;
2. Start deutetrabenazine immediate-release 6 mg BID;
3. Start valbenazine 40 mg daily;
4. Start tetrabenazine 12.5 TID; or
5. There is more than 1 appropriate treatment choice.

Come on guys. Dr Meyer is holding my boarding pass.

Okay, that - that was good. All right. Thank you.

Dr Meyer: Thank you very much, Dr Gupta.

Dr Gupta: Thank you.